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Sample records for oral administration

  1. Efficacy of oral administration and oral intake of edible vaccines.

    PubMed

    Lauterslager, Tosca G M; Hilgers, Luuk A T

    2002-12-03

    To evaluate whether vaccine administration via intragastric gavage is indicative for the outcome of edible vaccines, mice were orally immunised with ovalbumin (OVA) mixed with or without Vibrio cholerae toxin (CT) in various compositions via various routes: (1) OVA dissolved in saline and intragastrically (IG) administered ('IG'); (2) OVA mixed with food extract and administered IG ('food IG'); (3) food chow absorbed with OVA dissolved in saline and fed to the animals ('food'); and (4) OVA dissolved in saline and administered via drinking bottles ('drinking'). When given to naive mice, 'IG' and 'food IG' but not 'food' or 'drinking' induced anti-OVA IgG1 responses in serum, but oral boost immunisations were necessary. Serum IgA was not induced. Oral boosting of subcutaneously (SC) primed mice enhanced the IgG1 and IgA response in serum regardless of the route of immunisation or the vaccine composition. CT did not dramatically enhance the immune response. All immunisation routes except 'drinking' induced antigen-specific IgA antibody secreting cells (ASC) in the lamina propria of naive mice. But antigen-specific antibody responses in faeces were not observed. We concluded that oral (i.e. IG) administration is distinct from oral intake. The composition of the vaccine (food or saline) did not influence oral administration. We thus suggested that the route of administration greatly influenced the outcome of oral immunisation. Although oral administration is a well-accepted route to test the potentials of oral vaccines, our study demonstrated that it is merely indicative for the effectiveness of edible vaccines. Studies on the feasibility of edible vaccines should thus be performed by eating the vaccine.

  2. Voluntary Oral Administration of Losartan in Rats

    PubMed Central

    Diogo, Lucília N; Faustino, Inês V; Afonso, Ricardo A; Pereira, Sofia A; Monteiro, Emília C; Santos, Ana I

    2015-01-01

    Gavage is a widely performed technique for daily dosing in laboratory rodents. Although effective, gavage comprises a sequence of potentially stressful procedures for laboratory animals that may introduce bias into experimental results, especially when the drugs to be tested interfere with stress-dependent parameters. We aimed to test vehicles suitable for drug delivery by voluntary ingestion in rats. Specifically, Male Wistar rats (age, 2 to 3 mo) were used to test nut paste (NUT), peanut butter (PB), and sugar paste (SUG) as vehicles for long-term voluntary oral administration of losartan, an angiotensin II receptor blocker. Vehicles were administered for 28 d without drug to assess effects on the glucose level and serum lipid profile. Losartan was mixed with vehicles and either offered to the rats or administered by gavage (14 d) for subsequent quantification of losartan plasma levels by HPLC. After a 2-d acclimation period, all rats voluntarily ate the vehicles, either alone or mixed with losartan. NUT administration reduced blood glucose levels. The SUG group had higher concentrations of losartan than did the gavage group, without changes in lipid and glucose profiles. Our results showed that NUT, PB, and SUG all are viable for daily single-dose voluntary ingestion of losartan and that SUG was the best alternative overall. Drug bioavailability was not reduced after voluntary ingestion, suggesting that this method is highly effective for chronic oral administration of losartan to laboratory rodents. PMID:26424254

  3. Voluntary Oral Administration of Losartan in Rats.

    PubMed

    Diogo, Lucília N; Faustino, Inês V; Afonso, Ricardo A; Pereira, Sofia A; Monteiro, Emília C; Santos, Ana I

    2015-09-01

    Gavage is a widely performed technique for daily dosing in laboratory rodents. Although effective, gavage comprises a sequence of potentially stressful procedures for laboratory animals that may introduce bias into experimental results, especially when the drugs to be tested interfere with stress-dependent parameters. We aimed to test vehicles suitable for drug delivery by voluntary ingestion in rats. Specifically, Male Wistar rats (age, 2 to 3 mo) were used to test nut paste (NUT), peanut butter (PB), and sugar paste (SUG) as vehicles for long-term voluntary oral administration of losartan, an angiotensin II receptor blocker. Vehicles were administered for 28 d without drug to assess effects on the glucose level and serum lipid profile. Losartan was mixed with vehicles and either offered to the rats or administered by gavage (14 d) for subsequent quantification of losartan plasma levels by HPLC. After a 2-d acclimation period, all rats voluntarily ate the vehicles, either alone or mixed with losartan. NUT administration reduced blood glucose levels. The SUG group had higher concentrations of losartan than did the gavage group, without changes in lipid and glucose profiles. Our results showed that NUT, PB, and SUG all are viable for daily single-dose voluntary ingestion of losartan and that SUG was the best alternative overall. Drug bioavailability was not reduced after voluntary ingestion, suggesting that this method is highly effective for chronic oral administration of losartan to laboratory rodents.

  4. Urinary marker of oral pregnenolone administration.

    PubMed

    Saudan, Christophe; Desmarchelier, Aurélien; Sottas, Pierre-Edouard; Mangin, Patrice; Saugy, Martial

    2005-03-01

    Pregnenolone (PREG) can potentially be abused by athletes to maintain an equilibration of the steroidal environment after sex steroids administrations. Five men volunteers orally ingested 50 mg PREG to determine optimal urinary markers for detection of this steroid. Our findings show that ingestion of PREG has no significant effects on the testosterone/epitestosterone (T/E) and testosterone/luteinizing hormone (T/LH) ratios, whereas variable changes on the carbon isotopic values of three T metabolites: androsterone, etiocholanolone, 5beta-androstane-3alpha,17beta-diol (5beta-androstanediol) together with 16(5alpha)-androsten-3alpha-ol (androstenol) and 5beta-pregnane-3alpha,20alpha-diol (pregnanediol) have been observed. The difference between the carbon isotopic values (delta13C-values) of androstenol and pregnanediol is potentially the most reliable marker of exogenous PREG administration in males. For all subjects, the differences differ by 3.0 per thousand or more over a period of about 10 h and for both of them the detection window for positivity is extended over 40 h.

  5. Transfer of methylmercury to hens' eggs after oral administration

    SciTech Connect

    Kambamanoli-Dimou, A. ); Kamarianos, A.; Kilikidis, S. )

    1991-01-01

    The present investigation was performed to elucidate the possibility of transport of methylmercury into eggs after its oral administration. Also, to determine the quantity of mercury excreted via eggs after oral administration of a certain quantity of this element once or in doses.

  6. Sublingual administration improves systemic exposure of tacrolimus in kidney transplant recipients: comparison with oral administration.

    PubMed

    Federico, Stefano; Carrano, Rosa; Sabbatini, Massimo; Nappi, Riccardo; Russo, Luigi; Apicella, Luca; Balletta, Mario Maria; Santangelo, Michele; Mosca, Teresa; Tarantino, Giovanni; Capone, Domenico

    2016-07-01

    Tacrolimus (TCR) is an immunosuppressive drug used by oral administration. Intravenous (IV) TCR administration is required under conditions of gastrointestinal diseases or abdominal surgery at the onset of paralytic ileus. The infusion formulation needs a large dilution and therefore a careful technical management during continuous infusion by 24 h and may determine anaphylaxis, cardiac arrhythmia, QT prolongation and torsades de pointes. Sublingual (SL) TCR administration was suggested as an alternative route. The aim of this study was to compare in the same kidney transplanted patients the TCR pharmacokinetic profiles by both the routes coupled with the pharmacoeconomic analysis. The study enrolled eight subjects undergoing renal transplantation and treated with TCR and methylprednisolone. TCR was administered by oral route at the scheduled dosage while the 50% of oral dosage was used by SL route, taking into account the absence of liver first pass. Except for AUC, which resulted significantly increased after oral administration, all exposure parameters were not significantly different between the two routes of administration. Analysis of dose-adjusted exposure parameters showed significant increases in AUC and Cmin after SL administration confirming a better bioavailability of the SL route compared with oral route. Cost saving was obtained using the SL rather than the IV route of TCR delivery. When oral administration of TCR is not advised, SL delivery represents an attractive option to IV administration. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

  7. Loss of oral contraceptive efficacy by concurrent antibiotic administration.

    PubMed

    Zachariasen, R D

    1994-01-01

    There are approximately 10 million women in the United States who are currently taking oral contraceptives on a daily basis. Although the actual number is not known, it is also estimated that a large number of these same women are on concomitant drug therapy. In recent years there have been a number of published reports linking a loss of contraceptive efficacy with the concurrent administration of other drugs, including antibiotics. Whereas the actual risk of drug interaction between antibiotics and oral contraceptives is yet unknown, it is important that women who are on oral contraceptive therapy be aware of possible contraceptive failure. This article reviews the published incidence of oral contraceptive/antibiotic interaction, along with a discussion of the possible mechanisms by which this interaction occurs. Recommendations are also presented for the health management of women taking oral contraceptives and other prescribed drugs.

  8. Oral Nicotine Self-Administration in Rodents

    PubMed Central

    Collins, Allan C; Pogun, Sakire; Nesil, Tanseli; Kanit, Lutfiye

    2012-01-01

    Nicotine addiction is a complex process that begins with self-administration. Consequently, this process has been studied extensively using animal models. A person is usually not called “smoker” if s/he has smoked for a week or a month in a lifetime; in general, a smoker has been smoking for many years. Furthermore, a smoker has free access to cigarettes and can smoke whenever she/he wants, provided there are no social/legal restraints. Subsequently, in an animal model of tobacco addiction, it will be desirable to expose the animal to free access nicotine for 24 hours/day for many weeks, starting at different stages of development. PMID:23264883

  9. Medical outcomes associated with prescription opioid abuse via oral and non-oral routes of administration.

    PubMed

    Green, Jody L; Bucher Bartelson, Becki; Le Lait, M Claire; Roland, Carl L; Masters, Elizabeth T; Mardekian, Jack; Bailey, J Elise; Dart, Richard C

    2017-06-01

    Prescription opioid abuse and misuse is a serious and growing public health issue. While the most common form of abuse is swallowing intact tablets/capsules, some abusers manipulate, or tamper with, these medications by altering the dosage form to allow for non-oral routes of administration (e.g., injection, inhalation) in order to achieve more rapid or enhanced psychoactive effects. Because administration of opioids via non-oral routes results in greater systemic availability and more rapid central nervous system penetration, we hypothesized that death and major medical outcomes occur more frequently with non-oral routes compared to oral route alone. This retrospective cohort study analyzed data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Poison Center Program to investigate relative risk of prescription opioid abuse via oral and non-oral routes. While the oral route was the most commonly reported route of abuse (64.0%), non-oral routes were reported in 14.6% exposures and unknown routes in 21.4% exposures. The relative risk of an exposure resulting in death or major effect was 2.43 (95% CI 1.97, 2.99) if non-oral routes were reported compared to exposures involving oral route only. Analysis of acute health events recorded by poison centers indicates that death or major effects are twice as likely to occur with intentional abuse of prescription opioids via non-oral routes of administration than ingestion alone. Effective interventions to prevent abuse via non-oral routes of solid dosage forms of prescription opioids, such as abuse-deterrent formulations could have a significant public health impact. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Compounded preparations with nystatin for oral and oromucosal administration.

    PubMed

    Sklenár, Zbynek; Scigel, Vladimír; Horácková, Katerina; Slanar, Ondrej

    2013-01-01

    Therapy of oral, esophageal and gastrointestinal candidiasis is still a common problem that can be solved by an administration of antimycotics. Major disadvantage of registered commercial antifungal medicinal products is their price, so the health care system and its payers may profit from extemporaneous compounding. An appropriate drug therapy for candidiasis (trush) is nystatin, which is a substance available in the Czech Republic for the magistral preparation relatively recently, since 2010. Making formulas for extemporaneous compounding is quite simple and preparations particularly useful for dentists, pediatricians, otolaryngologists, oncologists and gastroenterologists. The authors formulated composition of viscous oromucosal suspension, oral/oromucosal hydrogel and oromucosal gelatine globule which may be present as compounded products containing nystatin for oromucosal and/or oral administration. The preparation is practically verified and magistral products have been already used in clinical practice.

  11. Oral Administration of Sustained Release Niacin Inhibits Platelet Aggregation.

    PubMed

    Norgard, Nicholas B; Bacon, Nicholas R; Agosti, Matthew

    2016-01-01

    Previous studies have suggested that niacin may have antiplatelet properties, however the effects of niacin on the platelet activity are not well defined. The purpose of this trial was to investigate whether the oral administration of niacin inhibits platelet aggregation. This study was run in three segments measuring the inhibitory effect of niacin: 1) 3 mmol/L niacin in vitro, 2) one hour after 1-gram sustained-release (SR) niacin administration, 3) twelve hours after 2-gram SR niacin administration. Platelet aggregation was measured using the VerifyNow-Aspirin and whole blood impedance aggregometry. Preincubation with niacin resulted in a significant inhibition of platelet aggregation. Significant inhibition of platelet aggregation was found one hour following the oral administration of 1 gram of SR niacin while the oral administration of a 2 gram dose of SR niacin did not produce significant platelet inhibition when platelet aggregation was measured 12 hours after the dose. Niacin has a small, direct effect on platelet aggregation. Niacin platelet inhibition is transient and may dissipate as it is converted into metabolites. The clinical significance is unknown.

  12. Intra-oral PTH administration promotes tooth extraction socket healing.

    PubMed

    Kuroshima, S; Kovacic, B L; Kozloff, K M; McCauley, L K; Yamashita, J

    2013-06-01

    Intermittent parathyroid hormone (PTH) administration increases systemic and craniofacial bone mass. However, the effect of PTH therapy on healing of tooth extraction sites is unknown. The aims of this study were to determine the effect of PTH therapy on tooth extraction socket healing and to examine whether PTH intra-oral injection promotes healing. The mandibular first molars were extracted in rats, and subcutaneous PTH was administered intermittently for 7, 14, and 28 days. In a second study, maxillary second molars were extracted, and PTH was administered by either subcutaneous or intra-oral injection to determine the efficacy of intra-oral PTH administration. Healing was assessed by micro-computed tomography and histomorphometric analyses. PTH therapy accelerated the entire healing process and promoted both hard- and soft-tissue healing by increasing bone fill and connective tissue maturation. PTH therapy by intra-oral injection was as effective as subcutaneous injection in promoting tooth extraction socket healing. The findings suggest that PTH therapy promotes tooth extraction socket healing and that intra-oral injections can be used to administer PTH.

  13. Stimulation of respiratory immunity by oral administration of Lactococcus lactis.

    PubMed

    Villena, Julio; Medina, Marcela; Vintiñi, Elisa; Alvarez, Susana

    2008-08-01

    This work demonstrates that non-recombinant Lactococcus lactis NZ, administered by the oral route at the proper dose, is able to improve resistance against pneumococcal infection. Lactococcus lactis NZ oral administration was able to improve pathogen lung clearance, increased survival of infected mice, and reduced lung injuries. This effect was related to an upregulation of the respiratory innate and specific immune responses. Administration of L. lactis NZ improved production of bronchoalveolar lavage (BAL) fluid TNF-alpha, enhanced recruitment of neutrophils into the alveolar spaces, and induced a higher activation of BAL phagocytes compared with the control group. Lactococcus lactis NZ administered orally stimulated the IgA cycle, increased IgA+ cells in intestine and bronchus, and improved production of BAL IL-4 and IL-10 during infection. Moreover, mice treated with L. lactis NZ showed higher levels of BAL anti-pneumococcal IgA and IgG. Taking into consideration that orally administered L. lactis NZ stimulates both the innate and the specific immune responses in the respiratory tract and that bacterial and viral antigens have been efficiently produced in this strain, L. lactis NZ is an excellent candidate for the development of an effective pneumococcal oral vaccine.

  14. Intra-oral PTH Administration Promotes Tooth Extraction Socket Healing

    PubMed Central

    Kuroshima, S.; Kovacic, B.L.; Kozloff, K.M.; McCauley, L.K.; Yamashita, J.

    2013-01-01

    Intermittent parathyroid hormone (PTH) administration increases systemic and craniofacial bone mass. However, the effect of PTH therapy on healing of tooth extraction sites is unknown. The aims of this study were to determine the effect of PTH therapy on tooth extraction socket healing and to examine whether PTH intra-oral injection promotes healing. The mandibular first molars were extracted in rats, and subcutaneous PTH was administered intermittently for 7, 14, and 28 days. In a second study, maxillary second molars were extracted, and PTH was administered by either subcutaneous or intra-oral injection to determine the efficacy of intra-oral PTH administration. Healing was assessed by micro-computed tomography and histomorphometric analyses. PTH therapy accelerated the entire healing process and promoted both hard- and soft-tissue healing by increasing bone fill and connective tissue maturation. PTH therapy by intra-oral injection was as effective as subcutaneous injection in promoting tooth extraction socket healing. The findings suggest that PTH therapy promotes tooth extraction socket healing and that intra-oral injections can be used to administer PTH. PMID:23611925

  15. Rehabilitation of a fearful dental patient with oral sedation: utilizing the incremental oral administration technique.

    PubMed

    Feck, Anthony S; Goodchild, Jason H

    2005-01-01

    The treatment of fearful or anxious patients presents a myriad of problems for the dentist. In-office sedation using oral (enteral) medications is an effective means of increasing patient tolerance of invasive dental procedures. The incremental oral administration technique is a protocol that can be utilized to treat fearful or anxious patients. A case is presented in which this technique was used as an adjunct to the rehabilitation of a debilitated mouth.

  16. Pharmacokinetics of ciprofloxacin after oral and parenteral administration.

    PubMed Central

    Höffken, G; Lode, H; Prinzing, C; Borner, K; Koeppe, P

    1985-01-01

    In 12 fasting volunteers, the pharmacokinetics of ciprofloxacin (Bay o 9867; 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carbonic acid) were determined after the administration of 50, 100, and 750 mg orally as well as 50 and 100 mg intravenously over 15 min. Serum and urine concentrations were detected with a bioassay. In addition, urine concentrations after a 50-mg dosing were measured by high-pressure liquid chromatography. The serum course of ciprofloxacin could best be described by an open three-compartment model. High volumes of distribution (exceeding 200 liters/100 kg) suggested effective diffusions in the extravascular space. The terminal half-life of ciprofloxacin ranged between 3 and 4 h. High total and renal clearances suggested additional elimination pathways, such as tubular secretion, metabolism, or biliary excretion. After oral administration, absorption was sufficient, and the absolute bioavailability varied between 0.77 and 0.63. Maximal serum concentrations were attained 0.5 to 1 h after dosing; the higher dosage tended towards a delay in absorption. The proportion of the relative amount of metabolites to the total amount of drug excreted in urine increased from 29.7% after intravenous administration to 42.7% after oral dosing, indicating a first-pass effect of the liver. Ciprofloxacin concentrations with a bioassay were 3 to 27% higher than with high-pressure liquid chromatography, which may indicate the presence of biologically active metabolites. No side effects were recorded. PMID:3158275

  17. Therapeutic effects on murine oral candidiasis by oral administration of cassia (Cinnamomum cassia) preparation.

    PubMed

    Taguchi, Yuuki; Takizawa, Toshio; Ishibashi, Hiroko; Sagawa, Takehito; Arai, Ryo; Inoue, Shigeharu; Yamaguchi, Hideyo; Abe, Shigeru

    2010-01-01

    We examined the effects of spices and herbs on Candida albicans growth using in vitro assay and therapeutic activity of some selected herbal preparations against murine oral candidiasis. All tested samples: lemongrass (Cymbopogon citratus), lemon balm (Melissa officinalis), thyme (Thymus vulgaris), rosemary (Rosmarinus officinalis), roselle (Hibiscus sabdariffa), green tea (Camellia sinensis), and cassia (Cinnamomum cassia) inhibited Candida mycelial growth in vitro. The results of this assay showed that the anti-Candida activity of lemongrass, green tea, and cassia is stronger than that of the other tested herbs. Oral administration of lemongrass or green tea did not result in significant improvement in the murine oral candidiasis, while the administration of cassia improved the symptoms and reduced the number of viable Candida cells in the oral cavity. The results of in vitro Candida growth assay including GC/MS analysis suggested that cinnamaldehyde in the cassia preparation was the principal component responsible for the inhibitory activity of Candida mycelial growth. These findings suggest that oral intake of a cassia preparation is a clinical candidate for a prophylactic or therapeutic tool against oral Candida infection.

  18. Anti-cancer activity of bromelain nanoparticles by oral administration.

    PubMed

    Bhatnagar, Priyanka; Patnaik, Soma; Srivastava, Amit K; Mudiam, Mohan K R; Shukla, Yogeshwer; Panda, Amulya K; Pant, Aditya B; Kumar, Pradeep; Gupta, Kailash C

    2014-12-01

    Oral administration of anti-cancer drugs is an effective alternative to improve their efficacy and reduce undesired toxicity. Bromelain (BL) is known as an effective anti-cancer phyto-therapeutic agent, however, its activity is reduced upon oral administration. In addressing the issue, BL was encapsulated in Poly(lactic-co-glycolic acid) (PLGA) to formulate nanoparticles (NPs). Further, the NPs were coated with Eudragit L30D polymer to introduce stability against the gastric acidic conditions. The resultant coated NPs were characterized for BL entrapment, proteolytic activity and mean particle size. The stability and release pattern of NPs were evaluated under simulated gastrointestinal tract (GIT) pH conditions. Cytotoxicity studies carried out in human cell lines of diverse origin have shown significant dose advantage (-7-10 folds) with NPs in reducing the IC50 values compared with free BL. The cellular uptake of NPs in MCF-7, HeLa and Caco-2 cells monolayer was significantly enhanced several folds as compared to free BL. Altered expression of marker proteins associated with apoptosis and cell death (P53, P21, Bcl2, Bax) also confirmed the enhanced anti-carcinogenic potential of formulated NPs. Oral administration of NPs reduced the tumor burden of Ehrlich ascites carcinoma (EAC) in Swiss albino mice and also increased their life-span (160.0 ± 5.8%) when compared with free BL (24 ± 3.2%). The generation of reactive oxygen species, induction of apoptosis and impaired mitochondrial membrane potential in EAC cells treated with NPs confirmed the suitability of Eudragit coated BL-NPs as a promising candidate for oral chemotherapy.

  19. Oral Administration of Peptide-Based Drugs: Beyond Lipinski's Rule.

    PubMed

    Santos, Gabriela B; Ganesan, A; Emery, Flavio S

    2016-10-19

    The use of peptides in therapy presents several limitations, from physicochemical characteristics to inadequate pharmacokinetic profiles for oral absorption. As peptides are gaining importance in the therapeutic arsenal, there is an increasing need to rationalize the main characteristics of this compound class in the market. Therefore, we performed an extensive analysis of all known peptide drugs and clinical candidates based on their peptide features, physicochemical and structural properties, and correlated these with their administration route and therapeutic classes. Peptide drugs are widely distributed across drug and pharmacological space, covering several therapeutic areas with structural diversity and complexity, distributed between groups of cyclic and linear compounds. Although structural and physicochemical properties are clear within these groups, we counter the consensus that cyclic peptides have better oral availability than linear peptides, as most of the orally administrated peptides have linear structures. This study and review furnishes information that could support peptide drug design, with a new cutoff of known descriptors that go beyond the Rule of Five.

  20. Medical treatment of Bell's palsy. Oral vs. intravenous administration.

    PubMed

    Tani, M; Kinishi, M; Takahara, T; Hosomi, H; Amatsu, M

    1988-01-01

    Infusion therapy using low-molecular dextran in combination with high-dose cortisone was modified from Stennert's original protocol and indicated in 50 cases of Bell's palsy. The effects of infusion were compared with the outcome in 36 cases treated by orally-administered steroids and vasodilators. In the case of incomplete palsy, the recovery rate was excellent regardless of the mode of treatment. If the palsy is not progressive, it is not necessary for patients with this condition to have infusion therapy. In the case of complete palsy, 95% of those with normal nerve excitability (NE) experienced complete recovery when treated by infusion. However, only 71% of this group experienced complete recovery when treated with oral administration. In the group with diminished or absent NE, complete recovery was obtained in 58% of the patients treated with infusion, whereas only 18% recovered completely when given oral administration. Thus, the recovery rate increased sharply in the case of infusion therapy. Therefore, the above-mentioned method of infusion therapy is indicated in cases of complete or progressively incomplete Bell's palsy except in those cases where its use is contra-indicated for some other reason.

  1. Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration.

    PubMed

    Ding, Yu-Shin; Gatley, S John; Thanos, Panayotis K; Shea, Colleen; Garza, Victor; Xu, Youwen; Carter, Pauline; King, Payton; Warner, Don; Taintor, Nicholas B; Park, Daniel J; Pyatt, Bea; Fowler, Joanna S; Volkow, Nora D

    2004-09-01

    Methylphenidate (MP) (Ritalin) is widely used for the treatment of attention deficit hyperactivity disorder (ADHD). It is a chiral drug, marketed as the racemic mixture of d- and l-threo enantiomers. Our previous studies (PET and microdialysis) in humans, baboons, and rats confirm the notion that pharmacological specificity of MP resides predominantly in the d-isomer. A recent report that intraperitoneally (i.p.) administered l-threo-MP displayed potent, dose-dependent inhibition of cocaine- or apomorphine-induced locomotion in rats, raises the question of whether l-threo-MP has a similar effect when given orally. It has been speculated that l-threo-MP is poorly absorbed in humans when it is given orally because of rapid presystemic metabolism. To investigate whether l-threo-MP or its metabolites can be delivered to the brain when it is given orally, and whether l-threo-MP is pharmacologically active. PET and MicroPET studies were carried out in baboons and rats using orally delivered C-11-labeled d- and l-threo-MP ([methyl-(11)C]d-threo-MP and [methyl-(11)C]l-threo-MP). In addition, we assessed the effects of i.p. l-threo-MP on spontaneous and cocaine-stimulated locomotor activity in mice. There was a higher global uptake of carbon-11 in both baboon and rat brain for oral [(11)C]l-threo-MP than for oral [(11)C]d-threo-MP. Analysis of the chemical form of radioactivity in rat brain after [(11)C]d-threo-MP indicated mainly unchanged tracer, whereas with [(11)C]l-threo-MP, it was mainly a labeled metabolite. The possibility that this labeled metabolite might be [(11)C]methanol or [(11)C]CO(2), derived from demethylation, was excluded by ex vivo studies in rats. When l-threo-MP was given i.p. to mice at a dose of 3 mg/kg, it neither stimulated locomotor activity nor inhibited the increased locomotor activity due to cocaine administration. These results suggest that, in animal models, l-threo-MP or its metabolite(s) is (are) absorbed from the gastrointestinal tract and

  2. Oral administration of hyaluronan reduces bone turnover in ovariectomized rats.

    PubMed

    Ma, Jenny; Granton, Patrick V; Holdsworth, David W; Turley, Eva A

    2013-01-16

    The effect of oral hyaluronan (HA) on bone loss in ovariectomized (OVX) 3-month-old rats was measured using serum markers of bone turnover and bone mineral density. OVX rats were administered 1 mg/kg HA (OVX + HA) or phosphate-buffered saline (PBS) (OVX + PBS) by oral gavage (5 days/week for 54 days). Additional controls included sham ovariectomy with PBS gavage (Sham + PBS) and no treatment. Oral administration of HA resulted in approximately 50% (p < 0.05) increases in serum HA. Gel filtration analyses showed this was high molecular weight HA (300-500 kDa). Osteopenia was mild due to the young age of the animals. Thus, ovariectomy resulted in a 30% increase in serum collagen N-terminal telopeptides (p < 0.001), a 20% increase in serum nitrate/nitrite levels (p = 0.05), and a 5-6% decrease in femur bone mineral density/content (p < 0.05). HA gavage blunted the development of osteopenia in this model as determined by preventing the 30% increase in serum collagen N-terminal telopeptide levels (p < 0.001) and by reducing bone mineral content loss from 6 to 4%. These results show that oral supplements of HA (gavage solution, 0.12% solution) significantly reduce bone turnover associated with mild osteopenia in rats.

  3. Hydrophilic cyclodextrin derivatives enable effective oral administration of steroidal hormones.

    PubMed

    Pitha, J; Harman, S M; Michel, M E

    1986-02-01

    Condensation products of beta-cyclodextrin with propylene oxide or epichlorohydrin, which are amorphous and thus very soluble in water, were used to form complexes with testosterone, progesterone, and estradiol. Sublingual/buccal administration of tablets of these complexes led to effective absorption and entry of the hormones into the systemic circulation, followed by gradual elimination; rapid first-pass loss was avoided. beta-Cyclodextrin itself, its 2,6-dimethyl derivative, and a nonionic detergent did not enable effective buccal absorption. Absorption from the GI tract of hormones complexed with hydrophilic cyclodextrins was also less effective. Effective absorption of drugs from the oral cavity requires (a) that the drug and solubilizer form a complex of the inclusion type which dissolves completely and rapidly and (b) that the solubilizer neither enters nor damages oral tissue.

  4. Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs.

    PubMed

    Kuroha, Masanori; Kayaba, Hideki; Kishimoto, Shizuka; Khalil, Waleed F; Shimoda, Minoru; Kokue, Eiichi

    2002-03-01

    The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans.

  5. Distribution of creatinine following intravenous and oral administration to rats.

    PubMed

    Watanabe, J; Hirate, J; Iwamoto, K; Ozeki, S

    1981-05-01

    To evaluate the distribution of creatinine in rats, urinary, fecal and expiratory excretion, plasma levels and whole-body autoradiography following intravenous or oral administration of [carbonyl-14C]creatinine was investigated. More than 90% of the exogeneous creatinine was excreted in the urine in 24 hr following intravenous administration, and both fecal and expiratory excretion were only about 1%. In case of oral administration, however, it was found that expiratory excretion could not be neglected, ranging from about 1 to 30%. Plasma creatinine concentration-time curves following the intravenous administration (70.4 micrograms/kg or 400 mg/kg as creatinine) were analyzed according to a two-compartment open model. There were significant but very small differences in the pharmacokinetic parameters for these two doses. When these parameters were compared with those of urea, k12 and k21, which are transfer rate constants between compartment 1 and 2, for creatinine were significantly smaller than those of urea. On the other hand, k10 was larger in creatinine. Furthermore, (V'd)extrap for creatinine was about three times that of urea. Whole-body autoradiograms at 5 minutes following intravenous administration showed that exogeneous creatinine distributes with higher concentrations in liver, lung and kidney than in muscle and fat. This results was remarkably different from that of urea which distributes almost uniformly throughout the body at the same time. This difference observed in the autoradiograms would be the consequence of the fact that urea has larger k12 and k21 than creatinine.

  6. Microsomal enzyme induction following repeated oral administration of LAAM.

    PubMed

    Masten, L W; Price, S R; Burnett, C J

    1978-04-01

    The oral administration of 1-alpha-acetylmethadol (LAAM) in the mouse was shown to cause a significant elevation in the hepatic LAAM N-demethylase activity. Compared to the self-induction phenomena found with methadone and propoxyphene, LAAM was three and two times more potent, respectively, on a molar basis than these two structurally similar narcotic analogs. Moreover, microsomal induction by LAAM resulted in significant elevations of aminopyrine N-demethylase and aniline hydroxylase activities. These effects were also correlated with a dose related decrement of pentobarbital sleeping time. Thus LAAM appears to be a relatively potent inducer of microsomal metabolism.

  7. Intracranial hemorrhage during administration of a novel oral anticoagulant

    PubMed Central

    Tempaku, Akira

    2016-01-01

    Objective: Oral anticoagulants are widely administered to patients with atrial fibrillation in order to prevent the onset of cardiogenic embolisms. However, intracranial bleeding during anticoagulant therapy often leads to fatal outcomes. Accordingly, the use of novel oral anticoagulants (NOACs), which less frequently have intracranial bleeding as a complication, is expanding. A nationwide survey of intracranial bleeding and its prognosis in Japan reported that intracranial bleeding of advanced severity was not common after NOAC administration. In this report, two cases from our institute are presented. Patients: Case 1 was an 85-year-old man with a right frontal lobe hemorrhage while under dabigatran therapy. Case 2 was an 81-year-old man who had cerebellar hemorrhage while under rivaroxaban therapy. Result: In both patients, the clinical course progressed without aggravation of bleeding or neurological abnormalities once anticoagulant therapy was discontinued. Conclusion: These observations suggest that intracranial hemorrhage during NOAC therapy is easily controlled by discontinuation of the drug. NOAC administration may therefore be appropriate despite the risk of such severe complications. Further case studies that include a subgroup analysis with respect to each NOAC or patient background will be required to establish appropriate guidelines for the prevention of cardiogenic embolisms in patients with atrial fibrillation. PMID:27928459

  8. Oral administration of geranylgeranylacetone to protect vestibular hair cells.

    PubMed

    Nagato, Shinpei; Sugahara, Kazuma; Hirose, Yoshinobu; Takemoto, Yousuke; Hashimoto, Makoto; Fujii, Hironori; Yamashita, Hiroshi

    2017-08-03

    We recently reported that the heat shock response played a major role in the protection of hair cells against stress. Oral administration of the heat shock inducer, geranylgeranylacetone (GGA) protected hair cells against intense noise. In our present study, we investigated the effect of GGA on vestibular hair cell death induced by an aminoglycoside. We used CBA/N mice aged 4-6 weeks. The mice were divided into two groups, GGA and control. Mice in the GGA group were fed a diet containing GGA (0.5%) for 4 weeks, and those in the control group were fed a standard diet. Immunohistochemical analyses for Hsp70 were performed in four animals. The utricles of the remaining animals were cultured in medium for 24h with neomycin to induce hair cell death. After fixation, the vestibular hair cells were immunohistochemically stained against calmodulin, and hair cell survival was evaluated. The vestibular hair cells of mice in the GGA group expressed Hsp70. In addition, after exposure to neomycin, vestibular hair cell survival was higher in the GGA group than in the control group. Our results demonstrated the oral administration of GGA induced the heat shock response in the vestibule and could protect sensory cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Systemic uptake of buprenorphine by cats after oral mucosal administration.

    PubMed

    Robertson, S A; Taylor, P M; Sear, J W

    2003-05-31

    The plasma concentration of buprenorphine was measured by radioimmunoassay in six female cats after the administration of 0.01 mg/kg (0.033 ml/kg) buprenorphine hydrochloride solution into the side of the cat's mouth. Blood samples were taken through a preplaced jugular catheter before and one, two, four, six, 10, 15, 30, 45 and 60 minutes, and two, four, six, 12 and 24 hours after the dose was administered. The buprenorphine was accepted well by all the cats and did not cause salivation or vomiting. Its median peak plasma concentration was 7.5 ng/ml and was reached after 15 minutes. The pharmacokinetic data were similar to the pharmacokinetic data obtained after the intramuscular and intravenous administration of buprenorphine to cats from the same colony, suggesting that the mucosal route of administration should be as effective as intravenous and intramuscular injections. In addition, the pH of the oral cavity of 26 cats was measured with pH paper, and 100 cat owners were asked their preferred method of administering drugs to cats. The pH of the cats' mouths was between 8 and 9, and the technique preferred by the cat owners was the use of drops placed in the mouth.

  10. Cetirizine in horses: pharmacokinetics and pharmacodynamics following repeated oral administration.

    PubMed

    Olsén, Lena; Bondesson, Ulf; Broström, Hans; Tjälve, Hans; Ingvast-Larsson, Carina

    2008-08-01

    The pharmacokinetics of the histamine H(1)-antagonist cetirizine and its effect on histamine-induced cutaneous wheal formation were studied in six healthy horses following repeated oral administration. After three consecutive administrations of cetirizine (0.2 mg/kg body weight, bw) every 12h, the trough plasma concentration of cetirizine was 16+/-4 ng/mL (mean+/-SD) and the wheal formation was inhibited by 45+/-23%. After four additional administrations of cetirizine (0.4 mg/kg bw) every 12 h, the trough plasma concentration was 48+/-15 ng/mL and the wheal formation was inhibited by 68+/-11%. The terminal half-life was about 5.8 h. A pharmacokinetic/pharmacodynamic link model showed that the maximal inhibition of wheal formation was about 95% and the EC(50) about 18 ng/mL. It is concluded that cetirizine in doses of 0.2-0.4 mg/kg bw administered at 12 h intervals exhibits favourable pharmacokinetic and pharmacodynamic properties without causing visible side effects, and the drug may therefore be a useful antihistamine in equine medicine.

  11. Effects of Oral Administration of Chitin Nanofiber on Plasma Metabolites and Gut Microorganisms

    PubMed Central

    Azuma, Kazuo; Izumi, Ryotaro; Kawata, Mari; Nagae, Tomone; Osaki, Tomohiro; Murahata, Yusuke; Tsuka, Takeshi; Imagawa, Tomohiro; Ito, Norihiko; Okamoto, Yoshiharu; Morimoto, Minoru; Izawa, Hironori; Saimoto, Hiroyuki; Ifuku, Shinsuke

    2015-01-01

    The aim of this study was to examine the effects of oral administration of chitin nanofibers (CNFs) and surface-deacetylated (SDA) CNFs on plasma metabolites using metabolome analysis. Furthermore, we determined the changes in gut microbiota and fecal organic acid concentrations following oral administrations of CNFs and SDACNFs. Healthy female mice (six-week-old) were fed a normal diet and administered tap water with 0.1% (v/v) CNFs or SDACNFs for 28 days. Oral administration of CNFs increased plasma levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and serotonin (5-hydroxytryptamine, 5-HT). Oral administration of SDACNFs affected the metabolisms of acyl-carnitines and fatty acids. The fecal organic level analysis indicated that oral administration of CNFs stimulated and activated the functions of microbiota. These results indicate that oral administration of CNFs increases plasma levels of ATP and 5-HT via activation of gut microbiota. PMID:26378523

  12. Effects of Oral Administration of Chitin Nanofiber on Plasma Metabolites and Gut Microorganisms.

    PubMed

    Azuma, Kazuo; Izumi, Ryotaro; Kawata, Mari; Nagae, Tomone; Osaki, Tomohiro; Murahata, Yusuke; Tsuka, Takeshi; Imagawa, Tomohiro; Ito, Norihiko; Okamoto, Yoshiharu; Morimoto, Minoru; Izawa, Hironori; Saimoto, Hiroyuki; Ifuku, Shinsuke

    2015-09-10

    The aim of this study was to examine the effects of oral administration of chitin nanofibers (CNFs) and surface-deacetylated (SDA) CNFs on plasma metabolites using metabolome analysis. Furthermore, we determined the changes in gut microbiota and fecal organic acid concentrations following oral administrations of CNFs and SDACNFs. Healthy female mice (six-week-old) were fed a normal diet and administered tap water with 0.1% (v/v) CNFs or SDACNFs for 28 days. Oral administration of CNFs increased plasma levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and serotonin (5-hydroxytryptamine, 5-HT). Oral administration of SDACNFs affected the metabolisms of acyl-carnitines and fatty acids. The fecal organic level analysis indicated that oral administration of CNFs stimulated and activated the functions of microbiota. These results indicate that oral administration of CNFs increases plasma levels of ATP and 5-HT via activation of gut microbiota.

  13. Disposition of Cannabinoids in Oral Fluid after Controlled Around-the-Clock Oral THC Administration

    PubMed Central

    Milman, Garry; Barnes, Allan J.; Schwope, David M.; Schwilke, Eugene W.; Darwin, William D.; Goodwin, Robert S.; Kelly, Deanna L.; Gorelick, David A.; Huestis, Marilyn A.

    2011-01-01

    Background Oral fluid, a promising alternative matrix for drug monitoring in clinical and forensic investigations, offers noninvasive sample collection under direct observation. Cannabinoid distribution into oral fluid is complex and incompletely characterized due to the lack of controlled drug administration studies. Methods To characterize cannabinoid disposition in oral fluid, we administered around-the-clock oral Δ9-tetrahydrocannabinol (THC) (Marinol®) doses to 10 participants with current daily cannabis use. We obtained oral fluid samples (n = 440) by use of Quantisal™ collection devices before, during, and after 37 20-mg THC doses over 9 days. Samples were extracted with multiple elution solvents from a single SPE column and analyzed by 2-dimensional GC-MS with electron-impact ionization for THC, 11-hydroxy-THC (11-OH-THC), cannabidiol, and cannabinol and negative chemical ionization for 11-nor-9-carboxy-THC (THCCOOH). Linear ranges were 0.5–50 μg/L, with the exception of cannabinol (1–50 μg/L) and THCCOOH (7.5–500 ng/L). Results THCCOOH was the most prevalent analyte in 432 samples (98.2%), with concentrations up to 1117.9 ng/L. In contrast, 11-OH-THC was not identified in any sample; cannabidiol and cannabinol were quantified in 3 and 8 samples, respectively, with maximum concentrations of 2.1 and 13 μg/L. THC was present in only 20.7% of samples, with highest concentrations near admission (median 4.2 μg/L, range 0.6–481.9) from previously self-administered smoked cannabis. Conclusions Measurement of THCCOOH in OF not only identifies cannabis exposure, but also minimizes the possibility of passive inhalation. THCCOOH may be a better analyte for detection of cannabis use. PMID:20530732

  14. Oral administration of GZ-793A, a VMAT2 inhibitor, decreases methamphetamine self-administration in rats

    PubMed Central

    Wilmouth, Carrie E.; Zheng, Guangrong; Crooks, Peter A.; Dwoskin, Linda P.; Bardo, Michael T.

    2013-01-01

    Despite the high prevalence of use of methamphetamine (METH), there is no FDA-approved pharmacological treatment available currently for METH addiction. The vesicular monoamine transporter (VMAT2) has been proposed as a novel target to treat METH abuse. GZ-793A, a lobelane analog and selective VMAT2 inhibitor, has been shown previously to decrease METH self-administration specifically when administered via the subcutaneous route in rats. Since oral administration is the preferred clinical route, the present experiments determined if oral administration of GZ-793A would decrease specifically METH self-administration. Experiments 1 and 2 assessed the dose-effect functions of oral administration of GZ-793A (30-240 mg/kg) on intravenous METH self-administration and food-maintained responding, respectively. Experiments 3 and 4 assessed the time-course (20-180 min pretreatment) of oral administration of GZ-793A on METH self-administration and food-maintained responding, respectively. Oral administration of GZ-793A dose-dependently decreased METH self-administration, with the highest dose (240 mg/kg) producing a 85% decrease compared to control baseline. The decrease in METH self-administration produced by GZ-793A (120 mg/kg) lasted at least 180 min. In contrast, GZ-793A failed to alter food-maintained responding at any of the doses or pretreatment intervals tested. The oral effectiveness and the specificity of GZ-793A to decrease methamphetamine self-administration supports the feasibility of developing VMAT2 inhibitors as treatments for METH abuse. PMID:24075974

  15. Oral administration of GZ-793A, a VMAT2 inhibitor, decreases methamphetamine self-administration in rats.

    PubMed

    Wilmouth, Carrie E; Zheng, Guangrong; Crooks, Peter A; Dwoskin, Linda P; Bardo, Michael T

    2013-11-01

    Despite the high prevalence of use of methamphetamine (METH), there is no FDA-approved pharmacological treatment available currently for METH addiction. The vesicular monoamine transporter (VMAT2) has been proposed as a novel target to treat METH abuse. GZ-793A, a lobelane analog and selective VMAT2 inhibitor, has been shown previously to decrease METH self-administration specifically when administered via the subcutaneous route in rats. Since oral administration is the preferred clinical route, the present experiments determined if oral administration of GZ-793A would decrease specifically METH self-administration. Experiments 1 and 2 assessed the dose-effect functions of oral administration of GZ-793A (30-240 mg/kg) on intravenous METH self-administration and food-maintained responding, respectively. Experiments 3 and 4 assessed the time-course (20-180 min pretreatment) of oral administration of GZ-793A on METH self-administration and food-maintained responding, respectively. Oral administration of GZ-793A dose-dependently decreased METH self-administration, with the highest dose (240 mg/kg) producing an 85% decrease compared to control baseline. The decrease in METH self-administration produced by GZ-793A (120 mg/kg) lasted at least 180 min. In contrast, GZ-793A failed to alter food-maintained responding at any of the doses or pretreatment intervals tested. The oral effectiveness and the specificity of GZ-793A to decrease methamphetamine self-administration support the feasibility of developing VMAT2 inhibitors as treatments for METH abuse. © 2013.

  16. Efficacy of topical antibiotic administration on the inhibition of perioperative oral bacterial growth in oral cancer patients: a preliminary study.

    PubMed

    Funahara, M; Hayashida, S; Sakamoto, Y; Yanamoto, S; Kosai, K; Yanagihara, K; Umeda, M

    2015-10-01

    Parenteral antibiotic prophylaxis is the current standard of therapy in clean-contaminated oral cancer surgery. Nevertheless, the incidence of surgical site infection (SSI) in oral oncological surgery is relatively high, especially in major surgery with reconstruction and tracheotomy. The aims of this study were to investigate the perioperative condition related to microorganisms in the oral cavity and to examine the efficacy of the topical administration of tetracycline in reducing the number of bacteria in the oropharyngeal fluid during intubation. The number of oral bacteria was measured during intubation in patients undergoing major oral cancer surgery. The efficacy of the topical administration of tetracycline or povidone iodine gel in reducing the bacteria was then investigated. Bacteria in the oropharyngeal fluid grew from 10(6)CFU/ml to 10(8)CFU/ml during the 3h after intubation (CFU, colony-forming units). When tetracycline was applied to the dorsum of the tongue, oral bacteria decreased immediately to 10(5)CFU/ml, and the number of bacteria in the oropharyngeal fluid was maintained below 10(7)CFU/ml for 7h. The concentration of tetracycline in the oropharyngeal fluid was extremely high for several hours after topical administration. The topical administration of tetracycline could reduce oral bacteria in patients undergoing clean-contaminated oral cancer surgery. This method is expected to be effective in the prevention of SSI.

  17. Residual keratan sulfate in chondroitin sulfate formulations for oral administration.

    PubMed

    Pomin, Vitor H; Piquet, Adriana A; Pereira, Mariana S; Mourão, Paulo A S

    2012-10-01

    Chondroitin sulfate is a biomedical glycosaminoglycan (GAG) mostly used as a dietary supplement. We undertook analysis on some formulations of chondroitin sulfates available for oral administration. The analysis was based on agarose-gel electrophoresis, strong anion-exchange chromatography, digestibility with specific GAG lyases, uronic acid content, NMR spectroscopy, and size-exclusion chromatography. Keratan sulfate was detected in batches from shark cartilage, averaging ∼16% of the total GAG. Keratan sulfate is an inert material, and hazardous effects due to its presence in these formulations are unlikely to occur. However, its unexpected high percentage compromises the desired amounts of the real ingredient specified on the label claims, and forewarns the pharmacopeias to update their monographs. The techniques they recommended, especially cellulose acetate electrophoresis, are inefficient in detecting keratan sulfate in chondroitin sulfate formulations. In addition, this finding also alerts the manufacturers for improved isolation procedures as well as the supervisory agencies for better audits. Analysis based on strong anion-exchange chromatography is shown to be more reliable than the methods presently suggested by standard pharmacopeias.

  18. Formulation approaches in mitigating toxicity of orally administrated drugs.

    PubMed

    Kadiyala, Irina; Tan, Elijah

    2013-01-01

    This paper provides an overview of current formulation approaches to mitigate toxicity of orally administrated drugs. The formulation approaches are characterized by their intended impact on a drug's pharmacokinetic parameters, pharmacological properties or metabolic pathways. Regulatory opportunities and constraints with focus on U.S. regulations in optimizing a drug's safety or efficacy profile are reviewed. The following formulation approaches are described: (i) pharmacokinetic-modulating and (ii) pharmacodynamic-modulating. In the pharmacokinetic-modulating approach, the pharmacokinetic profile of drug release is modified by, for example, a reduction in peak drug plasma concentration while preserving or improving AUC, thereby potentially reducing toxic effects that may be related to C(max). In the pharmacodynamic-modulating approach, the drug is co-dosed with pharmacologically active or nonpharmacologically active agent or agents intended for mitigation of the drug's toxicity. The pharmacodynamic-modulating approach requires information on the specificity of drug interactions with other compounds and also on metabolic pathways. Examples demonstrating successful formulation work in reducing drug toxicity are provided. The in-depth knowledge of the drug's PK and PD properties combined with a greater understanding of the biology of diseases are necessary for successful drug product formulation leading to optimized in vivo exposure and minimized toxicity.

  19. Administrative Challenges to the Integration of Oral Health With Primary Care

    PubMed Central

    Maxey, Hannah L.; Randolph, Courtney; Gano, Laura; Kochhar, Komal

    2017-01-01

    Inadequate access to preventive oral health services contributes to oral health disparities and is a major public health concern in the United States. Federally Qualified Health Centers play a critical role in improving access to care for populations affected by oral health disparities but face a number of administrative challenges associated with implementation of oral health integration models. We conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis with health care executives to identify strengths, weaknesses, opportunities, and threats of successful oral health integration in Federally Qualified Health Centers. Four themes were identified: (1) culture of health care organizations; (2) operations and administration; (3) finance; and (4) workforce. PMID:27218701

  20. 77 FR 40069 - Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-06

    ... HUMAN SERVICES Food and Drug Administration Single-Ingredient, Immediate-Release Drug Products Containing Oxycodone for Oral Administration and Labeled for Human Use; Enforcement Action Dates AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA or Agency...

  1. Oral Administration of N-Acetyl-D-Glucosamine Polymer Particles Down-Regulates Airway Allergic Responses

    DTIC Science & Technology

    2007-03-01

    AD_________________ Award Number: DAMD17-03-1-0004 TITLE: Oral Administration of N- Acetyl -D...Oral Administration of N- Acetyl -D-Glucosamine Polymer Particles Down-Regulates 5a. CONTRACT NUMBER Airway Allergic Responses...TERMS Childhood asthma, N- acetyl -D-glucosamine polymer, IL-12, GATA-3, T-bet, macrophages, airway hyperreactivity 16. SECURITY CLASSIFICATION OF

  2. Oral administration of lipopolysaccharides for the prevention of various diseases: benefit and usefulness.

    PubMed

    Inagawa, Hiroyuki; Kohchi, Chie; Soma, Gen-Ichiro

    2011-07-01

    It is well known that intravenous administration of lipopolysaccharide (LPS) induces severe toxicity in mammals. The maximum tolerated dose of intravenous administration of LPS in humans is reported to be only 1 to 4 ng/kg body weight. However, oral administration of a high dose of LPS caused no toxicity or systemic inflammation in other mammals, birds, or fish. Two weeks of oral administration of a high dose of LPS (2 mg/kg) did not induce toxicity in a rat experiment. Moreover, several experiments have reported that oral administration of LPS had preventative and curative properties against various diseases, including allergic, and lifestyle-related diseases. These results demonstrate that mucosal administration of LPS acts via a different regulatory mechanism in biological responses from that of parenteral administration. Mucosal administration of LPS is thought to be quite promising for prevention of diseases, but LPS is rarely used. In order to expand the usage of oral administration of LPS for preventing lifestyle and allergic diseases, it will be necessary to clarify the mechanisms that arouse immune responses after oral administration of LPS. This short review presents a recent observation of the usefulness of orally administered LPS.

  3. Administration of oral medication by parents at home.

    PubMed

    Boztepe, Handan; Özdemir, Handan; Karababa, Çiğdem; Yıldız, Özlem

    2016-11-01

    The objective of this study was to determine parents' experiences and problems with administering medication to their children at home. Parents' experiences and access to information for the treatment of their children's illnesses at home is necessary for their children's safety. A descriptive cross-sectional study. Four hundred parents from children's hospital outpatient clinics were included. A questionnaire was used to determine parents' experiences and problems with administering medication to their children at home. Descriptive statistical analyses were performed using the spss software package (version 22.00). Antipyretics (59%) and antibiotics (25%) were the most commonly used medicines by parents without prescription. Nearly half of the parents stated that they gave liquid medicine with a household spoon. It was found that 54% of the parents whose children refused to take tablets or liquid medicine mixed these medications into foods. Treatment was delayed in 20·7% of the children who refused to take tablets and in 29·1% of the children who refused to take liquid medicine. As a result of the project, a form and device were developed as a solution to the problems experienced by parents while administering oral medication in the home environment. The results of the study showed that a significant percentage of the parents did not use the correct equipment to administer medications, used non-prescription medicines, did not administer medications at correct intervals and mixed medication into foods. Healthcare professionals, especially nurses, should continually evaluate medication administration by parents at home and the readmission rate in the emergency department to further improve children's health. © 2016 John Wiley & Sons Ltd.

  4. Nucleotide Analog Prodrug, Tenofovir Disoproxil, Enhances Lymphoid Cell Loading Following Oral Administration in Monkeys

    PubMed Central

    Durand-Gasselin, Lucie; Van Rompay, Koen K.A.; Vela, Jennifer E.; Henne, Ilana N.; Lee, William A.; Rhodes, Gerry R.; Ray, Adrian S.

    2009-01-01

    The antiviral drug tenofovir (TFV) is orally administered as the fumarate salt of its disoproxil prodrug (TFV disoproxil fumarate (TDF)). TFV is a di-anion at physiological pH and, as a result, has poor lipid membrane permeability. Administration of the lipophilic and cell permeable prodrug, TFV disoproxil, enhances the oral absorption of TFV. In order to determine if oral administration of TDF also increases distribution to sites of viral infection, the plasma and circulating lymphoid cell pharmacokinetics of TFV and its phosphorylated metabolites were assessed following a single oral TDF or subcutaneous TFV administration at doses yielding equivalent plasma exposures to TFV in macaques. Despite TFV disoproxil’s lack of plasma stability and undetectable levels in the first plasma samples taken, oral administration of TDF resulted in 7.9-fold higher peripheral blood mononuclear cell exposures to the active metabolite, TFV-diphosphate. The apparent plasma terminal half-life (t1/2) of TFV was also longer following oral TDF relative to subcutaneous TFV administration (median t1/2 of 15.3 and 3.9 h, respectively), suggesting broader distribution to cells and tissues outside of the central plasma compartment. In conclusion, the disoproxil pro-moiety not only enhances the oral absorption of TFV but also tissue and lymphoid cell loading. These results illustrate that administration of even a fleeting prodrug can increase target tissue loading and gives valuable insight for future prodrug development. PMID:19545170

  5. Bioavailability of the Yuzpe and levonorgestrel regimens of emergency contraception: vaginal vs. oral administration.

    PubMed

    Kives, Sari; Hahn, Philip M; White, Emily; Stanczyk, Frank Z; Reid, Robert L

    2005-03-01

    Separate crossover studies compared the bioavailability of oral vs. vaginal routes of administration for the Yuzpe (n=5) and levonorgestrel regimens (n=4) of emergency contraception. Twice the standard dose of the Yuzpe regimen (200 microg of ethinyl estradiol, 1000 microg of levonorgestrel) or the levonorgestrel regimen (1500 microg of levonorgestrel) was self-administered vaginally. One week later, each subject received orally the standard dose of the assigned medication. Serial blood samples were collected over 24 h and assayed for levonorgestrel and ethinyl estradiol (for the Yuzpe regimen only). Paired t tests were used to compare oral vs. vaginal administration for maximum concentration (Cmax), time to maximum concentration (Tmax) and area under the curve over 24 h (AUC0-24). Relative bioavailability (vaginal/oral) was derived from AUC0-24. Vaginal administration of double the standard dose of the Yuzpe regimen resulted in a lower Cmax (vaginal=5.4 vs. oral=14.6 ng/mL, p=.038) and a later Tmax (5.9 vs. 2.0 h, p=.066) for levonorgestrel, compared to oral administration. Corresponding ethinyl estradiol concentrations were higher (786 vs. 391 pg/mL, p=.039) and peaked later (4.0 vs. 1.9 hr, p=.154) with vaginal administration. Relative bioavailabilities for levonorgestrel and ethinyl estradiol were 58% and 175%, respectively. Similarly, vaginal administration of the levonorgestrel regimen resulted in a lower Cmax (vaginal=5.4 vs. oral=15.2 ng/mL, p=.006) and a later Tmax (7.4 vs. 1.3 h, p=.037) for levonorgestel, compared to oral administration. The relative bioavailability was 62%. Our preliminary data suggest that vaginal administration of these emergency contraception regimens appears to require at least three times the standard oral dose to achieve equivalent systemic levonorgestrel concentrations.

  6. Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets.

    PubMed

    Le Traon, G; Burgaud, S; Horspool, L J I

    2009-06-01

    Long-term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post-treatment (t(max) = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half-life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed (t(max) = 2.25 h) and decreased the rate and extent of absorption (AUC) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs.

  7. Comparative bioavailability of fluoxetine after transdermal and oral administration to healthy cats.

    PubMed

    Ciribassi, John; Luescher, Andrew; Pasloske, Kirby S; Robertson-Plouch, Carol; Zimmerman, Alan; Kaloostian-Whittymore, Liane

    2003-08-01

    To determine bioavailability, pharmacokinetics, and safety for transdermal (TD) and oral administration of fluoxetine hydrochloride to healthy cats. 12 healthy mixed-breed sexually intact 1- to 4-year-old purpose-bred cats. A single-dose pharmacokinetic study involving 3 groups of 4 cats each was conducted in parallel. Fluoxetine in a formulation of pluronic lecithin organogel (PLO gel) was applied to the hairless portion of the pinnae of cats at 2 dosages (5 or 10 mg/kg), or it was administered orally in capsules at a dosage of 1 mg/kg. Plasma samples were obtained and submitted for liquid chromatography-mass spectrometry-mass spectrometry analysis of fluoxetine and its active metabolite, norfluoxetine. Peak fluoxetine concentration (Cmax) was lower and time to Cmax longer for TD administration versus oral administration. Relative bioavailability of each dose administered via the TD route was 10% of the value for oral administration of the drug. Mean plasma elimination half-life after oral administration was 47 and 55 hours for fluoxetine and norfluoxetine, respectively. This study provides evidence that fluoxetine in a 15% (wt:vol) PLO gel formulation can be absorbed through the skin of cats into the systemic circulation. However, the relative bioavailability for TD administration is approximately only 10% of that for the oral route of administration.

  8. Tissue, Dosimetry, Metabolism and Excretion of Pentavalent and Trivalent Dimethylated Arsenic in Mice after Oral Administration

    EPA Science Inventory

    Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic inmice after acute oral administration. Adult fema...

  9. Variability of serum indomethacin concentrations after oral and intravenous administration to preterm infants.

    PubMed

    Mrongovius, R; Imbeck, H; Wille, L; Müller, H; Seyberth, H W

    1982-03-01

    Fifteen preterm infants with patent ductus arteriosus and respiratory distress syndrome were given indomethacin (0.2 mg/kg) at 12 h intervals up to three times, either orally or intravenously, in an uncontrolled, non-randomized study. Serum indomethacin concentrations were determined in blood samples taken 12 h after dosing. There was considerable variability in the serum indomethacin concentrations, especially after oral administration, although the mean concentrations after each of the three doses were similar after both oral and intravenous administration. The frequency of closures and transient closures of the ductus arteriosus was also similar for both routes of administration. There was, however, no relation between concentration and effect in individual patients. The sustained exposure to indomethacin which appears to be necessary for ductal closure can sometimes be attained by oral administration.

  10. Tissue, Dosimetry, Metabolism and Excretion of Pentavalent and Trivalent Dimethylated Arsenic in Mice after Oral Administration

    EPA Science Inventory

    Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic inmice after acute oral administration. Adult fema...

  11. [Skin penetration of sulfamethoxazole and trimethoprim after oral administration].

    PubMed

    Królicki, Andrzej

    2002-01-01

    The aim of this study was to determine the penetration of trimethoprim, sulphamethoxazole and its main metabolite--N4-acetylsulphamethoxazole into cantharidin-induced skin blister fluid following administration of a single oral combination dose of 320 mg trimethoprim and 1600 mg sulphamethoxazole. Moreover, penetration of the two drugs into skin blister fluid was compared with penetration into the theoretical peripheral compartment calculated on the basis of plasma levels found. The material consisted of 12 male patients with bacterial skin diseases, treated at the Department of Dermatology and Venerology, Pomeranian Academy of Medicine in Szczecin. The age of the patients was 19-64 years (mean 42 +/- 14), weight 61-112 kg (mean 77 +/- 15), height 166-196 cm (mean 175 +/- 8). Prior to enrollment, normal function of gastrointestinal tract, liver and kidneys, and absence of allergy to the drugs studied was ascertained. The susceptibility of pathogens of cotrimoxazole (trimethoprim + sulphamethoxazole) was confirmed with bacteriological tests. Skin blisters were induced by applying 0.25% cantharidin ointment. Drug concentrations in plasma and skin blister fluid were measured with high-performance liquid chromatography. Peak concentrations of trimethoprim in plasma and skin blister fluid were 8.5 +/- 1.1 mumol/L after 3 +/- 1 h and 5.6 +/- 0.8 mumol/L after 7 +/- 2 h, respectively. The differences between both compartments as to parameters measured were statistically significant. In the theoretical peripheral compartment, peak concentration was 5.8 +/- 2.2 mumol/L after 9 +/- 6 h. Half-times of trimethoprim in plasma and skin blister fluid were 11.1 +/- 4.5 h and 12.3 +/- 4.9 h, respectively, and did not differ significantly. The degree of drug penetration into blister fluid defined as the ratio of area under concentration-time curves for blister fluid and plasma was 0.94 +/- 0.23. The differences between pharmacokinetic parameters of trimethoprim in skin blister fluid

  12. Coronary Spastic Angina Induced after Oral Desmopressin (DDAVP) Administration

    PubMed Central

    Adachi, Yusuke; Sakakura, Kenichi; Akashi, Naoyuki; Wada, Hiroshi; Momomura, Shin-ichi; Fujita, Hideo

    2016-01-01

    A 60-year-old man was prescribed oral desmopressin (1-deamino-8-D-arginine vasopressin acetate trihydrate; DDAVP) for nocturnal polyuria. One week after starting to take desmopressin, he frequently felt chest pain while resting. Coronary angiography revealed no organic stenosis; however, an acetylcholine provocation test showed severe coronary spasm with ST elevation. He was diagnosed with coronary spastic angina, and we stopped the oral desmopressin and added diltiazem. While DDAVP should dilate the coronary vessels in healthy subjects, it may provoke coronary vasospasm in patients with endothelial dysfunction. We should be careful to avoid triggering coronary spasm when administering DDAVP to patients that may have potential endothelial dysfunction. PMID:27980260

  13. Dipyridamole thallium-201 myocardial imaging. Complications associated with oral and intravenous routes of administration

    SciTech Connect

    Aksut, S.V.; Port, S.; Collier, B.D.; Hoffmann, R.G.; Massardo, T.; Hellman, R.S.; Isitman, A.T.; Carnell, A.; Devich, E.C.

    1988-11-01

    Previous reports have shown that TI-201 myocardial imaging with either an oral or intravenous administration of dipyridamole is a suitable diagnostic examination for patients at risk for coronary artery disease who cannot perform treadmill exercise. To compare the incidence of complications associated with these two routes of drug administration, the records of 78 oral and 97 intravenous dipyridamole TI-201 imaging studies were reviewed. The oral administration is associated with a significantly higher incidence of nausea (15% vs. 4%). Despite the higher incidence of nausea, the percentage of patients having one or more dipyridamole-induced symptoms was no greater for the oral (29%) than for the intravenous (37%) administration. Intravenous administration produced both a significantly higher incidence of atypical angina (14% vs. 4%) and a significantly greater increase in heart rate (16.6 vs. 10.2 beats per minute). No patient in either the oral or intravenous dipyridamole protocols had life-threatening arrhythmias or myocardial infarctions. In clinical practice, the difference in complications associated with the oral and intravenous administration of dipyridamole for TI-201 imaging is not significant.

  14. Methamphetamine and amphetamine pharmacokinetics in oral fluid and plasma after controlled oral methamphetamine administration to human volunteers.

    PubMed

    Schepers, Raf J F; Oyler, Jonathan M; Joseph, Robert E; Cone, Edward J; Moolchan, Eric T; Huestis, Marilyn A

    2003-01-01

    Methamphetamine (METH) and amphetamine (AMP) concentrations in 200 plasma and 590 oral fluid specimens were used to evaluate METH pharmacokinetics and pharmacodynamics after oral administration of sustained-release METH. Eight participants received four oral 10-mg S-(+)-METH hydrochloride sustained-release tablets within 7 days. Three weeks later, five participants received four oral 20-mg doses. Blood samples were collected for up to 24 h and oral fluid for up to 72 h after drug administration. After the first oral dose, initial plasma METH detection was within 0.25-2 h; c(max) was 14.5-33.8 micro g/L (10 mg) and 26.2-44.3 micro g/L (20 mg) within 2-12 h. In oral fluid, METH was detected as early as 0.08-2 h; c(max) was 24.7-312.2 micro g/L (10 mg) and 75.3-321.7 micro g/L (20 mg) and occurred at 2-12 h. The median oral fluid-plasma METH concentration ratio was 2.0 across 24 h and was highly variable. Neutral cotton swab collection yielded significantly higher METH and AMP concentrations than citric acid candy-stimulated expectoration. Mean (SD) areas under the curve for AMP were 21% +/- 25% and 24% +/- 11% of those observed for METH in plasma and oral fluid, respectively. After a single low or high dose, plasma METH was >2.5 micro g/L for up to 24 h in 9 of 12 individuals (mean, 7.3 +/- 5.5 micro g/L at 24 h); in oral fluid the detection window was at least 24 h (mean, 18.8 +/- 18.0 micro g/L at 24 h). The plasma and oral fluid 24-h METH detection rates were 54% and 60%, respectively. After four administrations, METH was measurable for 36-72 h (mean, 58.3 +/- 14.5 h). Perceived advantages of oral fluid for verifying METH exposure compared with urine include simpler specimen collection and reduced potential for adulteration, but urine offers higher analyte concentrations and a greater window of detection.

  15. Lamb deaths associated with administration of oral minerals.

    PubMed

    2016-10-22

    Deaths in preweaned lambs associated with administering oral minerals containing copperCongenital malformations in calvesIdiopathic necrotising enteritis in calvesAbomasal obstruction due to trichobezoars in suckled calvesRadial neuropathy (kangaroo gait) in a ewe These are among matters discussed in the disease surveillance report for July 2016 from SAC Consulting: Veterinary Services (SAC C VS).

  16. Administration diluents differentiate Neoral from a generic cyclosporine oral solution.

    PubMed

    Kovarik, John M; Barilla, Denise; McMahon, Louis; Wang, Yibin; Kisicki, James; Schmouder, Robert

    2002-08-01

    A non-microemulsion cyclosporine oral solution was recently recalled from the market because of the lack of bioequivalence when administered with apple juice compared with water as the diluent. This open-label, randomized, two-period, crossover study assessed the effect of apple juice on Neoral, a microemulsion cyclosporine oral solution. The study enrolled 34 subjects who received 180 mg Neoral oral solution diluted in 200 mL tap water or apple juice. Cyclosporine was measured in whole blood by a liquid chromatography method. Pharmacokinetic parameters were compared by standard bioequivalence tests. With water vs. apple juice, cyclosporine Cmax was 1263 +/- 203 vs. 1191 +/- 225 ng/mL and AUC was 4714 +/- 1117 vs. 4788 +/- 1320 ng h/mL, respectively. Bioequivalence was demonstrated for both parameters. These data were comparable with those from a previous study in which subjects received 180 mg Neoral oral solution with orange juice. Cyclosporine bioavailability is unaltered when Neoral is administered diluted in apple juice or orange juice compared with tap water which conforms to the cyclosporine product label.

  17. Pharmacokinetic behavior of gentiopicroside from decoction of Radix Gentianae, Gentiana macrophylla after oral administration in rats: a pharmacokinetic comaprison with gentiopicroside after oral and intravenous administration alone.

    PubMed

    Wang, Chang-Hong; Cheng, Xue-Mei; He, Yu-qi; White, Kenneth N; Bligh, S W Annie; Branford-White, Christopher J; Wang, Zheng-tao

    2007-09-01

    The pharmacokinetics in rats of gentiopicroside (GPS) from orally administered decoctions of Radix Gentianae (DRG) and Gentiana macrophlla (DGM) were compared with that of GPS alone administered at 150 mg/kg orally and 30 mg/kg intravenously. The metabolic profile of GPS after intravenous injection could be fitted to two-compartment model whereas oral administration decoctions DRG or DGM, or GPS alone, could all be fitted to a one-compartment model. After oral administration of GPS alone, GPS was absorbed quickly and reached a maximum plasma concentration (Cmax) value, 5.78 +/- 2.24 microg/mL within 0.75 +/- 0.62 h. The plasma level of GPS declined with a T1/2ke, 3.35 +/- 0.76 h. After oral administration of decoctions DRG and DGM, GPS was absorbed and reached significantly higher maximum concentrations of 10.53 +/- 3.20 microg/mL (p < 0.01) and 7.43 +/- 1.64 microg/mL (p < 0.05) at later time points 1.60 +/- 0.76 (p < 0.01) and 2.08 +/- 0.74 h (p < 0.05), for DRG and DGM respectively, compared with oral GPS alone. Significantly larger AUC values were found for decoctions of GPS (83.49 +/- 20.8 microgxh/mL for DRG and 59.43 +/- 12.9 microgxh/mL for DGM) compared with oral GPS alone (32.67 +/- 12.9 microgxh/mL). The results demonstrate that the bioavailability of GPS was markedly improved when administered as a decoction than as purified GPS. The decoction from Radix Gentianae provided 2.5 times better bioavailability and that from Gentiana macrophlla 1.8 times higher. The study confirms the importance of careful pharmacokinetic analysis in the characterization of herbal medicines when applied for future clinical applications.

  18. Urothelial conversion of 5-aminolevulinic acid to protoporphyrin IX following oral or intravesical administration

    NASA Astrophysics Data System (ADS)

    Moore, Ronald B.; Miller, Gerald G.; Brown, Kevin; Bhatnagar, Rakesh; Tulip, John; McPhee, Malcolm S.

    1995-03-01

    Preferential conversion of 5-aminolevulinic acid (5-ALA) to protoporphyrin-IX (Pp-IX) occurs in malignant tissue, with accumulation to diagnostic and therapeutic levels. Recent studies have suggested selective conversion in epithelial tissue following oral or intravenous administration. Topical application avoids systemic photosensitization. However, the glycosaminoglycan (GAG) layer lining the urinary bladder is believed to be a protective barrier generally limiting mucosal absorption. Our objective was to evaluate uptake and conversion of 5-ALA following intravesical or oral administration. Using a rat model, Pp-IX content within epithelial and muscularis layers was quantitated by fluorescence confocal microscopy. Following intravesical administration, Pp-IX accumulated predominantly in the urothelium; whereas following oral administration, Pp-IX accumulated in both the urothelium and muscularis. Intravesical 5-ALA administration is feasible and may afford selective photosensitization of the urothelium for treatment of carcinoma in situ.

  19. Methylmalonic acidemia controlled with oral administration of vitamin B12.

    PubMed Central

    Gordon, B. A.; Carson, R. A.

    1976-01-01

    A 3-month-old male infant had two episodes of fever, projectile vomiting, dehydration, generalized fine tremors and gross metabloic ketoacidosis. Methylmalonic acid was found in high concentration in both serum and urine, although the concentration of serum vitamin B12 was normal. A therapeutic trial of vitamin B12, administered parenterally, reduced greatly the methylmalonic aciduria. The patient has since been given vitamin B12 supplements continuously, initially 1 mg intramuscularly every other day, then 15 mg/d orally, and the protein in his diet was subsequently restricted. The most effected control of the methylmalonic aciduria was achieved with the combined regimen of oral vitamin therapy and dietary protein restriction. His physical and intellectual development have progressed normally and he has survived several acute respiratory tract infections without recurrence of metabolic acidosis. PMID:953884

  20. Oral administration of Chlorella vulgaris augments concomitant antitumor immunity.

    PubMed

    Tanaka, K; Tomita, Y; Tsuruta, M; Konishi, F; Okuda, M; Himeno, K; Nomoto, K

    1990-01-01

    Chlorella vulgaris, an unicellular green algae, or its acetone-extract (Ac-Ex) were administered orally to Meth A tumor bearing BALB/c or (BALB/c x DBA/2)F1 (CDF1) mice. When CDF1 mice were fed daily with 10% dried powder of Chlorella vulgaris (CVP) containing diet before and after Meth A tumor inoculation, the growth of rechallenged Meth A tumor was significantly suppressed in an antigen-specific manner. Augmentation of antitumor resistance was exhibited also by Winn assay using lymph node cells of tumor-bearing mice orally administered with CVP or Ac-Ex. Antigen-specific concomitant immunity in these mice were mediated by cytostatic T cells but not by cytotoxic T cells. Natural killer cells seemed not to contribute in antitumor resistance in this system.

  1. Relationship between lethal toxicity in oral administration and injection to mice: effect of exposure routes.

    PubMed

    Wang, Yu; Ning, Zhong H; Tai, Hong W; Long, Shuang; Qin, Wei C; Su, Li M; Zhao, Yuan H

    2015-03-01

    The lethal toxicity (LD₅₀) in oral administration, intravenous, intraperitoneal, intramuscular and subcutaneous injections were used to investigate relationships of log 1/LD₅₀ from different exposure routes. Regression analysis showed that log 1/LD₅₀ in oral route was related to the toxicity in injection route. This relationship in lethality between the two routes is apparently due to the same mechanisms of the compounds to the same species. However, the scatter in the correlation curve indicates that exposure route is an important factor that influences the relationship. Some compounds with low intestinal absorption exhibit much less toxicity in oral administration than that in the injection route. A systemic bias of log 1/LD₅₀ between oral and injection routes indicates that tissue distribution of compounds between blood and target site is a very rapid process, leading to log 1/LD₅₀ in injection greater than those in oral administration. Although compounds can be metabolized in the body both from oral and injection routes, first-pass metabolism occurs in oral route but not in injection route. This will result in decrease of toxicity in oral route for most compounds as compared with injection route. In addition, experimental uncertainty, differences in gender, and species can also affect relationships of log1/LD₅₀ between exposure routes.

  2. Human Temperature Regulation during Exercise after Oral Pyridostigmine Administration

    DTIC Science & Technology

    1990-03-01

    or vasomotor elements) which may or during exercise . Tsk was different in the three conditions by result from increased cholinergic activity after...of cholines- oration during steady-state exercise in control experi- terase enzyme activity units by the manual delta pH method ments. Thus, the small...Reprint & Copyright © by Aerospace Medical Association, Washington. DC D T IC ELECTF 0 Human Temperature Regulation * ~During Exercise After N Oral

  3. Disintegration of chemotherapy tablets for oral administration in patients with swallowing difficulties.

    PubMed

    Siden, Rivka; Wolf, Matthew

    2013-06-01

    The administration of oral chemotherapeutic drugs can be problematic in patients with swallowing difficulties. Inability to swallow solid dosage forms can compromise compliance and may lead to poor clinical outcome. The current technique of tablet crushing to aid in administration is considered an unsafe practice. By developing a technique to disintegrate tablets in an oral syringe, the risk associated with tablet crushing can be avoided. The purpose of this study was to determine the feasibility of using disintegration in an oral syringe for the administration of oral chemotherapeutic tablets. Eight commonly used oral chemotherapeutic drugs were tested. Tablets were placed in an oral syringe and allowed to disintegrate in tap water. Various volumes and temperatures were tested to identify which combination allows for complete disintegration of the tablet in the shortest amount of time. The oral syringe disintegration method was considered feasible if disintegration occurred in ≤15 min and in ≤20 mL of water and the dispersion passed through an oral syringe tip. The following tablets were shown to disintegrate within 15 min and in <20 mL of water: busulfan, cyclophosphamide 50 mg, dasatinib, imatinib, methotrexate, and thioguanine. For these drugs, drug-specific information pamphlets can be prepared for patient or caregiver use. Mercaptopurine, cyclophosphamide 25 mg, and mitotane tablets did not pass the disintegration test. Disintegrating oral chemotherapeutic tablets in a syringe provides a closed system to administer hazardous drugs and allows for the safe administration of oral chemotherapeutic drugs in a tablet form to patients with swallowing difficulties.

  4. Metabolomic Analyses of Blood Plasma after Oral Administration of D-Glucosamine Hydrochloride to Dogs

    PubMed Central

    Osaki, Tomohiro; Azuma, Kazuo; Kurozumi, Seiji; Takamori, Yoshimori; Tsuka, Takeshi; Imagawa, Tomohiro; Okamoto, Yoshiharu; Minami, Saburo

    2012-01-01

    D-Glucosamine hydrochloride (GlcN∙HCl) is an endogenous amino monosaccharide synthesized from glucose that is useful in the treatment of joint diseases in both humans and animals. The aim of this study was to examine amino acid metabolism in dogs after oral administration of GlcN∙HCl. Accelerated fumarate respiration and elevated plasma levels of lactic acid and alanine were observed after administration. These results suggest that oral administration of GlcN∙HCl induces anaerobic respiration and starvation in cells, and we hypothesize that these conditions promote cartilage regeneration. Further studies are required to evaluate the expression of transforming growth factor-beta (TGF-β). PMID:23015778

  5. Orally administrated dipeptide Ser-Tyr efficiently stimulates noradrenergic turnover in the mouse brain.

    PubMed

    Ichinose, Takashi; Moriyasu, Kazuki; Nakahata, Akane; Tanaka, Mitsuru; Matsui, Toshiro; Furuya, Shigeki

    2015-01-01

    In this study, we examined the effect of orally administrated dipeptides containing Tyr (Y) on the metabolism of catecholamines in mouse brains. We found that among eight synthetic dipeptides whose sequences are present frequently in soy proteins, Ser-Tyr (SY), Ile-Tyr, and Tyr-Pro had the highest apparent permeability coefficients in monolayers of human intestinal epithelial Caco-2 cells. When administrated orally, SY markedly increased tyrosine content in the cerebral cortex compared to the vehicle control, Ile-Tyr, Tyr-Pro, and Y alone. The oral administration of SY more effectively increased 3-methoxy-4-hydroxyphenylethyleneglycol, the principal metabolite of noradrenaline, in the cerebral cortex and hippocampus than did Ile-Tyr, Tyr-Pro, or Y alone. Central noradrenergic turnover was also markedly stimulated by SY administration. These in vivo observations strongly suggest that SY is more potent in boosting central catecholamine transmission, particularly the noradrenergic system, than Y alone or other dipeptides that include Y.

  6. Dosage Form Developments of Nanosuspension Drug Delivery System for Oral Administration Route.

    PubMed

    Chen, Ang; Shi, Ye; Yan, Zhiqiang; Hao, Hongxun; Zhang, Yong; Zhong, Jian; Hou, Huiming

    2015-01-01

    A large amount of new drug candidates are practically insoluble in aqueous solvents and are even simultaneously poorly soluble in organic solvents. Nanosuspension drug delivery system (DDS) was firstly developed in 1994 and has attracted more and more attention as a formation solution for the poorly soluble drugs. By nansizing the poorly soluble drugs, nanosuspensions have several outstanding advantages for drug delivery. Among many administration routes of drug delivery, oral administration is the most preferred route due to its advantages such as ease of ingestion, versatility to accommodate various types of drug candidates, low production cost, high safety, good patient compliance, and pain avoidance. Current marketed pharmaceutical nanosuspension DDS products are mostly for oral administration. This review is to systematically summarize the nanosuspension DDS dosage form developments of poorly soluble drugs for oral administration use.

  7. Terbinafine pharmacokinetics after single dose oral administration in the dog.

    PubMed

    Sakai, Mary R; May, Elizabeth R; Imerman, Paula M; Felz, Charles; Day, Timothy A; Carlson, Steve A; Noxon, James O

    2011-12-01

    Terbinafine is an allylamine antifungal prescribed for the treatment of mycoses in humans. It is increasingly being used in veterinary patients. The purpose of this study was to evaluate the pharmacokinetic properties of terbinafine in dogs after a single oral dose. Ten healthy adult dogs were included in the study. A single dose of terbinafine (30-35 mg/kg) was administered orally, and blood samples were periodically collected over a 24 h period during which dogs were monitored for adverse effects. Two of 10 dogs developed transient ocular changes. A high-performance liquid chromatography assay was developed and used to determine plasma terbinafine concentrations. Pharmacokinetic analysis was performed using PK Solutions(®) computer software. Area under the curve (AUC) from time 0 to 24 h was 15.4 μg·h/mL (range 5-27), maximal plasma concentration (C(max) ) was 3.5 μg/mL (range 3-4.9 μg/mL) and time to C(max) (T(max) ) was 3.6 h (range 2-6 h). The time above minimal inhibitory concentration (T > MIC) as well as AUC/MIC was calculated for important invasive fungal pathogens and dermatophytes. The T > MIC was 17-18 h for Blastomyces dermatitidis, Histoplasma capsulatum and dermatophytes (Microsporum spp. and Trichophyton mentagrophytes), while the MIC for Sporothrix schenckii and Coccidioides immitis was exceeded for 9.5-11 h. The AUC/MIC values ranged from 9 to 13 μg h/mL for these fungi. Our results provide evidence supporting the use of terbinafine as an oral therapeutic agent for treating systemic and subcutaneous mycoses in dogs.

  8. Oral transmucosal administration of dexmedetomidine for sedation in 4 dogs

    PubMed Central

    Cohen, Anne E.; Bennett, Sara L.

    2015-01-01

    Injectable dexmedetomidine (DM) is widely used for sedation, restraint, anxiolysis, and analgesia in veterinary medicine. Oral transmucosal dexmedetomidine (OTM DM) has been evaluated in horses, cats, and humans, but not in dogs. In this case series, OTM DM (mean dose of 32.6 μg/kg body weight) was given in the buccal pouch to 4 aggressive dogs in a hospital setting. Two of the dogs were subsequently euthanized, and in the other 2, sedation was reversed with atipamezole. Satisfactory sedation was achieved in all cases. PMID:26538668

  9. Oral transmucosal administration of dexmedetomidine for sedation in 4 dogs.

    PubMed

    Cohen, Anne E; Bennett, Sara L

    2015-11-01

    Injectable dexmedetomidine (DM) is widely used for sedation, restraint, anxiolysis, and analgesia in veterinary medicine. Oral transmucosal dexmedetomidine (OTM DM) has been evaluated in horses, cats, and humans, but not in dogs. In this case series, OTM DM (mean dose of 32.6 μg/kg body weight) was given in the buccal pouch to 4 aggressive dogs in a hospital setting. Two of the dogs were subsequently euthanized, and in the other 2, sedation was reversed with atipamezole. Satisfactory sedation was achieved in all cases.

  10. Evaluating oral flavorant effects on nicotine self-administration behavior and phasic dopamine signaling.

    PubMed

    Wickham, Robert J; Nunes, Eric J; Hughley, Shannon; Silva, Phillip; Walton, Sofia N; Park, Jinwoo; Addy, Nii A

    2017-09-21

    Understanding how tobacco product flavor additives, such as flavorants in electronic cigarettes, influence smoking behavior and addiction is critical for informing public health policy decisions regarding tobacco product regulation. Here, we developed a combined intraoral (i.o.) and intravenous (i.v.) self-administration paradigm in rats to determine how flavorants influence self-administration behavior. By combining i.o. flavorant delivery with fast scan cyclic voltammetry (FSCV) or i.v. nicotine self-administration in adult, male rats, we examined whether flavors alter phasic dopamine (DA) signaling and nicotine self-administration. Oral administration of 10% sucrose or 0.32% saccharin, but not 0.005% menthol, increased phasic DA release in the nucleus accumbens (NAc). Oral sucrose or saccharin, when combined with i.v. nicotine delivery, also led to increased self-administration behavior. Specifically, combined i.o. sucrose and i.v. nicotine decreased responding compared to sucrose alone, and increased responding compared to nicotine alone. In contrast, i.o. flavorants did not alter motivational breakpoint in a progressive ratio task. Oral menthol, which did not alter i.v. nicotine administration, reversed oral nicotine aversion (50 and 100 mg/L) in a two-bottle choice test. Here, we demonstrate that i.o. appetitive flavorants that increase phasic DA signaling also increase self-administration behavior when combined with i.v. nicotine delivery. Additionally, oral menthol effects were specific to oral nicotine, and were not observed with i.v. nicotine-mediated reinforcement. Together, these preclinical findings have important implications regarding menthol and sweet flavorant additive effects on tobacco product use and can be used to inform policy decisions on tobacco product flavorant regulation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Characterization of muscarinic receptor binding and inhibition of salivation after oral administration of tolterodine in mice.

    PubMed

    Oki, Tomomi; Maruyama, Shuji; Takagi, Yukiko; Yamamura, Henry I; Yamada, Shizuo

    2006-01-04

    The current study was undertaken to characterize the effects of oral administration of tolterodine on muscarinic receptor binding in the bladder and submaxillary gland and on salivation in mice. In the in vitro experiment, tolterodine and its metabolite (5-hydroxymethyl metabolite: 5-HM) competed concentration-dependently with [N-methyl-(3)H]-scopolamine ([(3)H]NMS) in the mouse bladder, submaxillary gland and heart, and the potencies of both agents were greater than that of oxybutynin. After oral administration of tolterodine (6.31, 21.0 micromol/kg) and oxybutynin (76.1 micromol/kg), there was a dose and time-dependent increase in K(d) values for specific [(3)H]NMS binding in the bladder, prostate, submaxillary gland, heart, colon and lung, compared with control values, suggesting significant muscarinic receptor binding in each tissue. The K(d) increase in each tissue by oral oxybutynin reached a maximum value of 0.5 h after oral administration and then rapidly declined, while that by tolterodine was greatest 2 h after the administration and it was maintained for at least 6 or 12 h, depending on the dose and on the tissue. Thus, muscarinic receptor binding of oral tolterodine was slower in onset and of a longer duration than that of oxybutynin. Also, oral oxybutynin showed relatively greater receptor binding in the submaxillary gland as compared with other tissues, but such high selectivity to the exocrine gland muscarinic receptors was not observed by oral tolterodine. Oral administration of tolterodine and oxybutynin reduced significantly the pilocarpine-induced salivary secretion in mice, and the attenuation of oral tolterodine appeared more slowly and it was more persistent than that of oral oxybutynin. The antagonistic effect of oral tolterodine on the dose-response curves to pilocarpine was significantly weaker than that of oxybutynin. These data suggest that oral tolterodine, compared with the case of oral oxybutynin, binds more selectively to muscarinic

  12. Effects of Copaiba Oil Topical Administration on Oral Wound Healing.

    PubMed

    Wagner, Vivian Petersen; Webber, Liana Preto; Ortiz, Lisley; Rados, Pantelis Varvaki; Meurer, Luise; Lameira, Osmar Alves; Lima, Rafael Rodrigues; Martins, Manoela Domingues

    2017-08-01

    The effects of topical copaiba oil extract and topical corticosteroid were assessed on oral wound healing in an in vivo model using 96 male Wistar rats. Traumatic ulcers were caused in the dorsum of the tongue using a 3-mm punch tool. The animals were divided into: Control; Corticosteroid; Placebo and Copaiba oil Group. The animals received two daily applications of the products. The control group received only daily handling. Six rats in each group were euthanized at days 3, 5, 10 and 14. The animals were monitored daily to determine wound status. The weigh was assessed at day 0 and euthanasia day. The percentage of repair was calculated, and histopathological aspects were analyzed. The Kruskal-Wallis test was used to compare the results between groups and times of evaluation. Closing time was assessed through the log-rank test. The corticosteroid group lost more weight at days 10 and 14 than the control group (p < 0.05). Moreover, the healing time of corticosteroid group was longer than the control group (p = 0.007). No differences were observed between the copaiba oil group and the control group. We concluded that topical copaiba oil, in spite of being safe, did not accelerate the process of oral wound healing. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  13. Preservation of liquid drug preparations for oral administration.

    PubMed

    Scheler, Stefan; Saupe, Sebastian; Herre, Angela; Fahr, Alfred

    2010-01-01

    The aim of this study was to investigate functional interactions between sorbic acid, alcoholic cosolvents, and pH with respect to pharmacopeial requirements for the antimicrobial preservation of oral liquids. Twenty-seven test formulations of sugar-free syrups with varying amounts of glycerol (18-36%), propylene glycol (4-21%), and sorbic acid (0-0.15%) and with different pH values (5-8) were tested for antimicrobial preservation efficacy after inoculation with spores of Aspergillus niger. Multivariate data analysis revealed that at pH 5 the minimum concentration of sorbic acid necessary for a tenfold decrease of viable spores ranges between 0.08% and 0.10% exhibiting only minor dependence on the cosolvents concentration. Various interactions between sorbic acid and cosolvents could be observed and were discussed on basis of the degree of dissociation and distribution of sorbic acid. All tested preparations, even those free of sorbic acid, met the criteria for oral products with aqueous bases according to USP32-NF27 and JP XV which claim no increase from the initial spore count at 14 and 28 days. The EP requirement, not less than 1 log(10) reduction from the initial count at 14 days, was only met by preparations with pH 5 and not less than 0.15% sorbic acid.

  14. Oral administration of diazepam and promazine hydrochloride to immobilize pronghorn.

    PubMed

    Pusateri, F M; Hibler, C P; Pojar, T M

    1982-01-01

    Oral tranquilizers were mixed with a grain bait and fed to pronghorn (Antilocapra americana) in an attempt to immobilize and thus facilitate their capture. Diazepam, administered at 6 mg/kg body weight immobilized a tame pronghorn fawn within 30 min. Tranquilization was still apparent after 8 h. A minimum dose of 23 mg/kg body weight was necessary to immobilize a wild adult pronghorn. Immobilization occurred after 60 min and tranquilization was apparent 24 h post ingestion. Excitement severely impeded the effect of the drug and although easily captured, the animal struggled wildly when handled. Wild pronghorn fawns showed moderate tranquilization when administered diazepam at 23 mg/kg body weight but were unapproachable. Doses of diazepam between 13 and 23 mg/kg body weight were used to capture tame yearling and adult pronghorn held in a 132 ha enclosure. A dose of 23 mg/kg body weight was excessive in that the animals did not recover for 48 to 54 h post ingestion and had difficulty maintaining a sternal bedding position. Diazepam at 13 mg/kg body weight failed to tranquilize the animals sufficiently for easy capture. Promazine hydrochloride at doses of 2 to 17 mg/kg body weight, given orally to wild pronghorn fawns and an adult, did not produce visible signs of tranquilization. Animals refused to eat bait containing doses of promazine hydrochloride greater than 17 mg/kg body weight.

  15. Difficulties experienced during preparation and administration of oral drugs

    PubMed Central

    Boztepe, Handan; Özdemir, Handan; Karababa, Çiğdem; Yıldız, Özlem

    2014-01-01

    Aim: It was aimed to determine the difficulties experienced by pediatric nurses working in the wards of a university hospital during preparation and administration of drugs and to determine solution recommendations. Material and Methods: One hundred and eight nurses who accepted to participate in the study constituted the sample of the study. Open-ended questions were asked in order to obtain detailed information about the attitudes and views of the participants and face to face interview was used. The problems experienced during preparation and administration of drugs were collected using the data collection form prepared by the investigators. Institution approval, ethics committee approval (HEK12/193) and written informed consent from the nurses who wished to participate in the study were obtained to conduct the study. The data obtained were expressed as figures and percentages. Results: The most commonly reported problems in preparation of drugs included incomplete dissolution of tablets or non-homogeneous distribution in fluids (54.6%) and difficulty in breaking tablets in appropriate doses (45.3%). The most commonly reported problem experienced during administration of drugs was rejection of drugs which tasted bad by babies/children or spitting out the drug (75.9%). In our study, the nurses also mentioned the problems related with drug administration equipment. These problems included fear of injectors (25.9%), escape of the drugs into the respiratory way (15.7%) and lack of appropriate equipment for administering the drugs (7.4%). Conclusions: In our study, it was found that all nurses experienced difficulty in preparing and administering drugs. The problems experienced by the nurses and solution recommendations for these problems were reported to the hospital administration. PMID:26078668

  16. Effects of oral administration of titanium dioxide fine-sized particles on plasma glucose in mice.

    PubMed

    Gu, Ning; Hu, Hailong; Guo, Qian; Jin, Sanli; Wang, Changlin; Oh, Yuri; Feng, Yujie; Wu, Qiong

    2015-12-01

    Titanium dioxide (TiO2) is an authorized additive used as a food colorant, is composed of nano-sized particles (NP) and fine-sized particles (FP). Previous study reported that oral administration of TiO2 NPs triggers an increase in plasma glucose of mice. However, no previous studies have focused on toxic effects of TiO2 FPs on plasma glucose homeostasis following oral administration. In the current study, mice were orally administered TiO2 FPs greater than 100 nm in size (64 mg/kg body weight per day), and effects on plasma glucose levels examined. Our results showed that titanium levels was not changed in mouse blood, livers and pancreases after mice were orally administered TiO2 FPs. Biochemical analyzes showed that plasma glucose and ROS levels were not affected by TiO2 FPs. Histopathological results showed that TiO2 FPs did not induce pathology changes in organs, especially plasma glucose homeostasis regulation organs, such as pancreas and liver. Western blotting showed that oral administration of TiO2 FPs did not induce insulin resistance (IR) in mouse liver. These results showed that, TiO2 FPs cannot be absorbed via oral administration and affect plasma glucose levels in mice.

  17. Bioavailability of amprolium in fasting and nonfasting chickens after intravenous and oral administration.

    PubMed

    Hamamoto, K; Koike, R; Machida, Y

    2000-02-01

    The bioavailability of amprolium (APL) was measured after intravenous (i.v.) and oral (p.o.) administration to chickens. Twelve healthy chickens weighing 1.28-1.41 kg received a dose of 13 mg APL/kg intravenously, and 13 or 26 mg APL/kg orally in both a fasted and a nonfasted condition in a Latin square design. Plasma samples were taken from the subwing vein for determination of APL concentration by HPLC method. The data following intravenous and oral administration were best fitted by 2-compartment and 1-compartment models, respectively, using weighted nonlinear least squares regression. The half-life beta t(1/2)beta, volume of distribution (Vd) and total body clearance (Cl) after intravenous administration were 0.21 h, 0.12 L/kg and 1.32 L/h.kg, respectively. The elimination half-life (t(1/2) Kel) after oral administration was 0.292-0.654 h which is 1.5-3.2 times longer than after intravenous administration, suggesting the presence of a 'flip-flop' phenomenon in chickens. The maximum plasma concentration (Cmax) of 13 mg/kg APL administered orally to chickens during fasting was significantly (about four times) higher than that during nonfasting (P < 0.05). Bioavailability during nonfasting was from 2.3 to 2.6%, and 6.4% during fasting.

  18. [Teratogenicity study of sodium chlorite in rats by oral administration].

    PubMed

    Sakemi, K; Usami, M; Kurebayashi, H; Ohno, Y

    1999-01-01

    The teratogenicity of sodium chlorite (NaClO2) was assessed in Wistar rats (Crj: Wistar). Sodium chlorite dissolved in distilled water was given to pregnant Wistar rats by gavage once a day from day 6 through 15 of pregnancy at doses of 0, 25, 50 and 100 mg/kg/day. The pregnant rats were sacrificed on day 20 of pregnancy, and their fetuses were examined for malformations. Sodium chlorite caused decreased food consumption, anemia, sedation, hematuria, and death in the pregnant rats at 100 mg/kg, but no fetal effects, such as malformations or growth retardation, were observed even at 100 mg/kg. It was concluded that sodium chlorite has no teratogenicity in rats when administered orally. The no-observed-adverse-effect level was 50 mg/kg/day for pregnant rats and 100 mg/kg/day or more for rat fetuses.

  19. Clonic Seizures in GAERS Rats after Oral Administration of Enrofloxacin

    PubMed Central

    Bauquier, Sebastien H; Jiang, Jonathan L; Lai, Alan; Cook, Mark J

    2016-01-01

    The aim of this study was to evaluate the effect of oral enrofloxacin on the epileptic status of Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Five adult female GAERS rats, with implanted extradural electrodes for EEG monitoring, were declared free of clonic seizures after an 8-wk observation period. Enrofloxacin was then added to their drinking water (42.5 mg in 750 mL), and rats were observed for another 3 days. The number of spike-and-wave discharges and mean duration of a single discharge did not differ before and after treatment, but 2 of the 5 rats developed clonic seizures after treatment. Enrofloxacin should be used with caution in GAERS rats because it might induce clonic seizures. PMID:27298247

  20. Intraluminal Administration of Poly I:C Causes an Enteropathy That Is Exacerbated by Administration of Oral Dietary Antigen

    PubMed Central

    Araya, Romina E.; Jury, Jennifer; Bondar, Constanza

    2014-01-01

    Systemic administration of polyinosinic:polycytidylic acid (poly I:C), mimics virally-induced activation of TLR3 signalling causing acute small intestine damage, but whether and how mucosal administration of poly I:C causes enteropathy is less clear. Our aim was to investigate the inflammatory pathways elicited after intraluminal administration of poly I:C and determine acute and delayed consequences of this locally induced immune activation. Intraluminal poly I:C induced rapid mucosal immune activation in C57BL/6 mice involving IFNβ and the CXCL10/CXCR3 axis, that may drive inflammation towards a Th1 profile. Intraluminal poly I:C also caused enteropathy and gut dysfunction in gliadin-sensitive NOD-DQ8 mice, and this was prolonged by concomitant oral administration of gliadin. Our results indicate that small intestine pathology can be induced in mice by intraluminal administration of poly I:C and that this is exacerbated by subsequent oral delivery of a relevant dietary antigen. PMID:24915573

  1. Intraluminal administration of poly I:C causes an enteropathy that is exacerbated by administration of oral dietary antigen.

    PubMed

    Araya, Romina E; Jury, Jennifer; Bondar, Constanza; Verdu, Elena F; Chirdo, Fernando G

    2014-01-01

    Systemic administration of polyinosinic:polycytidylic acid (poly I:C), mimics virally-induced activation of TLR3 signalling causing acute small intestine damage, but whether and how mucosal administration of poly I:C causes enteropathy is less clear. Our aim was to investigate the inflammatory pathways elicited after intraluminal administration of poly I:C and determine acute and delayed consequences of this locally induced immune activation. Intraluminal poly I:C induced rapid mucosal immune activation in C57BL/6 mice involving IFNβ and the CXCL10/CXCR3 axis, that may drive inflammation towards a Th1 profile. Intraluminal poly I:C also caused enteropathy and gut dysfunction in gliadin-sensitive NOD-DQ8 mice, and this was prolonged by concomitant oral administration of gliadin. Our results indicate that small intestine pathology can be induced in mice by intraluminal administration of poly I:C and that this is exacerbated by subsequent oral delivery of a relevant dietary antigen.

  2. Pharmacokinetics of terbinafine after oral administration of a single dose to Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Evans, Erika E; Emery, Lee C; Cox, Sherry K; Souza, Marcy J

    2013-06-01

    To determine pharmacokinetics after oral administration of a single dose of terbinafine hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). 6 healthy adult Hispaniolan Amazon parrots. A single dose of terbinafine hydrochloride (60 mg/kg) was administered orally to each bird, which was followed immediately by administration of a commercially available gavage feeding formula. Blood samples were collected at the time of drug administration (time 0) and 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration. Plasma concentrations of terbinafine were determined via high-performance liquid chromatography. Data from 1 bird were discarded because of a possible error in the dose of drug administered. After oral administration of terbinafine, the maximum concentration for the remaining 5 fed birds ranged from 109 to 671 ng/mL, half-life ranged from 6 to 13.5 hours, and time to the maximum concentration ranged from 2 to 8 hours. No adverse effects were observed. Analysis of the results indicated that oral administration of terbinafine at a dose of 60 mg/kg to Amazon parrots did not result in adverse effects and may be potentially of use in the treatment of aspergillosis. Additional studies are needed to determine treatment efficacy and safety.

  3. Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats.

    PubMed

    Pelser, Andries; Müller, Douw G; du Plessis, Jeanetta; du Preez, Jan L; Goosen, Colleen

    2002-09-01

    The intranasal route of administration provides a potential useful way of administering a range of systemic drugs. In order to assess the feasibility of this approach for the treatment of nausea and vomiting, doxylamine succinate was studied in rats for the pharmacokinetics (AUC, C(max), t(max)) following intranasal, oral and intravenous administrations. Subjects (six male Sprague-Dawley rats per time interval for each route of administration) received 2-mg doses of doxylamine succinate orally and I-mg doses intranasally and intravenously, respectively. The various formulations were formulated in isotonic saline (0.9% w/v) at 25 +/- 1 degrees C. Doxylamine succinate concentrations in plasma were determined with a high-performance liquid chromatographic assay and a liquid-liquid extraction procedure. Intranasal and oral bioavailabilities were determined from AUC values relative to those after intravenous dosing. Intranasal bioavailability was greater than that of oral doxylamine succinate (70.8 vs 24.7%). The intranasal and oral routes of administration differed significantly from the intravenous route of administration. Peak plasma concentration (C(max)) was 887.6 ng/ml (S.D. 74.4), 281.4 ng/ml (S.D. 24.6) and 1296.4 ng/ml (S.D. 388.9) for the intranasal, oral and intravenous routes, respectively. The time to achieve C(max) for the intranasal route (t(max)=0.5 h) was faster than for the oral route (t(max)=1.5 h), but no statistically significant differences between the C(max) values were found using 95% confidence intervals. The results of this study show that doxylamine succinate is rapidly and effectively absorbed from the nasal mucosa.

  4. Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior?

    PubMed

    Fenlon, S; Collyer, J; Giles, J; Bidd, H; Lees, M; Nicholson, J; Dulai, R; Hankins, M; Edelman, N

    2013-03-01

    Paracetamol formulations provide effective analgesia after surgery [Duggan ST, Scott LJ. Intravenous paracetamol (acetominophen). Drugs 2009; 69: 101-13; Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database Syst Rev 2008: CD004602]. I.V. paracetamol is superior to oral for pain rescue (Jarde O, Boccard E. Parenteral versus oral route increases paracetamol efficacy. Clin Drug Invest 1997; 14: 474-81). By randomized, double-blinded trial, we aimed to determine whether preoperative oral paracetamol provides inferior postoperative analgesia to preoperative i.v. paracetamol. One hundred and thirty participants received either oral paracetamol and i.v. placebo (Group OP), or oral placebo and i.v. paracetamol (Perfalgan™) (Group IP). Oral preparations were given at least 45 min before surgery; i.v. preparations after induction of anaesthesia. Pain was assessed by a 100 mm visual analogue scale (VAS) 1 h from the end of surgery. Rescue analgesia was given on request. A total of 128 patients completed the study. There were no significant differences in baseline characteristics or intraoperative variables between the groups. The study was designed to reveal whether OP is inferior to IP, with an inferiority margin of 20%. The number of patients reporting satisfactory analgesia at 1 h with VAS ≤ 30 mm were 15 (OP) and 17 (IP), respectively. The secondary outcome measure of the mean (standard deviation) VAS (mm) for the whole of each group was 52 (22) for OP and 47 (22) for IP. Analysis of confidence intervals indicates that oral paracetamol is not inferior to i.v. paracetamol. The median survival (90% CI) to rescue analgesia request was 54.3 (51.2-57.4) min in Group OP and 57.3 (55.4-59.2) min in Group IP; there was no significant difference in this measure. In this study of lower third molar extraction, oral paracetamol is not inferior to i.v. for postoperative analgesia. ISRCTN Registration

  5. Oral Fluid and Plasma Cannabinoid Ratios after Around-the-Clock Controlled Oral Δ9-Tetrahydrocannabinol Administration

    PubMed Central

    Milman, Garry; Schwope, David M.; Schwilke, Eugene W.; Darwin, William D.; Kelly, Deanna L.; Goodwin, Robert S.; Gorelick, David A.; Huestis, Marilyn A.

    2013-01-01

    BACKGROUND Oral fluid (OF) testing is increasingly important for drug treatment, workplace, and drugged-driving programs. There is interest in predicting plasma or whole-blood concentrations from OF concentrations; however, the relationship between these matrices is incompletely characterized because of few controlled drug-administration studies. METHODS Ten male daily cannabis smokers received around-the-clock escalating 20-mg oral Δ9-tetrahydrocannabinol (THC, dronabinol) doses (40–120 mg/day) for 8 days. Plasma and OF samples were simultaneously collected before, during, and after dosing. OF THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC (THCCOOH) were quantified by GC-MS at 0.5-μg/L, 0.5-μg/L, and 7.5-ng/L limits of quantification (LOQs), respectively. In plasma, the LOQs were 0.25 μg/L for THC and THCCOOH, and 0.5 μg/L for 11-hydroxy-THC. RESULTS Despite multiple oral THC administrations each day and increasing plasma THC concentrations, OF THC concentrations generally decreased over time, reflecting primarily previously self-administered smoked cannabis. The logarithms of the THC concentrations in oral fluid and plasma were not significantly correlated (r = −0.10; P = 0.065). The OF and plasma THCCOOH concentrations, albeit with 1000-fold higher concentrations in plasma, increased throughout dosing. The logarithms of OF and plasma THCCOOH concentrations were significantly correlated (r = 0.63; P < 0.001), although there was high interindividual variation. A high OF/plasma THC ratio and a high OF THC/THCCOOH ratio indicated recent cannabis smoking. CONCLUSIONS OF monitoring does not reliably detect oral dronabinol intake. The time courses of THC and THCCOOH concentrations in plasma and OF were different after repeated oral THC doses, and high inter-individual variation was observed. For these reasons, OF cannabinoid concentrations cannot predict concurrent plasma concentrations. PMID:21875944

  6. Safe handling and administration considerations of oral anticancer agents in the clinical and home setting.

    PubMed

    Lester, Joanne

    2012-12-01

    The use of hormonal, chemotherapeutic, and targeted biologic oral agents has exponentially increased since the early 2000s. Oral therapies have the advantage of persistent exposure of the cytotoxic drug to tumor cells and the tumor environment. The use of oral anticancer agents provides therapeutic drug treatment for patients with cancer in the comfort of their home or alternative settings, such as retirement homes and assisted living or extended-care facilities. Practices to ensure safe storage, handling, administration, and disposal of oral agents are necessary to prevent additional exposure of hazardous substances to the environment, professionals, patients, family members, and caretakers. Providers should consider potential barriers to adherence and compliance, and develop strategies to ensure optimal therapeutic benefit prior to initiation of oral agents.

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

    PubMed Central

    SAWAGUCHI, Akiyo; SASAKI, Kazuaki; MIYANAGA, Keisuke; NAKAYAMA, Mitsuhiro; NAGASUE, Masato; SHIMODA, Minoru

    2016-01-01

    The oral pharmacokinetics of diclofenac (DF) were evaluated in cattle by analyzing plasma concentration-time data after its intravenous and oral administration in order to propose the oral administration of DF as effective route to avoid long withdraw period. DF was intravenously and orally administered at 1 mg/kg to cattle using a crossover design with a 4-week washout period. Plasma concentrations of DF were determined by a HPLC analysis. The mean absorption time (MAT) and absorption half-life (t1/2ka) were 1.61 ± 0.61 and 1.51 ± 0.38 hr, respectively, and bioavailability was nearly 100%. The oral pharmacokinetics of acetaminophen (AAP) were also evaluated in cattle. Plasma concentrations of AAP were determined by a HPLC analysis. MAT and t1/2ka were 2.85 ± 0.93 and 1.53 ± 0.28 hr, respectively, and bioavailability was approximately 70%. In conclusion, the results of the present study indicate that DF and AAP are rapidly absorbed from the forestomach of cattle. Therefore, the appropriate efficacies of these drugs may be achieved via their oral administration, even in cattle. PMID:27320817

  8. Serum concentrations of gentamicin following oral administration to preterm newborns.

    PubMed

    Grylack, L; Boehnert, J; Scanlon, J

    1982-01-01

    Serum gentamicin concentration was measured in 31 newborn babies who received oral gentamicin for prophylaxis of necrotizing enterocolitis in order to determine the presence and degree of gastrointestinal absorption and its relationship to birth weight, gestational age, postnatal age and perinatal asphyxia. A dose of 2.5 mg/kg every 6 h by nasogastric tube was administered during a 3-week course after birth. The mean birth weight was 1,269 +/- 489 g; mean gestational age 29.6 +/- 3.7 weeks. The mean serum gentamicin levels were: 0.06 +/- 0.03 microgram/ml at 30 min after the first dose; 0.29 +/- 0.48 microgram/ml at 4 h; 1.62 +/- 1.43 microgram/ml at 24 h, and 0.33 +/- 0.57 microgram/ml at 7 days. The 24-hour and 7-day samples were taken before the next dose. The mean 24-hour level was significantly (p less than 0.001) higher than the other levels. There was no significant (p less than 0.05) relationship between the 24-hour serum gentamicin level and birth weight, gestational age or umbilical venous pH.

  9. Oral administration of d-galactose induces cognitive impairments and oxidative damage in rats.

    PubMed

    Budni, Josiane; Pacheco, Robson; da Silva, Sabrina; Garcez, Michelle Lima; Mina, Francielle; Bellettini-Santos, Tatiani; de Medeiros, Jesiel; Voss, Bruna Constantino; Steckert, Amanda Valnier; Valvassori, Samira da Silva; Quevedo, João

    2016-04-01

    d-Galactose (d-gal) is a reducing sugar that can be used to mimic the characteristics of aging in rodents; however, the effects of d-gal administration by oral route are not clear. Therefore, the aim of this study was to elucidate if the oral administration of d-gal induces cognitive impairments, neuronal loss, and oxidative damage, mimicking an animal model of aging. Male adult Wistar rats (4 months old) received d-gal (100mg/kg) via the oral route for a period of 1, 2, 4, 6 or 8 weeks. The results showed cognitive impairments in the open-field test in the 4th and 6th weeks after d-gal administration, as well as an impairment in spatial memory in the radial maze test after the 6th week of d-gal administration. The results indicated increase of levels of thiobarbituric acid reactive species-TBARS-and carbonyl group content in the prefrontal cortex from the 4th week, and in all weeks of d-gal administration, respectively. An increase in the levels of TBARS and carbonyl group content was observed in the hippocampus over the entire period of d-gal treatment. In the 8th week of d-gal administration, we also observed reductions in synaptophysin and TAU protein levels in the prefrontal cortex. Thus, d-gal given by oral route caused cognitive impairments which were accompanied by oxidative damage. Therefore, these results indicate that orally administered d-gal can induce the behavioral and neurochemical alterations that are observed in the natural aging process. However, oral d-gal effect in rats deserve further studies to be better described. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Hydroxyzine and cetirizine pharmacokinetics and pharmacodynamics after oral and intravenous administration of hydroxyzine to healthy dogs.

    PubMed

    Bizikova, Petra; Papich, Mark G; Olivry, Thierry

    2008-12-01

    Pharmacokinetic parameters of hydroxyzine and its active metabolite cetirizine were determined after oral and intravenous administration of 2 mg kg(-1) of hydroxyzine to six healthy dogs. Plasma drug levels were determined with high-pressure liquid chromatography. Pharmacodynamic studies evaluated the suppressive effect on histamine and anticanine IgE-mediated cutaneous wheal formation. Pharmacokinetic and pharmacodynamic correlations were determined with computer modelling. The mean systemic availability of oral hydroxyzine was 72%. Hydroxyzine was rapidly converted to cetirizine regardless of the route of administration. The mean area-under-the-curve was eight and ten times higher for cetirizine than hydroxyzine after intravenous and oral dosing, respectively. After oral administration of hydroxyzine, the mean peak concentration of cetirizine was approximately 2.2 microg mL(-1) and that of hydroxyzine 0.16 microg mL(-1). The terminal half-life for cetirizine varied between 10 and 11 h after intravenous and oral administration of hydroxyzine. A sigmoidal relationship was fit to the data comparing cetirizine plasma concentration to wheal suppression. Maximum inhibition (82% and 69% for histamine and anticanine IgE-mediated skin reactions, respectively) was observed during the first 8 h, which correlated with a plasma concentration of cetirizine greater than 1.5 microg mL(-1). Pharmacological modelling suggested that increasing either hydroxyzine dosages or frequencies of administration would not result in histamine inhibition superior to that obtained with twice daily hydroxyzine at 2 mg kg(-1). In conclusion, there was rapid conversion of hydroxyzine to cetirizine. The reduction of wheal formation appeared almost entirely due to cetirizine. Pharmacodynamic modelling predicted that maximal antihistamine effect would occur with twice daily oral administration of hydroxyzine at 2 mg kg(-1).

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

    PubMed Central

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

    2014-01-01

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

  12. Cannabinoid disposition in oral fluid after controlled smoked, vaporized, and oral cannabis administration.

    PubMed

    Swortwood, Madeleine J; Newmeyer, Matthew N; Andersson, Maria; Abulseoud, Osama A; Scheidweiler, Karl B; Huestis, Marilyn A

    2017-06-01

    Oral fluid (OF) is an important matrix for monitoring drugs. Smoking cannabis is common, but vaporization and edible consumption also are popular. OF pharmacokinetics are available for controlled smoked cannabis, but few data exist for vaporized and oral routes. Frequent and occasional cannabis smokers were recruited as participants for four dosing sessions including one active (6.9% Δ(9) -tetrahydrocannabinol, THC) or placebo cannabis-containing brownie, followed by one active or placebo cigarette, or one active or placebo vaporized cannabis dose. Only one active dose was administered per session. OF was collected before and up to 54 (occasional) or 72 (frequent) h after dosing from cannabis smokers. THC, 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), tetrahydrocannabivarin (THCV), cannabidiol (CBD), and cannabigerol (CBG) were quantified by liquid chromatography-tandem mass spectrometry. OF cannabinoid Cmax occurred during or immediately after cannabis consumption due to oral mucosa contamination. Significantly greater THC Cmax and significantly later THCV, CBD, and CBG tlast were observed after smoked and vaporized cannabis compared to oral cannabis in frequent smokers only. No significant differences in THC, 11-OH-THC, THCV, CBD, or CBG tmax between routes were observed for either group. For occasional smokers, more 11-OH-THC and THCCOOH-positive specimens were observed after oral dosing than after inhaled routes, increasing % positive cannabinoid results and widening metabolite detection windows after oral cannabis consumption. Utilizing 0.3 µg/L THCV and CBG cut-offs resulted in detection windows indicative of recent cannabis intake. OF pharmacokinetics after high potency CBD cannabis are not yet available precluding its use currently as a marker of recent use. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Published 2016. This article is a U.S. Government work and is in the public domain in the

  13. Administration of tauroursodeoxycholic acid prevents endothelial dysfunction caused by an oral glucose load

    PubMed Central

    Walsh, Lauren K.; Restaino, Robert M.; Neuringer, Martha; Manrique, Camila; Padilla, Jaume

    2017-01-01

    Postprandial hyperglycemia leads to a transient impairment in endothelial function; however, the mechanisms remain largely unknown. Previous work in cell culture models demonstrate that high glucose results in endoplasmic reticulum (ER) stress and, in animal studies, ER stress has been implicated as a cause of endothelial dysfunction. Herein we tested the hypothesis that acute oral administration of tauroursodeoxycholic acid (TUDCA, 1500mg), a chemical chaperone known to alleviate ER stress, would prevent hyperglycemia-induced endothelial dysfunction. In 12 young healthy subjects (seven men, five women), brachial artery flow-mediated dilation (FMD) was assessed at baseline, 1 hour, and 2 hours post an oral glucose challenge. Subjects were tested on two separate visits in a single-blind randomized crossover design: after oral ingestion of TUDCA or placebo capsules. FMD was reduced from baseline during hyperglycemia under the placebo condition (−32% at 1 hr and −28% at 2 hr post oral glucose load; p<0.05 from baseline) but not under the TUDCA condition (−4% at 1 hr and +0.3% at 2 hr post oral glucose load; p>0.05 from baseline). Postprandial plasma glucose and insulin were not altered by TUDCA ingestion. Plasma oxidative stress markers 3-nitrotyrosine and TBARs remained unaltered throughout the oral glucose challenge in both conditions. These results suggest that hyperglycemia-induced endothelial dysfunction can be mitigated by oral administration of TUDCA, thus supporting the hypothesis that ER stress may contribute to endothelial dysfunction during postprandial hyperglycemia. PMID:27503949

  14. Proline-containing dipeptide GVS-111 retains nootropic activity after oral administration.

    PubMed

    Ostrovskaya, R U; Mirsoev, T K; Romanova, G A; Gudasheva, T A; Kravchenko, E V; Trofimov, C C; Voronina, T A; Seredenin, S B

    2001-10-01

    Experiments on rats trained passive avoidance task showed that N-phenyl-acetyl-L-prolyl-glycyl ethyl ester, peptide analog of piracetam (GVS-111, Noopept) after oral administration retained antiamnesic activity previously observed after its parenteral administration. Effective doses were 0.5-10 mg/kg. Experiments on a specially-developed model of active avoidance (massive one-session learning schedule) showed that GVS-111 stimulated one-session learning after single administration, while after repeated administration it increased the number of successful learners among those animals who failed after initial training. In this respect, GVS-111 principally differs from its main metabolite cycloprolylglycine and standard nootropic piracetam.

  15. Reducing Tumour Hypoxia via Oral Administration of Oxygen Nanobubbles

    PubMed Central

    Owen, Joshua; McEwan, Conor; Nesbitt, Heather; Bovornchutichai, Phurit; Averre, Raymond; Borden, Mark; McHale, Anthony P.; Callan, John F.

    2016-01-01

    Hypoxia has been shown to be a key factor inhibiting the successful treatment of solid tumours. Existing strategies for reducing hypoxia, however, have shown limited efficacy and/or adverse side effects. The aim of this study was to investigate the potential for reducing tumour hypoxia using an orally delivered suspension of surfactant-stabilised oxygen nanobubbles. Experiments were carried out in a mouse xenograft tumour model for human pancreatic cancer (BxPc-3 cells in male SCID mice). A single dose of 100 μL of oxygen saturated water, oxygen nanobubbles or argon nanobubbles was administered via gavage. Animals were sacrificed 30 minutes post-treatment (3 per group) and expression of hypoxia-inducible-factor-1α (HIF1α) protein measured by real time quantitative polymerase chain reaction and Western blot analysis of the excised tumour tissue. Neither the oxygen saturated water nor argon nanobubbles produced a statistically significant change in HIF1α expression at the transcriptional level. In contrast, a reduction of 75% and 25% in the transcriptional and translational expression of HIF1α respectively (p<0.001) was found for the animals receiving the oxygen nanobubbles. This magnitude of reduction has been shown in previous studies to be commensurate with an improvement in outcome with both radiation and drug-based treatments. In addition, there was a significant reduction in the expression of vascular endothelial growth factor (VEGF) in this group and corresponding increase in the expression of arrest-defective protein 1 homolog A (ARD1A). PMID:28036332

  16. Propranolol concentrations after oral administration in term and preterm neonates.

    PubMed

    Filippi, L; Cavallaro, G; Fiorini, P; Malvagia, S; Della Bona, M L; Giocaliere, E; Bagnoli, P; Dal Monte, M; Mosca, F; Donzelli, G; la Marca, G

    2013-05-01

    While propranolol pharmacokinetics has been extensively studied in adults, this study reports the first evaluation of propranolol pharmacokinetics in term and preterm neonates. Propranolol concentrations were measured in four term and 32 preterm newborns treated with oral propranolol at the dose of 0.5 or 0.25 mg/kg every 6 h by serial dried blood spots. The levels of propranolol, although with high inter-individual variability, were proportional with the administered dose. Pharmacokinetic parameters evaluated at the steady state in newborns treated with 0.5 mg/kg/6 h showed values of maximal (71.7 ± 29.8 ng/mL), minimal (42.2 ± 20.8 ng/mL) and average concentration (60.8 ± 25.0 ng/mL), time of maximal concentration (2.6 ± 0.9 h) and area under the time-concentration curve (364.7 ± 150.2 ng/mL/h) similar to those observed in adults. In both dosing groups, elimination half-life was significantly longer (14.9 ± 4.3 and 15.9 ± 6.1 h), and apparent total body clearance (27.2 ± 13.9 and 31.3 ± 13.3 mL/kg/min) lower than those reported in adults, suggesting a slower metabolism in newborns. No differences were observed between newborns with different gestational age or different sex. Neonates treated with propranolol-exhibited drug concentrations proportional with the dose, with significant long half-life.

  17. Bioequivalence assessment of ambroxol orally-disintegrating tablet after a single oral-dose administration to healthy volunteers.

    PubMed

    Ni, Yaojun; Hou, Lili; Chen, Liang; Fan, Jiang

    2016-05-01

    In this study, a modified LC-MS/MS method was used to determine plasma ambroxol concentration and thereby examine the bioequivalence of two ambroxol medications among healthy Chinese male volunteers. The study used a single-dose, randomized, open-label design principle and calculated pharmacokinetic parameters for the comparison of the two formulations. Administration of a single oral dose of either the test drug or reference drug was found to be safe in healthy subjects. No severe, serious, or life-threatening clinical or drug-related side effects were reported during the study. The majority of clinical laboratory test results were within the normal range or not clinically significant. The pharmacokinetic parameters for ambroxol oral tablets and ambroxol orally disintegrating tablets were comparable. For the comparison of the two formulations, the 90% confidence intervals for the log-transformed pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-inf) fell within the bioequivalence< acceptance criteria (80-125%). The ambroxol oral tablets were bioequivalent to ambroxol orally-disintegrating tablets in healthy human adult male volunteers, under fasting conditions.

  18. Age-related alterations in trimethoprim-sulfadiazine disposition following oral or parenteral administration in calves.

    PubMed Central

    Guard, C L; Schwark, W S; Friedman, D S; Blackshear, P; Haluska, M

    1986-01-01

    Age-related changes in the absorption and distribution patterns of trimethoprim/sulfadiazine were studied following oral or subcutaneous administration of 15 mg/kg of the drug combination in calves. Following oral administration, the time course of trimethoprim/sulfadiazine appearance and dissipation in serum, synovial fluid and urine was followed for periods up to 48 hours in calves one day, one week and six weeks of age. The profiles of drug appearance-disappearance in these body fluids were also determined after subcutaneous administration in seven week old calves. The peak serum and synovial fluid levels of trimethoprim/sulfadiazine achieved following oral administration were substantially lower with increasing maturation. In ruminating (six and seven week old) calves, subcutaneous or oral administration of the combination led to high serum levels of sulfadiazine but little or no serum trimethoprim was detected in animals at this age. The data indicate that, while therapeutic concentrations and optimum ratios of the drugs may be achieved for extended time periods in neonatal life, this dosage is unable to produce optimum serum and synovial fluid concentrations as the calves mature. PMID:3742370

  19. Metabolomic Analysis of Blood Plasma after Oral Administration of N-acetyl-d-Glucosamine in Dogs

    PubMed Central

    Osaki, Tomohiro; Kurozumi, Seiji; Sato, Kimihiko; Terashi, Taro; Azuma, Kazuo; Murahata, Yusuke; Tsuka, Takeshi; Ito, Norihiko; Imagawa, Tomohiro; Minami, Saburo; Okamoto, Yoshiharu

    2015-01-01

    N-acetyl-d-glucosamine (GlcNAc) is a monosaccharide that polymerizes linearly through (1,4)-β-linkages. GlcNAc is the monomeric unit of the polymer chitin. GlcNAc is a basic component of hyaluronic acid and keratin sulfate found on the cell surface. The aim of this study was to examine amino acid metabolism after oral GlcNAc administration in dogs. Results showed that plasma levels of ectoine were significantly higher after oral administration of GlcNAc than prior to administration (p < 0.001). To our knowledge, there have been no reports of increased ectoine concentrations in the plasma. The mechanism by which GlcNAc administration leads to increased ectoine plasma concentration remains unclear; future studies are required to clarify this mechanism. PMID:26262626

  20. Effect of titanium dioxide nanoparticles on the cardiovascular system after oral administration.

    PubMed

    Chen, Zhangjian; Wang, Yun; Zhuo, Lin; Chen, Shi; Zhao, Lin; Luan, Xianguo; Wang, Haifang; Jia, Guang

    2015-12-03

    Titanium dioxide nanoparticles (TiO2 NPs) have been widely used in various consumer products, especially food and personal care products. Compared to the well-characterized adverse cardiovascular effect of inhaled ambient ultrafine particles, research on the health response to orally administrated TiO2 NPs is still limited. In our study, we performed an in vivo study in Sprague-Dawley rats to understand the cardiovascular effect of TiO2 NPs after oral intake. After daily gastrointestinal administration of TiO2 NPs at 0, 2, 10, 50 mg/kg for 30 and 90 days, heart rate (HR), blood pressure, blood biochemical parameters and histopathology of cardiac tissues was assessed to quantify cardiovascular damage. Mild and temporary reduction of HR and systolic blood pressure as well as an increase of diastolic blood pressure was observed after daily oral administration of TiO2 NPs for 30 days. Injury of cardiac function was observed after daily oral administration of TiO2 NPs for 90 days as reflected in decreased activities of lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBDH) and creatine kinase (CK). Increased white blood cells count (WBC) and granulocytes (GRN) in blood as well as increased concentrations of tumor necrosis factor α (TNF α) and interleukin 6 (IL-6) in the serum indicated inflammatory response initiated by TiO2 NPs exposure. It was hypothesize that cardiac damage and inflammatory response are the possible mechanisms of the adverse cardiovascular effects induced by orally administrated TiO2 NPs. Data from our study suggested that even at low dose of TiO2 NPs can induce adverse cardiovascular effects after 30 days or 90 days of oral exposure, thus warranting concern for the dietary intake of TiO2 NPs for consumers.

  1. The Effects of Oral Micronized Progesterone on Smoked Cocaine Self-Administration in Women

    PubMed Central

    Reed, Stephanie Collins; Evans, Suzette M.; Bedi, Gillinder; Rubin, Eric; Foltin, Richard W.

    2011-01-01

    There are currently no FDA-approved pharmacotherapies for cocaine abuse. Converging preclinical and clinical evidence indicates that progesterone may have potential as a treatment for cocaine-abusing women, who represent a growing portion of cocaine users. We have previously shown that oral progesterone reduced the positive subjective effects of cocaine in female cocaine users during the follicular phase of the menstrual cycle, when endogenous progesterone levels were low. To extend these findings, the present study assessed the effects of oral progesterone (150 mg BID) administered during the follicular phase on smoked cocaine self-administration in women relative to the normal follicular and luteal phases. Healthy, non-treatment seeking female cocaine smokers (N = 10) underwent three 4-day inpatient stays, during: 1) a normal follicular phase; 2) a normal luteal phase; and 3) a follicular phase when oral progesterone was administered. During each stay, participants completed 4 self-administration sessions in which they first smoked a sample dose of cocaine (0, 12, 25 or 50 mg) and then had 5 opportunities at 14-minute intervals to self-administer that dose at a cost of $5 per dose. Expected cocaine dose effects on self-administration, subjective effects, and cardiovascular effects were observed. However, there was no effect of oral progesterone administration or menstrual cycle phase on cocaine self-administration. Thus, oral progesterone was not effective in reducing cocaine use in women under the current conditions. However, based on previous literature, further research assessing the role of oral progesterone for the treatment of cocaine dependence in women is warranted. PMID:21192940

  2. Pharmacokinetics and selected pharmacodynamics of trazodone following intravenous and oral administration to horses undergoing fitness training.

    PubMed

    Knych, Heather K; Mama, Khursheed R; Steffey, Eugene P; Stanley, Scott D; Kass, Philip H

    2017-10-01

    OBJECTIVE To measure concentrations of trazodone and its major metabolite in plasma and urine after administration to healthy horses and concurrently assess selected physiologic and behavioral effects of the drug. ANIMALS 11 Thoroughbred horses enrolled in a fitness training program. PROCEDURES In a pilot investigation, 4 horses received trazodone IV (n = 2) or orally (2) to select a dose for the full study; 1 horse received a vehicle control treatment IV. For the full study, trazodone was initially administered IV (1.5 mg/kg) to 6 horses and subsequently given orally (4 mg/kg), with a 5-week washout period between treatments. Blood and urine samples were collected prior to drug administration and at multiple time points up to 48 hours afterward. Samples were analyzed for trazodone and metabolite concentrations, and pharmacokinetic parameters were determined; plasma drug concentrations following IV administration best fit a 3-compartment model. Behavioral and physiologic effects were assessed. RESULTS After IV administration, total clearance of trazodone was 6.85 ± 2.80 mL/min/kg, volume of distribution at steady state was 1.06 ± 0.07 L/kg, and elimination half-life was 8.58 ± 1.88 hours. Terminal phase half-life was 7.11 ± 1.70 hours after oral administration. Horses had signs of aggression and excitation, tremors, and ataxia at the highest IV dose (2 mg/kg) in the pilot investigation. After IV drug administration in the full study (1.5 mg/kg), horses were ataxic and had tremors; sedation was evident after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE Administration of trazodone to horses elicited a wide range of effects. Additional study is warranted before clinical use of trazodone in horses can be recommended.

  3. Oral Delivery of Therapeutic Proteins and Peptides: An Overview of Current Technologies and Recommendations for Bridging from Approved Intravenous or Subcutaneous Administration to Novel Oral Regimens.

    PubMed

    Philippart, M; Schmidt, J; Bittner, B

    2016-03-01

    Since the early 1980s, therapeutic proteins and peptides have become established as an important class of pharmaceuticals. Due to their low oral bioavailability, which results from pre-systemic degradation and poor gastrointestinal absorption, most therapeutic proteins and peptides are administered intravenously. While subcutaneous formulations of some therapeutic proteins and peptides have been shown to improve patient convenience and reduce medical resource utilization, oral administration is generally the preferred administration route. Some therapeutic proteins and peptides employing novel oral delivery technologies have reached late-stage clinical development. To develop a new oral formulation of a therapeutic protein or peptide currently marketed as an injectable product, technical, nonclinical, and clinical studies are required to demonstrate similar safety and efficacy compared with the existing administration route. Since there is little experience with oral therapeutic proteins and peptides, this review provides recommendations for bridging from an approved intravenous or subcutaneous regimen to novel oral administration of the same therapeutic protein or peptide, based on precedents from intravenous-to-subcutaneous bridging approaches for trastuzumab, rituximab, tocilizumab, and bortezomib. If the pharmacokinetic/pharmacodynamic relationship is well characterized, demonstration of comparability in prespecified pharmacokinetic parameters might form a basis for establishing similar efficacy and safety of the oral formulation vs. the reference product. Although oral administration of therapeutic proteins and peptides remains challenging, given recent progress with novel delivery technologies, intravenous/subcutaneous-to-oral nonclinical and clinical bridging programs may soon be utilized to support approval of new oral formulations.

  4. Novel oral administrated paclitaxel micelles with enhanced bioavailability and antitumor efficacy for resistant breast cancer.

    PubMed

    Zhang, Ting; Luo, Jingwen; Fu, Yao; Li, Hanmei; Ding, Rui; Gong, Tao; Zhang, Zhirong

    2017-02-01

    Paclitaxel (PTX) is a widely used antineoplastic drug in clinic. Due to poor aqueous solubility, it is administrated by intravenous infusion of cremophor EL containing formulation with serious adverse effects. The low oral bioavailability is a great challenge for oral formulation development. In addition, P-gp mediated multidrug resistance limit its clinical use in various resistant cancers. In this study, a novel super-antiresistant PTX micelle formulation for oral administration was developed. A P-gp inhibitor, bromotetrandrine (W198) was co-encapsulated in the micelle. The micelles were composed of Solutol HS 15 and d-a-tocopheryl polyethylene glycol succinate to avoid Cremophor EL induced toxicity. The micelles were round with a mean particle size of ∼13nm and an encapsulation efficiency of ∼90%. A series of in vitro evaluations were performed in non-resistant MCF-7 cells and resistant MCF-7/Adr cells. The super-antiresistant PTX micelles showed higher cell uptake efficiency, significantly increased cytotoxicity and antimitotic effect in drug resistant MCF-7/Adr cells when compared with Taxol and other PTX micelle formulations. Compared with Taxol, the super-antiresistant PTX micelles significantly improved bioavailability after oral administration in rats, and inhibited tumor growth in multidrug resistance xenografted MCF-7/Adr nude mice. In summary, the noval super-antiresistant PTX micelles showed a great potential for oral delivery of PTX against resistant breast cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Development of Alginate Microspheres Containing Chuanxiong for Oral Administration to Adult Zebrafish

    PubMed Central

    Lin, Li-Jen; Chiang, Chung-Jen; Chao, Yun-Peng; Wang, Shulhn-Der; Chiou, Yu-Ting; Wang, Han-Yu; Kao, Shung-Te

    2016-01-01

    Oral administration of Traditional Chinese Medicine (TCM) by patients is the common way to treat health problems. Zebrafish emerges as an excellent animal model for the pharmacology investigation. However, the oral delivery system of TCM in zebrafish has not been established so far. This issue was addressed by development of alginate microparticles for oral delivery of chuanxiong, a TCM that displays antifibrotic and antiproliferative effects on hepatocytes. The delivery microparticles were prepared from gelification of alginate containing various levels of chuanxiong. The chuanxiong-encapsulated alginate microparticles were characterized for their solubility, structure, encapsulation efficiency, the cargo release profile, and digestion in gastrointestinal tract of zebrafish. Encapsulation of chuanxiong resulted in more compact structure and the smaller size of microparticles. The release rate of chuanxiong increased for alginate microparticles carrying more chuanxiong in simulated intestinal fluid. This remarkable feature ensures the controlled release of encapsulated cargos in the gastrointestinal tract of zebrafish. Moreover, chuanxiong-loaded alginate microparticles were moved to the end of gastrointestinal tract after oral administration for 6 hr and excreted from the body after 16 hr. Therefore, our developed method for oral administration of TCM in zebrafish is useful for easy and rapid evaluation of the drug effect on disease. PMID:27403425

  6. Prolonged Oral Administration of Oleuropein Might Protect Heart against Aconitine-induced Arrhythmia

    PubMed Central

    Esmailidehaj, Mansour; Mirhosseini, Seyed-Jalil; Rezvani, Mohammad Ebrahim; Rasoulian, Bahram; Mosaddeghmehrjardi, Mohammad Hossein; Haghshenas, Damoon

    2012-01-01

    In this study, it was surveyed to know whether an oral single dose of oleuropein could mimic the cardiac preconditioning in rats’ hearts or whether its prolonged oral administration could protect the heart against the aconitine-induced arrhythmia in rats. Eighty male Wistar rats were divided into two series (n = 8 in each group). In the first series, all groups (except the control (Con) group) were given a single oral dose of oleuropein (20 mg/Kg) 1, 3, 24 and 48 h before the infusion of aconitine. In the second series, except the Con group, the other four groups were given oral oleuropein (20 mg/Kg/day) for 3, 7, 14 and 28 days, before the infusion of aconitine. Electrocardiogram was recorded to monitor arrhythmia. Data of the first series showed that the initiation time of arrhythmia, the initiation of ventricular tachycardia (VT), the numbers of reversible ventricular fibrillation (VF) and the death time had no significant difference compared with Con group. In the second series, a significant protection was occurred only in the 28 days group that was evident with increased initiation time of arrhythmia, increased initiation time of VT, and increased the number of reversible VF and death time in compared to the Con group. The findings of this study show that the oral administration of a single dose of oleuropein could not mimic the preconditioning effects in rat hearts, but the prolonged administration of oleuropein for about four weeks could protect the heart against aconitine-induced arrhythmia. PMID:24250560

  7. Opioid disposition in human sweat after controlled oral codeine administration.

    PubMed

    Schwilke, Eugene W; Barnes, Allan J; Kacinko, Sherri L; Cone, Edward J; Moolchan, Eric T; Huestis, Marilyn A

    2006-08-01

    Characterization of opioid excretion in sweat is important for accurate interpretation of sweat tests in drug treatment, criminal justice, and workplace drug testing programs. Participants (n=20) received placebo, 3 low (60 mg/70 kg) or 3 high (120 mg/70 kg) codeine sulfate doses (used as a model for opioid excretion) within 1 week. Codeine and metabolites in sweat were collected with PharmChek Sweat Patches; hourly patches were applied for 1 to 15 h (n=775) and weekly patches for 7 days (n=118). Patches were analyzed by solid-phase extraction and gas chromatography-mass spectrometry for codeine, norcodeine, morphine, normorphine, and 6-acetylmorphine. Limits of quantification were 2.5 ng/patch (codeine and morphine) and 5 ng/patch (other analytes). Codeine was the only analyte identified in 12.6% of hourly patches and 83.3% of weekly sweat patches worn during dosing. Weekly patch concentrations (SD) were 38.6 (59.9) ng/patch [median (range), 15.9 (0-225.1) ng/patch] for low and 34.1 (32.7) ng/patch [24.0 (0-96.2) ng/patch] for high codeine doses. Codeine detected 1 week after dosing was 4.6 (5.3) ng/patch [median (range), 4.0 (0-17.1) ng/patch; n=11] after low and 7.7 (7.1) ng/patch [6.9 (0-20.5) ng/patch; n=10] after high doses. In total, 2.6% of hourly, 38.5% of low-dose, and 45.5% of high-dose weekly patches contained codeine at the proposed Substance Abuse and Mental Health Services Administration cutoff. Codeine was the only analyte detected, at highly variable concentrations, up to 2 weeks after dosing. These results are consistent, considering the complex processes of codeine deposition in sweat. Sweat testing is a useful alternative technique for qualitative monitoring of opioid use.

  8. Pharmacokinetic evaluation of omeprazole suspension following oral administration in rats: effect of neutralization of gastric acid.

    PubMed

    Watanabe, K; Matsuka, N; Furuno, K; Eto, K; Kawasaki, H; Gomita, Y

    1996-08-01

    In order to evaluate a clinical use of omeprazole suspension, we examined the pharmacokinetics of omeprazole after oral administration in rats. Although the administration of omeprazole suspension buffered by NaHCO3 solution did not produce a significant increase in the area under the concentration-time curve (AUC) value compared with non-buffered group, the administration of NaHCO3 buffer immediately after dosing of omeprazole suspension buffered by NaHCO3 caused a significant increase in the AUC value. These results suggest that the NaHCO3 treatment following the administration of omeprazole buffered suspension effectively decreased the degradation of the compound by gastric acid. Therefore, the successive administration of NaHCO3 solution after the omeprazole dosing seems to be a simple and useful method for the administration to patients who cannot receive tablets.

  9. Comparability of Student Performance Between Regular and Oral Administrations for a High-Stakes Mathematics Test

    ERIC Educational Resources Information Center

    Huynh, Huynh; Meyer, J. Patrick; Gallant, Dorinda J.

    2004-01-01

    This study examined the effect of oral administration accommodations on test structure and student performance on the mathematics portion of the South Carolina High School Exit Examination (HSEE). The examination was given at Grade 10 and was untimed. Three groups of students were studied. Two groups took the regular form. One group had recorded…

  10. Oral Pyridostigmine Administration in Rats: Effects on Thermoregulation, Clinical Chemistry, and Performance in the Heat

    DTIC Science & Technology

    1984-01-01

    PERIOD COVERED " N Oral pyridostigmine administration in rats: .T 0 PTPR C E -,effects a thermoregulation, clinical chemistry , and performance in the heat...thermoregulation, clinical chemistry , and performance in the heat R. Francesconi, R. Hubbard, C. Matthew, N. Leva, J. Youxng, and V. Pense US Amny

  11. TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE AFTER ACUTE ORAL ADMINISTRATION

    EPA Science Inventory

    TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE
    AFTER ACUTE ORAL ADMINISTRATION

    Michael F. Hughes, Ph.D., Brenda C. Edwards, Carol T. Mitchell and Elaina M. Kenyon, Ph.D. United States Environmental Protection Agency, Office of Research and Development, Nation...

  12. TISSUE DOSIMETRY, METABOLISM AND EXCRETION OF PENTAVALENT AND TRIVALENT DIMETHYLATED ARSENIC IN MICE AFTER ORAL ADMINISTRATION

    EPA Science Inventory

    Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic in mice after acute oral administration. Adult female mice were...

  13. Pharmacokinetics and tissue distribution of gentiopicroside following oral and intravenous administration in mice.

    PubMed

    Wang, Chang-Hong; Wang, Zheng-Tao; Bligh, S W Annie; White, Kenneth N; White, Christopher J Branford

    2004-01-01

    The pharmacokinetics and tissue distribution of Gentiopicroside (GPS), one of the major active components of the Gentiana species of medicinal plants, was studied following oral and intravenous administration in mice. The distribution of GPS in mice after oral and intravenous doses could be fitted to a two-compartments open model. The serum half-life of GPS was 6.1 h and 2.8 h for intravenous and oral administration, respectively. The Tmax of GPS after oral administration was 0.50 h, and the bioavailability was 39.6%. The AUC gradient in individual tissues following intravenous administration was kidney >serum >liver >spleen >lung >thymus >fat >heart >muscle >stomach >intestinal >brain. The MRT gradient was muscle >serum >lung >spleen >lung >intestinal>heart >stomach >brain >liver >thymus >kidney >fat. Overall the data show that GPS could be absorbed rapidly in mice, but with a low bioavailability, and could distribute to tissues extensively, but was generally cleared quickly with short MRTs. The study demonstrates the need for repeated dosage, or better, a slow release formulation as an ideal means of administering GPS.

  14. Nightly oral administration of topiramate for benign childhood epilepsy with centrotemporal spikes.

    PubMed

    Liu, Chunrong; Song, Mei; Wang, Jiwen

    2016-05-01

    The objective of this study was to explore the feasibility of nightly oral administration of topiramate for treating benign childhood epilepsy with centrotemporal spikes (BECTS). Eighty-five children with BECTS receiving topiramate treatment were randomly divided into A group (44 patients) and B group (41 patients). In A group, topiramate was orally administrated once a night, with a final dose of 2 mg/kg/day. In B group, topiramate was orally administrated twice a day, with a final dose of 4 mg/kg/day. At the end of the 12-month follow-up period, clinical efficacy, changes in electroencephalographic (EEG) activity, and adverse reactions were analyzed. There was no significant difference in overall efficacy rate, percentages of patients achieving seizure free, or changes in EEG activity between the two groups (P > 0.05). The rate of adverse reactions for A group was 9.1 %, which was significantly lower than the 29.3 % for B group (χ (2) = 4.262, P < 0.05). Nightly oral administration of topiramate is a feasible strategy for the treatment of BECTS, with the advantages of comparable efficacy, convenience, and fewer adverse reactions.

  15. COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE

    EPA Science Inventory

    COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE
    Michael F. Hughes*1, Elaina M. Kenyon1, Brenda C. Edwards1, Carol T. Mitchell1, Luz Maria Del Razo2 and David J. Thomas1
    1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Pa...

  16. Oral administration of piperine for the control of aflatoxin intoxication in rats

    PubMed Central

    Gagini, Thalita B.; Silva, Robson E.; Castro, Isabela S.; Soares, Breno A.; Lima, Marco E.F.; Brito, Marilene F.; Mazur, Carlos; Direito, Glória M.; Danelli, Maria das Graças M.

    2010-01-01

    Aflatoxins are mycotoxins that have important toxic effects on human and animal health, even if consumed at low doses. The oral administration of piperine (1.12 mg/kg) during 23 days in rats seemingly interfered with the toxicity of aflatoxins, decreasing hepatic injuries and the leukocyte depletion in experimentally intoxicated animals. PMID:24031502

  17. Oral Medications: Proper Use and Administration. Book 1, Bosnian and Russian. Book 2, Nuer and Spanish.

    ERIC Educational Resources Information Center

    Anoka County Community Health and Environmental Services, Coon Rapids, MN.

    These two guides provide information in English, Bosnian, Russian, Nuer, and Spanish on the proper use and administration of oral medications. Topics covered include the reasons for taking medication, information on the prescription label, following special instructions, asking questions of the pharmacist, safe storage of medicine, child-proof…

  18. Safety of red ginseng oil for single oral administration in Sprague–Dawley rats

    PubMed Central

    Bak, Min-Ji; Kim, Kyu-Bong; Jun, Mira; Jeong, Woo-Sik

    2013-01-01

    The single oral administration of red ginseng oil (5000 mg/kg) to Sprague–Dawley rats induced no changes in behavioral patterns, clinical signs, and body weight, and hepatotoxicity parameters such as aspartate aminotransferase and alanine aminotransferase for 14 d. Therefore, these results suggest that the red ginseng oil is safe and nontoxic acutely. PMID:24558315

  19. COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE

    EPA Science Inventory

    COMPARATIVE METABOLISM OF ARSENIC IN MICE AFTER A SINGLE OR REPEATED ORAL ADMINISTRATION OF ARSENATE
    Michael F. Hughes*1, Elaina M. Kenyon1, Brenda C. Edwards1, Carol T. Mitchell1, Luz Maria Del Razo2 and David J. Thomas1
    1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Pa...

  20. TISSUE DOSIMETRY, METABOLISM AND EXCRETION OF PENTAVALENT AND TRIVALENT DIMETHYLATED ARSENIC IN MICE AFTER ORAL ADMINISTRATION

    EPA Science Inventory

    Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic in mice after acute oral administration. Adult female mice were...

  1. TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE AFTER ACUTE ORAL ADMINISTRATION

    EPA Science Inventory

    TISSUE DISPOSITION OF DIMETHYLARSINIC ACID IN THE MOUSE
    AFTER ACUTE ORAL ADMINISTRATION

    Michael F. Hughes, Ph.D., Brenda C. Edwards, Carol T. Mitchell and Elaina M. Kenyon, Ph.D. United States Environmental Protection Agency, Office of Research and Development, Nation...

  2. Errors of oral medication administration in a patient with enteral feeding tube

    PubMed Central

    Emami, Shahram; Hamishehkar, Hadi; Mahmoodpoor, Ata; Mashayekhi, Simin; Asgharian, Parina

    2012-01-01

    Enteral feeding tube is employed for feeding of critically ill patients who are unable to eat. In the cases of oral medication administration to enterally fed patients, some potential errors could happen. We report a 53-year-old man who was admitted to intensive care unit (ICU) of a teaching hospital due to the post-CPR hypoxemic encephalopathy. The patient was intubated and underwent mechanical ventilation. A nasogastric (NG) tube was used as the enteral route for nutrition and administration of oral medications. Oral medications were crushed then dissolved in tap water and were given to the patient through NG tube. In present article we report several medication errors occurred during enterally drug administration, including errors in dosage form selection, methods of oral medication administration and drug interactions and incompatibility with nutrition formula. These errors could reduce the effects of drugs and lead to unsuccessful treatment of patient and also could increase the risk of potential adverse drug reactions. Potential leading causes of these errors include lack of drug knowledge among physicians, inadequate training of nurses and lack of pharmacists participation in medical settings. PMID:24991587

  3. Oral Medications: Proper Use and Administration. Book 1, Bosnian and Russian. Book 2, Nuer and Spanish.

    ERIC Educational Resources Information Center

    Anoka County Community Health and Environmental Services, Coon Rapids, MN.

    These two guides provide information in English, Bosnian, Russian, Nuer, and Spanish on the proper use and administration of oral medications. Topics covered include the reasons for taking medication, information on the prescription label, following special instructions, asking questions of the pharmacist, safe storage of medicine, child-proof…

  4. Oral administration of moxidectin for treatment of murine acariosis due to Radfordia affinis.

    PubMed

    Pollicino, P; Rossi, L; Rambozzi, L; Farca, A M; Peano, A

    2008-02-14

    A field trial was conducted to assess the safety and efficacy of oral administration of moxidectin in mice naturally infected with the fur mites Radfordia affinis. The natural infection was diagnosed in two colonies within a large academic institution by direct hair examination. Animals received moxidectin (1% Cydectin, FortDodge) at an oral dosage of approximately 2 mg/kg body weight by micropipette; administration was repeated after 15 days. Forty mice served as an untreated control group. Moxidectin treatment resulted in clinical improvement within a few days after initial treatment, and mites were eradicated from all infested animals at day 30. No side effects or signs of ill health were observed in any of the treated animals. To our knowledge, this is the first report of oral moxidectin for treatment of murine acariosis.

  5. Two cases of "cannabis acute psychosis" following the administration of oral cannabis.

    PubMed

    Favrat, Bernard; Ménétrey, Annick; Augsburger, Marc; Rothuizen, Laura E; Appenzeller, Monique; Buclin, Thierry; Pin, Marie; Mangin, Patrice; Giroud, Christian

    2005-04-01

    Cannabis is the most commonly used illegal drug and its therapeutic aspects have a growing interest. Short-term psychotic reactions have been described but not clearly with synthetic oral THC, especially in occasional users. We report two cases of healthy subjects who were occasional but regular cannabis users without psychiatric history who developed transient psychotic symptoms (depersonalization, paranoid feelings and derealisation) following oral administration of cannabis. In contrast to most other case reports where circumstances and blood concentrations are unknown, the two cases reported here happened under experimental conditions with all subjects negative for cannabis, opiates, amphetamines, cocaine, benzodiazepines and alcohol, and therefore the ingested dose, the time-events of effects on behavior and performance as well as the cannabinoid blood levels were documented. While the oral route of administration achieves only limited blood concentrations, significant psychotic reactions may occur.

  6. Two cases of "cannabis acute psychosis" following the administration of oral cannabis

    PubMed Central

    Favrat, Bernard; Ménétrey, Annick; Augsburger, Marc; Rothuizen, Laura E; Appenzeller, Monique; Buclin, Thierry; Pin, Marie; Mangin, Patrice; Giroud, Christian

    2005-01-01

    Background Cannabis is the most commonly used illegal drug and its therapeutic aspects have a growing interest. Short-term psychotic reactions have been described but not clearly with synthetic oral THC, especially in occasional users. Case presentations We report two cases of healthy subjects who were occasional but regular cannabis users without psychiatric history who developed transient psychotic symptoms (depersonalization, paranoid feelings and derealisation) following oral administration of cannabis. In contrast to most other case reports where circumstances and blood concentrations are unknown, the two cases reported here happened under experimental conditions with all subjects negative for cannabis, opiates, amphetamines, cocaine, benzodiazepines and alcohol, and therefore the ingested dose, the time-events of effects on behavior and performance as well as the cannabinoid blood levels were documented. Conclusion While the oral route of administration achieves only limited blood concentrations, significant psychotic reactions may occur. PMID:15804348

  7. Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease.

    PubMed

    de Mello, Carlos Geraldo Campos; Branquinho, Renata Tupinambá; Oliveira, Maykon Tavares; Milagre, Matheus Marques; Saúde-Guimarães, Dênia Antunes; Mosqueira, Vanessa Carla Furtado; Lana, Marta de

    2016-09-01

    The etiological treatment of Chagas disease remains neglected. The compounds available show several limitations, mainly during the chronic phase. Lychnopholide encapsulated in polymeric nanocapsules (LYC-NC) was efficacious in mice infected with Trypanosoma cruzi and treated by intravenous administration during the acute phase (AP). As the oral route is preferred for treatment of chronic infections, such as Chagas disease, this study evaluated the use of oral LYC-NC in the AP and also compared it with LYC-NC administered to mice by the oral and intravenous routes during the chronic phase (CP). The therapeutic efficacy was evaluated by fresh blood examination, hemoculture, PCR, and enzyme-linked immunosorbent assay (ELISA). The cure rates in the AP and CP were 62.5% and 55.6%, respectively, upon oral administration of LYC-poly(d,l-lactide)-polyethylene glycol nanocapsules (LYC-PLA-PEG-NC) and 57.0% and 30.0%, respectively, with LYC-poly-ε-caprolactone nanocapsules (LYC-PCL-NC). These cure rates were significantly higher than that of free LYC, which did not cure any animals. LYC-NC formulations administered orally during the AP showed cure rates similar to that of benznidazole, but only LYC-NC cured mice in the CP. Similar results were achieved with intravenous treatment during the CP. The higher cure rates obtained with LYC loaded in PLA-PEG-NC may be due to the smaller particle size of these NC and the presence of PEG, which influence tissue diffusion and the controlled release of LYC. Furthermore, PLA-PEG-NC may improve the stability of the drug in the gastrointestinal tract. This work is the first report of cure of experimental Chagas disease via oral administration during the CP. These findings represent a new and important perspective for oral treatment of Chagas disease. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  8. Efficacy of Lychnopholide Polymeric Nanocapsules after Oral and Intravenous Administration in Murine Experimental Chagas Disease

    PubMed Central

    de Mello, Carlos Geraldo Campos; Branquinho, Renata Tupinambá; Oliveira, Maykon Tavares; Milagre, Matheus Marques; Saúde-Guimarães, Dênia Antunes; Mosqueira, Vanessa Carla Furtado

    2016-01-01

    The etiological treatment of Chagas disease remains neglected. The compounds available show several limitations, mainly during the chronic phase. Lychnopholide encapsulated in polymeric nanocapsules (LYC-NC) was efficacious in mice infected with Trypanosoma cruzi and treated by intravenous administration during the acute phase (AP). As the oral route is preferred for treatment of chronic infections, such as Chagas disease, this study evaluated the use of oral LYC-NC in the AP and also compared it with LYC-NC administered to mice by the oral and intravenous routes during the chronic phase (CP). The therapeutic efficacy was evaluated by fresh blood examination, hemoculture, PCR, and enzyme-linked immunosorbent assay (ELISA). The cure rates in the AP and CP were 62.5% and 55.6%, respectively, upon oral administration of LYC–poly(d,l-lactide)–polyethylene glycol nanocapsules (LYC-PLA-PEG-NC) and 57.0% and 30.0%, respectively, with LYC–poly-ε-caprolactone nanocapsules (LYC-PCL-NC). These cure rates were significantly higher than that of free LYC, which did not cure any animals. LYC-NC formulations administered orally during the AP showed cure rates similar to that of benznidazole, but only LYC-NC cured mice in the CP. Similar results were achieved with intravenous treatment during the CP. The higher cure rates obtained with LYC loaded in PLA-PEG-NC may be due to the smaller particle size of these NC and the presence of PEG, which influence tissue diffusion and the controlled release of LYC. Furthermore, PLA-PEG-NC may improve the stability of the drug in the gastrointestinal tract. This work is the first report of cure of experimental Chagas disease via oral administration during the CP. These findings represent a new and important perspective for oral treatment of Chagas disease. PMID:27324760

  9. A New Approach to the Oral Administration of Insulin and Other Peptide Drugs

    NASA Astrophysics Data System (ADS)

    Saffran, Murray; Sudesh Kumar, G.; Savariar, Celin; Burnham, Jeffrey C.; Williams, Frederick; Neckers, Douglas C.

    1986-09-01

    The oral administration of peptide drugs is well known to be precluded by their digestion in the stomach and small intestine. As a new approach to oral delivery, peptide drugs were coated with polymers cross-linked with azoaromatic groups to form an impervious film to protect orally administered drugs from digestion in the stomach and small intestine. When the azopolymer-coated drug reached the large intestine, the indigenous microflora reduced the azo bonds, broke the cross-links, and degraded the polymer film, thereby releasing the drug into the lumen of the colon for local action or for absorption. The ability of the azopolymer coating to protect and deliver orally administered peptide drugs was demonstrated in rats with the peptide hormones vasopressin and insulin.

  10. Oral fluid/plasma cannabinoid ratios following controlled oral THC and smoked cannabis administration.

    PubMed

    Lee, Dayong; Vandrey, Ryan; Milman, Garry; Bergamaschi, Mateus; Mendu, Damodara R; Murray, Jeannie A; Barnes, Allan J; Huestis, Marilyn A

    2013-09-01

    Oral fluid (OF) is a valuable biological alternative for clinical and forensic drug testing. Evaluating OF to plasma (OF/P) cannabinoid ratios provides important pharmacokinetic data on the disposition of drug and factors influencing partition between matrices. Eleven chronic cannabis smokers resided on a closed research unit for 51 days. There were four 5-day sessions of 0, 30, 60, and 120 mg oral ∆(9)-tetrahydrocannabinol (THC)/day followed by a five-puff smoked cannabis challenge on Day 5. Each session was separated by 9 days ad libitum cannabis smoking. OF and plasma specimens were analyzed for THC and metabolites. During ad libitum smoking, OF/P THC ratios were high (median, 6.1; range, 0.2-348.5) within 1 h after last smoking, decreasing to 0.1-20.7 (median, 2.1) by 13.0-17.1 h. OF/P THC ratios also decreased during 5-days oral THC dosing, and after the smoked cannabis challenge, median OF/P THC ratios decreased from 1.4 to 5.5 (0.04-245.6) at 0.25 h to 0.12 to 0.17 (0.04-5.1) at 10.5 h post-smoking. In other studies, longer exposure to more potent cannabis smoke and oromucosal cannabis spray was associated with increased OF/P THC peak ratios. Median OF/P 11-nor-9-carboxy-THC (THCCOOH) ratios were 0.3-2.5 (range, 0.1-14.7) ng/μg, much more consistent in various dosing conditions over time. OF/P THC, but not THCCOOH, ratios were significantly influenced by oral cavity contamination after smoking or oromucosal spray of cannabinoid products, followed by time-dependent decreases. Establishing relationships between OF and plasma cannabinoid concentrations is essential for making inferences of impairment or other clinical outcomes from OF concentrations.

  11. Pharmacokinetics of rabeprazole following single intravenous and oral administration to healthy subjects.

    PubMed

    Setoyama, T; Laurent, A; Humphries, T; Hasegawa, J

    2005-01-01

    The study was designed to determine the absolute bioavailability of 20 mg rabeprazole tablets in normal, healthy subjects in comparison with intravenous administration of 20 mg rabeprazole. Twenty-eight healthy subjects were enrolled in this study. The study was a randomized, balanced, open-label, 2-period crossover study. Each subject was randomized at the beginning of the study to receive either a single 20 mg dose of rabeprazole intravenously or orally during Period 1. Following a 7-day washout period, all subjects received the alternate formulation during Period 2. Intravenous dose was given in constant infusion over five minutes. The absolute bioavailability of rabeprazole was 51.8%. The elimination half-life of rabeprazole sodium (1.47 +/- 0.82 h) after oral administration was significantly longer than the elimination half-life after intravenous administration (1.02 +/- 0.63 h), probably due to slower rate of absorption than that of elimination. The mean total body clearance was 283 +/- 98 ml/minutes following a 20 mg intravenous dose. The administration of rabeprazole sodium was safe as evidenced by the lack of serious adverse events and the rapid resolution of the mostly mild adverse events that occurred during the study. Both treatments were well-tolerated throughout the study. Rabeprazole was well-absorbed after oral administration.

  12. Severe hyperphosphatemia and hypocalcemic tetany after oral laxative administration in a 3-month-old infant.

    PubMed

    Domico, Michele B; Huynh, Van; Anand, Sudhir K; Mink, Richard

    2006-11-01

    A 3-month-old infant presented to the pediatric emergency department with respiratory distress and tetany after ingestion of a phosphate-containing oral laxative. The initial phosphorus level was 38.3 mg/dL. With aggressive fluid resuscitation and intravenous calcium administration, the infant completely recovered. Although the risks of phosphate-containing enemas are well described, life-threatening hyperphosphatemia can also result from administration of phosphate-containing oral laxatives. Aggressive fluid hydration is the mainstay of treatment. Intravenous calcium administration may be necessary to avoid hemodynamic collapse despite the theoretical possibility of metastatic calcifications. Physicians should be alerted to the possibility of phosphate toxicity and hypocalcemic tetany in young children when treated with over-the-counter laxatives. Caregivers should be advised not to administer over-the-counter laxatives to infants without physician supervision.

  13. Cannabinoids and metabolites in expectorated oral fluid after 8 days of controlled around-the-clock oral THC administration.

    PubMed

    Milman, Garry; Barnes, Allan J; Schwope, David M; Schwilke, Eugene W; Goodwin, Robert S; Kelly, Deana L; Gorelick, David A; Huestis, Marilyn A

    2011-08-01

    Oral fluid (OF) is an increasingly accepted matrix for drug testing programs, but questions remain about its usefulness for monitoring cannabinoids. Expectorated OF specimens (n = 360) were obtained from 10 adult daily cannabis smokers before, during, and after 37 20-mg oral Δ(9)-tetrahydrocannabinol (THC) doses over 9 days to characterize cannabinoid disposition in this matrix. Specimens were extracted and analyzed by gas chromatography-mass spectrometry with electron-impact ionization for THC, 11-hydroxy-THC, cannabidiol, and cannabinol, and negative chemical ionization for 11-nor-9-carboxy-THC (THCCOOH). Linear ranges for THC, 11-hydroxy-THC, and cannabidiol were 0.25-50 ng/mL; cannabinol 1-50 ng/mL; and THCCOOH 5-500 pg/mL. THCCOOH was the most prevalent analyte in 344 specimens (96.9%), with concentrations up to 1,390.3 pg/mL. 11-hydroxy-THC, cannabidiol, and cannabinol were detected in 1, 1, and 3 specimens, respectively. THC was detected in only 13.8% of specimens. The highest THC concentrations were obtained at admission (median 1.4 ng/mL, range 0.3-113.6) from previously self-administered smoked cannabis. A total of 2.5 and 3.7% of specimens were THC-positive at the recommended Substance Abuse and Mental Health Services Administration (2 ng/mL) and Driving Under the Influence of Drugs, Alcohol and Medicines (DRUID) (1 ng/mL) confirmation cutoffs, respectively. THC is currently the only analyte for monitoring cannabis exposure in OF; however, these data indicate chronic therapeutic oral THC administration and illicit oral THC use are unlikely to be identified with current guidelines. Measurement of THCCOOH may improve the detection and interpretation of OF cannabinoid tests and minimize the possibility of OF contamination from passive inhalation of cannabis smoke.

  14. Early effects of oral administration of omeprazole and roxatidine on intragastric pH

    PubMed Central

    Iida, Hiroshi; Kato, Shingo; Sekino, Yusuke; Sakai, Eiji; Uchiyama, Takashi; Endo, Hiroki; Hosono, Kunihiro; Sakamoto, Yasunari; Fujita, Koji; Yoneda, Masato; Koide, Tomoko; Takahashi, Hirokazu; Tokoro, Chikako; Goto, Ayumu; Abe, Yasunobu; Kobayashi, Noritoshi; Kubota, Kensuke; Gotoh, Eiji; Maeda, Shin; Nakajima, Atsushi; Inamori, Masahiko

    2012-01-01

    Objective: The ideal medication for the treatment of acid-related diseases, e.g., peptic ulcers, stress-related gastric bleeding, functional dyspepsia, and gastroesophageal reflux disease, should have a rapid onset of action to promote hemostasis and relieve the symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of a proton pump inhibitor, omeprazole 20 mg, and an H2-receptor antagonist, roxatidine 75 mg. Methods: Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 h after single oral administration of omeprazole 20 mg and roxatidine 75 mg. Each administration was separated by a 7-d washout period. Results: During the 6-h study period, the average pH after administration of roxatidine was higher than that after administration of omeprazole (median: 4.45 vs. 2.65; P=0.0367). Also during the 6-h study period, a longer duration of maintenance at pH above 2, 5, and 6 was observed after administration of roxatidine 75 mg than after administration of omeprazole 20 mg (median: 90.6% vs. 55.2%, P=0.0284; 43.7% vs. 10.6%, P=0.0125; 40.3% vs. 3.3%, P=0.0125; respectively). Conclusions: In Helicobacter pylori-negative healthy male subjects, oral administration of roxatidine 75 mg increased the intragastric pH more rapidly than that of omeprazole 20 mg. PMID:22205617

  15. Oral Ondansetron Administration in Emergency Departments to Children with Gastroenteritis: An Economic Analysis

    PubMed Central

    Freedman, Stephen B.; Steiner, Michael J.; Chan, Kevin J.

    2010-01-01

    Background The use of antiemetics for children with vomiting is one of the most controversial decisions in the treatment of gastroenteritis in developed countries. Ondansetron, a selective serotonin receptor antagonist, has been found to be effective in improving the success of oral rehydration therapy. However, North American and European clinical practice guidelines continue to recommend against its use, stating that evidence of cost savings would be required to support ondansetron administration. Thus, an economic analysis of the emergency department administration of ondansetron was conducted. The primary objective was to conduct a cost analysis of the routine administration of ondansetron in both the United States and Canada. Methods and Findings A cost analysis evaluated oral ondansetron administration to children presenting to emergency departments with vomiting and dehydration secondary to gastroenteritis from a societal and health care payer's perspective in both the US and Canada. A decision tree was developed that incorporated the frequency of vomiting, intravenous insertion, hospitalization, and emergency department revisits. Estimates of the monetary costs associated with ondansetron use, intravenous rehydration, and hospitalization were derived from administrative databases or emergency department use. The economic burden in children administered ondansetron plus oral rehydration therapy was compared to those not administered ondansetron employing deterministic and probabilistic simulations. We estimated the costs or savings to society and health care payers associated with the routine administration of ondansetron. Sensitivity analyses considered variations in costs, treatment effects, and exchange rates. In the US the administration of ondansetron to eligible children would prevent approximately 29,246 intravenous insertions and 7,220 hospitalizations annually. At the current average wholesale price, its routine administration to eligible children

  16. Thallium-201 myocardial imaging during pharmacologic coronary vasodilation: comparison of oral and intravenous administration of dipyridamole

    SciTech Connect

    Taillefer, R.; Lette, J.; Phaneuf, D.C.; Leveille, J.; Lemire, F.; Essiambre, R.

    1986-07-01

    Although the diagnostic utility of thallium-201 myocardial imaging after dipyridamole infusion is well established, the intravenous form of the drug is not yet commercially available in North America. Fifty patients referred for coronary angiography were prospectively studied. Within a 2 week period, each patient underwent cardiac catheterization and thallium-201 myocardial imaging after both oral and intravenous dipyridamole administration. For the oral protocol, patients were randomly assigned to treatment with either 200 or 400 mg of dipyridamole in tablet form. Coronary artery stenoses of 70% or greater were considered significant. For the 25 patients who received a 200 mg oral dose of dipyridamole, the scintigraphic study showed perfusion defects in 65% of patients with significant coronary artery disease after the oral dose and in 85% of patients after the intravenous dose. For the 25 patients who received a 400 mg oral dose, the sensitivity of the scintigram was 84% after the oral dose and 79% after the intravenous dose. Except for headache and nausea, side effects were less severe and less frequent with oral (either 200 or 400 mg) than with intravenous dipyridamole. Because of the delayed and variable absorption of dipyridamole tablets, the oral studies required a longer period of medical supervision (45 to 60 minutes), and aminophylline was empirically administered after completion of the first set of thallium-201 images. It is concluded from this study that thallium-201 myocardial imaging after coronary vasodilation with a 400 mg oral dose of dipyridamole is a safe, widely available and reliable alternative for the evaluation of coronary artery disease in patients unable to achieve an adequate exercise level on stress testing.

  17. Immunomodulation of Experimental Autoimmune Encephalomyelitis by Oral Administration of Copolymer 1

    NASA Astrophysics Data System (ADS)

    Teitelbaum, Dvora; Arnon, Ruth; Sela, Michael

    1999-03-01

    The activity of copolymer 1 (Cop 1, Copax-one, glatiramer acetate) in suppressing experimental autoimmune encephalomyelitis (EAE) and in the treatment of multiple sclerosis patients when injected parenterally has been extensively demonstrated. In the present study we addressed the question of whether Cop 1 can induce oral tolerance to EAE similar to myelin basic protein (MBP). We now have demonstrated that oral Cop 1 inhibited EAE induction in both rats and mice. Furthermore, oral Cop 1 was more effective than oral MBP in suppressing EAE in rats. The beneficial effect of oral Cop 1 was found to be associated with specific inhibition of the proliferative and Th1 cytokine secretion responses to MBP of spleen cells from Cop 1-fed mice and rats. In all of these assays, oral Cop 1 was more effective than oral MBP. The tolerance induced by Cop 1 could be adoptively transferred with spleen cells from Cop 1-fed animals. Furthermore, Cop 1-specific T cell lines, which inhibit EAE induction in vivo, could be isolated from the above spleen cells. These T cell lines secrete the anti-inflammatory cytokines IL-10 and transforming growth factor type β , but not IL-4, in response to both Cop 1 and MBP. In conclusion, oral Cop 1 has a beneficial effect on the development of EAE that is associated with down-regulation of T cell immune responses to MBP and is mediated by Th2/3 type regulatory cells. These results suggest that oral administration of Cop 1 may modulate multiple sclerosis as well.

  18. Oral administration of a recombinant cholera toxin B subunit promotes mucosal healing in the colon.

    PubMed

    Baldauf, K J; Royal, J M; Kouokam, J C; Haribabu, B; Jala, V R; Yaddanapudi, K; Hamorsky, K T; Dryden, G W; Matoba, N

    2016-11-02

    Cholera toxin B subunit (CTB) is a component of a licensed oral cholera vaccine. However, CTB has pleiotropic immunomodulatory effects whose impacts on the gut are not fully understood. Here, we found that oral administration in mice of a plant-made recombinant CTB (CTBp) significantly increased several immune cell populations in the colon lamina propria. Global gene expression analysis revealed that CTBp had more pronounced impacts on the colon than the small intestine, with significant activation of TGFβ-mediated pathways in the colon epithelium. The clinical relevance of CTBp-induced impacts on colonic mucosa was examined. In a human colon epithelial model using Caco2 cells, CTBp, but not the non-GM1-binding mutant G33D-CTBp, induced TGFβ-mediated wound healing. In a dextran sodium sulfate (DSS) acute colitis mouse model, oral administration of CTBp protected against colon mucosal damage as manifested by mitigated body weight loss, decreased histopathological scores, and blunted escalation of inflammatory cytokine levels while inducing wound healing-related genes. Furthermore, biweekly oral administration of CTBp significantly reduced disease severity and tumorigenesis in the azoxymethane/DSS model of ulcerative colitis and colon cancer. Altogether, these results demonstrate CTBp's ability to enhance mucosal healing in the colon, highlighting its potential application in ulcerative colitis therapy besides cholera vaccination.Mucosal Immunology advance online publication 2 November 2016. doi:10.1038/mi.2016.95.

  19. Pharmacokinetics of meloxicam after intramuscular and oral administration of a single dose to American flamingos (Phoenicopertus ruber).

    PubMed

    Boonstra, Jennifer L; Cox, Sherry K; Martin-Jimenez, Tomas

    2017-03-01

    OBJECTIVE To determine pharmacokinetics after IM and oral administration of a single dose of meloxicam to American flamingos (Phoenicopertus ruber). ANIMALS 14 adult flamingos. PROCEDURES Flamingos were allocated to 2 groups. Each group received a dose of meloxicam (1 mg/kg) by the IM or oral route. After a 4-week washout period, groups received meloxicam via the other route of administration. Plasma meloxicam concentrations were measured with high-performance liquid chromatography. Data for each bird were analyzed. Estimated values of selected pharmacokinetic parameters were compared by use of a linear mixed-effects ANOVA. Pooled concentration-time profiles for each route of administration were analyzed to examine the influence of body weight on pharmacokinetics. RESULTS Mean ± SD maximum plasma concentration was 1.00 ± 0.88 μg/mL after oral administration. This was approximately 15% of the mean maximum plasma concentration of 5.50 ± 2.86 μg/mL after IM administration. Mean time to maximum plasma concentration was 1.33 ± 1.32 hours after oral administration and 0.28 ± 0.17 hours after IM administration. Mean half-life of the terminal phase after oral administration (3.83 ± 2.64 hours) was approximately twice that after IM administration (1.83 ± 1.22 hours). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the extent and rate of meloxicam absorption were less after oral administration than after IM administration. Intramuscular administration resulted in a short period during which mean plasma concentrations met or exceeded reported efficacious analgesic concentrations in other species, whereas oral administration did not. These results suggested that higher doses may be required for oral administration.

  20. Novel self assembling nanoparticles for the oral administration of fondaparinux: Synthesis, characterization and in vivo evaluation

    PubMed Central

    Ralay-Ranaivo, Bettina; Desmaële, Didier; Bianchini, Elsa P.; Lepeltier, Elise; Bourgaux, Claudie; Borgel, Delphine; Pouget, Thierry; Tranchant, Jean François; Couvreur, Patrick; Gref, Ruxandra

    2014-01-01

    Fondaparinux (Fpx) is the anticoagulant of choice in the treatment of short- and medium-term thromboembolic disease. To overcome the low oral bioavailability of Fpx, a new nanoparticulate carrier has been developed. The nanoparticles (NPs) contain squalenyl derivatives, known for their excellent oral bioavailability. They spontaneously self-assemble upon both electrostatic and hydrophobic interactions between the polyanionic Fpx and cationic squalenyl (CSq) derivatives. The preparation conditions were optimized to obtain monodisperse, stable NPs with a mean diameter in the range of 150–200 nm. The encapsulation efficiencies were around 80%. Fpx loadings reached 39 wt.%. According to structural and morphological analysis, Fpx and CSq organized in spherical multilamellar (“onion-type”) nanoparticles. Furthermore, in vivo studies in rats suggested that Fpx was well absorbed from the orally administered NPs, which totally dissociated when reaching the blood stream, leading to the release of free Fpx. The Fpx:CSq NPs improved the plasmatic concentration of Fpx in a dose-dependent manner. However, the oral bioavailability of these new NPs remained low (around 0.3%) but of note, the Cmax obtained after oral administration of 50 mg/kg NPs was close to the prophylactic plasma concentration needed to treat venous thromboembolism. Moreover, the oral bioavailability of Fpx could be dramatically increased up to 9% by including the nanoparticles into gastroresistant capsules. This study opens up new perspectives for the oral administration of Fpx and paves the way towards elaborating squalene-based NPs which self assemble without the need of covalently grafting the drug to Sq. PMID:25127657

  1. Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis.

    PubMed

    Dorr, Mary Beth; Nelson, Anita L; Mayer, Philip R; Ranganath, Radhika P; Norris, Paul M; Helzner, Eileen C; Preston, Richard A

    2010-11-01

    In this open-label, randomized, multiple-dose, two-treatment crossover study, 24 postmenopausal women with moderate to severe atrophic vaginitis received 0.3 mg conjugated estrogens daily for 14 days: 7 days orally (0.3 mg tablet) and 7 days vaginally (0.5 g cream). Steady-state plasma concentrations of E2 and estrone were one-third lower after vaginal versus oral administration of conjugated estrogens. Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  2. Can TiC nanoparticles produce toxicity in oral administration to rats?

    PubMed

    Laloy, Julie; Lozano, Omar; Alpan, Lütfiye; Mejia, Jorge; Toussaint, Olivier; Masereel, Bernard; Dogné, Jean-Michel; Lucas, Stéphane

    2014-01-01

    Titanium carbide (TiC) is used for ceramic metal composites in several industries and is regarded as a nanomaterial for catalyst and battery applications. However, there are very few studies in regard to the toxicological potential of TiC nanoparticles (NPs). To study the toxicodynamics and toxicokinetics of TiC NPs in Sprague Dawley rats in acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 1000 mg kg(-1); the subacute doses were 0.5 and 50 mg kg(-1). Organ histopathological examination (esophagus, stomach, intestines, spleen, liver, and kidneys) indicates the absence of damage at all applied doses, in both assessments. In the acute administration, alkaline phosphatases increased (5, 300 and 1000 mg kg(-1)), ASAT increased (1000 mg kg(-1)) and bile salts decreased (0.5 mg kg(-1)). No alterations in urine parameters (sodium, potassium, osmolarity) were found. Acute administration of TiC caused mineral changes in organs (liver, spleen, kidneys). TiC was mostly cleared by feces excretion 24 h after administration, in subacute administration causing variations in mineral absorption (Mg, Al, P, S, Ca, Zn). TiC could pass the intestinal barrier as TiC traces were detected in urine. No sign of toxicity was found after oral administration. TiC was excreted mostly in feces producing mineral absorption alterations. Low traces were retrieved in urine, indicating that TiC can cross the intestinal barrier.

  3. Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer's disease.

    PubMed

    Moreno, Lina Clara Gayoso E Ibiapina; Puerta, Elena; Suárez-Santiago, José Eduardo; Santos-Magalhães, Nereide Stela; Ramirez, Maria J; Irache, Juan M

    2017-01-30

    Quercetin has been identified as a promising compound with a neuroprotective potential against age-related neurodegenerative diseases such as Alzheimer's disease (AD). Nevertheless, the clinical application of quercetin is hampered by its low oral bioavailability. The aim of this work was to evaluate the capability of nanoencapsulated quercetin in zein nanoparticles (NPQ), that significantly improves the oral absorption and bioavailability of the flavonoid, as potential oral treatment for AD. For this purpose, SAMP8 mice were orally treated for two months with either NPQ (25mg/kg every 48h) or a solution of quercetin (Q; 25mg/kg daily). NPQ displayed a size of 260nm and a payload of about 70μg/mg. For Q, no significant effects were observed in animals. On the contrary, the oral administration of NPQ improved the cognition and memory impairments characteristics of SAMP8 mice. These observations appeared to be related with a decreased expression of the hippocampal astrocyte marker GFAP. Furthermore, significant levels of quercetin were quantified in the brain of mice treated with nanoparticles. These findings highlight the potential of zein nanoparticles to promote the oral absorption of quercetin as well as the therapeutic potential of this flavonoid in AD pathogenesis.

  4. Oral MSG administration alters hepatic expression of genes for lipid and nitrogen metabolism in suckling piglets.

    PubMed

    Chen, Gang; Zhang, Jun; Zhang, Yuzhe; Liao, Peng; Li, Tiejun; Chen, Lixiang; Yin, Yulong; Wang, Jinquan; Wu, Guoyao

    2014-01-01

    This experiment was conducted to investigate the effects of oral administration of monosodium glutamate (MSG) on expression of genes for hepatic lipid and nitrogen metabolism in piglets. A total of 24 newborn pigs were assigned randomly into one of four treatments (n = 6/group). The doses of oral MSG administration, given at 8:00 and 18:00 to sow-reared piglets between 0 and 21 days of age, were 0 (control), 0.06 (low dose), 0.5 (intermediate dose), and 1 (high dose) g/kg body weight/day. At the end of the 3-week treatment, serum concentrations of total protein and high-density lipoprotein cholesterol in the intermediate dose group were elevated than those in the control group (P < 0.05). Hepatic mRNA levels for fatty acid synthase, acetyl-coA carboxylase, insulin-like growth factor-1, glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase were higher in the middle-dose group (P < 0.05), compared with the control group. MSG administration did not affect hepatic mRNA levels for hormone-sensitive lipase or carnitine palmitoyl transferase-1. We conclude that oral MSG administration alters hepatic expression of certain genes for lipid and nitrogen metabolism in suckling piglets.

  5. Pharmacokinetics of ketoprofen enantiomers following intravenous and oral administration to exercised Thoroughbred horses.

    PubMed

    Knych, Heather K; Arthur, Rick M; Steinmetz, Stacy; McKemie, Dan S

    2016-01-01

    Ketoprofen (KTP) is currently only available as an injectable formulation for intravenous administration to horses. The primary goal of the study reported here was to characterize the pharmacokinetics of KTP, including determination of bioavailability following oral administration of the currently available injectable formulation as well as a paste formulation. KTP was administered intravenously and orally, and blood and urine samples were collected at various time points up to 96 h. KTP enantiomer concentrations were determined using LC–MS/MS, and pharmacokinetic analyses were performed. Mean ± standard error values for systemic clearance, steady state volume of distribution and terminal elimination half-life were 0.345 ± 0.033 [R(−) KTP] and 0.167 ± 0.016 [S(+) KTP] L/kg/h, 0.344 ± 0.044 [R(−) KTP] and 0.298 ± 0.025 [S(+) KTP] L/kg, and 2.49 ± 0.077 [R(−) KTP] and 2.86 ± 0.102 [S(+) KTP] h, respectively. Oral bioavailability was calculated as 69.5 ± 10.3% and 88.2 ± 15.9% for R(−) KTP and S(+) KTP, respectively, following administration of the injectable formulation and 53.0 ± 6.0 and 53.0 ± 16.0% for the R(−) KTP and S(+) KTP, respectively, following administration of KTP paste.

  6. Oral rabeprazole administration on a procedure day suppresses bleeding after endoscopic submucosal dissection for gastric neoplasms.

    PubMed

    Hikichi, Takuto; Sato, Masaki; Watanabe, Ko; Nakamura, Jun; Takagi, Tadayuki; Suzuki, Rei; Sugimoto, Mitsuru; Waragai, Yuichi; Kikuchi, Hitomi; Konno, Naoki; Ohira, Hiromasa; Obara, Katsutoshi

    2014-01-01

    The efficacy of pre-procedure oral proton pump inhibitor (PPI) administration for gastric endoscopic submucosal dissection (ESD) is unclear. This study evaluated oral PPI administration effectiveness on the day of ESD to prevent post-ESD bleeding. This study examined 55 patients who underwent ESD for gastric neoplasm. Group A comprised 31 patients who took rabeprazole sodium (RPZ) 20 mg/day beginning 7-8 hr before ESD. Group B comprised 24 who took RPZ 20 mg/day beginning three days before ESD. Gastric pH (G-pH) was measured at one month before ESD (pre-ESD pH), immediately before ESD (ESD pH), and seven days after ESD (post-ESD pH). The post-ESD bleeding rate and changes in G-pH were recorded. No significant difference in post-ESD bleeding rates was found (Group A 3.2%, Group B 0%). ESD pH and post-ESD pH were significantly higher than pre-ESD pH in both groups (P<0.001). The ESD pH for Group A was higher than 6 (6.5±1.1), providing hemostasis for intragastric bleeding. Oral RPZ administration on the day of gastric ESD can suppress post-ESD bleeding equivalently to administration three days before ESD.

  7. Oral administration of stavudine induces hyperalgesia without affecting activity in rats.

    PubMed

    Weber, Juliane; Mitchell, Duncan; Kamerman, Peter R

    2007-12-05

    We have investigated whether long-term oral administration of the nucleoside reverse transcriptase inhibitor (NRTI) stavudine affects nociception in Sprague-Dawley rats, and whether any changes of nociception are accompanied by deterioration in activity and appetite. Stavudine (50 mg kg(-1)) was administered to rats orally once daily for six weeks in gelatine cubes. Mechanical hyperalgesia of the tail was assessed using a bar algometer, and thermal hyperalgesia by tail immersion in 49 degrees C water. Withdrawal latencies were compared to those of rats receiving placebo gelatine cubes. Withdrawal latencies to the noxious thermal challenge were not affected by stavudine, but those to the mechanical challenge were significantly decreased in rats receiving stavudine, compared to rats receiving placebo, from week three to week six of drug administration (P<0.05, ANCOVA with Newman Keuls post-hoc comparisons). The overall condition of the rats was assessed by recording daily voluntary wheel running distance and maximum running speed, food intake and body mass. Daily stavudine administration did not adversely affect voluntary running activity, appetite or growth. We have shown that long-term daily oral administration of the NRTI stavudine results in mechanical hyperalgesia in rats within three weeks without affecting appetite, growth and physical activity.

  8. Pharmacokinetics of butorphanol after intravenous, intramuscular, and oral administration in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Guzman, David Sanchez-Migallon; Flammer, Keven; Paul-Murphy, Joanne R; Barker, Steven A; Tully, Thomas N

    2011-09-01

    Previous studies have validated the clinical use of opioids with kaap-receptor affinities for pain management in birds. Butorphanol, a kappa opioid receptor agonist and a mu opioid receptor antagonist, is currently considered by many clinicians to be the opioid of choice for this use. However, despite studies reporting the analgesic properties of butorphanol in psittacine birds, dosing intervals have not been established for any psittacine species. The goals of this study in the Hispaniolan Amazon parrot (Amazona ventralis) were to evaluate the pharmacokinetics of butorphanol tartrate after intravenous (IV), intramuscular (IM), and oral (PO) administration and to determine the bioavailability of butorphanol tartrate after oral administration. Twelve Hispaniolan Amazon parrots were used in the study, with a complete-crossover experimental design and a 3-month period separating each part of the study. The birds were randomly assigned to 3 groups (n = 4) for each stage. Butorphanol tartrate was administered once at a dose of 5 mg/kg in the basilic vein or pectoral muscles or as an oral solution delivered via feeding tube into the crop for the IV, IM, and PO studies, respectively. After butorphanol administration, blood samples were collected at 1, 5, 15, 30, 60, 90, 120, 180, and 240 minutes for the IV and IM studies and at 5, 15, 30, 60, 90, 120, 180, 240, and 300 minutes for the PO study. Because of the size limitation of the birds, naive pooling of datum points was used to generate a mean plasma butorphanol concentration at each time point. For each study, birds in each group (n = 4) were bled 3 times after dosing. Plasma butorphanol concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were calculated. Butorphanol tartrate was found to have high bioavailability and rapid elimination following IM administration. In contrast, oral administration resulted in low bioavailability (< 10%), thus

  9. Pharmacokinetic, pharmacodynamic and biodistribution following oral administration of nanocarriers containing peptide and protein drugs.

    PubMed

    Griffin, Brendan T; Guo, Jianfeng; Presas, Elena; Donovan, Maria D; Alonso, María J; O'Driscoll, Caitriona M

    2016-11-15

    The influence of nanoparticle (NP) formulations on the pharmacokinetic, pharmacodynamic and biodistribution profiles of peptide- and protein-like drugs following oral administration is critically reviewed. The possible mechanisms of absorption enhancement and the effects of the physicochemical properties of the NP are examined. The potential advantages and challenges of physiologically-based pharmacokinetic (PBPK) modelling to help predict efficacy in man are discussed. The importance of developing and expanding the regulatory framework to help translate the technology into the clinic and accelerate the availability of oral nanoparticulate formulations is emphasized. In conclusion, opportunities for future work to improve the state of the art of oral nanomedicines are identified. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Induction of Flavin-Containing Monooxygenase in Mice by Oral Administration of Phellinus baumii (Agaricomycetes) Extract.

    PubMed

    Sainkhuu, Batbayar; Park, Beom Su; Kim, Ha Won

    2016-01-01

    Phellinus baumii is a yellow mushroom long used in alternative medicine in Korea and other central Asian countries. To identify genes affected by a single or 7-day oral administration of a water extract of Ph. Baumii, mouse liver tissue was analyzed using microarrays. The results showed that 8 and 23 genes were upregulated and 3 and 11 genes downregulated more than 3-fold by single and multiple oral administrations of 100 mg/kg PBE, respectively. Among the upregulated genes, the expression of 3 flavin-containing monooxygenase (Fmo) family genes, Fmo2-4, was upregulated in a concentration-dependent manner. The microarray analysis also showed that single and multiple administrations of PBE increased Fmo3 expression in the mouse liver by 5.1- and 17.6-fold, respectively. To validate the Fmo expression microarray data, polymerase chain reaction was used to confirm the induction of Fmo subclass genes. Mice were orally administered Ph. Baumii extract (PBE), Ph. Baumii water, or Ph. Baumii β-glucan fraction (PBG) for 7 days, and induction of the expression of the Fmo subclasses in the liver, lung, and kidney was investigated. Fmo2, Fmo3, and Fmo4 expression was induced by both PBE and PBG in the lung, liver, and kidney, respectively. However, no induction of Fmo1 and Fmo5 was detected. To investigate the metabolic acceleration of xenobiotic by PBE, carbendazim was orally administered to mice and its clearance from the blood analyzed. High-performance liquid chromatography analysis showed accelerated clearance of serum carbendazim by oral administration of PBE for 7 days, as evidenced by the reduced peak plasma concentration, time to reach the peak plasma concentration, and area under the curve values. Moreover, PBE increased the carbendazim clearance rate at the higher concentration. These data indicate that oral administration of PBE resulted in modulation of gene expression: PBE was responsible for the induction of Fmo2, Fmo3, and Fmo4 expression. PBE also accelerated

  11. Oral Administration of Escin Inhibits Acute Inflammation and Reduces Intestinal Mucosal Injury in Animal Models

    PubMed Central

    Li, Minmin; Lu, Chengwen; Zhang, Leiming; Zhang, Jianqiao; Du, Yuan; Duan, Sijin; Fu, Fenghua

    2015-01-01

    The present study aimed to investigate the effects of oral administration of escin on acute inflammation and intestinal mucosal injury in animal models. The effects of escin on carrageenan-induced paw edema in a rat model of acute inflammation, cecal ligation and puncture (CLP) induced intestinal mucosal injury in a mouse model, were observed. It was shown that oral administration of escin inhibits carrageenan-induced paw edema and decreases the production of prostaglandin E2 (PGE2) and cyclooxygenase- (COX-) 2. In CLP model, low dose of escin ameliorates endotoxin induced liver injury and intestinal mucosal injury and increases the expression of tight junction protein claudin-5 in mice. These findings suggest that escin effectively inhibits acute inflammation and reduces intestinal mucosal injury in animal models. PMID:26199634

  12. Oral Administration of Escin Inhibits Acute Inflammation and Reduces Intestinal Mucosal Injury in Animal Models.

    PubMed

    Li, Minmin; Lu, Chengwen; Zhang, Leiming; Zhang, Jianqiao; Du, Yuan; Duan, Sijin; Wang, Tian; Fu, Fenghua

    2015-01-01

    The present study aimed to investigate the effects of oral administration of escin on acute inflammation and intestinal mucosal injury in animal models. The effects of escin on carrageenan-induced paw edema in a rat model of acute inflammation, cecal ligation and puncture (CLP) induced intestinal mucosal injury in a mouse model, were observed. It was shown that oral administration of escin inhibits carrageenan-induced paw edema and decreases the production of prostaglandin E2 (PGE2) and cyclooxygenase- (COX-) 2. In CLP model, low dose of escin ameliorates endotoxin induced liver injury and intestinal mucosal injury and increases the expression of tight junction protein claudin-5 in mice. These findings suggest that escin effectively inhibits acute inflammation and reduces intestinal mucosal injury in animal models.

  13. Plasma Concentrations of Digoxin after Oral Administration in the Fasting and Postprandial State

    PubMed Central

    White, R. J.; Chamberlain, D. A.; Howard, M.; Smith, T. W.

    1971-01-01

    After the oral administration of 0·5 mg of digoxin in tablet form to fasting subjects peak plasma levels were reached in 30 to 60 minutes. Levels then fell to reach a plateau at six to eight hours. When the same dose was given after food the peak plasma concentrations were significantly lower, but the concentrations reached in samples obtained from two to eight hours after the dose did not differ appreciably from corresponding samples obtained in the fasting experiments. In a four-week cross-over study of 21 patients on maintenance therapy, digoxin taken regularly in the fasting state produced plasma concentrations similar to those obtained when the drug was taken after meals. The rapid appearance of digoxin in the blood suggests that the oral route of administration is adequate for most patients who require rapid digitalization, and the timing of maintenance dosage in relation to meals is unimportant. PMID:5100372

  14. Single dose pharmacokinetics and pharmacodynamics of oral oxazepam during concomitant administration of propranolol and labetalol.

    PubMed Central

    Sonne, J; Døssing, M; Loft, S; Olesen, K L; Vollmer-Larsen, A; Victor, M A; Hamberg, O; Thyssen, H

    1990-01-01

    1. The oral kinetics of oxazepam after a single 15 mg oral dose was investigated in six healthy volunteers before and during concomitant administration of the beta-adrenoceptor antagonists propranolol (80 mg) and labetalol (200 mg) (racemates). 2. A possible pharmacodynamic interaction between oxazepam and the beta-adrenoceptor antagonists was examined using a simple reaction time test (SRT) and by measurement of postural sway. 3. The kinetics of oxazepam were not affected significantly by propranolol or labetalol, although oxazepam and labetalol share the glucuronidation pathway. 4. The SRT was increased by combination of both beta-adrenoceptor antagonists with oxazepam, with the greatest increase after the coadministration of oxazepam with propranolol. Administration of the beta-adrenoceptor antagonists alone had no significant effect. 5. Postural sway was affected significantly only by the combination of oxazepam and propranolol. PMID:2297460

  15. Effects of Oral Glucosamine Hydrochloride Administration on Plasma Free Amino Acid Concentrations in Dogs

    PubMed Central

    Azuma, Kazuo; Osaki, Tomohiro; Tsuka, Takeshi; Imagawa, Tomohiro; Okamoto, Yoshiharu; Takamori, Yoshimori; Minami, Saburo

    2011-01-01

    We examined the effects of oral glucosamine hydrochloride (GlcN), N-acetyl-d-glucosamine (GlcNAc) and d-glucose (Glc) administration on plasma total free amino acid (PFAA) concentrations in dogs. The PFAA concentrations increased in the control group and the GlcNAc group at one hour after feeding, and each amino acid concentration increased. On the other hand, in the GlcN group and the Glc group PFAA concentrations decreased at one hour after feeding. A significant decrease in amino acid concentration was observed for glutamate, glycine and alanine. Our results suggest the existence of differences in PFAA dynamics after oral administration of GlcN and GlcNAc in dogs. PMID:21673884

  16. Plasma levels of proglumetacin and its metabolites after intravenous or oral administration in the dog.

    PubMed

    Setnikar, I; Arigoni, R; Chisté, R; Makovec, F; Revel, L

    1987-06-01

    The absolute bioavailability of 1H-indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl 2-[4-[4-[[4-(benzoylamino)-1,5-dioxopentyl]oxy]propyl]-1- piperazinyl]-ethyl ester (+/-) (proglumetacin, CR 604) was studied in 12 dogs, in a triple cross-over experiment with single doses of i.v. proglumetacin diphosphate, oral proglumetacin diphosphate or oral proglumetacin dimaleate. Determined were proglumetacin, 2'-[4-(3-hydroxypropyl)-piperazin-1-yl]-ethyl-(1-p- chlorobenzoyl-5-methoxy-2-methylindol-3-yl)-acetic acid (CR 1015), indometacin and proglumide in plasma. Proglumetacin and CR 1015 were found in plasma only after the i.v. administration. Conversely indometacin and proglumide were found after all administration routes. The areas under the curve of indometacin and of proglumide did not differ significantly after the three treatments, as shown by the analysis of variance.

  17. Oral Administration of Interleukin-10 and Anti-IL-1 Antibody Ameliorates Experimental Intestinal Inflammation.

    PubMed

    Cardani, Diego; Dusio, Giuseppina F; Luchini, Patrizia; Sciarabba, Michele; Solimene, Umberto; Rumio, Cristiano

    2013-08-01

    To elucidate the effects of a solution containing interleukin-10 and anti-IL-1 antibody in modulating experimental intestinal inflammation. Colitis was induced in BALB/c mice by oral administration of dextran sodium sulphate; mice were then treated with interleukin-10 plus anti-IL-1 antibody at low dosage. Transepithelial electrical resistance of isolated mouse colon and colon lengths were evaluated. Cytokines concentrations in organocultures supernatants and plasma samples were evaluated by Enzyme-Linked Immuno Sorbent Assay. Tight junction proteins were evaluated by immunofluorescence, respectively. Oral administration of tested products restores intestinal barrier function during experimental intestinal inflammation in association with reduced levels of proinflammatory cytokines, increased interleukin-10 plasma concentrations and a tight junction architecture restoration. Obtained results may contribute to modelling an interesting strategy for the treatment of patients with inflammatory bowel diseases.

  18. Oral Administration of Interleukin-10 and Anti-IL-1 Antibody Ameliorates Experimental Intestinal Inflammation

    PubMed Central

    Cardani, Diego; Dusio, Giuseppina F; Luchini, Patrizia; Sciarabba, Michele; Solimene, Umberto; Rumio, Cristiano

    2013-01-01

    Background To elucidate the effects of a solution containing interleukin-10 and anti-IL-1 antibody in modulating experimental intestinal inflammation. Methods Colitis was induced in BALB/c mice by oral administration of dextran sodium sulphate; mice were then treated with interleukin-10 plus anti-IL-1 antibody at low dosage. Transepithelial electrical resistance of isolated mouse colon and colon lengths were evaluated. Cytokines concentrations in organocultures supernatants and plasma samples were evaluated by Enzyme-Linked Immuno Sorbent Assay. Tight junction proteins were evaluated by immunofluorescence, respectively. Results Oral administration of tested products restores intestinal barrier function during experimental intestinal inflammation in association with reduced levels of proinflammatory cytokines, increased interleukin-10 plasma concentrations and a tight junction architecture restoration. Conclusion Obtained results may contribute to modelling an interesting strategy for the treatment of patients with inflammatory bowel diseases. PMID:27785242

  19. Oral administration of pharmacologically active substances to squid: a methodological description.

    PubMed

    Berk, William; Teperman, Jake; Walton, Kerry D; Hirata, Kazunari; Sugimori, Mutsuyuki; Llinas, Rodolfo R

    2009-02-01

    The squid giant synapse is a well-defined experimental preparation for the study of ligand-dependant synaptic transmission. Its large size gives direct experimental access to both presynaptic and postsynaptic junctional elements, allowing direct optical, biophysical, and electrophysiological analysis of depolarization-release coupling. However, this important model has not been utilized in pharmacological studies, other than those implementable acutely in the in vitro condition. A method is presented for oral administration of bioactive substances to living squid. Electrophysiological characterization and direct determination of drug absorption into the nervous system demonstrate the administration method described here to be appropriate for pharmacological research.

  20. New immunosuppressive approaches: Oral administration of CD3-specific antibody to treat autoimmunity

    PubMed Central

    Ochi, Hirofumi; Abraham, Michal; Ishikawa, Hiroki; Frenkel, Dan; Yang, Kaiyong; Basso, Alexandre; Wu, Henry; Chen, Mei-Ling; Gandhi, Roopali; Miller, Ariel; Maron, Ruth; Weiner, Howard L.

    2011-01-01

    One of the major goals for the immunotherapy of autoimmune diseases is the induction of regulatory T cells that mediate immunologic tolerance. Parenteral administration of anti-CD3 monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We have found that oral administration of anti-CD3 monoclonal antibody is biologically active in the gut and suppresses experimental autoimmune encephalomyelitis both prior to disease induction and at the height of disease. Oral anti-CD3 antibody acts by inducing a unique type of regulatory T cell characterized by latency-associated peptide (LAP) on its cell surface that functions in vivo and in vitro via TGF-β dependent mechanism. Orally delivered antibody would not have side effects including cytokine release syndromes, thus oral anti-CD3 antibody is clinically applicable for chronic therapy. These findings identify a novel and powerful immunologic approach that is widely applicable for the treatment of human autoimmune conditions. PMID:18804221

  1. Biodistribution, excretion, and toxicity of mesoporous silica nanoparticles after oral administration depend on their shape.

    PubMed

    Li, Linlin; Liu, Tianlong; Fu, Changhui; Tan, Longfei; Meng, Xianwei; Liu, Huiyu

    2015-11-01

    Mesoporous silica nanoparticles (MSNs) have been proven to be effective drug carriers for oral delivery. However, little attention has been paid to their in vivo biodistribution and toxicity after oral administration. The effect of particle shape on their in vivo behavior is also unknown. In this study, we systematically studied the acute toxicity and biodistribution of three types of MSNs with aspect ratios (ARs) of 1, 1.75 and 5 after oral administration. The effect of particle shape as a key physicochemical parameter of MSNs was discussed. With the increase of AR, MSNs showed decreased in vivo biodegradation, systematic absorption and excretion, especially decreased liver distribution and urinal excretion. During the period of urinal excretion, MSNs induced a shape-dependent renal damage including hemorrhage, vascular congestion and renal tubular necrosis. These findings will enrich the knowledge to rationally engineer bionanomaterials, and bring new insights into nanotoxicity. Advances in nanotechnology have resulted in improvement in drug delivery, of which mesoporous silica nanoparticles have been used as carriers for oral drugs. Nonetheless, studies on their absorption, distribution, metabolism, excretion (ADME) and toxicity still need to be performed. In this article, authors evaluated the effects of particle size and shape on in vivo behavior. The findings would shine light on future design of future drug delivery systems. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Development and pharmacokinetic evaluation of erythromycin lipidic formulations for oral administration in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Serdoz, Francesca; Voinovich, Dario; Perissutti, Beatrice; Grabnar, Iztok; Hasa, Dritan; Ballestrazzi, Rodolfo; Coni, Ettore; Pellegrini, Enrico

    2011-08-01

    The aim of this work was to enhance the bioavailability of erythromycin base when administered orally in rainbow trout (Oncorhynchus mykiss). Since erythromycin is normally given in the form of medicated feed, in this study three new types of feed formulation were developed. A self-emulsifying system and two types of double microemulsions (O/W/O) were prepared, characterized and adsorbed on a commercial extruded diet for fish. The emulsified systems were based on saturated polyglycolized glycerides and mono- and diglycerides of medium-chain fatty acids (as oily phase), Tween 80 (as surfactant) and, in the case of double microemulsions, distilled water. The systems differed in percentage composition and for the amount and position of erythromycin in different phases. The three medicated feed were then administered orally by means of a gastric probe to rainbow trout and their relative bioavailability was estimated in comparison with that obtained after oral administration of feed with erythromycin powder. For each medicated feed, 80 fish were tested. Finally, plasma profiles of erythromycin after single administration of medicated feeds were used to predict profiles obtainable by administering once-daily medicated feeds for 7 consecutive days. The results proved that the feeds containing microemulsified erythromycin provided largely superior oral bioavailability and the advantage of obtaining the same efficacy against bacterial infections with a much lower dose of drug. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Improved high-fat diet-induced glucose intolerance by an oral administration of phytosphingosine.

    PubMed

    Murakami, Itsuo; Mitsutake, Susumu; Kobayashi, Naoyuki; Matsuda, Junko; Suzuki, Akemi; Shigyo, Tatsuro; Igarashi, Yasuyuki

    2013-01-01

    We have previously reported that phytoceramide and phytosphingosine (PHS) stimulated the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ) in cells. PPARγ is a therapeutic target for type 2 diabetes. We found in this study that an oral administration of PHS improved diet-induced glucose intolerance in mice. Since PHS is highly expressed in yeast, PHS in fermented foods may improve diabetes.

  4. Oral administration of Trapa taiwanensis Nakai fruit skin extracts conferring hepatoprotection from CCl4-caused injury.

    PubMed

    Wang, Shih-Hao; Kao, Ming-Yuan; Wu, She-Ching; Lo, Dan-Yuan; Wu, Jin-Yi; Chang, Ju-Chun; Chiou, Robin Y-Y

    2011-04-27

    As a folk medicine, the hot-water infusion of water caltrop fruits has been used to protect the liver. In this study, the outer skins of mature water caltrop fruits ( Trapa taiwanensis Nakai) were removed, forced-air-dried, pulverized, and subjected to extraction with hot water, and the infusion was lyophilized and pulverized to prepare a hot water extract of T. taiwanensis (HWETT). HWETT was subjected to assays of α,α-diphenyl-β-picrylhydrazyl scavenging activity, reducing power, Trolox equivalent antioxidant capacity, and antioxidative potency, and all determinations showed HWETT to be a potent antioxidant. As further analyzed with LC-MS, two major HPLC-detected components were elucidated as gallic acid and ellagic acid. Hepatoprotective activity of HWETT was assessed with Sprague-Dawley male rats by oral administration. Six groups of rats (n = 8 for each) were respectively treated, namely, control, CCl(4) (20% CCl(4)/olive oil by 2.0 mL/kg bw), CCl(4) and Silymarin (200 mg/kg bw), CCl(4) and low HWETT dose (12.5 mg/kg bw), CCl(4) and medium HWETT dose (25 mg/kg bw), and CCl(4) and high HWETT dose (125 mg/kg bw). After 8 weeks, all animals were fasted for an additional day and sacrificed to collect blood, liver, and kidney for analyses. Histopathological examinations showed that oral administrations with Silymarin and HWETT were effective in protecting the liver from CCl(4)-caused fatty change. Oral administration of HWETT at 125 mg/kg bw was more effective than was Silymarin at 200 mg/kg bw. On biochemical analyses, oral administrations with HWETT at medium and high doses were effective (p < 0.05) in lowering CCl(4)-caused increases of alanine aminotransferase and aspartate aminotransferase activities. It is of merit to demonstrate HWETT as a potent source of antioxidants and hepatoprotective agents.

  5. Oxycodone physical dependence and its oral self-administration in C57BL/6J mice.

    PubMed

    Enga, Rachel M; Jackson, Asti; Damaj, M Imad; Beardsley, Patrick M

    2016-10-15

    Abuse of prescription opioids, such as oxycodone, has markedly increased in recent decades. While oxycodone's antinociceptive effects have been detailed in several preclinical reports, surprisingly few preclinical reports have elaborated its abuse-related effects. This is particularly surprising given that oxycodone has been in clinical use since 1917. In a novel oral operant self-administration procedure, C57BL/6J mice were trained to self-administer water before introducing increasing concentrations of oxycodone (0.056-1.0mg/ml) under post-prandial conditions during daily, 3-h test sessions. As the concentration of oxycodone increased, the numbers of deliveries first increased, then decreased in an inverted U-shape fashion characteristic of the patterns of other drugs self-administered during limited access conditions. After post-prandial conditions were removed, self-administration at the highest concentration was maintained suggesting oral oxycodone served as a positive reinforcer. In other mice, using a novel regimen of physical dependence, mice were administered increasing doses of oxycodone (9.0-33.0mg/kg, s.c.) over 9 days, challenged with naloxone (0.1-10.0mg/kg, s.c.), and then observed for 30min. Naloxone dose-dependently increased the observed number of somatic signs of withdrawal, suggesting physical dependence of oxycodone was induced under this regimen. This is the first report demonstrating induction of oral operant self-administration of oxycodone and dose-dependent precipitations of oxycodone withdrawal in C57BL/6J mice. The use of oral operant self-administration as well as the novel physical dependence regimen provides useful approaches to further examine the abuse- and dependence-related effects of this highly abused prescription opioid.

  6. Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol

    SciTech Connect

    Maeda, Masayo; Murakami, Manabu; Takegami, Tsutomu; Ota, Takahide

    2008-06-01

    Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonly used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent.

  7. The pharmacokinetics of methimazole after oral administration of carbimazole and methimazole, in hyperthyroid patients.

    PubMed Central

    Skellern, G G; Knight, B I; Low, C K; Alexander, W D; McLarty, D G; Kalk, W J

    1980-01-01

    1 Methimazole plasma concentrations were measured in two groups of hyperthyroid subjects after the oral administration of either carbimazole or methimazole. 2 With the HPLC method it was also possible to measure the concentration of a methimazole metabolite, 3-methyl-2-thiohydantoin in one patient. 3 Large interindividual differences were observed, especially within the carbimazole group. 4 Incomplete absorption of carbimazole could explain particular high apparent volumes of distribution and apparent clearances. PMID:7356900

  8. Laminaria japonica increases plasma exposure of glycyrrhetinic acid following oral administration of Liquorice extract in rats.

    PubMed

    Zhao, Wei-Man; Jiang, Shu-Wen; Chen, Yang; Zhong, Ze-Yu; Wang, Zhong-Jian; Zhang, Mian; Li, Ying; Xu, Ping; Liu, Li; Liu, Xiao-Dong

    2015-07-01

    The present study was designed to investigate the effects of Laminaria japonica (Laminaria) on pharmacokinetics of glycyrrhetinic acid (GA) following oral administration of Liquorice extract in rats. Following oral administrations of single-dose and multi-dose Liquorice extract and Liquorice-Laminaria extract, respectively, plasma samples were obtained at various times and the concentrations of GA, liquiritigenin, and isoliquiritigenin were measured by LC-MS. The effects of Laminaria extract on pharmacokinetics of GA were also investigated, following single-dose and multidose of glycyrrhizic acid (GL). The effects of Laminaria extract on intestinal absorption of GA and GL were studied using the in situ single-pass intestinal perfusion model. The metabolism of GL to GA in the contents of small and large intestines was also studied. The results showed Liquorice-Laminaria extract markedly increased the plasma concentration of GA, accompanied by a shorter Tmax. Similar alteration was observed following multidose administration. However, pharmacokinetics of neither liquiritigenin nor isoliquiritigenin was affected by Laminaria. Similarly, Laminaria markedly increased concentration and decreased Tmax of GA following oral GL were observed. The data from the intestinal perfusion model showed that Laminaria markedly increased GL absorption in duodenum and jejunum, but did not affect the intestinal absorption of GA. It was found that Laminaria enhanced the metabolism of GL to GA in large intestine. In conclusion, Laminaria increased plasma exposures of GA following oral administration of liquorice or GL, which partly resulted from increased intestinal absorption of GL and metabolism of GL to GA in large intestine. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  9. Oral administration of a unicellular green algae, Chlorella vulgaris, prevents stress-induced ulcer.

    PubMed

    Tanaka, K; Yamada, A; Noda, K; Shoyama, Y; Kubo, C; Nomoto, K

    1997-10-01

    Oral administration of dry powder of Chlorella vulgaris (CVP) showed clear prophylactic effects in water-immersion restraint stress-induced and in cysteamine-induced peptic ulcer models, but not in Shay's rat model. Drugs that enhance the protective factors of ulcer formation are effective in the first two models. CVP may prevent ulcer formation mainly through the "immune-brain-gut" axis and protection of gastric mucosa by its own characteristics.

  10. In Vitro Activity and Fecal Concentration of Rifaximin after Oral Administration

    PubMed Central

    Jiang, Zhi-Dong; Ke, Shi; Palazzini, Ernesto; Riopel, Lise; Dupont, Herbert

    2000-01-01

    Rifaximin showed moderately high MICs (the MIC at which 90% of the isolates tested were inhibited = 50 μg/ml) for 145 bacterial enteropathogens from patients with traveler's diarrhea acquired in Mexico during the summers of 1997 and 1998. Rifaximin concentrations in stool the day after oral administration (800 mg daily for 3 days) were high (average, 7,961 μg/g), proving the value of the drug. PMID:10898704

  11. Detection of capecitabine (Xeloda®) on the skin surface after oral administration

    NASA Astrophysics Data System (ADS)

    Huang, Mao-Dong; Fuss, Harald; Lademann, Jürgen; Florek, Stefan; Patzelt, Alexa; Meinke, Martina C.; Jung, Sora

    2016-04-01

    Palmoplantar erythrodysesthesia (PPE), or hand-foot syndrome, is a cutaneous toxicity under various chemotherapeutics contributing to the most frequent side effects in patients treated with capecitabine (Xeloda®). The pathomechanism of PPE has been unclear. Here, the topical detection of capecitabine in the skin after oral application was shown in 10 patients receiving 2500 mg/m2/day capecitabine. Sweat samples were taken prior to and one week after oral administration of capecitabine. Using high-resolution continuum source absorption spectrometry, the changes in concentrations of fluorine, which is an ingredient of capecitabine, were quantified and statistically analyzed. Here, we show an increase in fluorine concentrations from 40±10 ppb (2±0.5 pM) before capecitabine administration to 27.7±11.8 ppm (14.6±6.5 nM) after application, p<0.001. The results show the secretion of capecitabine on the skin surface after oral administration, indicating a local toxic effect as a possible pathomechanism of PPE.

  12. Oral administration of nano-titanium dioxide particle disrupts hepatic metabolic functions in a mouse model.

    PubMed

    Yang, Julin; Luo, Min; Tan, Zhen; Dai, Manyun; Xie, Minzhu; Lin, Jiao; Hua, Huiying; Ma, Qing; Zhao, Jinshun; Liu, Aiming

    2017-01-01

    TiO2 nano-particle (TiO2 NP) is widely used in industrial, household necessities, as well as medicinal products. However, the effect of TiO2 NP on liver metabolic function has not been reported. In this study, after mice were orally administered TiO2 NP (21nm) for 14days, the serum and liver tissues were assayed by biochemical analysis, real time quantitative polymerase chain reaction, western blot and transmission electron microscopy. The serum bilirubin was increased in a dose dependent manner. Deposition of TiO2 NP in hepatocytes and the abnormality of microstructures was observed. Expression of metabolic genes involved in the endogenous and exogenous metabolism was modified, supporting the toxic phenotype. Collectively, oral administration of TiO2 NP (21nm) led to deposition of particles in hepatocytes, mitochondrial edema, and the disturbance of liver metabolism function. These data suggested oral administration disrupts liver metabolic functions, which was more sensitive than regular approaches to detect material hepatotoxicity. This study provided useful information for risk analysis and regulation of TiO2 NPs by administration agencies. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration

    PubMed Central

    Jochemsen, Roeline; Wesselman, J. G. J.; Hermans, J.; van Boxtel, C. J.; Breimer, D. D.

    1983-01-01

    1 Pharmacokinetics and bioavailability of brotizolam after i.v. and oral administration were studied in healthy young volunteers. 2 Kinetic parameters after i.v. administration were: volume of distribution 0.66 ± 0.19 1/kg, total plasma clearance 113 ± 28 ml/min, distribution half-life 11 ± 6 min, and elimination half-life 4.8 ± 1.4 h (mean values ± s.d.). 3 Kinetic parameters after oral administration were: absorption lag-time 8 ± 12 min, absorption half-life 10 ± 11 min, and elimination half-life 5.1 ± 1.2 h (mean values ± s.d.). 4 Bioavailability of brotizolam was 70 ± 22% when calculated by comparing oral and intravenous area-under-curve values, corrected for intra-individual half-life differences. An alternative calculation method, which is relatively independent of large clearance variations, provided a bioavailability of 70 ± 24% (range: 47-117%). PMID:6661374

  14. Effect of oral administration of sodium bicarbonate on surface EMG activity during repeated cycling sprints.

    PubMed

    Matsuura, Ryouta; Arimitsu, Takuma; Kimura, Takehide; Yunoki, Takahiro; Yano, Tokuo

    2007-11-01

    The purpose of this study was to determine the effect of oral administration of sodium bicarbonate (NaHCO3) on surface electromyogram (SEMG) activity from the vastus lateralis (VL) during repeated cycling sprints (RCS). Subjects performed two RCS tests (ten 10-s sprints) interspersed with both 30-s and 360-s recovery periods 1 h after oral administration of either NaHCO3 (RCSAlk) or CaCO3 (RCSPla) in a random counterbalanced order. Recovery periods of 360 s were set before the 5th and 9th sprints. The rate of decrease in plasma HCO3- concentration during RCS was significantly greater in RCSAlk than in RCSPla, but the rates of decline in blood pH during the two RCS tests were similar. There was no difference between change in plasma lactate concentration in RCSAlk and that in RCSPla. Performance during RCSAlk was similar to that during RCSPla. There were no differences in oxygen uptake immediately before each cycling sprint (preVO2) and in SEMG activity between RCSAlk and RCSPla. In conclusion, oral administration of NaHCO3 did not affect SEMG activity from the VL. This suggests that the muscle recruitment strategy during RCS is not determined by only intramuscular pH.

  15. Pharmacokinetics of amoxicillin/clavulanic acid combination after intravenous and oral administration in goats.

    PubMed

    Carceles, C M; Escudero, E; Vicente, M S; Serrano, J M; Carli, S

    1995-12-01

    The intravenous and oral pharmacokinetics of an amoxicillin and clavulanic acid combination (20 mg/kg of sodium amoxicillin and 5 mg/kg of potassium clavulanate) were studied in six goats. After intravenous administration the pharmacokinetics of both drugs could be described by an open two-compartment model. Amoxicillin had a greater distribution volume (0.19 +/- 0.01 l/kg) than clavulanic acid (0.15 +/- 0.01 l/kg), whereas the distribution and elimination constants were higher for the latter, which was eliminated more quickly than amoxicillin. After oral administration of both drugs their pharmacokinetic behaviour was best described by an open one-compartment model with first-order absorption. Elimination half-lives were twice as long after oral (2.15 +/- 0.20 h and 1.94 +/- 0.16 h for amoxicillin and clavulanic acid respectively) than after intravenous administration (1.20 +/- 0.16 h and 0.86 +/- 0.09, respectively). An apparent 'flip-flop' situation was evident in this study. Bioavailability was 27% for amoxicillin and 50% for clavulanic acid.

  16. Pharmacokinetics after oral and intravenous administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Souza, Marcy J; Sanchez-Migallon Guzman, David; Paul-Murphy, Joanne R; Cox, Sherry K

    2012-08-01

    To determine pharmacokinetics after IV and oral administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). 9 healthy adult Hispaniolan Amazon parrots (3 males, 5 females, and 1 of unknown sex). Tramadol (5 mg/kg, IV) was administered to the parrots. Blood samples were collected from -5 to 720 minutes after administration. After a 3-week washout period, tramadol (10 and 30 mg/kg) was orally administered to parrots. Blood samples were collected from -5 to 1,440 minutes after administration. Three formulations of oral suspension (crushed tablets in a commercially available suspension agent, crushed tablets in sterile water, and chemical-grade powder in sterile water) were evaluated. Plasma concentrations of tramadol and its major metabolites were measured via high-performance liquid chromatography. Mean plasma tramadol concentrations were > 100 ng/mL for approximately 2 to 4 hours after IV administration of tramadol. Plasma concentrations after oral administration of tramadol at a dose of 10 mg/kg were < 40 ng/mL for the entire time period, but oral administration at a dose of 30 mg/kg resulted in mean plasma concentrations > 100 ng/mL for approximately 6 hours after administration. Oral administration of the suspension consisting of the chemical-grade powder resulted in higher plasma tramadol concentrations than concentrations obtained after oral administration of the other 2 formulations; however, concentrations differed significantly only at 120 and 240 minutes after administration. Oral administration of tramadol at a dose of 30 mg/kg resulted in plasma concentrations (> 100 ng/mL) that have been associated with analgesia in Hispaniolan Amazon parrots.

  17. Effects of oral administration of furosemide and torsemide in healthy dogs.

    PubMed

    Hori, Yasutomo; Takusagawa, Fumihiko; Ikadai, Hiromi; Uechi, Masami; Hoshi, Fumio; Higuchi, Sei-ichi

    2007-10-01

    To investigate the diuretic effects, tolerability, and adverse effects of furosemide and torsemide after short- and long-term administration in healthy dogs. 8 mixed-breed dogs. In a crossover study, furosemide (2 mg/kg), torsemide (0.2 mg/kg), or placebo (bifidobacterium [1 mg/kg]) was administered orally to each dog every 12 hours for 14 days. Blood and urine samples were collected before the study (baseline data) and at intervals on the 1st (short-term administration) and 14th day (long-term administration) of treatment for assessment of urine volume and specific gravity and selected clinicopathologic variables including BUN, creatinine, and aldosterone concentrations, and creatinine clearance. Compared with the baseline value, short-term administration of furosemide or torsemide immediately increased urine volume significantly; after long-term administration of either drug, urine specific gravity decreased significantly. Compared with the effect of placebo, the 24-hour urine volume was significantly increased after short-term administra-tion of furosemide or torsemide. In addition, it was significantly increased after long-term administration of torsemide, compared with that of short-term administration. Long-term administration of furosemide or torsemide increased the BUN and plasma creatinine con-centrations, compared with the baseline value. Compared with the baseline value, plasma aldosterone concentration was significantly increased after long-term administration of either drug and was significantly higher after torsemide treatment than after furosemide treatment. In dogs, diuretic resistance developed after 14 days of furosemide, but not torsemide, administration; however, both loop diuretics were associated with increased BUN and plasma creatinine concentrations, compared with values before treatment.

  18. Improved stability and immunological potential of tetanus toxoid containing surface engineered bilosomes following oral administration.

    PubMed

    Jain, Sanyog; Harde, Harshad; Indulkar, Anura; Agrawal, Ashish Kumar

    2014-02-01

    The present study was designed with the objective to investigate the stability and potential of glucomannan-modified bilosomes (GM-bilosomes) in eliciting immune response following oral administration. GM-bilosomes exhibited desired quality attributes simultaneously maintaining the chemical and conformation stability of the tetanus toxoid (TT) entrapped in to freeze dried formulations. The GM-bilosomes exhibited excellent stability in different simulated biological fluids and sustained release profile up to 24 h. GM-bilosomes elicited significantly higher (P<0.05) systemic immune response (serum IgG level) as compared to bilosomes, niosomes and alum adsorbed TT administered through oral route. More importantly, GM-bilosomes were found capable of inducing mucosal immune response, i.e. sIgA titre in salivary and intestinal secretions as well as cell mediated immune response (IL-2 and IFN-γ levels in spleen homogenate) which was not induced by i.m. TT, the conventional route of immunization. Conclusively, GM-bilosomes could be considered as a promising carrier and adjuvant system for oral mucosal immunization. This team reports on the development and effects of a glucomannan-modified bilosome as an oral vaccine vector, using tetanus toxoid in the experiments. These GM-bilosomes not only elicited significantly higher systemic immune response as compared to bilosomes, niosomes and alum adsorbed orally administered TT, but also demonstrated mucosal immune response induction as well as cell mediated immune responses, which were not induced by the conventional route of immunization. © 2014.

  19. Plasma and milk kinetics of eprinomectin following topical or oral administration to lactating Chinese Holstein cows.

    PubMed

    Wen, Huiqiang; Pan, Baoliang; Wang, Yuwan; Wang, Fangfei; Yang, Zhenzhong; Wang, Ming

    2010-11-24

    Chinese Holstein, bred by mating the Holstein-Friesian to Chinese Yellow Cattle, is a major dairy cattle breed in China. Eprinomectin is widely used in the treatment of nematode and ectoparasite infections in lactating cattle. The pharmacokinetics of eprinomectin in the plasma and milk were determined in Chinese Holstein cows following topical (at 0.5 mg kg(-1)) or oral (at 0.2 mg kg(-1)) administration. For topical administration, the concentrations of eprinomectin in plasma reached peak values (C(max)) of 16.16 ± 6.02 ng ml(-1) at 3.20 ± 1.30 days (T(max)). In milk, the C(max) values of 2.28 ± 0.85 ng ml(-1) were obtained at 3.48 ± 0.65 days. The MRT values were 5.00 ± 0.96 days for plasma and 4.65 ± 0.60 days for milk. The AUC values were 91.00 ± 25.32 ng d ml(-1) for plasma and 10.53 ± 1.55 ng d ml(-1) for milk. The ratio of AUC milk/plasma was 0.124 ± 0.041. Significant differences were found in C(max) and AUC of eprinomectin in plasma between Chinese Holstein and Prim Holstein following topical administration. It was probably due to the lower storage of body fat in Chinese Holstein than in Prim Holstein. For oral administration, the concentrations of eprinomectin reach peak values of 30.02 ± 5.73 ng ml(-1) at 1.60 ± 0.55 days in plasma and 3.14 ± 0.88 ng ml(-1) at 1.40 ± 0.27 days in milk. The MRT values for plasma and milk were 3.00 ± 0.46 and 3.18 ± 0.55 days, respectively. The AUC values were 98.46 ± 24.75 ng d ml(-1) for plasma and 10.42 ± 4.22 ng d ml(-1) for milk. The ratio of AUC milk/plasma was 0.104 ± 0.022. Compared with the topical administration, a significantly shorter MRT of eprinomectin in plasma was obtained following oral administration, which would shorten residue time of this compound in faeces and reduce its ecotoxicological effect. The low exposure of eprinomectin in milk would favor the use of eprinomectin in lactating Chinese Holstein for topical or oral administration. Copyright © 2010 Elsevier B.V. All rights

  20. Antinociceptive effects after oral administration of tramadol hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Sanchez-Migallon Guzman, David; Souza, Marcy J; Braun, Jana M; Cox, Sherry K; Keuler, Nicholas S; Paul-Murphy, Joanne R

    2012-08-01

    To evaluate antinociceptive effects on thermal thresholds after oral administration of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). Animals-15 healthy adult Hispaniolan Amazon parrots. 2 crossover experiments were conducted. In the first experiment, 15 parrots received 3 treatments (tramadol at 2 doses [10 and 20 mg/kg] and a control suspension) administered orally. In the second experiment, 11 parrots received 2 treatments (tramadol hydrochloride [30 mg/kg] and a control suspension) administered orally. Baseline thermal foot withdrawal threshold was measured 1 hour before drug or control suspension administration; thermal foot withdrawal threshold was measured after administration at 0.5, 1.5, 3, and 6 hours (both experiments) and also at 9 hours (second experiment only). For the first experiment, there were no overall effects of treatment, hour, period, or any interactions. For the second experiment, there was an overall effect of treatment, with a significant difference between tramadol hydrochloride and control suspension (mean change from baseline, 2.00° and -0.09°C, respectively). There also was a significant change from baseline for tramadol hydrochloride at 0.5, 1.5, and 6 hours after administration but not at 3 or 9 hours after administration. Tramadol at a dose of 30 mg/kg, PO, induced thermal antinociception in Hispaniolan Amazon parrots. This dose was necessary for induction of significant and sustained analgesic effects, with duration of action up to 6 hours. Further studies with other types of noxious stimulation, dosages, and intervals are needed to fully evaluate the analgesic effects of tramadol hydrochloride in psittacines.

  1. Oral self-administration of buprenorphine in the diet for analgesia in mice.

    PubMed

    Molina-Cimadevila, M J; Segura, S; Merino, C; Ruiz-Reig, N; Andrés, B; de Madaria, E

    2014-07-01

    Postsurgical oral self-administration of analgesics in rodents is an interesting technique of providing analgesia, avoiding the negative effects of manipulation. Several strategies, using gelatin or nutella, have already been described. However, rodents require some habituation period to reach a good intake because of their neophobic behavior. The current study aimed to explore whether buprenorphine when mixed with an extruded diet offers a potential treatment option in the pain management of mice using a triple approach: by measuring the spontaneous intake in healthy animals; by using the hot-plate test; and finally by assessing the drug's ability to provide postoperative analgesia in a surgical intervention of moderate severity (intra-utero electroporation). Mice consumed during 20 hours, similar amounts of extruded diet alone, mixed with glucosaline, and mixed with buprenorphine (0.03 mg per pellet) or meloxicam (0.25 mg per pellet) both of which were diluted in glucosaline, showing that no neophobia was associated with these administrations. Relative increase from baseline latency (% maximal possible effect) in the hot-plate test at 20 h of administration was significantly higher for oral buprenorphine in diet 0.03 mg/pellet, and diet 0.15 mg/pellet, compared with placebo and no differences were found between those oral administrations and subcutaneous buprenorphine 0.1 mg/kg measured 3 h later. The treatment was also effective in attenuating the reductions in food consumption and body weight that occur after surgery. These data suggest that providing buprenorphine with the diet is a feasible and effective way of self-administration of analgesia in mice and does not cause neophobia and may easily contribute to the refinement of surgical procedures.

  2. Role of ethanol-derived acetaldehyde in operant oral self-administration of ethanol in rats.

    PubMed

    Peana, Alessandra T; Porcheddu, Valeria; Bennardini, Federico; Carta, Antonio; Rosas, Michela; Acquas, Elio

    2015-12-01

    The role of ethanol-derived acetaldehyde has not been examined yet on performance in a model of operant oral self-administration. However, previous studies reported that an acetaldehyde-sequestering agent, D-penicillamine (DP) and an inhibitor of catalase-mediated acetaldehyde production, 3-amino-1,2,4-triazole (3-AT) reduce voluntary ethanol consumption. The aim of our investigation was to evaluate the effects of DP and 3-AT on acquisition and maintenance of oral operant ethanol self-administration. Using operant chambers, rats learned to nose poke in order to receive ethanol solution (5-10 % v/v) under an FR1 schedule of reinforcement in which discrete light and tone cues were presented during ethanol delivery. DP and 3-AT impair the acquisition of ethanol self-administration, whereas its maintenance is not affected neither by drug given alone for both 10 or 5 % ethanol nor by drugs association for 5 % ethanol. Moreover, when the concentration of ethanol was diminished from 10 to 5 %, rats increased the rate of self-administration behaviour. These findings suggest that brain acetaldehyde plays a critical role during acquisition of operant self-administration in ethanol-naïve rats. In contrast, during the maintenance phase, acetaldehyde could contribute to ethanol self-administration by a combined mechanism: On one hand, its lack (by DP or 3-AT) might result in further ethanol-seeking and taking and, on the other, inhibition of ethanol metabolism (by 3-AT) might release an action of the un-metabolised fraction of ethanol that does not overall result in compromising maintenance of ethanol self-administration.

  3. Pharmacokinetics of meloxicam after intravenous, intramuscular, and oral administration of a single dose to Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Molter, Christine M; Court, Michael H; Cole, Gretchen A; Gagnon, David J; Hazarika, Suwagmani; Paul-Murphy, Joanne R

    2013-03-01

    To compare pharmacokinetics after IV, IM, and oral administration of a single dose of meloxicam to Hispaniolan Amazon parrots (Amazona ventralis). 11 healthy parrots. Cohorts of 8 of the 11 birds comprised 3 experimental groups for a crossover study. Pharmacokinetics were determined from plasma concentrations measured via high-performance liquid chromatography after IV, IM, and oral administration of meloxicam at a dose of 1 mg/kg. Initial mean ± SD plasma concentration of 17.3 ± 9.0 μg/mL was measured 5 minutes after IV administration, whereas peak mean concentration was 9.3 ± 1.8 μg/mL 15 minutes after IM administration. At 12 hours after administration, mean plasma concentrations for IV (3.7 ± 2.5 μg/mL) and IM (3.5 ± 2.2 μg/mL) administration were similar. Peak mean plasma concentration (3.5 ± 1.2 μg/mL) was detected 6 hours after oral administration. Absolute systemic bioavailability of meloxicam after IM administration was 100% but was lower after oral administration (range, 49% to 75%). Elimination half-lives after IV, IM, and oral administration were similar (15.9 ± 4.4 hours, 15.1 ± 7.7 hours, and 15.8 ± 8.6 hours, respectively). Pharmacokinetic data may provide useful information for use of meloxicam in Hispaniolan Amazon parrots. A mean plasma concentration of 3.5 μg/mL would be expected to provide analgesia in Hispaniolan Amazon parrots; however, individual variation may result in some birds having low plasma meloxicam concentrations after IV, IM, or oral administration. After oral administration, meloxicam concentration slowly reached the target plasma concentration, but that concentration was not sustained in most birds.

  4. 20 CFR 404.948 - Deciding a case without an oral hearing before an administrative law judge.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ....948 Deciding a case without an oral hearing before an administrative law judge. (a) Decision wholly... is based. (b) Parties do not wish to appear. (1) The administrative law judge may decide a case on... the administrative law judge must be based on this record. (c) Case remanded for a revised...

  5. 20 CFR 416.1448 - Deciding a case without an oral hearing before an administrative law judge.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... § 416.1448 Deciding a case without an oral hearing before an administrative law judge. (a) Decision... the administrative law judge must be based on this record. (c) Case remanded for a revised determination. (1) The administrative law judge may remand a case to the appropriate component of our office for...

  6. Appearance and reappearance of mutagens in urine from rats after oral administration of direct brown 95, due to coprophagy.

    PubMed

    Bos, R P; Koopman, J P; Theuws, J L; Kennis, H M; Henderson, P T

    1986-04-01

    Rats treated orally with direct brown 95, a benzidine-based dye, widely used in dyeing of textiles, plastics, paper and other materials, showed 2 peaks of excretion of mutagenic products in urine, one between 6 h and 18 h after administration and one about 30 h later. Prevention of coprophagy by fitting neck collars resulted in the disappearance of the second peak. Oral administration of carminic acid resulted in a biphasic excretion of this dye in the feces, due to coprophagy. The excretion pattern of mutagens in urine after administration of direct brown 95 corresponds with the excretion pattern in the feces of orally administered carminic acid.

  7. Monitoring the Level of 14C-Labelled Selegiline Following Oral Administration

    PubMed Central

    Kalász, Huba; Tekes, Kornélia; Faigl, Erzsébet B.; Pöstényi, Zita; Berekméri, Eszter; Karvaly, Gellért; Adeghate, Ernest

    2017-01-01

    Background: Selegiline [(-)-deprenyl] is widely used for the treatment of Parkinson’s disease in humans. Objective: Time-dependence of tissue distribution of selegiline following per os administration to rats. Method: Oral administration of radiolabeled selegiline to rats resulted in a pattern of tissue distribution similar to that following intraperitoneal injection. Analyses were done using both reversed-phase HPLC and also by counting radioactivity in various body compartments of rats. Results: As a consequence of oral administration of 30 mg/kg of selegiline, its level in the stomach was extremely high (179.57 µg/g tissue through 54.67 µg/g at 15 min to 120 min), that is one magnitude higher than that in the serum level. High selegiline concentrations were also detected in the lacrimal glands (7.45 µg/g), kidneys (6.87 µg/g), livers (6.01 µg/g) and lungs (3.47 µg/g) after 30 minutes of application, which were higher than after intraperitoneal injections. Conclusion: The relatively high tissue levels remained for 120 min monitoring. Selegiline levels in the brain (1.69 µg/g) and in the testes (1.88 µg/g) were also considerably higher than following intraperitoneal administration during the entire period of observation (15 to 120 min). PMID:28567124

  8. Bioavailability and pharmacokinetic profile of levofloxacin following intravenous, intramuscular and oral administration in turkeys.

    PubMed

    Aboubakr, M; Uney, K; Elmas, M

    2014-02-01

    1. The pharmacokinetics and bioavailability of levofloxacin in turkeys were investigated after a single intravenous (IV), intramuscular (IM) and oral (PO) administration of 10 mg/kg body weight. 2. The concentrations of levofloxacin in plasma samples were assayed using a microbiological assay method and pharmacokinetic parameters were calculated by non-compartmental analysis. 3. Following IV administration, the elimination half-life (t0.5(β)), volume of distribution at steady state (Vdss) and total body clearance (Cl) were 4.49 h, 1.31 l/kg and 0.23 l/h/kg, respectively. 4. After single IM and PO administrations at the same dose, levofloxacin was rapidly absorbed as indicated by an absorption half-life (t0.5ab) of 1.02 and 0.76 h, respectively; maximum plasma concentrations (Cmax) of 5.59 and 5.15 μg/ml were obtained at a maximum time (Tmax) of 2 h for both routes and levofloxacin bioavailability (F) was 96.5 h and 79.9% respectively after IM and PO administration. In vitro plasma protein binding of levofloxacin was 24.3%. 5. Based on these pharmacokinetic parameters, a dose of 10 mg/kg body weight given intramuscularly or orally every 24 h in turkeys can maintain effective plasma concentrations with bacterial infections with (minimum inhibitory concentration) MIC90 > 0.1 μg/ml.

  9. Pharmacokinetics of meloxicam in koalas (Phascolarctos cinereus) after intravenous, subcutaneous and oral administration.

    PubMed

    Kimble, B; Black, L A; Li, K M; Valtchev, P; Gilchrist, S; Gillett, A; Higgins, D P; Krockenberger, M B; Govendir, M

    2013-10-01

    The pharmacokinetic profile of meloxicam in clinically healthy koalas (n = 15) was investigated. Single doses of meloxicam were administered intravenously (i.v.) (0.4 mg/kg; n = 5), subcutaneously (s.c.) (0.2 mg/kg; n = 1) or orally (0.2 mg/kg; n = 3), and multiple doses were administered to two groups of koalas via the oral or s.c. routes (n = 3 for both routes) with a loading dose of 0.2 mg/kg for day 1 followed by 0.1 mg/kg s.i.d for a further 3 days. Plasma meloxicam concentrations were quantified by high-performance liquid chromatography. Following i.v. administration, meloxicam exhibited a rapid clearance (CL) of 0.44 ± 0.20 (SD) L/h/kg, a volume of distribution at terminal phase (Vz ) of 0.72 ± 0.22 L/kg and a volume of distribution at steady state (Vss ) of 0.22 ± 0.12 L/kg. Median plasma terminal half-life (t(1/2)) was 1.19 h (range 0.71-1.62 h). Following oral administration either from single or repeated doses, only maximum peak plasma concentration (C(max) 0.013 ± 0.001 and 0.014 ± 0.001 μg/mL, respectively) was measurable [limit of quantitation (LOQ) >0.01 μg/mL] between 4-8 h. Oral bioavailability was negligible in koalas. Plasma protein binding of meloxicam was ~98%. Three meloxicam metabolites were detected in plasma with one identified as the 5-hydroxy methyl derivative. This study demonstrated that koalas exhibited rapid CL and extremely poor oral bioavailability compared with other eutherian species. Accordingly, the currently recommended dose regimen of meloxicam for this species appears inadequate. © 2013 John Wiley & Sons Ltd.

  10. The mode of oral bovine lactoferrin administration influences mucosal and systemic immune responses in mice.

    PubMed

    Sfeir, Rose Mary; Dubarry, Michel; Boyaka, Prosper N; Rautureau, Michèle; Tomé, Daniel

    2004-02-01

    Food protein intake interacts with the immune system. In earlier nutritional and immunological studies, nutrients, particularly milk whey proteins, were generally administered in soluble form and by gavage. However, orogastric intubation does not represent a natural way of ingesting nutrients such as lactoferrin (Lf). We examined how different modes of oral administration of Lf could affect the regulatory effect of this molecule on intestinal and systemic immune responses. Groups of 10 female BALB/c mice were administered Lf daily for 6 wk. To address the influence of the oral modes of administration, mice were given Lf either in solution, by gastric intubation or in the drinking water, or as a powder, by buccal deposition or in the diet. Mucosal and systemic immune responses, including specific immunoglobulin (Ig) secretion, cell proliferation, and cytokine production, were analyzed and compared with those of naïve mice given water under the same conditions or positive control mice that were administered Lf by i.m. injection. The addition of Lf to the drinking water had no visible effect on the immune status. Gastric intubation, single buccal doses, and continuous doses of Lf in the diet stimulated transient systemic and intestinal antibody responses against Lf. All of these oral modes of Lf exposure biased mucosal and systemic T-cell responses toward Thelper (Th)2-types and elevated IgA production by mucosal cells. However, the less natural gastric intubation also promoted Th1-type responses as evidenced by serum IgG(2a) antibodies and the secretion of Th1 cytokine by mucosal and systemic T cells in vitro. Thus, one should carefully consider the oral mode of administration for understanding regulation of immune responses by food proteins such as Lf.

  11. Oral nicotine administration decreases tumor necrosis factor-alpha expression in fat tissues in obese rats.

    PubMed

    Liu, R H; Kurose, T; Matsukura, S

    2001-01-01

    To investigate the effect of oral nicotine administration on insulin resistance and insulin secretion in an animal model of obesity, Zucker fatty rats were administered nicotine tartrate dihydrate orally through tap water (4.6 mg/kg/d, N group). Plasma nicotine concentrations in N group were 33.67 +/- 10.49 ng/mL. The control (C) group consisted of pair-fed control rats. After 8 weeks of nicotine administration, both groups of rats were administered glucose (2 g/kg) orally in an anesthetized state, and blood was collected for glucose and plasma insulin measurements. The pancreases were isolated and perfused in vitro under pentobarbital anesthesia 1 week after glucose administration. The fat tissues were excised. The levels of tumor necrosis factor (TNF)-alpha protein were assessed using enzyme-linked immunosorbent assay (ELISA) or Western blot analysis. Serum leptin levels were measured using radioimmunoassay (RIA). Blood glucose levels in N group were significantly lower than in C group before and 120 minutes after glucose administration. The insulin secretion from the isolated perfused pancreases of N group appeared to be decreased compared with C group, but there was no significant difference. Histologic examination showed that the mean size of the pancreatic islets in N group was significantly smaller than in C group. The composition ratios of alpha and beta cell mass of the pancreatic islets and fibroelastic tissues were not altered by nicotine administration. Portal TNF-alpha levels were comparable to peripheral levels in both groups. There were no significant differences in peripheral serum levels of TNF-alpha, free fatty acids (FFA), or leptin levels between N and C group. The TNF-alpha levels in visceral fat tissues in N group were significantly lower than those in C group. These results suggest that oral nicotine administration reduces insulin resistance in obese diabetic rats by decreasing production of TNF-alpha in the visceral fat tissues. Decreased

  12. Premedication with midazolam in intellectually disabled dental patients: Intramuscular or oral administration? A retrospective study

    PubMed Central

    Boku, Aiji; Sugimura, Mitsutaka; Oyamaguchi, Aiko; Inoue, Mika; Niwa, Hitoshi

    2016-01-01

    Background The use of midazolam for dental care in patients with intellectual disability is poorly documented. The purpose of this study was to determine which method of premedication is more effective for these patients, 0.15 mg/kg of intramuscular midazolam or 0.3 mg/kg of oral midazolam. Material and Methods This study was designed and implemented as a non-randomized retrospective study. The study population was composed of patients with intellectual disability who required dental treatment under ambulatory general anesthesia from August 2009 through April 2013. Patients were administered 0.15 mg/kg of midazolam intramuscularly (Group IM) or 0.3 mg/kg orally (Group PO). The predictor variable was the method of midazolam administration. The outcome variables measured were Observer’s Assessment of Alertness/ Sedation (OAA/S) Scale scores, the level of cooperation when entering the operation room and for venous cannulation, post-anesthetic agitation and recovery time. Results Midazolam was administered intramuscularly in 23 patients and orally in 21 patients. More patients were successfully sedated with no resistance behavior during venous cannulation in Group PO than in Group IM (p=0.034). There were no differences in demographic data and other variables between the groups. Conclusions The results of this study suggest that oral premedication with 0.3 mg/kg of midazolam is more effective than 0.15 mg/kg of midazolam administered intramuscularly, in terms of patient resistance to venous cannulation. If both oral and intramuscular routes of midazolam are acceptable in intellectually disabled patients, the oral route is recommended. Key words:Premedication, midazolam, intellectual disability. PMID:27031068

  13. Pharmacokinetics of ciprofloxacin in hospitalized geriatric patients: comparison between nasogastric tube and oral administration.

    PubMed

    Lubart, Emily; Berkovitch, Matitiahu; Leibovitz, Arthur; Britzi, Malka; Soback, Stefan; Bukasov, Yury; Segal, Rafael

    2013-10-01

    Drug administration to debilitated elderly patients on enteral feeding through a nasogastric tube (NGT) can modify the pharmacokinetic characteristics of the drug and influence its therapeutic blood concentration. The aim of this study was to evaluate the pharmacokinetics of ciprofloxacin administered through an NGT and to compare it with those of a group of patients receiving the drug orally. Twenty patients in stable clinical and hemodynamic condition from the long-term care ward of a geriatric multilevel hospital were studied. Patients in group 1 (n = 10) had oropharyngeal dysphagia and received food and medications, including ciprofloxacin, by NGT. Group 2 (n = 10) included age- and disease-matched orally fed patients from the same department receiving ciprofloxacin orally. Blood samples for ciprofloxacin concentration were taken at steady state, before drug administration, time 0, and at 1, 2, 3, 4, 6, 8, and 10 hours after drug administration. Ciprofloxacin was measured using liquid chromatography with tandem mass spectrometric detection. The mean daily dose was the same in both the groups: 1000 mg (500 mg twice daily). Pharmacokinetic parameters of ciprofloxacin were not significantly different between the 2 groups: trough concentrations were 1.24 ± 0.95 μg/mL (0.25-3.67 μg/mL) versus 1.30 ± 0.61 μg/mL (0.21-2.36 μg/mL) (P = 0.76); Cmax 3.30 ± 2.16 μg/mL (1.54-8.62 μg/mL) versus 4.24 ± 1.99 μg/mL (2.24-9.02 μg/mL) (P = 0.356); tmax 2.8 ± 1.5 versus 3.1 ± 2.8 hours (P = 0.799); and AUC0-10 20.2 ± 12.1 μg·h·mL (9-51.07 μg·h·mL) versus 24.4 ± 13.0 μg·h·mL (5.57-52.48 μg·h·mL) (P = 0.493), in the oral fed versus NGT, respectively. Ciprofloxacin pharmacokinetic parameters are not significantly different between patients receiving the drug through NGT compared with those who received it orally, and therefore, in frail elderly patients, this route of administration can be considered.

  14. Quantum Dot-Loaded Liposomes to Evaluate the Behavior of Drug Carriers after Oral Administration.

    PubMed

    Tahara, Kohei; Fujimoto, Shiho; Fujii, Fumihiko; Tozuka, Yuichi; Jin, Takashi; Takeuchi, Hirofumi

    2013-01-01

    We have developed submicron-sized liposomes modified with a mucoadhesive polymer to enhance peptide drug absorption after oral administration. Liposomal behavior in the gastrointestinal tract is a critical factor for effective peptide drug delivery. The purpose of this study was to prepare quantum dot- (QD-) loaded submicron-sized liposomes and examine liposomal behavior in the body after oral administration using in vivo fluorescence imaging. Two types of CdSe/CdZnS QDs with different surface properties were used: hydrophobic (unmodified) QDs and hydrophilic QDs with glutathione (GSH) surface modifications. QD- and GSH-QD-loaded liposomes were prepared by a thin film hydration method. Transmission electron microscopy revealed that QDs were embedded in the liposomal lipid bilayer. Conversely, GSH-QDs were present in the inner aqueous phase. Some of the GSH-QDs were electrostatically associated with the lipid membrane of stearylamine-bearing cationic liposomes. QD-loaded liposomes were detected in Caco-2 cells after exposure to the liposomes, and these liposomes were not toxic to the Caco-2 cells. Furthermore, we evaluated the in vivo bioadhesion and intestinal penetration of orally administered QD-loaded liposomes by observing the intestinal segment using confocal laser scanning microscopy.

  15. Quantum Dot-Loaded Liposomes to Evaluate the Behavior of Drug Carriers after Oral Administration

    PubMed Central

    Tahara, Kohei; Fujimoto, Shiho; Fujii, Fumihiko; Tozuka, Yuichi; Jin, Takashi; Takeuchi, Hirofumi

    2013-01-01

    We have developed submicron-sized liposomes modified with a mucoadhesive polymer to enhance peptide drug absorption after oral administration. Liposomal behavior in the gastrointestinal tract is a critical factor for effective peptide drug delivery. The purpose of this study was to prepare quantum dot- (QD-) loaded submicron-sized liposomes and examine liposomal behavior in the body after oral administration using in vivo fluorescence imaging. Two types of CdSe/CdZnS QDs with different surface properties were used: hydrophobic (unmodified) QDs and hydrophilic QDs with glutathione (GSH) surface modifications. QD- and GSH-QD-loaded liposomes were prepared by a thin film hydration method. Transmission electron microscopy revealed that QDs were embedded in the liposomal lipid bilayer. Conversely, GSH-QDs were present in the inner aqueous phase. Some of the GSH-QDs were electrostatically associated with the lipid membrane of stearylamine-bearing cationic liposomes. QD-loaded liposomes were detected in Caco-2 cells after exposure to the liposomes, and these liposomes were not toxic to the Caco-2 cells. Furthermore, we evaluated the in vivo bioadhesion and intestinal penetration of orally administered QD-loaded liposomes by observing the intestinal segment using confocal laser scanning microscopy. PMID:26555997

  16. Prevention of Infectious Mastitis by Oral Administration of Lactobacillus salivarius PS2 During Late Pregnancy.

    PubMed

    Fernández, Leónides; Cárdenas, Nivia; Arroyo, Rebeca; Manzano, Susana; Jiménez, Esther; Martín, Virginia; Rodríguez, Juan Miguel

    2016-03-01

    Previous studies have shown that oral administration of lactobacilli can be an efficient approach to treat lactational infectious mastitis. In this trial, we have evaluated the potential of Lactobacillus salivarius PS2 to prevent this condition when orally administered during late pregnancy to women who had experienced infectious mastitis after previous pregnancies. In this study, 108 pregnant women were randomly assigned to one of 2 groups. Those in the probiotic group (n = 55) ingested daily 9 log10 colony-forming units of L. salivarius PS2 from approximately week 30 of pregnancy until delivery, whereas those in the placebo group (n = 53) received a placebo. The occurrence of mastitis was evaluated during the first 3 months after delivery. Globally, 44 of 108 women (41%) developed mastitis; however, the percentage of women with mastitis in the probiotic group (25% [n = 14]) was significantly lower than in the control group (57% [n = 30]). When mastitis occurred, the milk bacterial counts in the probiotic group were significantly lower than those obtained in the placebo group. Oral administration of L. salivarius PS2 during late pregnancy appears to be an efficient method to prevent infectious mastitis in a susceptible population. NCT01505361. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  17. Pharmacokinetics of enrofloxacin following oral and subcutaneous administration in the common ringtail possum (Pseudocheirus peregrinus).

    PubMed

    Scheelings, T F; Devi, J L; Woodward, A P; Whittem, T

    2015-10-01

    [Correction added on 23 March 2015, after first online publication: Terminal half-life values of enrofloxacin is corrected in the fourth sentence of the abstract] Clinically healthy common ringtail possums (n = 5) received single doses of 10 mg/kg enrofloxacin orally and then 2 weeks later subcutaneously. Serial plasma samples were collected over 24 h for each treatment phase, and enrofloxacin concentrations were determined using a validated HPLC assay. Pharmacokinetic parameters were determined by noncompartmental analysis. Following oral administration, plasma concentrations were of therapeutic relevance (Cmax median 5.45 μg/mL, range 2.98-6.9 μg/mL), with terminal-phase half-life (t½ ) shorter than in other species (median 3.09 h, range 1.79-5.30 h). In contrast, subcutaneous administration of enrofloxacin did not achieve effective plasma concentrations, with plasma concentrations too erratic to fit the noncompartmental model except in one animal. On the basis of the AUC:MIC, enrofloxacin administered at 10 mg/kg orally, but not subcutaneously, is likely to be effective against a range of bacterial species that have been reported in common ringtail possums.

  18. Photodynamic detection of canine mammary gland tumours after oral administration of 5-aminolevulinic acid.

    PubMed

    Osaki, T; Yokoe, I; Ogura, S; Takahashi, K; Murakami, K; Inoue, K; Ishizuka, M; Tanaka, T; Li, L; Sugiyama, A; Azuma, K; Murahata, Y; Tsuka, T; Ito, N; Imagawa, T; Okamoto, Y

    2017-09-01

    5-Aminolevulinic acid (5-ALA) is widely used in photodynamic detection (PDD) and therapy. We evaluated the pharmacokinetics of 5-ALA-induced porphyrins and its effectiveness in PDD in dogs with mammary gland tumours (MGTs) following oral administration. Healthy dogs and those with MGTs (nine each) were orally administered 4 mg kg(-1) 5-ALA. Protoporphyrin IX (PpIX) was not detected in the plasma of healthy dogs but it peaked in dogs with MGT at 2 h after 5-ALA administration. In the PDD study, 16 dogs with MGT were orally administered 40 mg kg(-1) 5-ALA, and MGT but not normal tissue showed red fluorescence after 2-4 h. Photon counts were 6635-63 890 and 59-4011 (median, 19 943 and 919) for MGT and non-tumour tissues, respectively. Cell density strongly correlated with PpIX photon counts of MGT tissue of the dogs (R = 0.743, P = 0.0009). We suggest that 5-ALA-PDD might be an effective diagnostic tool for MGTs. © 2016 John Wiley & Sons Ltd.

  19. Renal, gastrointestinal, and hemostatic effects of oral administration of meloxicam to Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Dijkstra, Bas; Guzman, David Sanchez-Migallon; Gustavsen, Kate; Owens, Sean D; Hass, Carlyle; Kass, Philip H; Paul-Murphy, Joanne R

    2015-04-01

    To investigate renal, gastrointestinal, and hemostatic effects associated with oral administration of multiple doses of meloxicam to healthy Hispaniolan Amazon parrots (Amazona ventralis). 12 Hispaniolan Amazon parrots. Birds were assigned to receive meloxicam oral suspension (1.6 mg/kg, PO, q 12 h) and 2.5 mL of tap water inserted into the crop by use of a gavage tube (n = 8) or the equivalent volume of tap water only (control group; 4) for 15 days. Urine and feces were collected 2 hours after treatment administration each day. Feces were evaluated for occult blood. Results of a CBC and serum biochemical analysis and measured N-acetyl-β-d-glucosaminidase (NAG) activity and whole blood clotting time were evaluated before, during, and after completion of treatments. Results of urinalysis and measured urine NAG activity were also evaluated. Birds treated with meloxicam had a significant increase in number of WBCs and decrease in PCV from before to after treatment. The PCV also decreased significantly, compared with results for the control group; however, WBC count and PCV for all birds remained within reference ranges throughout the study. One parrot treated with meloxicam had a single high value for urine NAG activity. Meloxicam administered orally at the dosage used in this study caused no apparent negative changes in several renal, gastrointestinal, or hemostatic variables in healthy Hispaniolan Amazon parrots. Additional studies to evaluate adverse effects of NSAIDs in birds will be needed.

  20. Dose-proportional pharmacokinetics of risedronate on single-dose oral administration to healthy volunteers.

    PubMed

    Mitchell, D Y; Eusebio, R A; Sacco-Gibson, N A; Pallone, K A; Kelly, S C; Nesbitt, J D; Brezovic, C P; Thompson, G A; Powell, J H

    2000-03-01

    Risedronate is a pyridinyl bisphosphonate approved for the treatment of Paget's disease (US-FDA) and in development for the treatment and prevention of osteoporosis. This study examined risedronate pharmacokinetics and tolerability after oral administration using a randomized, double-blind, parallel-group design. Healthy male and female volunteers (n = 22-23 subjects per dose) received a single oral dose of 2.5, 5, or 30 mg risedronate. Serum and urine samples were collected for 72 and 672 hours, respectively, and risedronate concentrations were determined by ELISA. Safety was evaluated by monitoring adverse events, clinical laboratory measurements, vital signs, and electrocardiograms. Mean Cmax (0.41, 0.94, and 5.1 ng/mL for 2.5, 5, and 30 mg, respectively), AUC (1.8, 3.9, and 21 ng.h/mL for 2.5, 5, and 30 mg, respectively), and urinary excretion (22, 63, and 260 micrograms for 2.5, 5, and 30 mg, respectively) were dose proportional, and there were no significant differences in tmax or CLR among the three doses. All doses were well tolerated; no serious adverse events occurred, and all but one of the adverse events were mild or moderate in severity. There was no evidence of an acute phase reaction occurring after oral administration of risedronate.

  1. Pharmacokinetics of levofloxacin in Japanese quails (Coturnix japonica) following intravenous and oral administration.

    PubMed

    Aboubakr, M

    2012-01-01

    1. The pharmacokinetics of levofloxacin were investigated in Japanese quails after a single dose of 10 mg/kg BW, given either intravenously or orally. 2. Following intravenous administration, the mean value of distribution at steady state (Vd(ss)), total body clearance (Cl(tot)) and mean residence time (MRT) of levofloxacin were 1·25 l/kg, 0·39 l/h/kg and 2·72 h, respectively. 3. Following oral administration of levofloxacin, the peak plasma concentration (C(max)) was 3·31 µg/ml and was achieved at a maximum time (T(max)) of 2 h. Mean residence time (MRT), mean absorption time (MAT) and bioavailability were 4·26 h, 1·54 h and 69·01%, respectively. In vitro plasma protein binding of levofloxacin was 23·52%. 4. Based on pharmacokinetic and pharmacodynamic integration, an oral dose of 10 mg/kg levofloxacin for every 12 h is recommended for a successful clinical effect in quails.

  2. Effects of the Oral Administration of Mosapride Citrate on Capsule Endoscopy Completion Rate

    PubMed Central

    Ida, Yosuke; Hosoe, Naoki; Imaeda, Hiroyuki; Bessho, Rieko; Ichikawa, Riko; Naganuma, Makoto; Kanai, Takanori; Hibi, Toshifumi

    2012-01-01

    Background/Aims In capsule endoscopy (CE), the capsule does not always reach the cecum within its battery life, which may reduce its diagnostic yield. We evaluated the effect of mosapride citrate, a 5-hydroxytryptamine-4 agonist that increases gastrointestinal motility, on CE completion. Methods In a retrospective study, we performed univariate and multivariate analyses for 232 CE procedures performed at our hospital. To identify factors that affect CE completion, the following data were systematically collected: gender, age, gastric transit time (GTT), nonsteroidal anti-inflammatory drug administration, previous abdominal surgery, hospitalization, use of a polyethylene glycol solution, use of mosapride citrate (10 mg), body mass index (BMI), and total recording time. Results The univariate analysis showed that oral mosapride citrate, GTT, and BMI were associated with improved CE completion. Multivariate analyses showed that oral mosapride citrate (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.01 to 3.91) and GTT (OR, 2.34; 95% CI, 1.13 to 4.87) were significant factors for improving the CE completion. Oral mosapride citrate significantly shortened the GTT and small bowel transit time (SBTT). Conclusions Oral mosapride citrate reduced the GTT and SBTT during CE and improved the CE completion rate. PMID:22844562

  3. Pharmacokinetic-pharmacodynamic integration of moxifloxacin in rabbits after intravenous, intramuscular and oral administration.

    PubMed

    Fernández-Varón, E; Bovaira, M J; Espuny, A; Escudero, E; Vancraeynest, D; Cárceles, C M

    2005-08-01

    The pharmacokinetics of moxifloxacin was studied following intravenous (i.v.), intramuscular (i.m.) and oral dose of 5 mg/kg to healthy white New Zealand rabbits (n = 6). Moxifloxacin concentrations were determined by HPLC assay with fluorescence detection. The moxifloxacin plasma concentration vs. time data after i.v. administration could best be described by a two-compartment open model. The disposition of i.m. and orally administered moxifloxacin was best described by a one-compartment model. The plasma moxifloxacin clearance (Cl) for the i.v route was (mean +/- SD) 0.80 +/- 0.02 L/h.kg. The steady-state volume of distribution (Vss) was 1.95 +/- 0.18 L/kg. The terminal half-life (t(1/2lambdaz)) was (mean +/- SD) 1.84 +/- 0.12, 2.09 +/- 0.05 and 2.15 +/- 0.07 h after i.v., i.m. and oral, respectively. Minimal inhibitory concentration (MIC) assays of moxifloxacin against different strains of S. aureus were performed in order to compute pharmacodynamic surrogate markers. From these data, it is concluded that a 5 mg/kg dose moxifloxacin would be effective by i.m. and oral routes in rabbits against bacterial isolates with MIC < or = 0.06 microg/mL and possibly for MIC < or = 0.12 microg/mL, but in the latter case a higher dose would be required.

  4. Metabolic fate of poly-(lactic-co-glycolic acid)-based curcumin nanoparticles following oral administration

    PubMed Central

    Harigae, Takahiro; Nakagawa, Kiyotaka; Miyazawa, Taiki; Inoue, Nao; Kimura, Fumiko; Ikeda, Ikuo; Miyazawa, Teruo

    2016-01-01

    Purpose Curcumin (CUR), the main polyphenol in turmeric, is poorly absorbed and rapidly metabolized following oral administration, which severely curtails its bioavailability. Poly-(lactic-co-glycolic acid)-based CUR nanoparticles (CUR-NP) have recently been suggested to improve CUR bioavailability, but this has not been fully verified. Specifically, no data are available about curcumin glucuronide (CURG), the major metabolite of CUR found in the plasma following oral administration of CUR-NP. Herein, we investigated the absorption and metabolism of CUR-NP and evaluated whether CUR-NP improves CUR bioavailability. Methods Following oral administration of CUR-NP in rats, we analyzed the plasma and organ distribution of CUR and its metabolites using high-performance liquid chromatography-tandem mass spectrometry. To elucidate the mechanism of increased intestinal absorption of CUR-NP, we prepared mixed micelles comprised of phosphatidylcholine and bile salts and examined the micellar solubility of CUR-NP. Additionally, we investigated the cellular incorporation of the resultant micelles into differentiated Caco-2 human intestinal cells. Results Following in vivo administration of CUR-NP, CUR was effectively absorbed and present mainly as CURG in the plasma which contained significant amounts of the metabolite compared with other organs. Thus, CUR-NP increased intestinal absorption of CUR rather than decreasing metabolic degradation and conversion to other metabolites. In vitro, CUR encapsulated in CUR-NP was solubilized in mixed micelles; however, whether the micelles contained CUR or CUR-NP had little influence on cellular uptake efficiency. Therefore, we suggest that the high solubilization capacity of CUR-NP in mixed micelles, rather than cellular uptake efficiency, explains the high intestinal absorption of CUR-NP in vivo. Conclusion These findings provide a better understanding of the bioavailability of CUR and CUR-NP following oral administration. To improve

  5. Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats.

    PubMed

    Gáll, Zsolt; Vancea, Szende; Szilágyi, Tibor; Gáll, Orsolya; Kolcsár, Melinda

    2015-02-20

    Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox-Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1 mg/kg body weight (bw), 5 mg/kg bw, and 20 mg/kg bw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450 g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography-mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13 h, depending on route of administration--intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01 ± 3.80 ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52 ± 39.45 ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1 mg/kg bw and 5 mg/kg bw was 0.89 ± 0.09 μg/ml and 3.188 ± 0.71 μg/ml, respectively. The median (range) time to reach maximum plasma concentration (t(max)) was 4 (2-8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514 ± 0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC(0-t)) of 0.441 ± 0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Sensitive analysis and simultaneous assessment of pharmacokinetic properties of crocin and crocetin after oral administration in rats.

    PubMed

    Zhang, Yue; Fei, Fei; Zhen, Le; Zhu, Xuanxuan; Wang, Jiankun; Li, Sijia; Geng, Jianliang; Sun, Runbin; Yu, Xiaoyi; Chen, Tingting; Feng, Siqi; Wang, Pei; Yang, Na; Zhu, Yejin; Huang, Jingqiu; Zhao, Yuqing; Aa, Jiye; Wang, Guangji

    2017-02-15

    Crocin and crocetin in rat plasma were simultaneously analysed using ultra-performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS), and method was fully validated. For the first time, levels of both crocin and crocetin in plasma were profiled after oral administration of crocin, and this UPLC-MS/MS approach was applied to evaluate pharmacokinetics and relative bioavailability of crocin and crocetin in rats. It was shown that crocin transformed into crocetin quickly in the gastrointestinal tract, and crocetin was 56-81 fold higher exposed in rat plasma than crocin after oral administration of crocin. A comparison study revealed that an oral administration of equal molar crocin achieved higher exposure of crocetin in rat plasma than that of crocetin. It was suggested that oral administration of crocin has the advantages over crocetin, and crocetin may be the active component potentially responsible for the pharmacological effect of crocin.

  7. Pharmacokinetics of flunixin meglumine in mature swine after intravenous, intramuscular and oral administration

    PubMed Central

    2013-01-01

    Background The purpose of this study was to determine intravenous (IV), intramuscular (IM) and oral (PO) FM PK in mature swine. Appropriate pain management for lameness in swine is a critical control point for veterinarians and producers, but science-based guidance on optimal housing, management and treatment of lameness is deficient. Six mature swine (121–168 kg) were administered an IV, IM, or PO dose of flunixin meglumine at a target dose of 2.2 mg/kg in a cross-over design with a 10 day washout period between treatments. Plasma samples collected up to 48 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. Results No adverse effects were observed with flunixin meglumine administration for all routes. Flunixin meglumine was administered at an actual mean dose of 2.21 mg/kg (range: 2.05-2.48 mg/kg) IV, IM and PO. A mean peak plasma concentration (CMAX) for IM and PO administration was 3748 ng/ml (range: 2749–6004 ng/ml) and 946 ng/ml (range: 554–1593 ng/ml), respectively. TMAX was recorded at 1.00 hour (range: 0.50-2.00 hours) and 0.61 hours (range: 0.17-2.00 hours) after PO and IM administration. Half-life (T ½ λz) for IV, IM and PO administration was 6.29 hours (range: 4.84-8.34 hours), 7.49 hours (range: 5.55-12.98 hours) and 7.08 hours (range: 5.29-9.15 hours) respectively. In comparison, bioavailability (F) for PO administration was 22% (range: 11-44%) compared to IM F at 76% (range: 54-92%). Conclusions The results of the present study suggest that FM oral administration is not the most effective administration route for mature swine when compared to IV and IM. Lower F and Cmax of PO-FM in comparison to IM-FM suggest that PO-FM is less likely to be an effective therapeutic administration route. PMID:23941181

  8. Pharmacokinetics of flunixin meglumine in mature swine after intravenous, intramuscular and oral administration.

    PubMed

    Pairis-Garcia, Monique D; Karriker, Locke A; Johnson, Anna K; Kukanich, Butch; Wulf, Larry; Sander, Suzanne; Millman, Suzanne T; Stalder, Kenneth J; Coetzee, Johann F

    2013-08-13

    The purpose of this study was to determine intravenous (IV), intramuscular (IM) and oral (PO) FM PK in mature swine. Appropriate pain management for lameness in swine is a critical control point for veterinarians and producers, but science-based guidance on optimal housing, management and treatment of lameness is deficient. Six mature swine (121-168 kg) were administered an IV, IM, or PO dose of flunixin meglumine at a target dose of 2.2 mg/kg in a cross-over design with a 10 day washout period between treatments. Plasma samples collected up to 48 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. No adverse effects were observed with flunixin meglumine administration for all routes. Flunixin meglumine was administered at an actual mean dose of 2.21 mg/kg (range: 2.05-2.48 mg/kg) IV, IM and PO. A mean peak plasma concentration (CMAX) for IM and PO administration was 3748 ng/ml (range: 2749-6004 ng/ml) and 946 ng/ml (range: 554-1593 ng/ml), respectively. TMAX was recorded at 1.00 hour (range: 0.50-2.00 hours) and 0.61 hours (range: 0.17-2.00 hours) after PO and IM administration. Half-life (T ½ λz) for IV, IM and PO administration was 6.29 hours (range: 4.84-8.34 hours), 7.49 hours (range: 5.55-12.98 hours) and 7.08 hours (range: 5.29-9.15 hours) respectively. In comparison, bioavailability (F) for PO administration was 22% (range: 11-44%) compared to IM F at 76% (range: 54-92%). The results of the present study suggest that FM oral administration is not the most effective administration route for mature swine when compared to IV and IM. Lower F and Cmax of PO-FM in comparison to IM-FM suggest that PO-FM is less likely to be an effective therapeutic administration route.

  9. Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase.

    PubMed

    Sumi, H; Hamada, H; Nakanishi, K; Hiratani, H

    1990-01-01

    The existence of a potent fibrinolytic enzyme (nattokinase, NK) in the traditional fermented food called 'natto', was reported by us previously. It was confirmed that oral administration of NK (or natto) produced a mild and frequent enhancement of the fibrinolytic activity in the plasma, as indicated by the fibrinolytic parameters, and the production of tissue plasminogen activator. NK capsules were also administered orally to dogs with experimentally induced thrombosis, and lysis of the thrombi was observed by angiography. The results obtained suggest that NK represents a possible drug for use not only in the treatment of embolism but also in the prevention of the disease, since NK has a proven safety and can be massproduced.

  10. Augmentation of protective immune responses against viral infection by oral administration of schizophyllan

    PubMed Central

    Itoh, Wataru

    1997-01-01

    An oral administration of fungal polysaccharide schizophyllan has augmented protective immune responses to Sendai virus infection in mice and the rodshaped DNA virus of Penaeus japonicus (RV-PJ) infection in Kuruma shrimps. When schizophyllan was administered orally at a dose of 50 or 100 mg/kg body weight per day, the survival rates after virus challenge were significantly higher than those of the control groups. High phagocytic activities were observed in the haemocytes of the schizophyllan-fed shrimps.These results suggest that schizophyllan confers effective protection against viral infection by increasing antiviral immune responses, and that it could be used to boost immunity to virus infection in animals or in invertebrates. PMID:18472856

  11. Pharmacokinetics of gallium nitrate after oral administration in adult horses--pilot study.

    PubMed

    Pollina, G F; Zagotto, G; Maritan, P; Iacopetti, I; Busetto, R

    2012-10-01

    Gallium (Ga), a metal in group IIIA of the periodic table, has shown a remarkable activity against bone resorption and could therefore possibly prove useful in the treatment of certain diseases in sport horses, for example navicular disease. The aim of this study was to gain more information concerning the kinetics of Ga after oral administration of gallium nitrate (GaN) in adult horses. Six horses received a single dose of 10 mg/kg of GaN mixed with the food ration. Absorption was slow (T(max) = 10 ± 3 h, T(½abs) = 2 ± 0.8 h), and a C(max) of 26 ± 11 μg/L was achieved. Excretion followed a one-phase elimination model, with a long half-life (T(½el) = 52 ± 14 h). By means of a mathematical model, we estimated that the plasmatic levels should reach 93 μg/L (1.33 μm) at steady state, following the repeated daily administration of 10 mg/kg of GaN. A three times lower concentration has been demonstrated as effective in inhibiting the osteolytic activity of osteoclasts in vitro. The results of this study suggest that the administration of oral GaN at a rate of 10 mg/kg per day may be considered for future clinical studies. © 2011 Blackwell Publishing Ltd.

  12. Creatine Metabolism and Safety Profiles after Six-Week Oral Guanidinoacetic Acid Administration in Healthy Humans

    PubMed Central

    Ostojic, Sergej M.; Niess, Barbara; Stojanovic, Marko; Obrenovic, Milos

    2013-01-01

    Objectives; Guanidinoacetic acid (GAA) is a natural precursor of creatine, yet the potential use of GAA as a nutritional additive for restoring creatine availability in humans has been limited by unclear efficacy and safety after exogenous GAA administration. The present study evaluated the effects of orally administered GAA on serum and urinary GAA, creatine and creatinine concentration, and on the occurrence of adverse events in healthy humans. Methods and Results; Twenty-four healthy volunteers were randomized in a double-blind design to receive either GAA (2.4 grams daily) or placebo (PLA) by oral administration for 6 weeks. Clinical trial registration: www.clinicaltrials.gov, identification number NCT01133899. Serum creatine and creatinine increased significantly from before to after administration in GAA-supplemented participants (P < 0.05). The proportion of participants who reported minor side effects was 58.3% in the GAA group and 45.5% in the placebo group (P = 0.68). A few participants experienced serum creatine levels above 70 µmol/L. Conclusion; Exogenous GAA is metabolized to creatine, resulting in a significant increase of fasting serum creatine after intervention. GAA had an acceptable side-effects profile with a low incidence of biochemical abnormalities. PMID:23329885

  13. Kinetic characteristics and toxic effects of benzalkonium chloride following intravascular and oral administration in rats.

    PubMed

    Xue, Yuying; Hieda, Yoko; Kimura, Kojiro; Takayama, Koji; Fujihara, Junko; Tsujino, Yoshio

    2004-11-05

    Kinetic characteristics and toxic effects of benzalkonium chloride (BZK) following injection via jugular vein (JV), femoral artery (FA) and oral administration (PO) were experimentally investigated using rats. The BZK concentrations in blood and tissues (lung, liver and kidney) were determined by high-performance liquid chromatography with solid phase extraction. Toxic doses of 15 and 250 mg/kg of BZK were used for intravascular (JV and FA) and PO administration, respectively. The fatal effects appeared soon after the dose in JV-rats, while delayed in FA- or PO-rats. The blood BZK concentrations and the elimination half-lives were similar between JV- and FA-rats, while the distribution of BZK in tissues was slightly different. In PO administration, the rats that aspirated BZK into their lungs had some symptoms, while the rats that did not aspirate BZK appeared to be normal. The BZK concentrations in blood and tissues were significantly higher in the aspirated PO-rats. The toxic degree of BZK was correlated with the BZK concentration in orally dosed rats. Lung and kidney had higher BZK concentrations compared to blood or liver, and they could be the target organs of BZK.Keyword: Benzalkonium chloride

  14. A novel protocol for the oral administration of test chemicals to adult zebrafish.

    PubMed

    Zang, Liqing; Morikane, Daizo; Shimada, Yasuhito; Tanaka, Toshio; Nishimura, Norihiro

    2011-12-01

    A novel protocol using gluten as a carrier material was developed to administer chemicals to adult zebrafish, per os (p.o.). To evaluate the capacity of gluten to retain chemicals, we prepared gluten granules containing eight types of chemicals with different Log P(ow) values and immersed them in water. Less than 5% of chemicals were eluted from gluten granules within 5 min, a standard feeding time for zebrafish. Although retention capability was dependent on the hydrophilicity and hydrophobicity of the chemicals, the gluten granules retained 62%-99% of the total amount of chemical, even after immersion in water for 60 min. Vital staining dyes, such as 4-Di-2-Asp and Nile red, administered p.o., were delivered into the gastrointestinal tract where they were digested and secreted. Subsequently, we conducted a pharmacokinetic study of oral administration of felbinac and confirmed that it was successfully delivered into the blood of zebrafish. This indicates that chemicals administered using gluten granules are satisfactorily absorbed from the digestive tract and delivered into the metabolic system. The absorption, distribution, and pharmacokinetics of chemicals given by oral administration were also compared with those of chemicals given by alternative administration routes such as intraperitoneal injection and exposure to chemical solution.

  15. Evaluation of student nurses' perception of preparedness for oral medication administration in clinical practice: a collaborative study.

    PubMed

    Aggar, Christina; Dawson, Sonja

    2014-06-01

    Attainment of oral medication administration skills and competency for student nurses is challenging and medication errors are common. The ability of nurses to master a clinical skill is dependent upon educational instruction and practice. The aim of this study was to evaluate nursing students' perception of preparedness for oral medication administration in two practice environments and determine possible relationship between student demographics and their perceived preparedness for oral medication administration. This was a cross sectional, exploratory study. Eighty-eight second year students from a baccalaureate nursing course from two metropolitan Australian tertiary institutions participated. Student nurses' perception of preparedness for oral medication administration was measured via a self-administered, adapted, and validated questionnaire. The overall mean Total Preparedness Score was 86.2 (range 71-102). There was no significant difference for perceived total preparedness to administer oral medications between the two facilities. Whilst there was no significant relationship established between student demographics and their perceived preparedness to administer oral medications, four single questions related to clinical practice were shown to be significant. Low fidelity simulated teaching environments that incorporate time management and post medication situations, may improve student nurses' perceived preparedness for oral medication administration. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Disposition kinetics of a dipeptide ester prodrug of acyclovir and its metabolites following intravenous and oral administrations in rat.

    PubMed

    Talluri, Ravi S; Gaudana, Ripal; Hariharan, Sudharshan; Jain, Ritesh; Mitra, Ashim K

    2009-01-01

    The objective of this work was to study the disposition kinetics of valine-valine-acyclovir (VVACV), a dipeptide ester prodrug of acyclovir following intravenous and oral administrations in rat. A validated LC-MS/MS analytical method was developed for the analysis VVACV, Valine-Acyclovir (VACV), and Acyclovir (ACV) using a linear Ion Trap Quadrupole. ACV was administered orally for comparison purpose. In the VVACV group, both blood and urine samples and in the ACV group only blood samples were collected. All the samples were analyzed using LC-MS/MS. The LLOQ for ACV, VACV, and VVACV were 10, 10, and 50 ng/ml, respectively. Relevant pharmacokinetic parameters were obtained by non-compartmental analyses of data with WinNonlin. Following i.v. administration of VVACV, AUC(0-inf) (min*µM) values for VVACV, VACV, and ACV were 55.06, 106, and 466.96, respectively. The AUC obtained after oral administration of ACV was 178.8. However, following oral administration of VVACV, AUC(0-inf) values for VACV and ACV were 89.28 and 810.77, respectively. Thus the exposure of ACV obtained following oral administration of VVACV was almost 6-fold higher than ACV. This preclinical pharmacokinetic data revealed that VVACV has certainly improved the oral bioavailability of ACV and is an effective prodrug for oral delivery of ACV.

  17. Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys.

    PubMed

    Czoty, P W; Blough, B E; Fennell, T R; Snyder, R W; Nader, M A

    2016-06-02

    Chronic treatment with the monoamine releaser d-amphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine (PM), to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio (FR) schedule of reinforcement and self-administered cocaine (0.003-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose-response curve, sessions were suspended and PDM was administered (1.0-9.0 mg/kg, p.o., b.i.d.). Cocaine self-administration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was re-determined. Daily PDM treatment decreased cocaine self-administration by 30-90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food-maintained responding in the third monkey and in the fourth subject, fluctuations were observed that were lower in magnitude than effects on cocaine self-administration. Cocaine dose-effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d-amphetamine extend to a more clinically viable pharmacotherapy.

  18. The absorption and metabolism of a single L-menthol oral versus skin administration: Effects on thermogenesis and metabolic rate.

    PubMed

    Valente, Angelica; Carrillo, Andres E; Tzatzarakis, Manolis N; Vakonaki, Elena; Tsatsakis, Aristidis M; Kenny, Glen P; Koutedakis, Yiannis; Jamurtas, Athanasios Z; Flouris, Andreas D

    2015-12-01

    We investigated the absorption and metabolism pharmacokinetics of a single L-menthol oral versus skin administration and the effects on human thermogenesis and metabolic rate. Twenty healthy adults were randomly distributed into oral (capsule) and skin (gel) groups and treated with 10 mg kg(-1) L-menthol (ORALMENT; SKINMENT) or control (lactose capsule: ORALCON; water application: SKINCON) in a random order on two different days. Levels of serum L-menthol increased similarly in ORALMENT and SKINMENT (p > 0.05). L-menthol glucuronidation was greater in ORALMENT than SKINMENT (p < 0.05). Cutaneous vasoconstriction, rectal temperature and body heat storage showed greater increase following SKINMENT compared to ORALMENT and control conditions (p < 0.05). Metabolic rate increased from baseline by 18% in SKINMENT and 10% in ORALMENT and respiratory exchange ratio decreased more in ORALMENT (5.4%) than SKINMENT (4.8%) compared to control conditions (p < 0.05). Levels of plasma adiponectin and leptin as well as heart rate variability were similar to control following either treatment (p > 0.05). Participants reported no cold, shivering, discomfort, stress or skin irritation. We conclude that a single L-menthol skin administration increased thermogenesis and metabolic rate in humans. These effects are minor following L-menthol oral administration probably due to faster glucuronidation and greater blood menthol glucuronide levels.

  19. Pharmacokinetics and Pharmacodynamic Effects of Flunixin after Intravenous, Intramuscular and Oral Administration to Dairy Goats

    PubMed Central

    Königsson, K; Törneke, K; Engeland, IV; Odensvik, K; Kindahl, H

    2003-01-01

    The pharmacokinetics and the prostaglandin (PG) synthesis inhibiting effect of flunixin were determined in 6 Norwegian dairy goats. The dose was 2.2 mg/kg body weight administered by intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) routes using a cross-over design. Plasma flunixin content was analysed by use of liquid chromatography and the PG synthesis was evaluated by measuring plasma 15-ketodihydro-PGF2α by a radioimmuno-assay. Results are presented as median (range). The elimination half-lives (t1/2·λ) were 3.6 (2.0–5.0), 3.4 (2.6–6.8) and 4.3 (3.4–6.1) h for i.v., i.m. and p.o. administration, respectively. Volume of distribution at steady state (Vdss) was 0.35 (0.23–0.41) L/kg and clearance (CL), 110 (60–160) mL/h/kg. The plasma concentrations after oral administration showed a double-peak phenomenon with the two peaks occurring at 0.37 (0.25–1) and 3.5 (2.5–5.0) h, respectively. Both peaks were in the same order of magnitude. Bioavailability was 79 (53–112) and 58 (35%–120)% for i.m. and p.o. administration, respectively. 15-Ketodihydro-PGF2α plasma concentrations decreased after flunixin administration independent of the route of administration. PMID:15074628

  20. Oral administration of antimicrobials increase antimicrobial resistance in E. coli from chicken--a systematic review.

    PubMed

    Simoneit, C; Burow, E; Tenhagen, B-A; Käsbohrer, A

    2015-01-01

    Antimicrobials play an important role in animal and human health care. It was the aim of this systematic review to assess the effects of oral administration of antimicrobials on the development of antimicrobial resistance (AMR) in Escherichia coli (E. coli) from chickens. Moreover, the effects of the administration of more than one antimicrobial and of different dosages were studied. Literature was searched in November 2012 from the electronic databases ISI Web of Science, PubMed, Scopus and a national literature database (DIMDI) as well as the database ProQuest LLC. The search was updated in March 2014. Original studies describing a treatment (A) and a control group of either non-treatment (C) or initial value (0) and determining AMR in E. coli at different sample points (SP) were included. The literature search resulted in 35 full text articles on the topic, seven (20%) of which contained sufficient information on the administered antimicrobial and the impact of treatment on AMR. Most papers described the use of more than one antimicrobial, several dosages, controls (non-treatment or pre-treatment) and measured AMR at different SPs leading to a total of 227 SPs on the impact of the use of antimicrobials on AMR in chickens. 74% of the SPs (168/227) described a higher AMR-rate in E. coli from treated animals than from controls. After the administration of a single antimicrobial, AMR increased at 72% of the SPs. Administration of more than one antimicrobial increased AMR at 82% of the SPs. Higher dosages were associated with similar or higher AMR rates. The limited number of studies for each antimicrobial agent and the high variability in the resistance effect call for more well designed studies on the impact of oral administration on AMR development and spread. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis.

    PubMed

    Mogensen, Stine; Sverrisdóttir, Eva; Sveinsdóttir, Kolbrún; Treldal, Charlotte; Jensen, Kenneth; Jensen, Anders Bonde; Kristensen, Claus Andrup; Jacobsen, Jette; Kreilgaard, Mads; Petersen, Janne; Andersen, Ove

    2017-01-01

    The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5, 10, 25 and 50 mg bupivacaine, respectively, was administered as single dose to 10 healthy individuals, and a lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to five patients with HNC. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the patients with HNC, respectively, after administration. The plasma concentration-time profiles of bupivacaine were fitted to pharmacokinetic models using nonlinear mixed-effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two-compartment distribution model with absorption transit compartments. All the observed plasma concentrations were well below the bupivacaine concentrations (2000-2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was two times higher in HNC patients with oral mucositis grade 1-2 and three times higher in HNC patients with oral mucositis grade 3-4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for five days. The 25-mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every two hours for 16 hr a day, the lozenges can be administered with minimum risk of exceeding the toxic limit.

  2. Oral administration of aflatoxin G₁ induces chronic alveolar inflammation associated with lung tumorigenesis.

    PubMed

    Liu, Chunping; Shen, Haitao; Yi, Li; Shao, Peilu; Soulika, Athena M; Meng, Xinxing; Xing, Lingxiao; Yan, Xia; Zhang, Xianghong

    2015-02-03

    Our previous studies showed oral gavage of aflatoxin G₁ (AFG₁) induced lung adenocarcinoma in NIH mice. We recently found that a single intratracheal administration of AFG₁ caused chronic inflammatory changes in rat alveolar septum. Here, we examine whether oral gavage of AFG₁ induces chronic lung inflammation and how it contributes to carcinogenesis. We evaluated chronic lung inflammatory responses in Balb/c mice after oral gavage of AFG₁ for 1, 3 and 6 months. Inflammatory responses were heightened in the lung alveolar septum, 3 and 6 months after AFG₁ treatment, evidenced by increased macrophages and lymphocytes infiltration, up-regulation of NF-κB and p-STAT3, and cytokines production. High expression levels of superoxide dismutase (SOD-2) and hemoxygenase-1 (HO-1), two established markers of oxidative stress, were detected in alveolar epithelium of AFG₁-treated mice. Promoted alveolar type II cell (AT-II) proliferation in alveolar epithelium and angiogenesis, as well as increased COX-2 expression were also observed in lung tissues of AFG₁-treated mice. Furthermore, we prolonged survival of the mice in the above model for another 6 months to examine the contribution of AFG₁-induced chronic inflammation to lung tumorigenesis. Twelve months later, we observed that AFG₁ induced alveolar epithelial hyperplasia and adenocarcinoma in Balb/c mice. Up-regulation of NF-κB, p-STAT3, and COX-2 was also induced in lung adenocarcinoma, thus establishing a link between AFG₁-induced chronic inflammation and lung tumorigenesis. This is the first study to show that oral administration of AFG₁ could induce chronic lung inflammation, which may provide a pro-tumor microenvironment to contribute to lung tumorigenesis.

  3. Toxicokinetics of the ciguatoxin P-CTX-1 in rats after intraperitoneal or oral administration.

    PubMed

    Bottein, Marie-Yasmine Dechraoui; Wang, Zhihong; Ramsdell, John S

    2011-06-18

    Ciguatoxins are voltage-gated selective algal toxins responsible for ciguatera fish poisoning. In this study we evaluate the toxicokinetics of one of the most common ciguatoxins found in the Pacific, the P-CTX-1, in rat after an oral or intraperitoneal (ip) dose of 0.26 μg/kg body weight. We report levels of ciguatoxin activity assessed over time in blood, urine and feces, and at 4 days in liver, muscle and brain, using the functional in vitro N2A cytotoxicity assay. Following exposure, the ciguatoxin activity exhibited a rapid systemic absorption that was followed by a bi-exponential decline, and data best fit a two-compartment model analysis. Maximum blood concentrations were reached at 1.97 and 0.43 h after the oral and ip dose, respectively. Ciguatoxin elimination from blood was slow with terminal half lives (t(½)β) estimated at 82 h for oral and 112 h for ip dosing. Ciguatoxin activity remained in liver, muscle and brain 96 h after ip and oral administration. While smaller amounts appeared in the urine, the main excretion route was feces, with peak rates reaching > 10 pg P-CTX-1 equivalents/h in both routes of administration. Assay guided fractionation showed the presence in the feces and liver of peaks of activity corresponding to the P-CTX-1 and to other less polar metabolites. In conclusion, biologically active ciguatoxins are detectable in blood, liver, muscle and brain, and continued to be excreted in urine and feces 4 days following exposure. Blood, as well as urine and feces may be useful matrices for low-invasive testing methods for ciguatera clinical cases.

  4. Comparative pharmacokinetics of arctigenin in normal and type 2 diabetic rats after oral and intravenous administration.

    PubMed

    Zeng, Xiao-yan; Dong, Shu; He, Nan-nan; Jiang, Chun-jie; Dai, Yue; Xia, Yu-feng

    2015-09-01

    Arctigenin is the main active ingredient of Fructus Arctii for the treatment of type 2 diabetes. In this study, the pharmacokinetics of arctigenin in normal and type 2 diabetic rats following oral and intravenous administration was investigated. As compared to normal rats, Cmax and AUC(0-10h) values of oral arctigenin in diabetic rats increased by 356.8% and 223.4%, respectively. In contrast, after intravenous injection, the Cmax and AUC(0-10h) values of arctigenin showed no significant difference between diabetic and normal rats. In order to explore how the bioavailability of oral arctigenin increased under diabetic condition, the absorption behavior of arctigenin was evaluated by in situ single-pass intestinal perfusion (SPIP). The results indicated that arctigenin was a substrate of P-glycoprotein (P-gp). The absorption difference of arctigenin in the normal and diabetic rats could be eliminated by the pretreatment of classic P-gp inhibitor verapamil, suggesting that P-gp might be the key factor causing the absorption enhancement of arctigenin in diabetic rats. Further studies revealed that the uptake of rhodamine 123 (Rho123) in diabetic rats was significantly higher, indicating that diabetes mellitus might impair P-gp function. Consistently, a lower mRNA level of P-gp in the intestine of diabetic rats was found. In conclusion, the absorption of arctigenin after oral administration was promoted in diabetic rats, which might be partially attribute to the decreased expression and impaired function of P-gp in intestines. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate.

    PubMed

    Pichlmeier, Uwe; Heuer, Kay-Uwe

    2014-01-01

    Methotrexate (MTX) is recognised as the cornerstone of treatment for rheumatoid arthritis. For some patients, oral MTX demonstrates variable bioavailability, especially at higher doses. Such concerns may be mitigated by subcutaneous (SC) MTX administration. This study investigated the relative bioavailability, safety, and tolerability of MTX administered either by SC injection with a prefilled autoinjector pen (MTX pen) or orally. This single-centre, open-label, randomised, 2-period, 2-sequence, single-dose, crossover study enrolled healthy subjects aged 18 to 55 years into 1 of 4 dose groups (7.5 mg, 15 mg, 22.5 mg, and 30 mg), where they received a single dose of SC MTX and of the oral MTX tablets. Blood samples were collected from subjects predose and at prespecified time points postdose for pharmacokinetic analyses. Adverse events (AEs) were recorded to assess differences in safety and tolerability. Bioavailability, as measured by maximum plasma concentrations (Cmax) and area under the plasma-concentration curves (AUC0-t), was generally higher with the SC MTX pen compared with oral administration for all dose groups. AUC0-t ratios increased with ascending doses; Cmax ratios did not increase. A total of 80 AEs were reported in 35/62 subjects; none were severe. Differences in the safety profiles were related to the route of administration. Single administrations with the MTX pen were well tolerated at the injection site. Single-dose administration with the SC MTX pen resulted in a higher relative bioavailability compared with oral administration. SC MTX pen administration was associated with fewer gastrointestinal AEs than oral MTX.

  6. Clinical pharmacokinetics of norfloxacin-glycine acetate after intravenous and oral administration in pigs.

    PubMed

    Chang, Zhi-Qiang; Oh, Byung-Chol; Kim, Jong-Choon; Jeong, Kyu-Shik; Lee, Myung-Heon; Yun, Hyo-In; Hwang, Mi-Hyun; Park, Seung-Chun

    2007-12-01

    The pharmacokinetics and dosage regimen of norfloxacin-glycine acetate (NFLXGA) was investigated in pigs after a single intravenous (i.v.) or oral (p.o.) administration at a dosage of 7.2 mg/kg body weight. After both i.v. and p.o. administration, plasma drug concentrations were best fitted to an open two-compartment model with a rapid distribution phase. After i.v. administration of NFLXGA, the distribution (t(1/2alpha)) and elimination half-life (t(1/2beta)) were 0.36 +/- 0.07 h and 7.42 +/- 3.55 h, respectively. The volume of distribution of NFLXGA at steady state (Vd(ss)) was 4.66 +/- 1.39 l/kg. After p.o. administration of NFLXGA, the maximal absorption concentration (C(max)) was 0.43 +/- 0.06 microg/ ml at 1.36 +/- 0.39 h (T(max)). The mean absorption (t(1/2ka)) and elimination half-life (t(1/2beta)) of NFLXGA were 0.78 +/- 0.27 h and 7.13 +/- 1.41 h, respectively. The mean systemic bioavailability (F) after p.o. administration was 31.10 +/- 15.16%. We suggest that the optimal dosage calculated from the pharmacokinetic parameters is 5.01 mg/kg per day i.v. or 16.12 mg/kg per day p.o.

  7. Effects of oral administration of metronidazole and doxycycline on olfactory capabilities of explosives detection dogs.

    PubMed

    Jenkins, Eileen K; Lee-Fowler, Tekla M; Angle, T Craig; Behrend, Ellen N; Moore, George E

    2016-08-01

    OBJECTIVE To determine effects of oral administration of metronidazole or doxycycline on olfactory function in explosives detection (ED) dogs. ANIMALS 18 ED dogs. PROCEDURES Metronidazole was administered (25 mg/kg, PO, q 12 h for 10 days); the day prior to drug administration was designated day 0. Odor detection threshold was measured with a standard scent wheel and 3 explosives (ammonium nitrate, trinitrotoluene, and smokeless powder; weight, 1 to 500 mg) on days 0, 5, and 10. Lowest repeatable weight detected was recorded as the detection threshold. There was a 10-day washout period, and doxycycline was administered (5 mg/kg, PO, q 12 h for 10 days) and the testing protocol repeated. Degradation changes in the detection threshold for dogs were assessed. RESULTS Metronidazole administration resulted in degradation of the detection threshold for 2 of 3 explosives (ammonium nitrate and trinitrotoluene). Nine of 18 dogs had a degradation of performance in response to 1 or more explosives (5 dogs had degradation on day 5 or 10 and 4 dogs had degradation on both days 5 and 10). There was no significant degradation during doxycycline administration. CONCLUSIONS AND CLINICAL RELEVANCE Degradation in the ability to detect odors of explosives during metronidazole administration at 25 mg/kg, PO, every 12 hours, indicated a potential risk for use of this drug in ED dogs. Additional studies will be needed to determine whether lower doses would have the same effect. Doxycycline administered at the tested dose appeared to be safe for use in ED dogs.

  8. Metabolites of protoberberine alkaloids in human urine following oral administration of Coptidis Rhizoma decoction.

    PubMed

    Yang, Yihui; Kang, Ning; Xia, Hongjun; Li, Jun; Chen, Lixia; Qiu, Feng

    2010-11-01

    Coptidis Rhizoma has been used as a traditional Chinese herbal medicine to treat typhoid, pharyngolaryngitis, diabetes mellitus, gastroenteritis and secretory diarrhea for more than a thousand years in China. However, there is little information on the IN VIVO chemical constituents of Coptidis Rhizoma following oral administration. In this paper, the alkaloid constituents in urine were studied in humans following oral administration of Coptidis Rhizoma decoction. Using macroporous adsorption resin chromatography, open ODS column chromatography, and preparative high-performance liquid chromatography, twelve protoberberine alkaloid constituents were isolated. Their structures were elucidated by chemical evidence, enzymatic deconjugation and analyses of mass, (1)H-NMR and NOESY spectra. The identified alkaloid constituents include berberine ( P1), groenlandicine 3-O- β-D-glucuronide (M1), dehydrocheilanthifoline 2-O-β-D-glucuronide (M2), thalifendine 10-O-β-D-glucuronide (M3), jatrorrhizine 3-O-β-D-glucuronide (M4), columbamine 2-O-β-D-glucuronide (M5), berberrubine 9-O-β-D-glucuronide (M6), jatrorrhizine 3-O-sulfate (M7), demethyleneberberine 2-O-sulfate (M8), dehydrocorydalmine 10-O-sulfate (M9), 3,10-demethylpalmatine 10-O-sulfate (M10) and 2,3,10-trihydroxyberberine 2-O-sulfate ( M11). No other parent protoberberine alkaloids from Coptidis Rhizoma except for a trace of berberine were found in the urine. These findings suggested that the protoberberine alkaloids, which were absorbed in vivo following oral administration of Coptidis Rhizoma decoction, were mainly conjugated with glucuronic acid or sulfuric acid to form phase II metabolites directly or after biotransformation to phase I metabolites, and finally excreted in urine.

  9. Excretion and metabolism of milnacipran in humans after oral administration of milnacipran hydrochloride.

    PubMed

    Li, Fanying; Chin, Christina; Wangsa, Julie; Ho, John

    2012-09-01

    The pharmacokinetics, excretion, and metabolism of milnacipran were evaluated after oral administration of a 100-mg dose of [¹⁴C]milnacipran hydrochloride to healthy male subjects. The peak plasma concentration of unchanged milnacipran (∼240 ng/ml) was attained at 3.5 h and was lower than the peak plasma concentration of radioactivity (∼679 ng Eq of milnacipran/ml) observed at 4.3 h, indicating substantial metabolism of milnacipran upon oral administration. Milnacipran has two chiral centers and is a racemic mixture of cis isomers: d-milnacipran (1S, 2R) and l-milnacipran (1R, 2S). After oral administration, the radioactivity of almost the entire dose was excreted rapidly in urine (approximately 93% of the dose). Approximately 55% of the dose was excreted in urine as unchanged milnacipran, which contained a slightly higher proportion of d-milnacipran (∼31% of the dose). In addition to the excretion of milnacipran carbamoyl O-glucuronide metabolite in urine (∼19% of the dose), predominantly as the l-milnacipran carbamoyl O-glucuronide metabolite (∼17% of the dose), approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite. No additional metabolites of significant quantity were excreted in urine. Similar plasma concentrations of milnacipran and the l-milnacipran carbamoyl O-glucuronide metabolite were observed after dosing, and the maximum plasma concentration of l-milnacipran carbamoyl O-glucuronide metabolite at 4 h after dosing was 234 ng Eq of milnacipran/ml. Lower plasma concentrations (<25 ng Eq of milnacipran/ml) of N-desethyl milnacipran and d-milnacipran carbamoyl O-glucuronide metabolites were observed.

  10. Phenytoin blood concentrations in hospitalized geriatric patients: oral versus nasogastric feeding tube administration.

    PubMed

    Lubart, Emilia; Berkovitch, Matitiahu; Leibovitz, Arthur; Orly, Dafni; Segal, Refael

    2010-04-01

    Many medications administered to frail geriatric patients are not in a liquid form, but are crushed and dissolved in water before their administration through a nasogastric tube (NGT). Some medications are enteric coated and others are extended release. Only sparse information is available on their pharmacokinetics when administered through NGT. The aim of our study was to evaluate the pharmacokinetics of phenytoin administered through an NGT and to compare these with the pharmacokinetics of a group of patients receiving the drug orally. Twenty patients were studied in a stable clinical condition, from the long-term care ward of the Geriatric Medical Center Shmuel Harofeh. They were consistently treated with phenytoin for the prevention of seizure disorders. Patients in group 1 (n = 12) had oropharyngeal dysphagia and received feeding and medications by NGT. Group 2 (n = 8), included age-matched orally fed patients from the same department, who received phenytoin orally. Blood samples for phenytoin concentration were taken at baseline, time 0, and at 1, 3, 4, 6, and 8 hours postdrug administration; phenytoin was measured using the AxSYM assay. The mean daily dose was not statistically different between the 2 groups: 291 +/- 28 (200-300) mg/d and 300 +/- 53 (200-400) mg/d, in the NGT, and the orally fed group, respectively, in one dose. Pharmacokinetic parameters of phenytoin were not significantly different between the 2 groups; trough concentrations, 1.9 +/- 1.7 (0.5-4.9) versus 2.2 +/- 1.8 (1.0-6.5) microg/mL; Cmax, 6.6 +/- 3.4 (2.5-9.1) versus 7.3 +/- 6.7 (2.7-8.4) microg/mL; tmax, 5.1 +/- 3.1 (3.1-8.2) versus 4.6 +/- 2.7 (2.3-8.4) hours; area under the curve, 52.2 +/- 40.1 (41.1-61.2) versus 62.3 +/- 84.7 (30.2-77.2) microg/h/mL, in the NGT fed versus the oral fed, respectively. Phenytoin pharmacokinetic parameters are not significantly different between patients receiving the drug through NGT as compared with those who received it orally, but the implication

  11. Effects of oral administration of a high-molecular-weight crosslinked polyacrylate in rats.

    PubMed

    Lindenschmidt, R C; Stone, L C; Seymour, J L; Anderson, R L; Forshey, P A; Winrow, M J

    1991-07-01

    Oral feeding studies of a crosslinked, high-molecular-weight polyacrylate polymer (PA) were conducted to (1) characterize the biological effects following exposure to either 0, 300, 1000, or 3000 mg PA/kg/day for 93 days; (2) characterize the fecal and urinary mineral excretion at these same dose levels; and (3) monitor the absorption, distribution, and excretion (ADE) of radiolabeled PA following a single oral exposure. The subchronic study results indicate that dietary intake of up to 3000 mg/kg/day PA had no adverse histopathology, hematology, body weight, or clinical chemistry effects in rats. Dietary exposure to PA did, however, result in an elevation in urinary excretion of sodium and phosphorus, whereas excretion of magnesium, calcium, and potassium was lowered. A more detailed study demonstrated that although the urinary excretion of these minerals was changed, total recovery of the minerals (feces + urine), except for sodium, was not different from that for controls. An increase in sodium excretion was expected since PA was in the form of a sodium salt. The ADE studies following a single oral dose of PA indicate that the majority of dosed PA (91.9%) was excreted in the feces. As expected, a small percentage (approximately 3.5%) was absorbed, possibly metabolized, and excreted. In summary, the oral administration of high levels of PA resulted in (1) no histological, hematological, or clinical chemistry changes; (2) no alteration in the overall mineral excretion (feces + urine) with the exception of sodium; and (3) primarily fecal excretion of orally administered PA.

  12. Experimental study of biological effects of leads and aluminum following oral administration.

    PubMed Central

    Krasovskiĭ, G N; Vasukovich, L Y; Chariev, O G

    1979-01-01

    A wide spectrum of the biological effects of lead and aluminum ions is noted during short-term and long-term oral administration to laboratory animals. The general toxic and gonadotoxic effects of these metals during a short-term experiment appeared to be identical, and the correlation of these effects was preserved during chronic experiments. Lead (0.03 mg/l.) and aluminum (0.5 mg/l.) concentrations in water may be dangerous to the health of the population, and hygienic standards are recommended for inclusion in the standard for drinking water quality. PMID:446457

  13. Oral administration of cyclosporin A for recipients of allogeneic marrow transplants: implications of clinical gut dysfunction.

    PubMed

    Atkinson, K; Biggs, J C; Britton, K; Short, R; Mrongovius, R; Concannon, A; Dodds, A

    1984-02-01

    Cyclosporin A (CyA) was used to minimize graft-versus-host disease (GVHD) in 28 recipients of allogeneic marrow transplants. When given orally, the absorption of CyA was markedly dependent on normal gut function. Patients without gut dysfunction showed normal serum concentration-time curves while those with diarrhoea from any cause (chemo-radiation enteritis, acute GVHD of the gut, infectious enteritis) showed minimal absorption of the drug. These data indicate the desirability of the intravenous administration of CyA during periods of gut dysfunction in marrow transplant recipients.

  14. Immunogenicity and tolerance following HIV-1/HBV plant-based oral vaccine administration.

    PubMed

    Guetard, Denise; Greco, Raffaella; Cervantes Gonzalez, Minerva; Celli, Susanna; Kostrzak, Anna; Langlade-Demoyen, Pierre; Sala, Francesco; Wain-Hobson, Simon; Sala, Monica

    2008-08-18

    Transgenic tobacco plants expressing a HIV-1 polyepitope associated with hepatitis B (HBV) virus-like particles (VLPs) were previously described. It is demonstrated here that oral administration of these transgenic plants to humanized HSB mice to boost DNA-priming can elicit anti-HIV-1 specific CD8+ T cell activation detectable in mesenteric lymph nodes. Nevertheless, a significant regulatory T cell activation was induced in vivo by the vaccination protocols. The balance between tolerance and immunogenicity remains the main concern in the proof of concept of plant-based vaccine.

  15. Pharmacokinetics and bioavailability of cimicifugosides after oral administration of Cimicifuga foetida L. extract to rats.

    PubMed

    Gai, Yun-Yun; Liu, Wan-Hui; Sha, Chun-Jie; Wang, Ying-Lin; Sun, Yan-Tong; Li, Xiao-Jiao; Paul Fawcett, J; Gu, Jing-Kai

    2012-08-30

    Cimicifuga foetida L., a traditional Chinese medicine, has been used as an anti-inflammatory, antipyretic and analgesic remedy. The primary active constituents are believed to be present in the triterpene glycoside fraction. To develop an LC-MS/MS assay for four major cimicifugosides [cimicifugoside H-1 (Cim A), 23-epi-26-deoxyactein (Cim B), cimigenolxyloside (Cim C) and 25-O-acetylcimigenoside (Cim D)] obtained from C. foetida L. and apply it to investigate their pharmacokinetic (PK) properties and bioavailabilities through oral administration of C. foetida L. extract (12.5, 25 and 50mg/kg) and single intravenous (i.v.) doses (5mg/kg) of the individual cimicifugosides in rat. PK parameters were estimated by non-compartmental analysis. All calibration curves showed excellent linear regressions (all r>0.995) within the range of tested concentrations. The intra- and inter-day variations were <15% in terms of RSD. The molar ratio of Cims A, B, C, and D in the extract was 20.7:1.4:2.9:1. PK parameters for Cims A, B, C, and D following oral administration of the extract were respectively: C(max) 4.05-17.69, 90.93-395.7, 407.1-1180 and 21.56-45.09pmol/mL; T(max) 0.46-1.28, 2.00-4.67, 14.67-19.67 and 8.08-14.27h; absolute oral bioavailability (F) 1.86-6.97%, 26.8-48.5%, 238-319% and 32.9-48%. PK parameters after i.v. administration of individual cimicifugosides were respectively: elimination half-life 1.1, 2.5, 5.7 and 4.2h; clearance 15.7, 0.48, 0.24 and 1.13mL/hkg. Systemic exposure to Cims B, C and D following oral administration of the extract was significantly greater than to Cim A despite the predominance of Cim A in the extract. Significantly different clearance and interconversion from Cim A to Cim C probably accounts for the different exposure to the four cimicifugosides. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  16. Oral fluid and plasma 3,4-methylenedioxymethamphetamine (MDMA) and metabolite correlation after controlled oral MDMA administration.

    PubMed

    Desrosiers, Nathalie A; Barnes, Allan J; Hartman, Rebecca L; Scheidweiler, Karl B; Kolbrich-Spargo, Erin A; Gorelick, David A; Goodwin, Robert S; Huestis, Marilyn A

    2013-05-01

    Oral fluid (OF) offers a noninvasive sample collection for drug testing. However, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in OF has not been adequately characterized in comparison to plasma. We administered oral low-dose (1.0 mg/kg) and high-dose (1.6 mg/kg) MDMA to 26 participants and collected simultaneous OF and plasma specimens for up to 143 h after dosing. We compared OF/plasma (OF/P) ratios, time of initial detection (t first), maximal concentrations (C max), time of peak concentrations (t max), time of last detection (t last), clearance, and 3,4-methylenedioxyamphetamine (MDA)-to-MDMA ratios over time. For OF MDMA and MDA, C max was higher, t last was later, and clearance was slower compared to plasma. For OF MDA only, t first was later compared to plasma. Median (range) OF/P ratios were 5.6 (0.1-52.3) for MDMA and 3.7 (0.7-24.3) for MDA. OF and plasma concentrations were weakly but significantly correlated (MDMA: R(2) = 0.438, MDA: R(2) = 0.197, p < 0.0001). Median OF/P ratios were significantly higher following high dose administration: MDMA low = 5.2 (0.1-40.4), high = 6.0 (0.4-52.3, p < 0.05); MDA low = 3.3 (0.7-17.1), high = 4.1 (0.9-24.3, p < 0.001). There was a large inter-subject variation in OF/P ratios. The MDA/MDMA ratios in plasma were higher than those in OF (p < 0.001), and the MDA/MDMA ratios significantly increased over time in OF and plasma. The MDMA and MDA concentrations were higher in OF than in plasma. OF and plasma concentrations were correlated, but large inter-subject variability precludes the estimation of plasma concentrations from OF.

  17. Effects of Repeated Oral Administration of Pazufloxacin Mesylate and Meloxicam on the Antioxidant Status in Rabbits

    PubMed Central

    Khan, Adil Mehraj; Rampal, Satyavan

    2014-01-01

    Prolonged antibiotic and antiinflammatory therapy for complicated infections exposes the body to xenobiotics that can produce several adverse effects for which oxidative damage is the proposed underlying mechanism. In this context, we evaluated the effect of pazufloxacin, a fluoroquinolone antimicrobial, and meloxicam, a nonsteroidal antiinflammatory drug, on antioxidant parameters and lipid peroxidation in rabbits after oral administration for 21 d. Reduced glutathione levels were significantly decreased in rabbits (n = 4 per group) given pazufloxacin, meloxicam, or their combination. In addition, glutathione peroxidase activity was induced in the rabbits treated with pazufloxacin only. Administration of pazufloxacin and meloxicam, as single agents as well as in combination, produced significant lipid peroxidation compared with levels in untreated controls. In conclusion, both pazufloxacin and meloxicam potentially can induce oxidative damage in rabbits. PMID:25199097

  18. Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients.

    PubMed Central

    Dhillon, S; Oxley, J; Richens, A

    1982-01-01

    1 The absorption of single doses of diazepam in six adult epileptic subjects following intravenous, oral and rectal administration were studied in order to evaluate the usefulness of the latter in emergency situations in the adult. 2 Diazepam tablets (Valium, Roche) and rectal solution (Valium solution for intravenous administration) produced similar peak serum concentrations after delays of 15-90 min. 3 Two suppository formulations showed statistically significant differences in absorption characteristics. 4 Serum diazepam levels above 400 ng ml-1 (suggested to be necessary for a satisfactory anticonvulsant effect) were reached in only a few subjects after rectal doses of 10-20 mg of solution, and then usually after a delay of over 2 h. PMID:7059446

  19. [Lanthanides and microanalysis. Effects of oral administration of two lanthanides: ultrastructural and microanalytical study].

    PubMed

    Fehri, E; Ayadi, A; Boubaker, S; Karray, S; Jaafoura, H; El Hili, A; Galle, P; Tekaya, L

    2005-01-01

    The subcellular localization of cerium and lanthanum in the intestinal mucosa was studied after oral administration of cerium chloride or lanthanum chloride or lanthanum chloride followed 30 minutes after of cerium chloride to young adults Wistar rats. Two methods of observation and microanalysis were used. The transmission electron microscopy revealed the presence of dense electron granulations in the lysosmes of the duodenum enterocyte, when these elements were administrated simultaneously. The ion mass microanalysis permits to detect the presence of La and Ce as bright points outlining the intestinal villi. These points correspond to the lysosomes containing the granulations previously described. These granulations are formed by the cerium and the lanthanum associated to the phosphor and forming probably insoluble salts of Ce/La phosphate.

  20. The effects of naltrexone on cadmium-induced increases in oral ethanol self-administration.

    PubMed

    Nation, J R; Horger, B A; Pugh, C K; Bratton, G R; Rowe, L D

    1990-01-01

    Adult male rats were exposed to a standard laboratory diet (N = 20), or an adulterated diet containing 100 ppm added cadmium (N = 20), for 60 days. On Day 61, half the animals from each dietary condition received subcutaneous implants of two 30 mg naltrexone pellets, and the remaining half the animals received identical implants of 30 mg placebo pellets. One week later, animals from groups created by this interaction (Groups Control-Placebo, Control-Naltrexone, Cadmium-Placebo, Cadmium-Naltrexone) were tested in an ethanol self-administration paradigm that presented a 10% ethanol solution (v/v) in both a choice and nonchoice format. The results indicated that cadmium exposure increased the oral self-administration of ethanol in the choice setting where water was offered as an alternative, and the opiate antagonist naltrexone failed to attenuate this effect.

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

    PubMed

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

    2005-01-01

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

  2. Enantiospecific ketoprofen concentrations in plasma after oral and intramuscular administration in growing pigs

    PubMed Central

    2012-01-01

    Background Ketoprofen is a non-steroidal anti-inflammatory drug which has been widely used for domestic animals. Orally administered racemic ketoprofen has been reported to be absorbed well in pigs, and bioavailability was almost complete. The objectives of this study were to analyze R- and S-ketoprofen concentrations in plasma after oral (PO) and intra muscular (IM) routes of administration, and to assess the relative bioavailability of racemic ketoprofen for both enantiomers between those routes of administration in growing pigs. Methods Eleven pigs received racemic ketoprofen at dose rates of 4 mg/kg PO and 3 mg/kg IM in a randomized, crossover design with a 6-day washout period. Enantiomers were separated on a chiral column and their concentrations were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated and relative bioavailability (Frel) was determined for S and R –ketoprofen. Results S-ketoprofen was the predominant enantiomer in pig plasma after administration of the racemic mixture via both routes. The mean (± SD) maximum S-ketoprofen concentration in plasma (7.42 mg/L ± 2.35 in PO and 7.32 mg/L ± 0.75 in IM) was more than twice as high as that of R-ketoprofen (2.55 mg/L ± 0.99 in PO and 3.23 mg/L ± 0.70 in IM), and the terminal half-life was three times longer for S-ketoprofen (3.40 h ± 0.91 in PO and 2.89 h ± 0.85 in IM) than R-ketoprofen (1.1 h ± 0.90 in PO and 0.75 h ± 0.48 in IM). The mean (± SD) relative bioavailability (PO compared to IM) was 83 ± 20% and 63 ± 23% for S-ketoprofen and R-ketoprofen, respectively. Conclusions Although some minor differences were detected in the ketoprofen enantiomer concentrations in plasma after PO and IM administration, they are probably not relevant in clinical use. Thus, the pharmacological effects of racemic ketoprofen should be comparable after intramuscular and oral routes of administration in growing pigs

  3. Enhanced absorption of anthocyanins after oral administration of phytic acid in rats and humans.

    PubMed

    Matsumoto, Hitoshi; Ito, Kyoko; Yonekura, Kumiko; Tsuda, Takanori; Ichiyanagi, Takashi; Hirayama, Masao; Konishi, Tetsuya

    2007-03-21

    Many studies on the bioavailability of polyphenols have been reported. However, the relative urinary excretions of AC are also low, ranging from 0.004% to 0.1%. By contrast, other polyphenols show higher urinary excretion levels. Here, we studied the enhancing effects of phytic acid (IP6) on absorption of blackcurrant anthocyanins (BCAs) in rats and humans. In rats after oral administration of BCAs (as 241 mg of AC/kg body weight) in IP6 (0%, 0.25%, 0.5%, 1%, 2.5%) solution, the ACs recovery in urine was increased dependent on IP6 dose. These results suggest that the IP6 enhances gastrointestinal absorption of ACs. At the further analysis of IP6 enhancement effect in rat, whereas BCAs were normally passed through the stomach and duodenum within 2 h, in IP6 group, after 2-6 h post-administration, stomach and jejunum content's weights were specifically heavy, and large amounts of ACs were also detected in stomach, duodenum, and jejunum. These results suggested that the mixture of BCAs and IP6 reduced the gastrointestinal motility. Prolongation of ACs residue in gastrointestinal tract then caused the enhancing effects of IP6 on absorption of AC. In the human study, each subject was orally administrated a BCA beverage containing BCA concentrate (AC 4 mg/kg body weight), 1% of IP6, and 1% of sodium citrate as a pH stabilizer. Both the plasma level and the urinary excretion of AC were increased as compared to BCA administration without IP6. AC intake with IP6 may increase the bioavailability of AC to the comparative level as other polyphenols. Yet, phytic acid, being a strong chelator of important minerals, contributes to mineral deficiencies. An interference with iron uptake has been reported. Safety tests are therefore necessary before high dose IP6 can be used in foods.

  4. Pharmacokinetics of omeprazole after intravenous and oral administration to rats with liver cirrhosis induced by dimethylnitrosamine.

    PubMed

    Lee, Dae Y; Lee, Inchul; Lee, Myung G

    2007-02-07

    The aim of this study is to report the pharmacokinetics of omeprazole after intravenous (20 mg/kg) and oral (40 mg/kg) administration to rats with liver cirrhosis induced by dimethylnitrosamine (cirrhotic rats) with respect to CYP isozyme changes. The expressions of CYP1A2 and 3A1 decreased in cirrhotic rats and omeprazole is reported to be mainly metabolized via CYP1A1/2, 2D1, and 3A1/2 in male Sprague-Dawley rats. Hence, the pharmacokinetics of omeprazole could be changed in cirrhotic rats. After intravenous administration to cirrhotic rats, the AUC (1180 microg min/ml versus 474 microg min/ml) and CL(NR) (17.4 ml/min/kg versus 42.3 ml/min/kg) of omeprazole were significantly greater and slower, respectively, than the controls. This could be due to decrease in the expressions of CYP1A2 and 3A1 in cirrhotic rats. The significantly slower CL(NR) could be supported by significantly slower in vitro CL(int) for the disappearance of omeprazole from hepatic microsomal study (0.102 ml/min/mg protein versus 0.144 ml/min/mg protein) and slower hepatic blood flow rate in cirrhotic rats. After oral administration to cirrhotic rats, the AUC difference was considerably greater (451% versus 149%) than that after intravenous administration, possibly due to decrease in intestinal first-pass effect of omeprazole in addition to decrease in hepatic metabolism of omeprazole in cirrhotic rats.

  5. [Determination of cinnamic acid and glycyrrhizic acid in rat serum and its pharmacokinetics after oral administration of Dangguisini decoction].

    PubMed

    Gao, Yu-Qin; Wu, Jie; Jiang, Ren-Wang; Zhao, Guo-Ping

    2011-03-01

    To mensurate concentrations and pharmacokinetics of cinnamic acid and glycyrrhizic acid in rats after oral adiministration Dangguisini decoction. To Determine serum concentration of cinnamic acid and glycyrrhizic acid by High-Performance Liquid Chromatography and calculate its parameter of pharmacokinetics in rats after oral administration of Dangguisini decoction via 3P97 software. Parameters of Pharmacokinetics of cinnamic acid and glycyrrhizic acid were Cmax 9.2008 (mg/L), AUC 304.0734 (mg/L) x min and Cmax 51.1330(mg/L), AUC 21476.9688 (mg/L) x min respectively in rats after oral administration of Dangguisini decoction. Absorption of cinnamic acid is quick and its metabolize is quick too, but metabolism of glycyrrhizic acid is oppositely slow in rats after oral administration of Dangguisini decoction.

  6. Oral administration of BCG as an adjuvant to surgical treatment of carcinoma of the bronchus.

    PubMed Central

    Miller, A B; Taylor, H E; Baker, M A; Dodds, D J; Falk, R; Frappier, A; Hill, D P; Jindani, A; Landi, S; Macdonald, A S; Thomas, J W; Wall, C

    1979-01-01

    A controlled clinical trial of the value of bacille Calmette--Guérin (BCG) vaccine given orally to patients with resectable carcinoma of the lung was conducted in 18 centres across Canada. A total of 308 patients were included in the analysis, 155 in the BCG group and 153 in the control group. The two groups were similar at the time of admission to the trial. BCG (120 mg) was given orally at weekly intervals for 1 month, every 2 weeks up to 3 months and then every 3 months until the total duration of therapy was 18 months. Over a 3- to 5-year follow-up period after the operation there was no difference in survival between the two groups, the proportion alive at 2 years being 61% in the BCG group and 58% in the control group. There was also no evidence of differences in the time to the detection of recurrent or metastatic disease or in the distribution of such disease. An analysis of prognostic factors confirmed the poor survival associated with histologically confirmed lymph node involvement. It may be concluded that no favourable effect from the oral administration of BCG was demonstrated. PMID:466592

  7. Liberation of hydrogen from gastric acid following administration of oral magnesium.

    PubMed

    Sack, D A; Stephensen, C B

    1985-12-01

    We are in the process of developing a noninvasive test for gastric acid secretion based on the reaction of orally administered magnesium metal with gastric acid: Mg + 2HCl in equilibrium with MgCl2 + H2. We hypothesized that the hydrogen gas thus evolved could be detected in exhaled air and belches and that the amount of hydrogen released could be related to the amount of acid in the stomach. To validate this hypothesis, we gave magnesium to two groups of young adult volunteers following either betazole stimulation or cimetidine inhibition of acid secretion. In group I we gave subcutaneous betazole and gave magnesium in doses from 10 to 200 mg. In group II we gave oral betazole and used a constant dose of 150 mg of magnesium. In both groups we consistently detected significant increases in breath and belch hydrogen following magnesium in the betazole-stimulated volunteers. This response was blocked by cimetidine. The magnitude of the response was related to the magnesium dose, with 150 mg appearing to induce a maximum response. Administration of oral magnesium up to 200 mg was not associated with any untoward effects. We conclude that magnesium led to the release of hydrogen gas in vivo and that the quantity of hydrogen gas recovered was related to the amount of gastric acid. With further development, this principle might be used to develop a simple noninvasive test for gastric acid secretion.

  8. Gastro-oesophageal function in normal subjects after oral administration of ranitidine.

    PubMed Central

    Wallin, L; Madsen, T; Boesby, S

    1983-01-01

    The aim of the study was to investigate gastro-oesophageal function in normal subjects after oral administration of 150 mg ranitidine as a single dose. The study was designed as a double blind crossover investigation. Ten healthy men, aged 26-49 years (median 29 years) joined the study. A series of oesophageal function tests were performed, starting 90 minutes after oral intake of ranitidine or placebo. Gastro-oesophageal sphincter pressure was measured using a perfused catheter system and a continuous pull-through technique. No changes in sphincter pressure could be demonstrated. Peristaltic amplitude in the body of the oesophagus as well as the duration and velocity of the peristalsis were measured after wet swallows (bolus 5 ml of water). We found no changes in these variables. Intragastric pH was measured and was higher after ranitidine than after placebo (p less than 0.005). Plasma ranitidine concentration did not correlate with intragastric pH. No effect of ranitidine could be demonstrated on the results of a standard acid clearing test. It is concluded that ranitidine, given orally in sufficient doses to suppress gastric acid secretion, does not influence gastro-oesophageal sphincter pressure or peristaltic activity in the oesophagus of normal subjects. PMID:6133814

  9. Pharmacokinetics of tramadol following intravenous and oral administration in male rhesus macaques (Macaca mulatta)

    PubMed Central

    Kelly, Kristi R.; Pypendop, Bruno H.; Christe, Kari L.

    2014-01-01

    Recently, tramadol and its active metabolite, O-desmethyltramadol (M1), have been studied as analgesic agents in various traditional veterinary species (e.g. dogs, cats, etc.). This study explores the pharmacokinetics of tramadol and M1 after intravenous (IV) and oral (PO) administration in rhesus macaques (Macaca mulatta), a nontraditional veterinary species. Rhesus macaques are Old World monkeys that are commonly used in biomedical research. Effects of tramadol administration to monkeys are unknown, and research veterinarians may avoid inclusion of this drug into pain management programs due to this limited knowledge. Four healthy, socially-housed, adult male rhesus macaques (Macaca mulatta) were used in this study. Blood samples were collected prior to, and up to 10 h post tramadol administration. Serum tramadol and M1 were analyzed using liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis was performed. Tramadol clearance was 24.5 (23.4-32.7) mL/min/kg. Terminal half-life of tramadol was 111 (106-127) min IV and 133 (84.9-198) min PO. Bioavailability of tramadol was poor [3.47% (2.14-5.96%)]. Maximum serum concentration of M1 was 2.28 (1.88-2.73) ng/mL IV and 11.2 (9.37-14.9) ng/mL PO. Sedation and pruritus were observed after IV administration (180 words). PMID:25488714

  10. Pharmacokinetics of tramadol following intravenous and oral administration in male rhesus macaques (Macaca mulatta).

    PubMed

    Kelly, K R; Pypendop, B H; Christe, K L

    2015-08-01

    Recently, tramadol and its active metabolite, O-desmethyltramadol (M1), have been studied as analgesic agents in various traditional veterinary species (e.g., dogs, cats, etc.). This study explores the pharmacokinetics of tramadol and M1 after intravenous (IV) and oral (PO) administration in rhesus macaques (Macaca mulatta), a nontraditional veterinary species. Rhesus macaques are Old World monkeys that are commonly used in biomedical research. Effects of tramadol administration to monkeys are unknown, and research veterinarians may avoid inclusion of this drug into pain management programs due to this limited knowledge. Four healthy, socially housed, adult male rhesus macaques (Macaca mulatta) were used in this study. Blood samples were collected prior to, and up to 10 h post-tramadol administration. Serum tramadol and M1 were analyzed using liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis was performed. Tramadol clearance was 24.5 (23.4-32.7) mL/min/kg. Terminal half-life of tramadol was 111 (106-127) min IV and 133 (84.9-198) min PO. Bioavailability of tramadol was poor [3.47% (2.14-5.96%)]. Maximum serum concentration of M1 was 2.28 (1.88-2.73) ng/mL IV and 11.2 (9.37-14.9) ng/mL PO. Sedation and pruritus were observed after IV administration.

  11. Oral administration of Lactobacillus gasseri SBT2055 is effective for preventing influenza in mice.

    PubMed

    Nakayama, Yosuke; Moriya, Tomohiro; Sakai, Fumihiko; Ikeda, Noriko; Shiozaki, Takuya; Hosoya, Tomohiro; Nakagawa, Hisako; Miyazaki, Tadaaki

    2014-04-10

    The Lactobacillus gasseri SBT2055 (LG2055) is a probiotic lactic acid bacterium with properties such as bile tolerance and ability to improve the intestinal environment. In this study, we established that the oral administration of LG2055 exhibits efficacy to protect mice infected with the influenza virus A/PR8. The body weight losses were lower with the LG2055 administration after the PR8 virus infection. At 5 days after the infection, the virus titer was significantly decreased as was the amount of produced IL-6 in the lung tissue, the number of total cells in the bronchoalveolar lavage fluid was reduced by the LG2055 administration. The expression of the Mx1 and Oas1a genes, critical for the viral clearance in the lung tissues was increased by the pre-treatment with LG2055. These findings suggest that the LG2055 administration is effective for the protection against influenza A virus infection by the down-regulation of viral replication through the induction of antiviral genes expression.

  12. Effect of intermittent oral administration of ponazuril on experimental Sarcocystis neurona infection of horses.

    PubMed

    Mackay, Robert J; Tanhauser, Susan T; Gillis, Karen D; Mayhew, Ian G; Kennedy, Tom J

    2008-03-01

    To evaluate the effect of intermittent oral administration of ponazuril on immunoconversion against Sarcocystis neurona in horses inoculated intragastrically with S neurona sporocysts. 20 healthy horses that were seronegative for S neurona-specific IgG. 5 control horses were neither inoculated with sporocysts nor treated. Other horses (5 horses/group) each received 612,500 S neurona sporocysts via nasogastric tube (day 0) and were not treated or were administered ponazuril (20 mg/kg, PO) every 7 days (beginning on day 5) or every 14 days (beginning on day 12) for 12 weeks. Blood and CSF samples were collected on day - 1 and then every 14 days after challenge for western blot assessment of immunoconversion. Clinical signs of equine protozoal myeloencephalitis (EPM) were monitored, and tissues were examined histologically after euthanasia. Sera from all challenged horses yielded positive western blot results within 56 days. Immunoconversion in CSF was detected in only 2 of 5 horses that were treated weekly; all other challenged horses immunoconverted within 84 days. Weekly administration of ponazuril significantly reduced the antibody response against the S neurona 17-kd antigen in CSF. Neurologic signs consistent with EPM did not develop in any group; likewise, histologic examination of CNS tissue did not reveal protozoa or consistent degenerative or inflammatory changes. Administration of ponazuril every 7 days, but not every 14 days, significantly decreased intrathecal anti-S neurona antibody responses in horses inoculated with S neurona sporocysts. Protocols involving intermittent administration of ponazuril may have application in prevention of EPM.

  13. Oral administration of Lactobacillus plantarum lysates attenuates the development of atopic dermatitis lesions in mouse models.

    PubMed

    Kim, Hangeun; Kim, Hye Rim; Kim, Na-Ra; Jeong, Bong Jun; Lee, Jong Suk; Jang, Soojin; Chung, Dae Kyun

    2015-01-01

    Lactobacillus plantarum is a well-documented probiotic that has been used in clinical trials for the regulation of the immune system and treatment of gastrointestinal diseases. In this study, we evaluated the effects of L. plantarum cell lysates on the immune regulation through the in vitro and in vivo studies. L. plantarum lysates were prepared by sonication method, and we observed that the repetition of disruption step increased indicator components within the bacterial lysates. Indicator components might affect TNF-α production. L. plantarum lysates did not induce TNF-α production, while LPS-induced TNF-α production was dramatically inhibited in a sonication-dependent manner in THP-1 cells. Oral administration of L. plantarum lysates effectively attenuated the horny layer formation and decreased epidermal thickening in NC/Nga mice skin. The damage to barrier function after the 8 weeks oral administration was reduced by L. plantarum lysates as compared to that in the atopic dermatitis (AD) mice. Further study revealed that L. plantarum lysates polarized Th1 response via induction of IL-12 and IFN-γ production and inhibition of IL-4 and IgE production in NC/Nga mice. Together, our results suggest that L. plantarum lysates are remarkable material for host homeostasis and it could be used for the treatment of inflammatory diseases.

  14. Excretion of berberine and its metabolites in oral administration in rats.

    PubMed

    Ma, Jing-Yi; Feng, Ru; Tan, Xiang-Shan; Ma, Chao; Shou, Jia-Wen; Fu, Jie; Huang, Min; He, Chi-Yu; Chen, Shuo-Nan; Zhao, Zhen-Xiong; He, Wen-Yi; Wang, Yan; Jiang, Jian-Dong

    2013-11-01

    Berberine (BBR) has been confirmed to show extensive bioactivities for the treatments of diabetes and hypercholesterolemia in clinic. However, there are few pharmacokinetic studies to elucidate the excretions of BBR and its metabolites. Our research studied the excretions of BBR and its metabolites in rats after oral administration (200 mg/kg). Metabolites in bile, urine, and feces were detected by liquid chromatography coupled to ion trap time-of-flight mass spectrometry; meanwhile, a validated liquid chromatography coupled with tandem mass spectrometry method was developed for their quantifications. Sixteen metabolites, including 10 Phase I and six Phase II metabolites were identified and clarified after dosing in vivo. Total recovered rate of BBR was 22.83% (19.07% of prototype and 3.76% of its metabolites) with 9.2 × 10(-6) % in bile (24 h), 0.0939% in urine (48 h), and 22.74% in feces (48 h), respectively. 83% of BBR was excreted as thalifendine (M1) from bile, whereas thalifendine (M1) and berberrubine (M2) were the major metabolites occupying 78% of urine excretion. Most of BBR and its metabolites were found in feces containing 84% of prototype. In summary, we provided excretion profiles of BBR and its metabolites after oral administration in rats in vivo.

  15. Terpenes transfer to milk and cheese after oral administration to sheep fed indoors.

    PubMed

    Poulopoulou, I; Zoidis, E; Massouras, T; Hadjigeorgiou, I

    2012-04-01

    Terpenes have been proposed as potential biomarkers in verifying the diets of grazing animals. A study of the relationships between the intake of terpenes and their presence in animal tissues (blood and milk) as well as in the final product (cheese) was conducted. Eight dairy sheep were divided into two equal groups, representing control (C) and treatment group (T). In T group oral administration of a mixture of terpenes, α-pinene, limonene and β-caryophyllene, was applied over a period of 18 days. Blood and milk samples were collected regularly and terpenes were identified by extraction using petroleum ether and the solid phase micro-extraction (SPME) method, respectively, followed by GC-MS analysis. Cheese was produced, from C and T animals separately, twice during the period of terpenes oral administration. Terpenes contents and chemical properties of the produced cheeses were investigated. Limonene and α-pinene were found in all blood and milk samples of the T group after a lag-phase of 2 days, while β-caryophyllene was detected in few plasma samples and in all milk samples. None of the terpenes was traced in blood and milk of C animals. The contents of cheese, in dosed terpenes, presented a more complicated pattern suggesting terpenes non-credible as biomarkers. We conclude terpenes can be used as biomarkers for authentification of ewes' milk, but further research is required on factors affecting their transfer to dairy products from grazing diets.

  16. Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration.

    PubMed

    Vandenbroucke, V; Bousquet-Melou, A; De Backer, P; Croubels, S

    2008-10-01

    The first aim of the study was to investigate the pharmacokinetics of eight anticoagulant rodenticides (brodifacoum, bromadiolone, chlorophacinone, coumatetralyl, difenacoum, difethialone, flocoumafen and warfarin) in plasma and liver of the mouse after single oral administration. Eight groups of mice dosed orally with a different anticoagulant rodenticide in a dose equal to one-half the lethal dose 50 (LD(50)), were killed at various times up to 21 days after administration. The eight anticoagulant rodenticides were assayed in plasma and liver by an LC-ESI-MS/MS method. Depending on the compound, the limit of quantification was set at 1 or 5 ng/mL in plasma. In liver, the limit of quantification was set at 250 ng/g for coumatetralyl and warfarin and at 100 ng/g for the other compounds. The elimination half-lives in plasma for first-generation rodenticides were shorter than those for second-generation rodenticides. Coumatetralyl, a first-generation product, had a plasma elimination half-life of 0.52 days. Brodifacoum, a second-generation product, showed a plasma elimination half-life of 91.7 days. The elimination half-lives in liver varied from 15.8 days for coumatetralyl to 307.4 days for brodifacoum. The second aim of the study was to illustrate the applicability of the developed method in a clinical case of a dog suspected of rodenticide poisoning.

  17. Oral administration of protease inhibits enterotoxigenic Escherichia coli receptor activity in piglet small intestine.

    PubMed Central

    Mynott, T L; Luke, R K; Chandler, D S

    1996-01-01

    The virulence of enterotoxigenic Escherichia coli (ETEC) is attributed to their ability to adhere via fimbrial adhesins to specific receptors located on the intestinal mucosa. A novel approach to preventing ETEC induced diarrhoea would be to prevent attachment of ETEC to intestine by proteolytically modifying the receptor attachment sites. This study aimed to examine the effect of bromelain, a proteolytic extract obtained from pineapple stems, on ETEC receptor activity in porcine small intestine. Bromelain was administered orally to piglets and K88+ ETEC attachment to small intestine was measured at 50 cm intervals using an enzyme immunoassay. K88+ ETEC attachment to intestinal sections that were not treated with bromelain varied appreciably between sampling sites. Variability in receptor activity along the intestinal surface is though to be caused by the localised effects of endogenous proteases. Oral administration of exogenous protease inhibited K88+ ETEC attachment to pig small intestine in a dose dependent manner (p < 0.05). Attachment of K88+ ETEC was negligible after treatment, resembling the levels of attachment of K88 to piglets of the genetically determined non-adhesive phenotype, which are resistant to K88+ ETEC infection. Serum biochemical analysis and histopathological examination of treated piglets showed no adverse effects of the bromelain treatment. It is concluded that administration of bromelain can inhibit ETEC receptor activity in vivo and may therefore be useful for prevention of K88+ ETEC induced diarrhoea. PMID:8566855

  18. Effect of dronedarone on the pharmacokinetics of carvedilol following oral administration to rats.

    PubMed

    Kim, Min-Soo; Baek, In-Hwan

    2017-09-20

    Dronedarone is a CYP2D6 inhibitor; therefore, it is prudent to exercise caution when concurrently administering CYP2D6-metabolized β-blockers because of a lack of published data on potential drug interactions. The aim of this study was to investigate the effect of dronedarone on the pharmacokinetics of orally administered carvedilol in rats. Twenty male Sprague-Dawley rats were randomly divided into two groups and 10mg/kg carvedilol was administered to the rat with or without dronedarone pretreatment in a parallel design. Blood samples were collected before and after 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, and 24h of drug administration. The plasma concentration of carvedilol was determined using LC-MS/MS. The systemic exposure to carvedilol was significantly increased and elimination of carvedilol was significantly decreased in the dronedarone-pretreated rats than in the vehicle-pretreated rats. The one-compartment model with first-order absorption and elimination was sufficient to explain the pharmacokinetic characters after single oral administration of carvedilol to both vehicle-pretreated and dronedarone-pretreated rats. This study suggests that dronedarone inhibits CYP2D6-mediated carvedilol metabolism, and dose adjustment is needed in carvedilol and dronedarone combination therapy. Further studies are needed to clarify the effect of dronedarone on carvedilol and CYP2D6 substrates in clinical use. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Reduction of Escherichia coli O157:H7 excretion in sheep by oral lactoferrin administration.

    PubMed

    Yekta, M Atef; Cox, E; Goddeeris, B M; Vanrompay, D

    2011-06-02

    Ruminants are an important reservoir of Escherichia coli O157:H7, therefore reducing E. coli O157:H7 excretion by these animals could play a key role in reducing human infections. The present study investigates the potential of bovine lactoferrin, a natural antimicrobial-immunomodulatory protein of milk, to prevent colonization and excretion of E. coli O157:H7 in sheep. The effect of two different doses of lactoferrin (1.5 g or 0.15 g per 12h) was evaluated on colonization of sheep intestine and faecal excretion of the NCTC12900 strain. Hereto, lactoferrin was orally administered to sheep during 30 consecutive days and sheep were experimentally infected with E. coli O157:H7 on the second day of the lactoferrin administration. Interestingly, both lactoferrin dosages significantly reduced the number of E. coli O157:H7 in faeces as well as the duration of faecal excretion. The high dose group showed a significantly higher antibody response against EspA and EspB, two structural proteins of the bacterial type III secretion system (TTSS), than the colonization control group. The results suggest that oral lactoferrin administration could be used to prevent persistent colonization of sheep with E. coli O157:H7. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. Polyethylene glycol-polyvinyl alcohol grafted copolymer: study of the bioavailability after oral administration to rats.

    PubMed

    Heuschmid, Franziska F; Schuster, Paul; Lauer, Birthe; Fabian, Eric; Leibold, Edgar; van Ravenzwaay, Bennard

    2013-07-01

    The absorption, urinary excretion, and the biliary excretion of a single oral dose of 10 or 1000 mg/kg bw of (14)C-polyethylene glycol-polyvinyl alcohol (PEG-PVA) grafted copolymer were studied in adult male and female rats. In a balance/excretion experiment, the total excretion of ingested radioactivity was determined over a period of 168 h and residual radioactivity was detected in selected tissues and the carcass. In a biliary excretion experiment, excretion of radioactivity via the bile duct was determined over a period of 48 h after administration of the substance to cannulated rats. Most, if not all, of the radioactivity (>100%) was excreted within 48 h via the feces regardless of sex or dose. Urinary excretion was very limited: 0.45-0.50% of dose at the low dose and 0.22-0.27% of dose at the high dose. At both dose levels, residual radioactivity in the carcass and all organs and tissues after 168 h was ≤ 0.02% of dose. Biliary excretion was 0.01-0.02% of dose. Based on these findings, the bioavailability of PEG-PVA grafted copolymer was determined to be <1% demonstrating that absorption was virtually negligible following a single oral administration to male and female rats.

  1. Oral administration of squid lecithin-transphosphatidylated phosphatidylserine improves memory impairment in aged rats.

    PubMed

    Lee, Bombi; Sur, Bong-Jun; Han, Jeong-Jun; Shim, Insop; Her, Song; Lee, Yang-Seok; Lee, Hye-Jung; Hahm, Dae-Hyun

    2015-01-02

    Recently, lecithin-derived phosphatidylserine (PS), which originates from marine life, has received much attention as a viable alternative to bovine cerebral cortex PS. In this study, the use of squid phosphatidylcholine-transphosphatidylated PS (SQ-PS) was evaluated through examination of its ameliorating effects on age-associated learning and memory deficits in rats. Aged rats were orally administered SQ-PS (10, 20, or 50 mg/kg per day) once a day for seven days 30 min prior to behavioral assessment in a Morris water maze. SQ-PS administration produced significant dose-dependent improvements in escape latency for finding the platform in the Morris water maze in the aged rats even though Soy-PS administration also exhibited comparable improvements with SQ-PS. Biochemical alterations in the hippocampal cholinergic system, including changes in choline acetyltransferase and acetylcholinesterase immunoreactivity, were consistent with the behavioral results. In addition, SQ-PS treatment significantly restored age-associated decreases of choline transporter and muscarinic acetylcholine receptor type 1 mRNA expression in the hippocampus. These results demonstrate that orally administered SQ-PS dose-dependently aids in the improvement of memory deficits that occur during normal aging in rats. This suggests that SQ-PS may be a useful therapeutic agent in the treatment of diminished memory function in elderly people.

  2. Toxicokinetics of short-chain chlorinated paraffins in Sprague-Dawley rats following single oral administration.

    PubMed

    Geng, Ningbo; Zhang, Haijun; Xing, Liguo; Gao, Yuan; Zhang, Baoqin; Wang, Feidi; Ren, Xiaoqian; Chen, Jiping

    2016-02-01

    Short-chain chlorinated paraffins (SCCPs) have attracted considerable attention for their characteristic of persistent organic pollutants. However, very limited information is available for their toxicokinetic characteristics, limiting the evaluation of their health risks. In this study, we performed a toxicokinetics study to explore the absorption and excretion processes of SCCPs (a mixture of C10-, C11-, C12- and C13-CPs) after a single oral administration to the Sprague-Dawley rats. The toxicokinetic results showed that peak blood concentration of total SCCPs was attained at 2.8 day with Cmax value of 2.3 mg L(-1). The half-lives of total SCCPs in blood for the absorption t1/2 (ka), distribution t1/2 (α) and elimination phases t1/2 (β) were calculated to be 1.0, 1.7 and 6.6 days, respectively. During the 28 days post-dosing, about 27.9% and 3.5% of orally administrated SCCPs were excreted through feces and urine without metabolism, respectively. Congener group abundance profiles indicate a relative increase of Cl5-SCCPs in blood and urine in the elimination stage, and a higher accumulation of Cl8-10-SCCPs in feces. The distribution discrepancies of SCCPs congener groups in blood and excreta were more dependent on chlorine contents than on carbon chain lengths.

  3. Display of human proinsulin on the Bacillus subtilis spore surface for oral administration.

    PubMed

    Feng, Fan; Hu, Ping; Chen, Liang; Tang, Qi; Lian, Chaoqun; Yao, Qin; Chen, Keping

    2013-07-01

    With the continuous improvement of the living standards of human society, the number of diabetics worldwide is growing rapidly. To date, the main effective therapy for diabetic is intravenous injection of insulin, which is accompanied by a lot of shortage such as high cost and side effects. To obtain long-term bioactive anti-diabetic drug for oral administration, we used human proinsulin (hpi) as a foreign gene to construct a recombinant plasmid pJS700-HPI with an enterokinase site Asp-Asp-Asp-Asp-Lys suitable for digestion. Plasmid pJS700-HPI was transformed into Bacillus subtilis by double cross-over and an amylase inactivated mutant was produced. After induction of spores formation, western blot was used to monitor HPI surface expression on spores. Oral administration to the silkworms with spores implied that the HPI protein displayed on recombinant spores may be digested and absorbed into the silkworm's hemolymph due to the resistant characters of spores and the addition of enterokinase site.

  4. Immunomodulaton and attenuation of lethal influenza A virus infection by oral administration with KIOM-C.

    PubMed

    Kim, Eun-Ha; Pascua, Philippe Noriel Q; Song, Min-Suk; Baek, Yun Hee; Kwon, Hyeok-Il; Park, Su-Jin; Lim, Gyo-Jin; Kim, Se Mi; Decano, Arun; Lee, Kwang Jin; Cho, Won-Kyung; Ma, Jin Yeul; Choi, Young Ki

    2013-06-01

    Herbal medicine is used to treat many conditions such as asthma, eczema, premenstrual syndrome, rheumatoid arthritis, migraine, headaches, menopausal symptoms, chronic fatigue, irritable bowel syndrome, cancer, and viral infections such as influenza. In this study, we investigated the antiviral effect of KIOM-C for the treatment of influenza A virus infection. Our results show that oral administration of KIOM-C conferred a survival benefit to mice infected with the 2009 pandemic H1N1 [A(H1N1)pdm09] virus, and resulted in a 10- to 100-fold attenuation of viral replication in ferrets in a dose-dependent manner. Additionally, oral administration of KIOM-C increased the production of antiviral cytokines, including IFN-γ and TNF-α, and decreased levels of pro-inflammatory cytokines (IL-6) and chemokines (KC, MCP-1) in the Bronchoalveolar lavage fluid (BALF) of A(H1N1)pdm-infected mice. These results indicate that KIOM-C can promote clearance of influenza virus in the respiratory tracts of mice and ferrets by modulating cytokine production in hosts. Taken together, our results suggest that KIOM-C is a potential therapeutic compound mixture for the treatment of influenza virus infection in humans.

  5. Pharmacokinetic alteration of baclofen by multiple oral administration of herbal medicines in rats.

    PubMed

    Kim, Tae Hwan; Park, Gi-Young; Shin, Soyoung; Kwon, Dong Rak; Seo, Won Sik; Shin, Jeong Cheol; Choi, Jin Ho; Joo, Sang Hoon; Weon, Kwon-Yeon; Min, Byung Sun; Baek, Kyung Min; Upadhyay, Mahesh; Zhao, Bing Tian; Woo, Mi Hee; Kwon, So Hee; Shin, Beom Soo

    2014-01-01

    The potential pharmacokinetic (PK) interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY) and Achyranthes bidentata radix (AB) extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW), OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg) was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42-4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (C max) and longer time to reach C max (T max) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (F urine). The absorption rate (K a ) of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance.

  6. Oral L-glutamine administration attenuated cutaneous wound healing in Wistar rats.

    PubMed

    Goswami, Saurabh; Kandhare, Amit; Zanwar, Anand A; Hegde, Mahabaleshwar V; Bodhankar, Subhash L; Shinde, Sudhir; Deshmukh, Shahaji; Kharat, Ravindran

    2016-02-01

    The objective of this study was to evaluate the wound healing potential of L-glutamine in laboratory rats using excision and incision wound models. Excision wounds of size 500 mm(2) and depth 2 mm were made on the dorsal portion of male Wistar rats (230-250 g) and were used for the study of oral L-glutamine (1 g/kg) treatment on the rate of contraction of wound and epithelisation. Histological evaluation of wound tissue was also performed. Six-centimetre-long two linear-paravertebral incisions in male Wistar rats (230-250 g) were used to study the effect of L-glutamine (1 g/kg, p.o.) treatment on tensile strength, total protein and hydroxyproline content in the incision model. Oral administration of L-glutamine (1 g/kg) significantly decreased wound area, epithelisation period and wound index, whereas the rate of wound contraction significantly increased (P < 0·001) when compared with vehicle control rats in the excision wound model. Tensile strength, hydroxyproline content and protein level were significantly increased (P < 0·001) in L-glutamine (1 g/kg, p.o.)-treated rats when compared with vehicle control rats in the incision wound model. Histological evaluation of wound tissue from L-glutamine (1 g/kg, p.o.)-treated rats showed complete epithelialisation with new blood vessel formation and high fibrous tissues in the excision wound model. In conclusion, oral administration of l-glutamine (1 g/kg) promotes wound healing by acting on various stages of wound healing such as collagen synthesis, wound contraction and epithelialisation.

  7. Lecithin-based novel cationic nanocarriers (Leciplex) II: improving therapeutic efficacy of quercetin on oral administration.

    PubMed

    Date, Abhijit A; Nagarsenker, Mangal S; Patere, Shilpa; Dhawan, Vivek; Gude, R P; Hassan, P A; Aswal, V; Steiniger, Frank; Thamm, Jana; Fahr, Alfred

    2011-06-06

    The objective of the present investigation was to evaluate ability of the novel self-assembled phospholipid- based cationic nanocarriers (LeciPlex) in improving the therapeutic efficacy of a poorly water-soluble natural polyphenolic agent, quercetin (QR), on oral administration. Quercetin loaded LeciPlex (QR-LeciPlex) were successfully fabricated using a biocompatible solvent Transcutol HP. The QR-LeciPlex were characterized for particle size, encapsulation efficiency, zeta potential, and particle morphology by cryo-TEM. UV and fluorescence spectral characterization was carried out to find out the association of QR with LeciPlex. Small angle neutron scattering studies (SANS) were carried out to understand the internal structure of Leciplex and to evaluate the influence of the incorporation of QR in the LeciPlex. Anti-inflammatory and antitumorigenic activity of QR-LeciPlex was determined in comparison to QR suspension to evaluate the potential of LeciPlex in improving oral delivery of QR. QR-LeciPlex exhibited a particle size of ∼400 nm and had excellent colloidal stability. The QR-LeciPlex had a zeta potential greater than +30 mV and exhibited very high encapsulation efficiency of QR (>90%). UV and fluorescence spectral characterization indicated the interaction/association of QR with LeciPlex components. Cryo-TEM studies showed that LeciPlex and QR-LeciPlex have a unilamellar structure. SANS confirmed the unilamellar structure of LeciPlex and indicated that the incorporation of QR does not have any effect on the internal structure of the LeciPlex. QR-LeciPlex exhibited significantly higher anti-inflammatory and antitumorigenic activity (p < 0.01) as compared to that of QR suspension on oral administration.

  8. ACTIVITY AND ISOZYME CONTENT OF LACTATE DEHYDROGENASE UNDER LONG-TERM ORAL TAURINE ADMINISTRATION TO RATS.

    PubMed

    Ostapiv, R D; Humenyuk, S L; Manko, V V

    2015-01-01

    The effect of long-term oral taurine administration to rats on activity of lactate dehydrogenase (LDH), its isozyme content and activity in the whole blood, liver, thigh muscle, brain and testes tissues were studied in the present work. For this purpose male Wistar rats with body weight 190-220 g were randomly divided into three groups, they were orally administered drinking water (control group) or taurine solution 40 and 100 mg per kg of body weight ( groups I and II, respectively). The total lactate dehydrogenase activity was measured spectrophotometrically, the percentage content of isozymes was determined by electrophoresis in 7.5% poliacrylamide gel withfurther staining according to J. Garbus. It was found that the total lactate dehydrogenase activity increased in all studied tissues. In testes of animals of both groups and in brain of group I animals, the total percentage contents of isozymes that are responsible for lactate production (LDH4+LDH5) increased. In liver of animals of both groups and in whole blood of group II animals, the total percentage content of isozymes that produce pyruvate (LDH1+LDH2) increased. In thigh muscle of both groups and in brain of group II animals the balance between LDH1+LDH2 and LDH4+LDH5 content did not differ from control values, though total lactate dehydrogenase activity was significantly higher, than that in the control group. Thus, the increase in the lactate dehydrogenase activity under long-term oral taurine administration in different rat tissues was found to be tissue- and dose-dependent and was caused by the increase in the content of different isozymes. Such increase in group I animals might be explained by adaptive mechanisms to hypoxia caused by high doses of taurine. For group II animals high doses of taurine were toxic and directly affected metabolic processes in the animal bodies.

  9. The effect of the oral administration of polymeric nanoparticles on the efficacy and toxicity of tamoxifen.

    PubMed

    Jain, Amit K; Swarnakar, Nitin K; Godugu, Chandraiah; Singh, Raman P; Jain, Sanyog

    2011-01-01

    The present investigation reports on the conditions for preparation of tamoxifen loaded PLGA nanoparticles (Tmx-NPs) for oral administration. Tmx-NPs with >85% entrapment efficiency and 165.58 ± 3.81 nm particle size were prepared and freeze dried. Freeze dried Tmx-NPs were found to be stable in various simulated GIT media (pH 1.2, pH 3.5, pH 6.8, SGF & SIF). No significant changes in characteristics of Tmx-NPs were observed after 3 months accelerated stability studies. The cell viability in C127I cells was found to be relatively lower in Tmx-NP treated cells as compared to free Tmx treated cells. CLSM imaging reveled that nanoparticles were efficiently localized into the nuclear region of C127I cells. Oral bioavailability of Tmx was increased by 3.84 and 11.19 times as compared to the free Tmx citrate and Tmx base respectively, when formulated in NPs. In vivo oral antitumor efficacy of Tmx-NPs was carried out in DMBA induced breast tumor model and tumor size was reduced up to 41.56% as compared to untreated groups which showed an increase in tumor size up to 158.66%. Finally, Tmx-NPs showed the marked reduction in hepatotoxicty when compared with free Tmx citrate as evidenced by histopathological examination of liver tissue as well as AST, ALT and MDA levels. Therefore Tmx-NPs could have the significant value for the oral chronic breast cancer therapy with reduced hepatotoxicity. Copyright © 2010 Elsevier Ltd. All rights reserved.

  10. Effects of oral and vaginal administration of levonorgestrel emergency contraception on markers of endometrial receptivity.

    PubMed

    Meng, C-X; Marions, L; Byström, B; Gemzell-Danielsson, K

    2010-04-01

    The standard regimen of the levonorgestrel-only pill (1.5 mg either in a single dose or in a dose of 0.75 mg twice, 12 h apart) administered orally for emergency contraception (EC) has been shown to have no effect on endometrial development and markers of endometrial receptivity. We aimed to explore whether repeated oral and single vaginal administration of levonorgestrel affect the endometrium and thus potentially increase the EC efficacy, compared with the standard regimen. Endometrial biopsies were taken from non-smoking, healthy women with proven fertility on cycle days LH + 6 to LH + 8 in control and levonorgestrel treatment cycles (each woman serving as her own control). Levonorgestrel was administered either orally (0.75 mg x 4, at 24 h intervals on LH + 1 to LH + 4; n = 8) or vaginally (a single dose of 1.5 mg on LH + 2; n = 7). Immunohistochemistry and real-time RT-PCR was performed to compare the levels of protein and mRNA for sex steroid receptors, interleukin-1beta, leukaemia inhibitory factor (LIF), vascular endothelial growth factor, cyclooxygenase-2, tumour necrosis factor-alpha, integrin alpha(v)beta(3) and mucin 1 in endometrial cells. Following the repeated oral treatment, the immunoreactivity of both progesterone receptor (PR)-A and PR-B declined in glandular epithelium (P = 0.03 and P = 0.02, respectively), whereas stromal immunoreactivity and mRNA expression of LIF increased compared with control (P < 0.001 and P = 0.03, respectively). However, vaginal levonorgestrel did not cause any significant endometrial changes. The two regimens of levonorgestrel caused either only minor or no alterations in markers of endometrial receptivity. New agents targeting the endometrial development should be explored in order to increase EC efficacy.

  11. Improved Oral Bioavailability and Brain Transport of Saquinavir Upon Administration in Novel Nanoemulsion Formulations

    PubMed Central

    Vyas, Tushar K.; Shahiwala, Aliasgar; Amiji, Mansoor M.

    2008-01-01

    The aim of this investigation was to develop novel oil-in-water (o/w) nanoemulsions containing saquinavir (SQV), an anti-HIV protease inhibitor, for enhanced oral bioavailability and brain disposition. SQV was dissolved in different types of edible oils rich in essential polyunsaturated fatty acids (PUFA) to constitute the internal oil phase of the nanoemulsions. The external phase consisted of surfactants Lipoid®-80 and deoxycholic acid dissolved in water. The nanoemulsions with an average oil droplet size of 100-200 nm, containing tritiated [3H]-SQV, were administered orally and intravenously to male Balb/c mice. The SQV bioavailability as well as distribution in different organ systems was examined. SQV concentrations in the systemic circulation administered in flax-seed oil nanoemulsions were 3-fold higher as compared to the control aqueous suspension. The oral bioavailability and distribution to the brain, a potential sanctuary site for HIV, were significantly enhanced with SQV delivered in nanoemulsion formulations. In comparing SQV in flax-seed oil nanoemulsion with aqueous suspension, the maximum concentration (Cmax) and the area-under-the-curve (AUC) values were found to be 5-fold and 3-fold higher in the brain, respectively, suggesting enhanced rate and extent of SQV absorption following oral administration of nanoemulsions. The results of this study show that oil-in-water nanoemulsions made with PUFA-rich oils may be very promising for HIV/AIDS therapy, in particular, for reducing the viral load in important anatomical reservoir sites. PMID:17651927

  12. Oral administration of amphotericin B nanoparticles: antifungal activity, bioavailability and toxicity in rats.

    PubMed

    Radwan, Mahasen A; AlQuadeib, Bushra T; Šiller, Lidija; Wright, Matthew C; Horrocks, Benjamin

    2017-11-01

    Amphotericin B (AMB) is used most commonly in severe systemic life-threatening fungal infections. There is currently an unmet need for an efficacious (AMB) formulation amenable to oral administration with better bioavailability and lower nephrotoxicity. Novel PEGylated polylactic-polyglycolic acid copolymer (PLGA-PEG) nanoparticles (NPs) formulations of AMB were therefore studied for their ability to kill Candida albicans (C. albicans). The antifungal activity of AMB formulations was assessed in C. albicans. Its bioavalability was investigated in nine groups of rats (n = 6). Toxicity was examined by an in vitro blood hemolysis assay, and in vivo nephrotoxicity after single and multiple dosing for a week by blood urea nitrogen (BUN) and plasma creatinine (PCr) measurements. The MIC of AMB loaded to PLGA-PEG NPs against C. albicans was reduced two to threefold compared with free AMB. Novel oral AMB delivery loaded to PLGA-PEG NPs was markedly systemically available compared to Fungizone® in rats. The addition of 2% of GA to the AMB formulation significantly (p < 0.05) improved the bioavailability from 1.5 to 10.5% and the relative bioavailability was > 790% that of Fungizone®. The novel AMB formulations showed minimal toxicity and better efficacy compared to Fungizone®. No nephrotoxicity in rats was detected after a week of multiple dosing of AMB NPs based on BUN and PCr, which remained at normal levels. An oral delivery system of AMB-loaded to PLGA-PEG NPs with better efficacy and minimal toxicity was formulated. The addition of glycyrrhizic acid (GA) to AMB NPs formulation resulted in a significant oral absorption and improved bioavailability in rats.

  13. Pharmacokinetics of grepafloxacin after oral administration of single and repeat doses in healthy young males.

    PubMed

    Efthymiopoulos, C; Bramer, S L; Maroli, A

    1997-01-01

    The pharmacokinetics of grepafloxacin in healthy male subjects following single oral administration of doses ranging from 200 to 1200 mg, and following repeated oral administration of 400 and 800 mg doses are reported. Plasma levels of grepafloxacin reached a peak within 2 hours (on average) following drug administration and then declined bi-exponentially with concentrations being detectable (> 5 micrograms/L) in the plasma for at least up to 72 hours postdose. The high values for the apparent volume of distribution (5 to 8 L/kg) suggested extensive distribution of grepafloxacin in the tissues. Only a small percentage of the administered dose (ranging from 6% to 9.5%) was recovered in the urine as unchanged grepafloxacin, suggesting that metabolism, rather than urinary excretion, is the major elimination route. The half-life of grepafloxacin was about 12 hours after single doses and about 15 hours after repeat doses. The trough levels increased significantly over the first 3 days of repeat administration; thereafter, the changes were small, with steady-state being reached by the fifth day. The area under the concentration-time curve (AUC24 h) values observed on days 7 and 14 of repeat administration, at each dose level, were similar, suggesting that steady-state is maintained. The area values increased more than proportionally after administration of increasing single and repeat doses, suggesting nonlinear kinetics. The elimination half-life and renal clearance did not change with increasing doses. Saturation in the metabolism of grepafloxacin and possibly in the distribution into a peripheral compartment, as suggested by a decrease in the total plasma clearance and in the apparent volume of distribution, could be the origin of the nonlinear kinetics. However, this deviation from linearity is unlikely to be of clinical significance, since it was very small over the recommended range of therapeutic doses (400 to 600 mg once daily). Compared with other quinolones

  14. “Twin peaks”: Searching for 4-hydroxynonenal urinary metabolites after oral administration in rats

    PubMed Central

    Keller, Julia; Baradat, Maryse; Jouanin, Isabelle; Debrauwer, Laurent; Guéraud, Françoise

    2014-01-01

    4-Hydroxynonenal (HNE) is a cytotoxic and genotoxic lipid oxidation secondary product which is formed endogenously upon peroxidation of cellular n-6 fatty acids. However, it can also be formed in food or during digestion, upon peroxidation of dietary lipids. Several studies have evidenced that we are exposed through food to significant concentrations of HNE that could pose a toxicological concern. It is then of importance to known how HNE is metabolized after oral administration. Although its metabolism has been studied after intravenous administration in order to mimick endogenous formation, its in vivo fate after oral administration had never been studied. In order to identify and quantify urinary HNE metabolites after oral administration in rats, radioactive and stable isotopes of HNE were used and urine was analyzed by radio-chromatography (radio-HPLC) and chromatography coupled with High Resolution Mass Spectrometry (HPLC–HRMS). Radioactivity distribution revealed that 48% of the administered radioactivity was excreted into urine and 15% into feces after 24 h, while 3% were measured in intestinal contents and 2% in major organs, mostly in the liver. Urinary radio-HPLC profiles revealed 22 major peaks accounting for 88% of the urinary radioactivity. For identification purpose, HNE and its stable isotope [1,2-13C]-HNE were given at equimolar dose to be able to univocally identify HNE metabolites by tracking twin peaks on HPLC–HRMS spectra. The major peak was identified as 9-hydroxy-nonenoic acid (27% of the urinary radioactivity) followed by classical HNE mercapturic acid derivatives (the mercapturic acid conjugate of di-hydroxynonane (DHN-MA), the mercapturic acid conjugate of 4-hydroxynonenoic acid (HNA-MA) in its opened and lactone form) and by metabolites that are oxidized in the terminal position. New urinary metabolites as thiomethyl and glucuronide conjugates were also evidenced. Some analyses were also performed on feces and gastro

  15. Embryo-fetal exposure and developmental outcome of thalidomide following oral and intravaginal administration to pregnant rabbits.

    PubMed

    Hui, Julia Y; Hoffmann, Matthew; Kumar, Gondi

    2014-09-01

    Studies in pregnant rabbits were conducted to evaluate if there are any differences in the uptake of thalidomide into the intrauterine compartment and developmental toxicity risk following oral and intravaginal administration. Thalidomide concentrations in maternal plasma, yolk sac cavity (YSC) fluid and embryo following intravaginal administration were 2- to 7-fold lower than their respective levels after oral administration. Ratios of thalidomide concentration in YSC fluid to maternal plasma were similar between these two routes, indicating no difference in uptake into the intrauterine compartment. A rabbit embryo-fetal development study using oral and intravaginal thalidomide administration at 2mg/kg/day (a dose >10,000-fold higher than the expected amount of thalidomide in human semen) did not result in any developmental abnormalities. These data demonstrated no preferential transfer mechanism of thalidomide from vagina to conceptus, and no additional embryo-fetal developmental toxicity risks with thalidomide exposure via the vaginal route.

  16. Comparative Pharmacokinetics of Levofloxacin in Healthy and Renal Damaged Muscovy Ducks following Intravenous and Oral Administration

    PubMed Central

    Soliman, Ahmed

    2014-01-01

    The pharmacokinetics aspects of levofloxacin were studied in healthy and experimentally renal damaged Muscovy ducks after single intravenous (IV) and oral (PO) dose of 10 mg kg−1 bwt. Following IV administration, elimination half-life (t 1/2(β)) and mean residence time (MRT) were longer in renal damaged ducks than in healthy ones. Total clearance (Cltot) in renal damaged ducks (0.20 L kg−1 h−1) was significantly lower as compared to that in healthy ones (0.41 L kg−1 h−1). Following PO administration, the peak serum concentration (C max) was higher in renal damaged than in healthy ducks and was achieved at maximum time (t max) of 2.47 and 2.05 h, respectively. The drug was eliminated (t 1/2(el)) at a significant slower rate (3.94 h) in renal damaged than in healthy ducks (2.89 h). The pharmacokinetic profile of levofloxacin is altered in renal damaged ducks due to the increased serum levofloxacin concentrations compared with that in clinically healthy ducks. Oral administration of levofloxacin at 10 mg kg−1 bwt may be highly efficacious against susceptible bacteria in ducks. Also, the dose of levofloxacin should be reduced in renal damaged ducks. Pharmacokinetic/pharmacodynamic integration revealed significantly higher values for C max/MIC and AUC/MIC ratios in renal damaged ducks than in healthy ones, indicating the excellent pharmacokinetic characteristics of levofloxacin in renal damaged ducks. PMID:24707439

  17. Population pharmacokinetics of zonisamide after oral administration in healthy Chinese volunteers.

    PubMed

    Qiu, Xuewen; Dai, Qing; Sun, Fengjun; Liu, Yao; Yang, Bo; Xiang, Rongfeng; Yu, Mingjie; Xiong, Lirong; Bi, Shanshan; Lu, Wei; Chen, Yongchuan; Xia, Peiyuan

    2016-05-01

    To develop a population-based pharmacokinetic model for the oral antiepileptic drug zonisamide using a cohort of healthy (nonepileptic) subjects and evaluate the effect of individual factors on the pharmacokinetics of zonisamide. 30 young adults (21-39 years) in good health were randomly assigned to 3 equal groups (1:1 sex ratio) for single-dose administration of zonisamide at 200 mg, 300 mg, or 400 mg. An additional 9 subjects (22-24 years) were administered once daily zonisamide at 300 mg for 14 days, and comprised the multiple dosing group. Venous blood samples were collected for analysis prior to (baseline, 0 hours) and after (1-300 hours) drug administration, providing 607 total samples used to build the pharmacokinetic model. The population pharmacokinetic analysis was performed by ICON's nonlinear mixed-effect modeling (NONMEM) software. Validation of the final model was carried out by nonparametric bootstrapping and visual predictive check. The zonisamide pharmacokinetics was best described by a two-compartment model with first-order elimination. In the final model, the estimated value of clearance (CL) was 23.25 L/h, the volume of distribution of the central compartment (Vc) was 34.50 L, the intercompartmental clearance (Q) was 20.22 L/h, and the Ka was 0.026 h(-1). The peripheral volume of distribution (Vp) was 1,429 L for single dose and 1,003 L for multiple doses. Body weight was the significant covariate affecting CL, Vc, Vp, and Q. Otherwise, female subjects had a lower Q than male subjects. The pharmacokinetics of zonisamide after oral administration could be described using a linear first-order elimination two-compartment model, which may provide a reference for clinical use of zonisamide in Chinese adults.

  18. Fluoxetine Administration Exacerbates Oral Tremor and Striatal Dopamine Depletion in a Rodent Pharmacological Model of Parkinsonism

    PubMed Central

    Podurgiel, Samantha J; Milligan, Meredith N; Yohn, Samantha E; Purcell, Laura J; Contreras-Mora, Hector M; Correa, Mercè; Salamone, John D

    2015-01-01

    The cardinal motor symptoms of Parkinson's disease (PD) include resting tremor, akinesia, bradykinesia, and rigidity, and these motor abnormalities can be modeled in rodents by administration of the VMAT-2 (type-2 vesicular monoamine transporter) inhibitor tetrabenazine (9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7, 11b hexahydrobenzo[a]quinolizin-2-one; TBZ). Depression is also commonly associated with PD, and clinical data indicate that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine ((±)-N-methyl-γ-[4-(trifluoromethyl)phenoxy]benzenepropanamine hydrochloride; FLX) are frequently used to treat depression in PD patients. The aim of the present study was to characterize the effect of FLX on the motor dysfunctions induced by a low dose of TBZ (0.75 mg/kg), and investigate the neural mechanisms involved. This low dose of TBZ was selected based on studies with rat models of depressive symptoms. In rats, coadministration of FLX (2.5, 5.0, and 10.0 mg/kg) increased TBZ-induced oral tremor (tremulous jaw movements), and decreased locomotor activity compared with administration of TBZ alone. Coadministration of the serotonin 5-HT2A/2C antagonist mianserin (2.5 and 5.0 mg/kg) attenuated the increase in oral tremor induced by coadministration of TBZ (0.75 mg/kg) with FLX (5.0 mg/kg). Consistent with these behavioral data, coadministration of TBZ and FLX decreased DA tissue levels in the rat ventrolateral neostriatum compared with TBZ alone, and coadministration of mianserin with TBZ and FLX attenuated this effect, increasing DA tissue levels compared with the TBZ/FLX condition. These data suggest that SSRI administration in PD patients may result in worsening of motor symptoms, at least in part, by exacerbating existing DA depletions through 5-HT2A/2C-mediated modulation of DA neurotransmission. PMID:25759301

  19. Oral Fluid Cocaine and Benzoylecgonine Concentrations Following Controlled Intravenous Cocaine Administration

    PubMed Central

    Ellefsen, Kayla N.; Concheiro, Marta; Pirard, Sandrine; Gorelick, David A.; Huestis, Marilyn A.

    2016-01-01

    Limited oral fluid (OF) pharmacokinetic data collected with commercially available collection devices after controlled cocaine administration hinder OF result interpretations. Ten cocaine-using adults provided OF, collected with Oral-Eze® (OE) and StatSure Saliva Sampler™ (SS) devices, an hour prior to and up to 69 h after 25 mg intravenous (IV) cocaine administration. Cocaine and benzoylecgonine (BE) were quantified by a validated 2D-GC-MS method. Large inter-subject variability was observed. Cocaine was detected in OF in the first 0.17 h sample after IV administration, with much more rapid elimination than BE. OE median observed Cmax (range) was 932 (394–1,574) μg/L for cocaine and 248 (96.9–953) μg/L for BE. SS median (range) observed cocaine and BE Cmax trended lower at 732 (83.3–1,892) μg/L and 360 (77.2–836) μg/L, respectively. OE and SS cocaine OF detection times were 12.5 and 6.5 h and for BE 30.5 and 28.0 h, respectively at 1 μg/L. There were no significant pharmacokinetic differences between OE and SS OF collection devices, except cocaine half-life was significantly shorter in SS OF specimens. This difference could be attributed to differences in stabilizing buffers present in OF collection devices, which may affect cocaine stability in OF specimens, or decreased recovery from collection pads. Both OE and SS OF collection devices were effective in monitoring cocaine and metabolite concentrations with similar detection windows. Furthermore, we demonstrated that different confirmatory OF cutoffs can be selected to produce shorter or longer cocaine and metabolite detection windows to address specific needs of clinical and forensic drug testing programs. PMID:26851651

  20. Oral fluid cocaine and benzoylecgonine concentrations following controlled intravenous cocaine administration.

    PubMed

    Ellefsen, Kayla N; Concheiro, Marta; Pirard, Sandrine; Gorelick, David A; Huestis, Marilyn A

    2016-03-01

    Limited oral fluid (OF) pharmacokinetic data collected with commercially available collection devices after controlled cocaine administration hinder OF result interpretations. Ten cocaine-using adults provided OF, collected with Oral-Eze(®) (OE) and StatSure Saliva Sampler™ (SS) devices, an hour prior to and up to 69 h after 25mg intravenous (IV) cocaine administration. Cocaine and benzoylecgonine (BE) were quantified by a validated 2D-GC-MS method. Large inter-subject variability was observed. Cocaine was detected in OF in the first 0.17 h sample after IV administration, with much more rapid elimination than BE. OE observed Cmax median (range) concentrations were 932 (394-1574)μg/L for cocaine and 248 (96.9-953)μg/L for BE. SS observed cocaine and BE Cmax median (range) concentrations trended lower at 732 (83.3-1892)μg/L and 360 (77.2-836)μg/L, respectively. OE and SS cocaine OF detection times were 12.5 and 6.5h and for BE 30.5 and 28.0 h, respectively at 1 μg/L. There were no significant pharmacokinetic differences between OE and SS OF collection devices, except cocaine half-life was significantly shorter in SS OF specimens. This difference could be attributed to differences in stabilizing buffers present in OF collection devices, which may affect cocaine stability in OF specimens, or decreased recovery from collection pads. Both OE and SS OF collection devices were effective in monitoring cocaine and metabolite concentrations with similar detection windows. Furthermore, we demonstrated that different confirmatory OF cutoffs can be selected to produce shorter or longer cocaine and metabolite detection windows to address specific needs of clinical and forensic drug testing programs. Published by Elsevier Ireland Ltd.

  1. Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives

    PubMed Central

    Benagiano, Giuseppe; Carrara, Sabina; Filippi, Valentina

    2009-01-01

    The progestational steroid norgestrel was synthesized and tested between 1960 and 1965 through an international cooperation between Wyeth, USA and Schering, Berlin. It is a mixture of two “enantiomers,” with only one form (designated as levonorgestrel) biologically active. When taken orally, it is rapidly absorbed, not subjected to a “first-pass” effect and is approximately 90% bioavailable, with a circulating half-life around 15 hours. Its contraceptive action is exerted at the central (hypothalamic) and peripheral (cervical mucus and endometrium) levels. Levonorgestrel (LNG), alone or in combination with ethinyl estradiol (EE), is the most widely employed contraceptive progestin: it is used in combined oral contraceptives, progestogen-only pills, long-acting contraceptive implants, intrauterine contraceptive systems and in emergency contraception. It is also the steroid of choice for new oral contraceptive regimens aimed at reducing the frequency of bleeding episodes. This novel approach, already tried more than 30 years ago, gained interest around the year 2000 when surveys of women’s attitudes toward monthly menstrual bleeding started to show a major change: more and more women declared that they would welcome a hormonal contraceptive method that reduced bleeding episodes to 4, 2 or even 1 per year. At this point, while the debate on the significance and “usefulness” of menstruation went on, attention focused on new regimens. The first new modality consisted of changing the 7-day medication-free interval, either shortening it to fewer than 7 days, or by the administration of low-dose estrogens during the interval between packages. Then, continuous administration regimens started to be investigated. This, however, did not happen suddenly, since, in specific situations, doctors had for years empirically utilized various continuous administration regimens. The first extended-cycle oral contraceptive regimen introduced in clinical practice is an 84

  2. Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives.

    PubMed

    Benagiano, Giuseppe; Carrara, Sabina; Filippi, Valentina

    2009-11-03

    The progestational steroid norgestrel was synthesized and tested between 1960 and 1965 through an international cooperation between Wyeth, USA and Schering, Berlin. It is a mixture of two "enantiomers," with only one form (designated as levonorgestrel) biologically active. When taken orally, it is rapidly absorbed, not subjected to a "first-pass" effect and is approximately 90% bioavailable, with a circulating half-life around 15 hours. Its contraceptive action is exerted at the central (hypothalamic) and peripheral (cervical mucus and endometrium) levels. Levonorgestrel (LNG), alone or in combination with ethinyl estradiol (EE), is the most widely employed contraceptive progestin: it is used in combined oral contraceptives, progestogen-only pills, long-acting contraceptive implants, intrauterine contraceptive systems and in emergency contraception. It is also the steroid of choice for new oral contraceptive regimens aimed at reducing the frequency of bleeding episodes. This novel approach, already tried more than 30 years ago, gained interest around the year 2000 when surveys of women's attitudes toward monthly menstrual bleeding started to show a major change: more and more women declared that they would welcome a hormonal contraceptive method that reduced bleeding episodes to 4, 2 or even 1 per year. At this point, while the debate on the significance and "usefulness" of menstruation went on, attention focused on new regimens. The first new modality consisted of changing the 7-day medication-free interval, either shortening it to fewer than 7 days, or by the administration of low-dose estrogens during the interval between packages. Then, continuous administration regimens started to be investigated. This, however, did not happen suddenly, since, in specific situations, doctors had for years empirically utilized various continuous administration regimens. The first extended-cycle oral contraceptive regimen introduced in clinical practice is an 84-day regimen that

  3. Pharmacokinetics of ketorolac tromethamine in horses after intravenous, intramuscular, and oral single-dose administration.

    PubMed

    Bianco, A W; Constable, P D; Cooper, B R; Taylor, S D

    2016-04-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are an integral component of equine analgesia, yet currently available NSAIDs are both limited in their analgesic efficacy and have adverse effects. The NSAID ketorolac tromethamine (KT) is widely used in humans as a potent morphine-sparing analgesic drug but has not been fully evaluated in horses. The purpose of this study was to determine the pharmacokinetic profile of KT in horses after intravenous (i.v.), intramuscular (i.m.), and oral (p.o.) administration. Nine healthy adult horses received a single 0.5-mg/kg dose of KT via each route of administration. Plasma was collected up to 48 h postadministration and analyzed for KT concentration using HPLC/MS/MS. Noncompartmental analysis of i.v. dosage indicated a mean plasma clearance of 8.4 (mL/min)/kg and an estimated mean volume of distribution at steady-state of 0.77 L/kg. Noncompartmental analysis of i.v., i.m., and p.o. dosages indicated mean residence times of 2.0, 2.6, and 7.1 h, respectively. The drug was rapidly absorbed after i.m. and p.o. administration, and mean bioavailability was 71% and 57% for i.m. and p.o. administration, respectively. Adverse effects were not observed after i.v., i.m., and p.o. administration. More studies are needed to evaluate the analgesic and anti-inflammatory properties of KT in horses. © 2015 John Wiley & Sons Ltd.

  4. Clinical pharmacokinetics of norfloxacin-glycine acetate after intravenous and oral administration in pigs

    PubMed Central

    Chang, Zhi-Qiang; Oh, Byung-Chol; Kim, Jong-Choon; Jeong, Kyu-Shik; Lee, Myung-Heon; Yun, Hyo-In; Hwang, Mi-Hyun

    2007-01-01

    The pharmacokinetics and dosage regimen of norfloxacin-glycine acetate (NFLXGA) was investigated in pigs after a single intravenous (i.v.) or oral (p.o.) administration at a dosage of 7.2 mg/kg body weight. After both i.v. and p.o. administration, plasma drug concentrations were best fitted to an open two-compartment model with a rapid distribution phase. After i.v. administration of NFLXGA, the distribution (t1/2α) and elimination half-life (t1/2β) were 0.36 ± 0.07 h and 7.42 ± 3.55 h, respectively. The volume of distribution of NFLXGA at steady state (Vdss) was 4.66 ± 1.39 l/kg. After p.o. administration of NFLXGA, the maximal absorption concentration (Cmax) was 0.43 ± 0.06 µg/ml at 1.36 ± 0.39 h (Tmax). The mean absorption (t1/2ka) and elimination half-life (t1/2β) of NFLXGA were 0.78 ± 0.27 h and 7.13 ± 1.41 h, respectively. The mean systemic bioavailability (F) after p.o. administration was 31.10 ± 15.16%. We suggest that the optimal dosage calculated from the pharmacokinetic parameters is 5.01 mg/kg per day i.v. or 16.12 mg/kg per day p.o. PMID:17993748

  5. Oral Administration of Probiotics Inhibits Absorption of the Heavy Metal Cadmium by Protecting the Intestinal Barrier.

    PubMed

    Zhai, Qixiao; Tian, Fengwei; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

    2016-07-15

    The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. Our previous work demonstrated that oral administration of probiotics can significantly inhibit Cd absorption in the intestines of mice, but further evidence is needed to gain insights into the related protection mode. The goal of this study was to evaluate whether probiotics can inhibit Cd absorption through routes other than the Cd binding, with a focus on gut barrier protection. In the in vitro assay, both the intervention and therapy treatments of Lactobacillus plantarum CCFM8610 alleviated Cd-induced cytotoxicity in the human intestinal cell line HT-29 and protected the disruption of tight junctions in the cell monolayers. In a mouse model, probiotics with either good Cd-binding or antioxidative ability increased fecal Cd levels and decreased Cd accumulation in the tissue of Cd-exposed mice. Compared with the Cd-only group, cotreatment with probiotics also reversed the disruption of tight junctions, alleviated inflammation, and decreased the intestinal permeability of mice. L. plantarum CCFM8610, a strain with both good Cd binding and antioxidative abilities, exhibited significantly better protection than the other two strains. These results suggest that along with initial intestinal Cd sequestration, probiotics can inhibit Cd absorption by protecting the intestinal barrier, and the protection is related to the alleviation of Cd-induced oxidative stress. A probiotic with both good Cd-binding and antioxidative capacities can be used as a daily supplement for the prevention of oral Cd exposure. The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. For the general population, food and drinking water are the main sources of Cd exposure due to the biomagnification of Cd within the food chain; therefore, the intestinal tract is the first organ that is susceptible to Cd contamination

  6. Oral Administration of Probiotics Inhibits Absorption of the Heavy Metal Cadmium by Protecting the Intestinal Barrier

    PubMed Central

    Zhai, Qixiao; Tian, Fengwei; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan

    2016-01-01

    ABSTRACT The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. Our previous work demonstrated that oral administration of probiotics can significantly inhibit Cd absorption in the intestines of mice, but further evidence is needed to gain insights into the related protection mode. The goal of this study was to evaluate whether probiotics can inhibit Cd absorption through routes other than the Cd binding, with a focus on gut barrier protection. In the in vitro assay, both the intervention and therapy treatments of Lactobacillus plantarum CCFM8610 alleviated Cd-induced cytotoxicity in the human intestinal cell line HT-29 and protected the disruption of tight junctions in the cell monolayers. In a mouse model, probiotics with either good Cd-binding or antioxidative ability increased fecal Cd levels and decreased Cd accumulation in the tissue of Cd-exposed mice. Compared with the Cd-only group, cotreatment with probiotics also reversed the disruption of tight junctions, alleviated inflammation, and decreased the intestinal permeability of mice. L. plantarum CCFM8610, a strain with both good Cd binding and antioxidative abilities, exhibited significantly better protection than the other two strains. These results suggest that along with initial intestinal Cd sequestration, probiotics can inhibit Cd absorption by protecting the intestinal barrier, and the protection is related to the alleviation of Cd-induced oxidative stress. A probiotic with both good Cd-binding and antioxidative capacities can be used as a daily supplement for the prevention of oral Cd exposure. IMPORTANCE The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. For the general population, food and drinking water are the main sources of Cd exposure due to the biomagnification of Cd within the food chain; therefore, the intestinal tract is the first organ that is susceptible to Cd

  7. Methotrexate efficacy and tolerability after switching from oral to subcutaneous route of administration in juvenile idiopathic arthritis.

    PubMed

    Żuber, Zbigniew; Turowska-Heydel, Dorota; Sobczyk, Małgorzata; Banach-Górnicka, Marta; Rusnak, Katarzyna; Piszczek, Anna; Mężyk, Elżbieta

    2016-01-01

    Methotrexate (MTX) is one of the most frequently used, highly effective disease-modifying drugs in juvenile idiopathic arthritis (JIA) therapy. The drug can be administered orally or subcutaneously, but the efficacy and tolerance of these two routes of administration raise doubts in JIA patients. The aim of the study was to evaluate MTX efficacy and tolerability after switching from the oral to the subcutaneous route of administration in children with JIA. A single-centre, questionnaire-based assessment of MTX efficacy and tolerance in 126 unselected JIA patients with longer than 6 months of follow-up was performed. In all patients, MTX was initially administered orally. The response to MTX treatment was analysed according to American College of Rheumatology (ACR) paediatric criteria. Six-month MTX therapy was effective (ACR score ≥ 30) in 83 children (65.9%). The oral route of MTX administration was changed to subcutaneous in 32 patients after a mean period of 14 months due to intolerance (n = 20) or reluctance to take the oral formulation (n = 12). This group of children was significantly younger (p = 0.02) but did not differ from the group of children that continued oral treatment in other aspects, including MTX dose. Six months after switching from oral to subcutaneous MTX the ACR score remained unchanged. Three children (9.4%) still reported symptoms of drug intolerance. The switch from oral to subcutaneous MTX may increase the response rate in JIA patients with intolerance of its oral formulation. The reluctance to take oral MTX can be anticipated in early childhood, and should be considered in the individualization of therapy, having also in mind the lower risk of severe gastrointestinal adverse drug reactions.

  8. Oral Administration of Cilostazol Increases Ocular Blood Flow in Patients with Diabetic Retinopathy

    PubMed Central

    Hwang, Duck Jin; Shin, Joo Young

    2017-01-01

    Purpose To investigate the effect of cilostazol on ocular hemodynamics and to determine whether the administration of cilostazol increases the ocular blood flow in patients with diabetic retinopathy. Methods This prospective observational study investigated the effect of orally administered cilostazol on diabetic retinopathy. Before and after administration for 1 week, pulsatile ocular blood flow (POBF) and retrobulbar hemodynamics were measured using a POBF analyzer and transcranial Doppler imaging, respectively. Visual acuity, intraocular pressure, and blood pressure were also evaluated before and after treatment. Results Twenty-five eyes of 25 patients were included in this study. POBF increased significantly (16.8 ± 4.6 µL/sec vs. 19.6 ± 6.2 µL/sec, p < 0.001) after administration of cilostazol, while no significant change was identified in visual acuity, intraocular pressure, and blood pressure. Mean flow velocity in the ophthalmic artery as measured with transcranial Doppler imaging also increased significantly after medication (23.5 ± 5.6 cm/sec vs. 26.0 ± 6.9 cm/sec, p = 0.001). The change in POBF directly correlated with the change in mean flow velocity (r = 0.419, p = 0.007). Conclusions Cilostazol was effective in increasing ocular blood flow in patients with diabetic retinopathy, possibly by modulating retrobulbar circulation. PMID:28367040

  9. A Single Oral Administration of Theaflavins Increases Energy Expenditure and the Expression of Metabolic Genes.

    PubMed

    Kudo, Naoto; Arai, Yasunori; Suhara, Yoshitomo; Ishii, Takeshi; Nakayama, Tsutomu; Osakabe, Naomi

    2015-01-01

    Theaflavins are polyphenols found in black tea, whose physiological activities are not well understood. This study on mice evaluated the influence of a single oral administration of theaflavins on energy metabolism by monitoring the initial metabolic changess in skeletal muscle and brown adipose tissue (BAT). Oxygen consumption (VO2) and energy expenditure (EE) were increased significantly in mice treated with theaflavin rich fraction (TF) compared with the group administered vehicle alone. There was no difference in locomotor activity. Fasting mice were euthanized under anesthesia before and 2 and 5, 20-hr after treatment with TF or vehicle. The mRNA levels of uncoupling protein-1 (UCP-1) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in BAT were increased significantly 2-hr after administration ofTF. The levels of UCP-3 and PGC-1α in the gastrocnemius muscle were increased significantly 2 and 5-hr after administration of TF. The concentration of phosphorylated AMP-activated protein kinase (AMPK) 1α was also increased significantly in the gastrocnemius 2 and 5-hr after treatment with TF. These results indicate that TF significantly enhances systemic energy expenditure, as evidenced by an increase in expression of metabolic genes.

  10. Analysis and distribution of esculetin in plasma and tissues of rats after oral administration.

    PubMed

    Kim, Ji-Sun; Ha, Tae-Youl; Ahn, Jiyun; Kim, Suna

    2014-12-01

    In this study, we developed a method to quantify esculetin (6,7-dihydroxycoumarin) in plasma and tissues using HPLC coupled with ultraviolet detection and measured the level of esculetin in rat plasma after oral administration. The calibration curve for esculetin was linear in the range of 4.8 ng/mL to 476.2 ng/mL, with a correlation coefficient (r(2)) of 0.996, a limit of detection value of 33.2 ng/mL, and a limit of quantification value of 100.6 ng/mL. Recovery rates for the 95.2 ng/mL and 190.5 ng/mL samples were 95.2% and 100.3%, within-runs and 104.8% and 101.0% between-runs, respectively. The relative standard deviation was less than 7% for both runs. In the pharmacokinetic analysis, the peak plasma esculetin level was reached 5 min after administration (Cmax=173.3 ng/mL; T1/2=45 min; AUC0 ~180 min=5,167.5 ng · min/mL). At 180 min post-administration (i.e., after euthanasia), esculetin was only detectable in the liver (30.87±11.33 ng/g) and the kidney (20.29±7.02 ng/g).

  11. Hydroxytyrosyl alkyl ether derivatives inhibit platelet activation after oral administration to rats.

    PubMed

    Muñoz-Marín, Javier; De la Cruz, José Pedro; Reyes, José Julio; López-Villodres, Juan Antonio; Guerrero, Ana; López-Leiva, Inmaculada; Espartero, José Luis; Labajos, María Teresa; González-Correa, José Antonio

    2013-08-01

    The low lipophilicity of hydroxytyrosol (HT) has motivated efforts to synthesize homologous series with better lipid solubility, such as the ethers, which are more lipophilic than HT. Because HT inhibits platelet aggregation, the aim of the study was to assess the possible anti-platelet effect of five HT ether derivatives (ethyl, butyl, hexyl, octyl and dodecyl) after oral administration to rats. Whole blood collagen-induced platelet aggregation and calcium-induced thromboxane B2 (TxB2), aortic 6-keto-prostaglandin F1α (6-keto-PGF1α) and nitrites+nitrates, plasma concentration of lipid peroxides (TBARS) and red blood cell content of reduced glutathione (GSH) were measured. The administration of 20 mg/kg/day inhibited platelet aggregation, TxB2 and TBARS in a non-linear manner related to the length of the carbon chain, with a cut-off effect in the hexyl derivative. Aortic nitrite and red blood cell GSH production were also increased. The aortic production of 6-keto-PGF1α was unaltered except in the group treated with the dodecyl derivative. The administration of 50 mg/kg/day showed a similar pharmacodynamic profile but without the non-linear effect. In conclusion, HT ethers, especially the hexyl derivative, are a potential alternative to hydroxytyrosol, and their effect merits additional research to determine their role in the prophylaxis of vascular disease.

  12. Oral administration of kefiran exerts a bifidogenic effect on BALB/c mice intestinal microbiota.

    PubMed

    Hamet, M F; Medrano, M; Pérez, P F; Abraham, A G

    2016-01-01

    The activity of kefiran, the exopolysaccharide present in kefir grains, was evaluated on intestinal bacterial populations in BALB/c mice. Animals were orally administered with kefiran and Eubacteria, lactobacilli and bifidobacteria populations were monitored in faeces of mice at days 0, 2, 7, 14 and 21. Profiles obtained by Denaturing Gradient Gel Electrophoresis (DGGE) with primers for Eubacteria were compared by principal component analysis and clearly defined clusters, correlating with the time of kefiran consumption, were obtained. Furthermore, profile analysis of PCR products amplified with specific oligonucleotides for bifidobacteria showed an increment in the number of DGGE bands in the groups administered with kefiran. Fluorescent In Situ Hybridisation (FISH) with specific probes for bifidobacteria showed an increment of this population in faeces, in accordance to DGGE results. The bifidobacteria population was also studied on distal colon content after 0, 2 and 7 days of kefiran administration. Analysis of PCR products by DGGE with Eubacteria primers showed an increment in the number and intensity of bands with high GC content of mice administered with kefiran. Sequencing of DGGE bands confirmed that bifidobacteria were one of the bacterial populations modified by kefiran administration. DGGE profiles of PCR amplicons obtained by using Bifidobacterium or Lactobacillus specific primers confirmed that kefiran administration enhances bifidobacteria, however no changes were observed in Lactobacillus populations. The results of the analysis of bifidobacteria populations assessed on different sampling sites in a murine model support the use of this exopolysaccharide as a bifidogenic functional ingredient.

  13. Tenofovir Disoproxil Fumarate: Toxicity, Toxicokinetics, and Toxicogenomics Analysis After 13 Weeks of Oral Administration in Mice

    PubMed Central

    Ng, Hanna H.; Stock, Howard; Rausch, Linda; Bunin, Deborah; Wang, Abraham; Brill, Shirley; Gow, Jason; Mirsalis, Jon C.

    2014-01-01

    Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against human immunodeficiency virus (HIV) and hepatitis B. The goals of this study were to evaluate the molecular mechanism of TDF-induced toxicity in mice after 13 weeks of daily oral administration (50–1000 mg/kg) by correlating transcriptional changes with plasma drug levels and traditional toxicology endpoints. Plasma levels and systemic exposure of tenofovir increased less than dose-proportionally, and were similar on Days 1 and 91. No overt toxicity was observed following the completion of TDF administration. The kidneys of TDF-treated mice were histopathologically normal. This result is consistent with the genomic microarray results, which showed no significant differences in kidney transcriptional levels between TDF-treated animals and controls. In liver, cytomegaly was observed in mice treated with 1000 mg/kg of TDF after 4 and 13 weeks of TDF-treatment, but mice recovered from this effect following cessation of administration. Analysis of liver transcripts on Day 91 reported elevated levels of Cdkn1a in TDF-treated animals compared with controls, which may have contributed to the inhibition of liver cell cycle progression. PMID:25568137

  14. [Patients' preferences for nurses' nonverbal expressions of warmth during nursing rounds and administration of oral medication].

    PubMed

    Kim, H S; Kim, M S

    1990-12-01

    Nursing involves deep human interpersonal relationships between nurses and patients. But in modern Korea, the nurse-patient relationship tends to be ritualistic and mechanestic. Patients usually express the hope that nurses be more tender and kind. Patients expect nurses to express their warmth especially through nonverbal behaviour. This study was conducted to identify patients' preferences for nurse's nonverbal expressions of warmth. Through the confirmation of these preferences, nurses may learn how to enhance their interpersonal relationships with patients. Subjects for the study were 73 patients who had been admitted to a university teaching hospital for at least three days and agreed to be interviewed by the investigator. The interactions were studied nonverbal expressions of warmth during nursing rounds and administration of oral medication. The interview schedule was especially designed by the investigator to measure the nurse's posture, the distance between the nurse and the patient, the nurse's eye contact, facial expression, hand motion and head nodding. Data analysis included frequencies, percentages and X2-test. The results of this study may be summerized as follows: 1. Patient's preferences for nurse's nonverbal expressions of warmth during nursing rounds. Preferred nurse's posture was sitting (50.7%) or standing (49.3%) opposite the patient. Preferred distance between the nurse and the patient was close to the bed (93.2%), less than 1m. Preferred eye contact was directed to the patient's eyes or their affected part (41.1%). Preferred facial expression was a smile (97.3%). Preferred hand motions were light gestures (41.1%). Patients preferred head nodding which approved their own opinions (69.9%). 2. Patient's preferences for nurse's nonverbal expressions of warmth during administration of oral medication. Preferred nurse's posture was standing and waiting to confirm that the medication had been taken (58.9%). Preferred distance from the patient was

  15. Toxicokinetics and biotransformation of 3-(4-methylbenzylidene)camphor in rats after oral administration

    SciTech Connect

    Voelkel, Wolfgang; Colnot, Thomas; Schauer, Ute M.D.; Broschard, Thomas H.; Dekant, Wolfgang . E-mail: dekant@toxi.uni-wuerzburg.de

    2006-10-15

    3-(4-Methylbenzylidene)camphor (4-MBC) is an UV-filter frequently used in sunscreens and cosmetics. Equivocal findings in some screening tests for hormonal activity initiated a discussion on a possible weak estrogenicity of 4-MBC. In this study, the toxicokinetics and biotransformation of 4-MBC were characterized in rats after oral administration. Male and female Sprague-Dawley rats (n = 3 per group) were administered single oral doses of 25 or 250 mg/kg bw of 4-MBC in corn oil. Metabolites formed were characterized and the kinetics of elimination for 4-MBC and its metabolites from blood and with urine were determined. Metabolites of 4-MBC were characterized by {sup 1}H NMR and LC-MS/MS as 3-(4-carboxybenzylidene)camphor and as four isomers of 3-(4-carboxybenzylidene)hydroxycamphor containing the hydroxyl group located in the camphor ring system with 3-(4-carboxybenzylidene)-6-hydroxycamphor as the major metabolite. After oral administration of 4-MBC, only very low concentrations of 4-MBC were present in blood and the peak concentrations of 3-(4-carboxybenzylidene)camphor were approximately 500-fold above those of 4-MBC; blood concentrations of 3-(4-carboxybenzylidene)-6-hydroxycamphor were below the limit of detection. Blood concentration of 4-MBC and 3-(4-carboxybenzylidene)camphor peaked within 10 h after 4-MBC administration and then decreased with half-lives of approximately 15 h. No major differences in peak blood levels between male and female rats were seen. In urine, one isomer of 3-(4-carboxybenzylidene)hydroxycamphor was the predominant metabolite [3-(4-carboxybenzylidene)-6-hydroxycamphor], the other isomers and 3-(4-carboxybenzylidene)camphor were only minor metabolites excreted with urine. However, urinary excretion of 4-MBC-metabolites represents only a minor pathway of elimination for 4-MBC, since most of the applied dose was recovered in feces as 3-(4-carboxybenzylidene)camphor and, to a smaller extent, as 3-(4-carboxybenzylidene)-6-hydroxycamphor

  16. Pharmacokinetics of enrofloxacin after intravenous, intramuscular and oral administration in houbara bustard (Chlamydotis undulata macqueenii).

    PubMed

    Bailey, T A; Sheen, R S; Silvanose, C; Samour, J H; Garner, A; Harron, D W

    1998-08-01

    The in-vitro activity of enrofloxacin against 117 strains of bacteria isolated from bustards was determined. Minimum inhibitory concentrations for 72% of the Proteus spp., E. coli, Salmonella spp. and Klebsiella spp. (n = 61) and for 48% of the Streptococci spp. and Staphylococci spp. (n = 31) were < or = 0.5 microg/mL. The minimum inhibitory concentration (MIC) of 76% of Pseudomonas spp. (n = 25) was < or = 2 microg/mL. Fourteen strains were resistant to concentrations > or = 128 microg/mL. The elimination half-lives (t1/2 elim beta) (mean +/- SEM) of 10 mg/kg enrofloxacin in eight houbara bustards (Chlamydotis undulata) were 6.80 +/- 0.79, 6.39 +/- 1.49 and 5.63 +/- 0.54 h after oral (p.o.), intramuscular (i.m.) and intravenous (i.v.) administration, respectively. Enrofloxacin was rapidly absorbed from the bustard gastro-intestinal tract and maximum plasma concentrations of 1.84 +/- 0.16 microg/mL were achieved after 0.66 +/- 0.05 h. Maximum plasma concentration after i.m. administration of 10 mg/kg was 2.75 +/- 0.11 microg/mL at 1.72 +/- 0.19 h. Maximum plasma concentration after i.m. administration of 15 mg/kg in two birds was 4.86 microg/mL. Bioavailability was 97.3 +/- 13.7% and 62.7 +/- 11.1% after i.m. and oral administration, respectively. Plasma concentrations of enrofloxacin > or = 0.5 microg/mL were maintained for at least 12 h for all routes at 10 mg/kg and for 24 h after i.m. administration at 15 mg/kg. Plasma enrofloxacin concentrations were monitored during the first 3 days of treatment in five houbara bustards and kori bustards (Ardeotis kori) with bacterial infections receiving a single daily i.m. injection of 10 mg/kg for 3 days. The mean plasma enrofloxacin concentrations in the clinical cases at 27 and 51 h (3.69 and 3.86 microg/mL) and at 48 h (0.70 microg/mL) were significantly higher compared with the 3 h and 24 h time intervals from clinically normal birds. The maximum plasma concentration (Cmax)/MIC ratio was ranked i.v. (10/mg/kg) > i

  17. Effects of Administration of Fostamatinib on Blood Concentrations of an Oral Contraceptive in Healthy Female Subjects

    ClinicalTrials.gov

    2012-02-17

    Scientific Terminology Rheumatoid Arthritis, Healthy Female Volunteers, Pharmacokinetics, Oral Contraceptive, Drug-drug Interaction; Laymen Terminology Level of Oral Contraceptive in Blood, Oral Contraceptive, Rheumatoid Arthritis, Drug -Drug Interaction

  18. Comparisons of pharmacokinetics and NO-releasing of nitrofibriate and fenofibrate after oral administration in rats.

    PubMed

    Yang, Yujie; Cheng, Qiang; Liu, Xiumei; Liu, Zejuan; Li, Tingting; Jiang, Xuehua; Wang, Ling

    2016-12-01

    Nitrofibriate, a new compound of hypolipidemic, is modified based on fenofibrate. Both of them are used for prevention and treatment of cardiovascular diseases. In this study, an accurate and sensitive analytical method of reversed-phase high-performance liquid chromatography was developed to determine fenofibric acid, which is an active metabolite of both nitrofibriate and fenofibrate in rat plasma. This method was validated and successfully applied to pharmacokinetic study of nitrofibriate and fenofibrate after oral administration. The results suggested that the pharmacokinetic behavior of nitrofibriate followed a nonlinear process, while fenofibrate was linear, demonstrating that the two drugs were different in pharmacokinetic behaviors. Moreover, the effect of fenofibrate and nitrofibriate on releasing NO in rat serum was explored. This study showed that nitrofibriate, as a nitric oxide donor, could slowly release nitric oxide in vivo. This study provided a biopharmaceutical basis for further study of nitrofibriate. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Eudragit EPO nanoparticles: application in improving therapeutic efficacy and reducing ulcerogenicity of meloxicam on oral administration.

    PubMed

    Khachane, Parag; Date, Abhijit A; Nagarsenker, Mangal S

    2011-08-01

    The objective of this investigation was to evaluate the potential of Eudragit EPO nanoparticles (EPO NP) in improving therapeutic efficacy of meloxicam (MLX). MLX loaded EPO NP were prepared by nanoprecipitation method and were characterized for particle size, encapsulation efficiency and for morphology. The in vitro dissolution profile of MLX loaded EPO NP and MLX suspension was evaluated. MLX loaded EPO NP had particle size of approximately 100 nm and the encapsulation efficiency of MLX was approximately 90%. The EPO NP significantly improved anti-inflammatory activity of MLX (P < 0.01) as compared to that of MLX suspension. The enhanced anti-inflammatory effect was maintained for a longer duration (6 h) in case of MLX loaded EPO NP Oral administration of MLX loaded EPO NP also resulted in lesser ulcerogenicity as compared to that of MLX suspension indicating that nanoparticles can also decrease the adverse effects associated with MLX treatment.

  20. Tissue distribution comparison between healthy and fatty liver rats after oral administration of hawthorn leaf extract.

    PubMed

    Yin, Jingjing; Qu, Jianguo; Zhang, Wenjie; Lu, Dongrui; Gao, Yucong; Ying, Xixiang; Kang, Tingguo

    2014-05-01

    Hawthorn leaves, a well-known traditional Chinese medicine, have been widely used for treating cardiovascular and fatty liver diseases. The present study aimed to investigate the therapeutic basis treating fatty liver disease by comparing the tissue distribution of six compounds of hawthorn leaf extract (HLE) in fatty liver rats and healthy rats after oral administration at first day, half month and one month, separately. Therefore, a sensitive and specific HPLC method with internal standard was developed and validated to determine chlorogenic acid, vitexin-4''-O-glucoside, vitexin-2''-O-rhamnoside, vitexin, rutin and hyperoside in the tissues including heart, liver, spleen, kidney, stomach and intestine. The results indicated that the six compounds in HLE presented some bioactivity in treating rat fatty liver as the concentrations of the six compounds varied significantly in inter- and intragroup comparisons (healthy and/or fatty liver group).

  1. Influence of acute and subchronic oral administration of dehydroepiandrosterone (DHEA) on nociceptive threshold in rats.

    PubMed

    Gąsińska, Emilia; Bujalska-Zadrożny, Magdalena; Sar, Monika; Makulska-Nowak, Helena

    2012-01-01

    Dehydroepiandrosterone (DHEA), a neurosteroid, is known to be the most abundant hormone in the human body. Its role in the central nervous system has not been well defined. Previous studies indicate that DHEA is synthesized in the spinal cord and plays an important role in pain modulation. In the present study, we investigated the effect of DHEA on pain threshold in rats after both acute and subchronic treatment. Rats were orally administered with DHEA at a dose of 10 mg/kg once daily and the pain threshold was measured with mechanical and thermal stimuli. After acute treatment, DHEA exhibited pronociceptive effects which lasted up to 150 min. After subchronic administration, DHEA showed an opposite effect by elevating the pain threshold. The results suggest that DHEA could be indicated as a drug to improve treatment of chronic pain disorders.

  2. Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies

    PubMed Central

    Dang, Michelle; Henderson, Rachel E.; Garraway, Levi A.

    2016-01-01

    ABSTRACT Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Challenges in the form of drug delivery-related trauma and anesthesia-related toxicity have excluded the adult zebrafish from long-term drug efficacy studies. Here, we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform. As a proof of principle, we established drug efficacy of the FDA-approved BRAFV600E inhibitor, Vemurafenib, in adult zebrafish harboring BRAFV600E melanoma tumors. In the model, adult casper zebrafish intraperitoneally transplanted with a zebrafish melanoma cell line (ZMEL1) and exposed to daily sub-lethal dosing at 100 mg/kg of Vemurafenib for 2 weeks via oral gavage resulted in an average 65% decrease in tumor burden and a 15% mortality rate. In contrast, Vemurafenib-resistant ZMEL1 cell lines, generated in culture from low-dose drug exposure for 4 months, did not respond to the oral gavage treatment regimen. Similarly, this drug treatment regimen can be applied for treatment of primary melanoma tumors in the zebrafish. Taken together, we developed an effective long-term drug treatment system that will allow the adult zebrafish to be used to identify more effective anti-melanoma combination therapies and opens up possibilities for treating adult models of other diseases. PMID:27482819

  3. Oral Administration of Methylphenidate Blocks the Effect of Cocaine on Uptake at the Drosophila Dopamine Transporter

    PubMed Central

    2013-01-01

    Although our understanding of the actions of cocaine in the brain has improved, an effective drug treatment for cocaine addiction has yet to be found. Methylphenidate binds the dopamine transporter and increases extracellular dopamine levels in mammalian central nervous systems similar to cocaine, but it is thought to elicit fewer addictive and reinforcing effects owing to slower pharmacokinetics for different routes of administration between the drugs. This study utilizes the fruit fly model system to quantify the effects of oral methylphenidate on dopamine uptake during direct cocaine exposure to the fly CNS. The effect of methylphenidate on the dopamine transporter has been explored by measuring the uptake of exogenously applied dopamine. The data suggest that oral consumption of methylphenidate inhibits the Drosophila dopamine transporter and the inhibition is concentration dependent. The peak height increased to 150% of control when cocaine was used to block the dopamine transporter for untreated flies but only to 110% for methylphenidate-treated flies. Thus, the dopamine transporter is mostly inhibited for the methylphenidate-fed flies before the addition of cocaine. The same is true for the rate of the clearance of dopamine measured by amperometry. For untreated flies the rate of clearance changes 40% when the dopamine transporter is inhibited with cocaine, and for treated flies the rate changes only 10%. The results were correlated to the in vivo concentration of methylphenidate determined by CE-MS. Our data suggest that oral consumption of methylphenidate inhibits the Drosophila dopamine transporter for cocaine uptake, and the inhibition is concentration dependent. PMID:23402315

  4. Absorption of enrofloxacin and marbofloxacin after oral and subcutaneous administration in diseased koalas (Phascolarctos cinereus).

    PubMed

    Griffith, J E; Higgins, D P; Li, K M; Krockenberger, M B; Govendir, M

    2010-12-01

    Koalas (n = 43) were treated daily for up to 8 weeks with enrofloxacin: 10 mg/kg subcutaneously (s.c.), 5 mg/kg s.c., or 20 mg/kg per os (p.o.); or marbofloxacin: 1.0-3.3 mg/kg p.o., 10 mg/kg p.o. or 5 mg/kg s.c. Serial plasma drug concentrations were determined on day 1 and again at approximately 2 weeks, by liquid chromatography. The median (range) plasma maximum concentrations (C(max) ) for enrofloxacin 5 mg/kg s.c. and 10 mg/kg s.c. were 0.83 (0.68-1.52) and 2.08 (1.34-2.96) μg/mL and the median (range) T(max) were 1.5 h (1-2) and 1 h (1-2) respectively. Plasma concentrations of orally dosed marbofloxacin were too low to be quantified. Oral administration of enrofloxacin suggested absorption rate limited disposition pharmacokinetics; the median (range) C(max) for enrofloxacin 20 mg/kg p.o. was 0.94 (0.76-1.0) μg/mL and the median (range) T(max) was 4 h (2-8). Oral absorption of both drugs was poor. Plasma protein binding for enrofloxacin was 55.4 ± 1.9% and marbofloxacin 49.5 ± 5.3%. Elevations in creatinine kinase activity were associated with drug injections. Enrofloxacin and marbofloxacin administered at these dosage and routes are unlikely to inhibit the growth of chlamydial pathogens in vivo. © 2010 Blackwell Publishing Ltd.

  5. Some pharmacokinetic indices of oral fluconazole administration to koalas (Phascolarctos cinereus) infected with cryptococcosis.

    PubMed

    Govendir, M; Black, L A; Jobbins, S E; Kimble, B; Malik, R; Krockenberger, M B

    2016-08-01

    Three asymptomatic koalas serologically positive for cryptococcosis and two symptomatic koalas were treated with 10 mg/kg fluconazole orally, twice daily for at least 2 weeks. The median plasma Cmax and AUC0-8 h for asymptomatic animals were 0.9 μg/mL and 4.9 μg/mL·h, respectively; and for symptomatic animals 3.2 μg/mL and 17.3 μg/mL·h, respectively. An additional symptomatic koala was treated with fluconazole (10 mg/kg twice daily) and a subcutaneous amphotericin B infusion twice weekly. After 2 weeks the fluconazole Cmax was 3.7 μg/mL and the AUC0-8 h was 25.8 μg/mL*h. An additional three koalas were treated with fluconazole 15 mg/kg twice daily for at least 2 weeks, with the same subcutaneous amphotericin protocol co-administered to two of these koalas (Cmax : 5.0 μg/mL; mean AUC0-8 h : 18.1 μg/mL*h). For all koalas, the fluconazole plasma Cmax failed to reach the MIC90 (16 μg/mL) to inhibit C. gattii. Fluconazole administered orally at either 10 or 15 mg/kg twice daily in conjunction with amphotericin is unlikely to attain therapeutic plasma concentrations. Suggestions to improve treatment of systemic cryptococcosis include testing pathogen susceptibility to fluconazole, monitoring plasma fluconazole concentrations, and administration of 20-25 mg/kg fluconazole orally, twice daily, with an amphotericin subcutaneous infusion twice weekly. © 2015 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

  6. Collecting psychosocial self-report data in oral health research: impact of literacy level and computerised administration

    PubMed Central

    Randall, Cameron L.; McNeil, Daniel W.; Crout, Richard J.; Weyant, Robert J.; Marazita, Mary L.

    2014-01-01

    Objectives In oral and other health research, participant literacy levels may impact the quality of data obtained through self-report (e.g., degree of data missingness). This study addressed whether computerized administration of a battery of psychosocial instruments used in an oral health disparities research protocol yielded more complete data than paper-and-pencil administration and aimed to determine the role of general literacy in differences in data missingness between administration types. Design Oral health data were obtained from 1,652 adolescent and adult participants who were administered a large questionnaire battery via either paper-and-pencil or tablet personal computer. Number of unanswered items for each participant was compared across administration mode. For a subset of 171 participants who were randomized to one of the administration modes, general literacy and satisfaction with the questionnaire experience also were assessed. Results Participants assigned to complete the oral health questionnaire battery via tablet PC were significantly more likely than those assigned to the paper-and-pencil condition to have missing data for at least one item (p < .001); however, for participants who had at least one missing item, paper-and-pencil administration was associated with a greater number of items missed than was tablet PC administration (p < .001). Across administration modes, participants with higher literacy level completed the questionnaire battery more rapidly than their lower literacy counterparts (p < .001). Participant satisfaction was similar for both modes of questionnaire administration (p ≥ .29). Conclusions These results suggest that a certain type of data missingness may be decreased through the use of a tablet computer for questionnaire administration. PMID:26306161

  7. Collecting psychosocial self-report data in oral health research: impact of literacy level and computerised administration.

    PubMed

    Randall, Cameron L; McNeil, Daniel W; Crout, Richard J; Weyant, Robert J; Marazita, Mary L

    2013-09-01

    In oral and other health research, participant literacy levels may impact the quality of data obtained through self-report (e.g., degree of data missingness). This study addressed whether computerized administration of a battery of psychosocial instruments used in an oral health disparities research protocol yielded more complete data than paper-and-pencil administration and aimed to determine the role of general literacy in differences in data missingness between administration types. Oral health data were obtained from 1,652 adolescent and adult participants who were administered a large questionnaire battery via either paper-and-pencil or tablet personal computer. Number of unanswered items for each participant was compared across administration mode. For a subset of 171 participants who were randomized to one of the administration modes, general literacy and satisfaction with the questionnaire experience also were assessed. Participants assigned to complete the oral health questionnaire battery via tablet PC were significantly more likely than those assigned to the paper-and-pencil condition to have missing data for at least one item (p < .001); however, for participants who had at least one missing item, paper-and-pencil administration was associated with a greater number of items missed than was tablet PC administration (p < .001). Across administration modes, participants with higher literacy level completed the questionnaire battery more rapidly than their lower literacy counterparts (p < .001). Participant satisfaction was similar for both modes of questionnaire administration (p ≥ .29). These results suggest that a certain type of data missingness may be decreased through the use of a tablet computer for questionnaire administration.

  8. Acute oral 18-methoxycoronaridine (18-MC) decreases both alcohol intake and IV nicotine self-administration in rats.

    PubMed

    Rezvani, Amir H; Cauley, Marty C; Slade, Susan; Wells, Corinne; Glick, Stanley; Rose, Jed E; Levin, Edward D

    The ibogaine derivative 18-methoxycoronaridine (18-MC) has been found to decrease self-administration of morphine, nicotine and alcohol in rats after systemic injection. However oral dosing is the preferred route clinically. The current study evaluated the effect of oral 18-MC dosing in rats on alcohol and nicotine self-administration. For the nicotine study, young adult female Sprague-Dawley rats were fitted with IV jugular infusion catheters and trained for nicotine self-administration in 45min. sessions. At weekly intervals they were administered by oral gavage doses of 18-MC (0, 10, 20 and 40mg/kg) following a repeated measures counterbalanced design twice. Acute oral 18-MC, at the 40mg/kg dosage, significantly reduced nicotine self-administration. There was a differential effect of 18-MC with rats above or below the median level of nicotine self-administration during the pretreatment baseline performance. Rats with lower baseline performance showed a significant reduction in nicotine self-administration with the 40mg/kg dosage, while those in the higher baseline group did not show a significant effect of 18-MC. In alcohol studies, the effects of the same doses of 18-MC were tested in both male and female alcohol preferring (P) rats that had free access to water and alcohol (10% v/v) 6h/day. The results show that 18-MC dose-dependently reduced alcohol intake in both male and female rats. All doses caused significant reductions in alcohol self-administration. These data reinforce previous findings that 18-MC is significantly effective in reducing alcohol intake and nicotine self-administration. The finding that 18-MC is also effective orally makes it advantageous for further development as a possible new therapy for treating alcoholism as well as smoking addiction. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Pharmacokinetics and in vitro efficacy of salicylic acid after oral administration of acetylsalicylic acid in horses.

    PubMed

    Buntenkötter, Kathrin; Osmers, Maren; Schenk, Ina; Schänzer, Wilhelm; Machnik, Marc; Düe, Michael; Kietzmann, Manfred

    2017-01-19

    Although acetylsalicylic acid (ASA) is not frequently used as a therapeutic agent in horses, its metabolite SA is of special interest in equestrianism since it is a natural component of many plants used as horse feed. This led to the establishment of thresholds by horse sport organizations for SA in urine and plasma. The aim of this study was to investigate plasma and urine concentrations of salicylic acid (SA) after oral administration of three different single dosages (12.5 mg/kg, 25 mg/kg and 50 mg/kg) of acetylsalicylic acid (ASA) to eight horses in a cross-over designed study. In the 12.5 mg/kg group, SA concentrations in urine peaked 2 h after oral administration (2675 μg/mL); plasma concentrations peaked at 1.5 h (17 μg/mL). In the 25 mg/kg group, maximum concentrations were detected after 2 h (urine, 2785 μg/mL) and 1.5 h (plasma, 23 μg/mL). In the 50 mg/kg group, maximum concentrations were observed after 5 h (urine, 3915 μg/mL) and 1.5 h (plasma, 45 μg/mL). The plasma half-life calculated for SA varied between 5.0 and 5.7 h. The urine concentration of SA fell below the threshold of 750 μg/mL (set by the International Equestrian Federation FEI and most of the horseracing authorities) between 7 and 26 h after administration of 12.5 and 25 mg/kg ASA and between 24 and 36 h after administration of 50 mg/kg ASA. For ASA, IC50 were 0.50 μg/mL (COX-1) and 5.14 μg/mL (COX-2). For salicylic acid, it was not possible to calculate an IC50 for either COX due to insufficient inhibition of both cyclooxygenases. The established SA thresholds of 750 μg//mL urine and 6.5 μg/mL plasma appear too generous and are leaving space for misuse of the anti-inflammatory and analgetic compound ASA in horses.

  10. Microencapsulation of tannic acid for oral administration to inhibit carbohydrate digestion in the gastrointestinal tract.

    PubMed

    Zhao, Wei; Iyer, Vidya; Flores, Floirendo P; Donhowe, Erik; Kong, Fanbin

    2013-06-01

    The prevalence of diabetes mellitus and obesity is rapidly rising worldwide. Recently, there is increasing evidence that phytochemicals such as polyphenols in our diet could directly inhibit the activities of key digestive enzymes, representing a novel method of controlling and preventing diabetes mellitus and obesity. More research is required to determine how to effectively utilize phytochemicals within the gastrointestinal (GI) tract to obtain maximum inhibition of digestive enzymes. This study investigated the inhibition efficiency of tannic acid (TA) on α-amylase as compared with other potential inhibitors using an in vitro method. The inhibition mode and kinetics were studied. The results showed that tannic acid (TA) is more effective in inhibiting α-amylase than a commercial starch blocker (Phase 2 Starch Blocker), and some selected flavonoids and polyphenols including quercetin, rutin, and polyphenon from green tea. It is also found that inhibition of α-amylase by TA in the GI tract is difficult if administered orally due to the non-specific and reversible noncompetitive interaction between tannic acid and α-amylase or other proteins. Accordingly, a pH-sensitive delivery system using calcium-alginate microspheres encapsulating tannic acid was successfully developed for oral administration to inhibit carbohydrate digestion in the GI tract. The encapsulated TA in calcium-alginate microspheres could be protected from the proteins in the stomach, and sustain release and inhibit α-amylase activity in the small intestine.

  11. [Density of adhesive proteins after oral administration of proteolytic enzymes in multiple myeloma].

    PubMed

    Sakalová, A; Kunze, R; Holománová, D; Hapalová, J; Chorváth, B; Mistrík, M; Sedlák, J

    1995-12-01

    The authors present information on the presence of adhesive proteins on membranes of myeloma and precursor cells isolated from bone marrow and blood from a group of 33 patients examined by fluorescent flow cytometry. They also compare the density of integrins (CD29, CD49e, CD41, CD51 and CD61) and adhesive proteins from the group of "homing" receptors (CD44) and IgG "superfamily" (LFA-1, LFA-3, ICAM-1, N-CAM) and their changes after a single oral dose of a mixture of proteolytic enzymes (Wobe Mugos, Wobenzym, MUCOS Pharma, FRG). The authors observed a significant drop of CD29, CD54 (ICAM-1), CD58 (LFA-3) after Wobe Mugos, CD49, CD51, CD58 after Wobenzyme. The insignificant decline of density of CD44 on cells, as well as of the soluble receptor of CD44 after oral administration of proteolytic enzymes in serum, incl. the mentioned changes of integrins and other adhesive proteins, indicate the importance of enzyme preparations in the supporting treatment of malignant processes.

  12. Toxicokinetics and recovery studies of dicamba dimethyl amine salt in goats following single oral administration.

    PubMed

    Mukherjee, Madhusudan; Muraleedharannair, Prashant; Karmakar, Utpal K; Datta, Bakul K; Sar, Tapas K; Chakraborty, Animesh K; Bhattacharya, Anjan; Choudhury, Ashim; Mandal, Tapan K

    2010-01-30

    Toxicokinetics and recovery studies of dicamba dimethyl amine salt (DDAS) were conducted to obtain more information about its toxicity and tissue retention in farm animals. The minimum oral toxic dose level of DDAS was determined as 1400 mg kg(-1) body weight. In the toxicokinetic study, blood DDAS concentration of 55.6 +/- 0.59 microg mL(-1) (mean +/- standard error) was detected at 0.08 h, which peaked to 102.3 +/- 5.03 microg mL(-1) at 0.25 h, and declined to a minimum of 4.1 +/- 0.06 microg mL(-1) at 36 h. In recovery studies, DDAS concentration in urine began to increase significantly (P < 0.05) from 12 h, peaked at 24 h and declined from 48 h onwards. Maximum excretion through faeces was at 24 h and was complete by 144 h. The residual level in tissues decreased significantly (P < 0.05) on day 7 as compared to day 4. In histopathological studies, cellular alterations in lungs, liver, kidney, adrenal gland and spleen were found. DDAS persists in the body for a shorter period and its major excretory route is through urine. DDAS has lower affinity to accumulate in tissues, and intensity of cellular alterations is not severe after single-dose oral administration. (c) 2009 Society of Chemical Industry.

  13. Genetically manipulated phages with improved pH resistance for oral administration in veterinary medicine

    PubMed Central

    Nobrega, Franklin L.; Costa, Ana Rita; Santos, José F.; Siliakus, Melvin F.; van Lent, Jan W. M.; Kengen, Servé W. M.; Azeredo, Joana; Kluskens, Leon D.

    2016-01-01

    Orally administered phages to control zoonotic pathogens face important challenges, mainly related to the hostile conditions found in the gastrointestinal tract (GIT). These include temperature, salinity and primarily pH, which is exceptionally low in certain compartments. Phage survival under these conditions can be jeopardized and undermine treatment. Strategies like encapsulation have been attempted with relative success, but are typically complex and require several optimization steps. Here we report a simple and efficient alternative, consisting in the genetic engineering of phages to display lipids on their surfaces. Escherichia coli phage T7 was used as a model and the E. coli PhoE signal peptide was genetically fused to its major capsid protein (10 A), enabling phospholipid attachment to the phage capsid. The presence of phospholipids on the mutant phages was confirmed by High Performance Thin Layer Chromatography, Dynamic Light Scattering and phospholipase assays. The stability of phages was analysed in simulated GIT conditions, demonstrating improved stability of the mutant phages with survival rates 102–107 pfu.mL−1 higher than wild-type phages. Our work demonstrates that phage engineering can be a good strategy to improve phage tolerance to GIT conditions, having promising application for oral administration in veterinary medicine. PMID:27976713

  14. Effect of food on the bioavailability of bromazepam following oral administration in healthy volunteers.

    PubMed

    Fujii, J; Inotsume, N; Nakano, M

    1990-05-01

    The effect of food on the rate and extent of bioavailability of bromazepam was examined in seven normal volunteers following a single oral dose of 10 mg bromazepam with 200 ml of water in the fasting and non-fasting states. Plasma concentrations of bromazepam were measured by high pressure liquid chromatography. A tmax value in a non-fasting state was prolonged from 2.3 +/- 0.3 (mean +/- S.E.M.) to 2.8 +/- 0.6 h but not significantly different (p greater than 0.05) whereas a Cmax value was significantly (p less than 0.05) decreased from 259 +/- 12.7 (mean +/- S.E.M.) to 169 +/- 13.9 ng/ml. The area under the plasma concentration-time curve in the non-fasting state was also significantly (p less than 0.05) decreased from 1844 +/- 145 (mean +/- S.E.M.) to 1233 +/- 98.1 ng.h/ml after oral administration of bromazepam.

  15. Oral administration of Brazilian propolis exerts estrogenic effect in ovariectomized rats.

    PubMed

    Okamoto, Yoshinori; Tobe, Takao; Ueda, Koji; Takada, Tatsuyuki; Kojima, Nakao

    2015-04-01

    Propolis, a natural product derived from plants by honeybees, is a mixture of several hundred chemicals, including flavonoids, coumaric acids, and caffeic acids, some of which show estrogen-like activity. In this study, the estrogenic activity of crude ethanolic extract of Brazilian propolis was determined using several in vitro and in vivo assays. Propolis was found to bind to human estrogen receptors (ERs). Furthermore, propolis induced the expression of estrogen-responsive genes in ER-positive MCF-7 and Ishikawa cells. These in vitro assays suggest that propolis exerts estrogenic activity; therefore, in vivo experiments were conducted using ovariectomized rats. Oral administration of propolis (55 or 550 mg/kg/day for 3 days) significantly increased uterine wet weight and luminal epithelium thickness in comparison with the corresponding values in the corn oil-treated control group. Moreover, propolis induced ductal cell proliferation in the mammary glands. These effects were completely inhibited by full ER antagonist ICI 182,780, confirming that the effects of propolis are mediated by the ER. Our data show that oral intake of propolis induces estrogenic activity in ER-expressing organs in vivo and suggest that Brazilian propolis is a useful dietary source of phytoestrogens and a promising treatment for postmenopausal symptoms.

  16. Toxicokinetic differences and toxicities of silver nanoparticles and silver ions in rats after single oral administration.

    PubMed

    Park, Kwangsik

    2013-01-01

    Blood levels, tissue distributions, and excretion of silver (Ag) were measured in male Sprague-Dawley rats (n = 5) up to 24 h after a single oral administration of silver nanoparticles (AgNP) and silver ions (Ag(+)), respectively. The AUC24hr of Ag(+) was 3.81 ± 0.57 μg/d/ml when rats were treated with a single dose of 20 mg/kg, whereas that of AgNP was 1.58 ± 0.25 μg/d/ml. Tissue distribution of Ag in liver, kidneys, and lungs was higher when Ag(+) was administered compared to AgNP. Orally administered AgNP were predominantly excreted through feces, suggesting low bioavailability. Death or body weight changes were not observed in the Ag(+)- or AgNP-treated groups. However, decreased red blood cell counts, hematocrit, and hemoglobin were found in the Ag(+)-treated groups, while increased platelet counts and mean platelet volume were noted in the AgNP-treated rats. A serum biochemical analysis showed that aspartate aminotransferase (AST) and alanine aminotransferase (ALT) rose significantly following Ag(+) treatment (20 mg/kg). AgNP treatment (2 or 20 mg/kg) also elevated AST, whereas infiltration of mononuclear cells with liver necrosis was found only in the 20 mg/kg Ag(+)-treated animals.

  17. Toxicokinetics and tissue distribution of titanium in ionic form after intravenous and oral administration.

    PubMed

    Golasik, Magdalena; Herman, Małgorzata; Olbert, Magdalena; Librowski, Tadeusz; Szklarzewicz, Janusz; Piekoszewski, Wojciech

    2016-04-15

    Titanium is widely used both in food and cosmetics, as well as in surgery and industry. Contrary to most studies, the present work focused on the determination of the toxicokinetic parameters of titanium in ionic form, as well as on its tissue biodistribution in rats. The animals were administered either a single intravenous dose of 6 mg Ti/kg b.w., or received the same dose orally every day for 30 days. The concentration of titanium in the serum and organs was measured by a graphite furnace atomic absorption spectrometry. Metal rapidly distributed from the circulation to the investigated organs after both routes of administration, and kidney was identified as the main target tissue, followed by liver and spleen. One month of oral exposure to Ti led to the increase of its concentration in liver, kidneys, spleen, and heart. In the intravenous study, both the highest area under concentration-time curves and the longest elimination half-life time were recorded in the kidney followed by serum, spleen and liver. The present study contributes to the knowledge of the toxicokinetics of titanium in ionic form, which may be especially useful when assessing the health risks of long-term exposure to titanium alloy implants in patients.

  18. Polyelectrolyte complex of carboxymethyl starch and chitosan as protein carrier: oral administration of ovalbumin.

    PubMed

    Assaad, Elias; Blemur, Lindsay; Lessard, Martin; Mateescu, Mircea Alexandru

    2012-01-01

    A novel carboxymethyl starch (CMS)/chitosan polyelectrolyte complex (PEC) was proposed as an excipient for oral administration of ovalbumin. The dissolution of ovalbumin from monolithic tablets (200 mg, 2.1 × 9.6 mm, 50% loading) obtained by direct compression was studied. When CMS was used as an excipient, more than 70% of the loaded ovalbumin remained undigested after 1 h of incubation in simulated gastric fluid (SGF) with pepsin. The complete dissolution, after transfer of tablets into simulated intestinal fluid (SIF) with pancreatin, occurred within a total time of about 6 h. Higher protection (more than 90% stability in SGF) and longer dissolution (more than 13 h) were obtained with 50% CMS/50% chitosan physical mixture or with PEC excipients. A lower proportion of chitosan was needed for PEC than for the CMS/chitosan mixture to obtain a similar dissolution profile. The high protection against digestion by pepsin, the various release times and the mucoadhesion properties of these excipients based on CMS favor the development of suitable carriers for oral vaccinations.

  19. Whole-body localization of 14C-tocopheryl acetate in the rat following oral administration.

    PubMed

    Fand, I; McNally, W P

    1981-03-01

    The whole-body localization of dl-alpha-[3, 4-14C2]-tocopheryl acetate was examined in the rat for intervals ranging between 12-96 hr following administration of a single oral dose. Quantitative evaluation of the macroautoradiograms revealed a rapid removal of 14C-vitamin E equivalents from the blood and gut and their accumulation in body tissues. When the densitometric data were expressed as dpm/mm2, the values for radioactivity uptake by the adrenal cortex were systematically the highest of all tissues examined for all time periods. At 12-96 hr after dosing, high activity was noted in spleen, bone marrow, liver, lymph nodes and fat; moderate activity was observed in myocardium, lung, gastric mucosa, pituitary, blood, hair follicles, Harder's gland and nasal mucosa; low values were found in brain, skeletal muscle and spinal cord. The nearly complete exclusion of radiovitamin E from the brain and its localization to the choroid plexus implied the operation of a blood-brain barrier. Labeled vitamin E uptake in brain, salivary glands and skeletal muscle was essentially linear and increased with time over 12-96 hr. For both early and late sacrifice periods, a differential pattern of 14C-radioactivity uptake was observed with the pituitary, where the pars nervosa exhibited 2.8 times greater activity than the pars distalis. The significance of the findings is discussed in relation to the suggested role of vitamin E in pituitary-adrenal functions, hemopoiesis and oral physiology.

  20. Mechanism of hepatic targeting via oral administration of DSPE–PEG–cholic acid-modified nanoliposomes

    PubMed Central

    Li, Ying; Zhu, Chunyan

    2017-01-01

    In oral administration, gastrointestinal physiological environment, gastrointestinal epithelial cell membranes, and blood circulation are typical biological barriers to hepatic delivery of ligand-modified nanoparticle drug delivery systems. To elucidate the mechanism of oral hepatic targeting of cholic acid receptor-mediated nanoliposomes (LPs) (distearoyl phosphatidylethanolamine–polyethylene glycol–cholic acid-modified LPs, CA-LPs), evaluations were performed on colon cancer Caco-2 cell monolayers, liver cancer HepG2 cells, and a rat intestinal perfusion model. CA-LPs, ~100 nm in diameter, exhibited sustained-release behavior and had the greatest stability in rat gastrointestinal fluid and serum for both size and entrapment efficiency. CA-LPs demonstrated highest transport across Caco-2 cells and highest cellular uptake by HepG2 cells. The enhanced endocytosis of CA-LPs was found to be mediated by Na+/taurocholate cotransporting polypeptide and involved the caveolin-mediated endocytosis pathway. Further, we used fluorescence resonance energy transfer (FRET) technology to show that the CA-LPs maintained their structural integrity in part during the transport across the Caco-2 cell monolayer and uptake by HepG2 cells. PMID:28280334

  1. Oral post-surgical complications following the administration of bisphosphonates given for osteopenia related to malignancy.

    PubMed

    Soileau, Kristi M

    2006-04-01

    This case report seeks to illustrate the clinical consequences of the administration of bisphosphonate therapy to prevent osteopenia secondary to malignancy in one patient. A 69-year-old white female with a history of breast cancer with metastasis presented with pain in the upper left quadrant and periodontal pocketing of at least 6 mm in each of the four quadrants of the oral cavity. One week following surgery on the lower right region, lingual bone exposure was noted, and several attempts at achieving healing over the course of 15 months proved unsuccessful. Upon referral to a surgeon at the Louisiana State University Medical Center, New Orleans, Louisiana, a potential causative factor was finally identified. The drug zoledronic acid, a bisphosphonate given for prevention of osteoclastic activity of bone metastasis, secondary to breast cancer, was identified as the possible cause of inhibition of healing, most likely from regional vascular insufficiency. The drug was immediately discontinued. The patient is healing very slowly with the aid of hyperbaric therapy; she has been unable to achieve smoking cessation, which is deterring thorough healing of the exposed bony area on the lower right lingual side. Physicians and dentists alike must become increasingly aware of impaired oral healing following the use of bisphosphonates given for malignancy-related osteopenia. A dental exam should be performed before bisphosphonate therapy, as recommended for radiation therapy related to malignancy.

  2. Tissue Distribution of trans-Resveratrol and Its Metabolites after Oral Administration in Human Eyes

    PubMed Central

    Weinreb, Robert N.

    2017-01-01

    Purpose. This study was performed to measure the concentration of trans-resveratrol and its three metabolites in human eyes. Methods. The patients who underwent pars plana vitrectomy for rhegmatogenous retinal detachment were included. The participants were orally given trans-resveratrol-based supplement (Longevinex®). A suitable amount of conjunctiva, aqueous humor, and vitreous humor were obtained during the operation. High-performance liquid chromatography (HPLC) with mass spectrometry (LC/MS/MS) was used to detect the concentration of trans-resveratrol and its three metabolites in the various samples. Results. The average concentration of resveratrol in the conjunctiva was 17.19 ± 15.32 nmol/g (mean ± SD). The concentration of resveratrol in the aqueous humor was close to the limit of detection, but its metabolites could be quantified. The concentrations of resveratrol metabolites in the aqueous humor can be detected. In the vitreous humor, the average concentration of resveratrol-3-O-sulfate was 62.95 ± 41.97 nmol/L. The sulfate conjugations of resveratrol were recovered in the conjunctiva, aqueous humor, and vitreous humor. Conclusions. Resveratrol and its three metabolites can be detected in the ocular tissues after oral administration. Although the concentration of parent resveratrol was low in the eyes, its metabolites could be detected and may have a role in the treatment of ocular diseases. PMID:28409021

  3. Pharmacokinetics in dogs after oral administration of two different forms of ascorbic acid.

    PubMed

    Wang, S; Berge, G E; Hoem, N O; Sund, R B

    2001-08-01

    The dog is able to synthesise ascorbic acid (AA), but is frequently given the vitamin in an attempt to improve health and performance. The pharmacokinetics of AA in this species, however, are not well studied. Using a selective analytical method and careful stability control, the pharmacokinetics of orally given AA was studied in 20 dogs, at two dosage levels (15 and 50 mg kg(-1)) and with two forms of supplement [crystalline AA and the vitamin C product Ester-C(Inter-Cal Corp., Prescott, AZ, USA)]. After oral administration, a rapid increase was found in the plasma level of AA, indicating a possible intestinal active transport mechanism in this species. The obtained C(max)and AUC values were found to increase in a non-linear fashion when the dose of AA was increased. The pharmacokinetic modeling of the elimination of AA was made difficult by a pronounced secondary peak appearing after about 9 hours. The comparison of crystalline AA and Ester-C did not indicate any significant differences in pharmacokinetic parameters between the two preparations of the vitamin. Copyright 2001 Harcourt Publishers Ltd.

  4. Urinary pharmacokinetics of methamphetamine and its metabolite, amphetamine following controlled oral administration to humans.

    PubMed

    Kim, Insook; Oyler, Jonathan M; Moolchan, Eric T; Cone, Edward J; Huestis, Marilyn A

    2004-12-01

    Methamphetamine is widely abused for its euphoric effects. Our objectives were to characterize the urinary pharmacokinetics of methamphetamine and amphetamine after controlled methamphetamine administration to humans and to improve the interpretation of urine drug test results. Participants (n = 8) received 4 daily 10-mg (low) oral doses of sustained-release (d)-methamphetamine hydrochloride within 7 days. After 4 weeks, 5 participants received 4 daily 20-mg (high) oral doses. All urine specimens were collected during the study. Methamphetamine and amphetamine were measured by GC-MS/PCI. Maximum excretion rates ranged from 403 to 4919 microg/h for methamphetamine and 59 to 735 microg/h for amphetamine with no relationship between dose and excretion rate. The mean molar percentage of dose in the urine as total methamphetamine and amphetamine were 57.5 +/- 21.7% (low dose) and 40.9 +/- 8.5% (high dose). Mean urinary terminal elimination half-lives across doses were 23.6 +/- 6.6 hours for methamphetamine and 20.7 +/- 7.3 hours for amphetamine. Methamphetamine renal clearance across doses was 175 +/- 102 mL/min. The mean amphetamine/methamphetamine percentage ratio based on the area under the urinary excretion-time curve increased over time from 13.4 +/- 6.5% to 35.7 +/- 26.6%. Slow urinary excretion results in drug accumulation and increases in detection time windows. Our findings also support the presence of an active renal excretion mechanism for methamphetamine.

  5. Effects of short-term oral salbutamol administration on exercise endurance and metabolism.

    PubMed

    Collomp, K; Candau, R; Lasne, F; Labsy, Z; Préfaut, C; De Ceaurriz, J

    2000-08-01

    The present study examined whether oral short-term administration of salbutamol (Sal) modifies performance and selected hormonal and metabolic variables during submaximal exercise. Eight recreational male athletes completed two cycling trials at 80-85% peak O(2) consumption until exhaustion after either gelatin placebo (Pla) or oral Sal (12 mg/day for 3 wk) treatment, according to a double-blind and randomized protocol. Blood samples were collected at rest, after 5, 10, and 15 min, and at exhaustion to determine growth hormone (GH), cortisol, testosterone, triiodothyronine (T(3)), C peptide, free fatty acid (FFA), blood glucose, lactate, and blood urea values. Time of cycling was significantly increased after chronic Sal intake (Sal: 30.5 +/- 3.1 vs. Pla: 23.7 +/- 1.6 min, P < 0.05). No change in any variable was found before cycling except a decrease in blood urea concentration and an increase in T(3) after Sal that remained significant throughout the exercise test (P < 0.05). Compared with rest, exercise resulted in a significant increase in GH, cortisol, testosterone, T(3), FFAs, and lactate and a decrease in C peptide after both treatments with higher exercise FFA levels and exhaustion GH concentrations after Sal (P < 0.05). Sal but not Pla significantly decreased exercise blood glucose levels. From these data, short-term Sal intake did appear to improve performance during intense submaximal exercise with concomitant increase in substrate availability and utilization, but the exact mechanisms involved need further investigation.

  6. Preparation, characterization and bioavailability by oral administration of O/W curcumin nanoemulsions stabilized with lysophosphatidylcholine.

    PubMed

    Chávez-Zamudio, Rubi; Ochoa-Flores, Angélica A; Soto-Rodríguez, Ida; Garcia-Varela, Rebeca; García, Hugo Sergio

    2017-09-20

    Curcumin is the main and most abundant bioactive component in Curcuma longa L. with documented properties in the prevention and treatment of chronic degenerative and infectious diseases. However, curcumin has low solubility in aqueous media, hence low bioavailability when administered orally. The use of nanoemulsions as carriers can provide a partial solution to bioavailability restrictions. In our study, O/W nanoemulsions of curcumin were prepared using lysophosphatidylcholine, a phospholipid with proven emulsification capacity; nevertheless, such qualities have not been previously reported in the preparation of nanoemulsions. Lysophosphatidylcholine was obtained by enzymatic removal of one fatty acid residue from phosphatidylcholine. The objective of our work was to formulate stable curcumin nanoemulsions and evaluate their bioavailability in BALB/c mice plasma after oral administration. Formulated nanoemulsions had a droplet size mean of 154.32 ± 3.10 nm, a polydispersity index of 0.34 ± 0.07 and zeta potential of -10.43 ± 1.10 mV; stability was monitored for 12 weeks. Lastly, in vivo pharmacokinetic parameters, using BALB/c mice, were obtained; namely, Cmax of 610 ± 65.0 μg mL(-1) and Tmax of 2 h. Pharmacokinetic data revealed a higher bioavailability of emulsified as opposed to free curcumin. Research regarding other potential emulsifiers that may provide better health benefits and carry nano-encapsulated bioactive compounds more effectively, is necessary. This study provides important data on the preparation and design of nanoencapsulated Curcumin using lysophosphatidylcholine as an emulsifier.

  7. Effective gastric acid suppression after oral administration of enteric-coated omeprazole granules.

    PubMed

    Mohiuddin, M A; Pursnani, K G; Katzka, D A; Gideon, R M; Castell, J A; Castell, D O

    1997-04-01

    Omeprazole is inactivated by exposure to gastric acid and is formulated as a gelatin capsule containing enteric-coated granules that release the drug in alkaline medium. In clinical situations where patients are unable to take the capsule orally, the optimum means of administration is uncertain. Eleven normal volunteers were given omeprazole 20 mg every day for one week before breakfast in random order as either a 20-mg capsule with water or free enteric-coated granules with either 8 oz of orange juice, 8 oz of water with 2 Alka-Seltzer antacid tablets (aspirin free), or 1 teaspoon of apple sauce. On day 7 of each regimen, an 8-hr intragastric pH study was performed following omeprazole 20 mg and standard breakfast. The median percentage of time of gastric acid pH > 4 after an omeprazole capsule was 68.5 (25-100); after granules with orange juice 59 (43-100); after granules in Alka-Seltzer solution 63 (31-100), and after granules in apple sauce 65 (30-99), with no significant differences (ANOVA). The time for the gastric pH to reach <4' after having been above was also similar for all four regimens (ANOVA). Omeprazole granules administered orally in a variety of ways achieve gastric acid suppression as effectively as the intact capsule.

  8. [Analog computer analysis of radioactivity kinetics in man following oral administration of tilidine HCl-14C].

    PubMed

    Ringwelski, L

    1975-03-01

    Models for studying the absorption and elimination kinetics of 14-C labelled DL-Ethyl-trans-2-dimethylamino-1-phenyl-cyclohex-3-ene-trans-1-carboxylate-hydrochloride (Tilidine - HCl, Valoron) are developed, based on the concentration vs. time of radioactivity in the plasma following a single oral administration in man. For this purpose, the average concentration values in the plasma of 3 healthy adults, as given by Vollmer and Poisson [12] were employed. 1. Two three-compartment-models were developed which simulate with sufficient accuracy the 14-C-Valoron concentration curve in the plasma. 2. Computer analysis enables one to determine the distribution of 14-C-Valoron among the intra- and extravasal compartments and the half life for absorption t1/2 equals 0.57 h, for transport from plasma into the extravasal compartment t1/2 equals 3.31 h, for resorption t1/2 equals 4.11 h, for elimination with feces t1/2 equals 29.5 h and for elimination in urine t1/2 equals 8.75 h. 3. The use of two different models allows one to draw conclusions concerning the participation of parenchymatous organs in storage and elimination. 4. The probable radioactivity curve is calculated for repeated oral application of 14-C-Valoron in 8 hours intervals.

  9. Oral administration of nasturtium affects peptide YY secretion in male subjects.

    PubMed

    Schiess, Sonja; Platz, Stefanie; Kemper, Margrit; Schreiner, Monika; Mewis, Inga; Rohn, Sascha; Bumke-Vogt, Christiane; Pivovarova, Olga; Pfeiffer, Andreas F H

    2017-08-01

    Nasturtium plants contain the glucosinolate glucotropaeolin and its corresponding breakdown product benzyl isothiocyanate (BITC), the latter being intensively studied with regard to cancer chemoprevention and anti-inflammatory properties. In addition, recent research has shown that isothiocyanates are able to activate the release of several gut hormones in vitro and in rodent studies. Here, we tested the effects of a dietary nasturtium administration on circulating levels of gut hormones in humans. Metabolically healthy males (n = 15) received a single oral dose of 10 g freeze-dried nasturtium leaf material suspended in water or only water (control). Blood samples were taken every hour and serum concentrations of insulin, C-peptide, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide (PYY) were analyzed. Oral nasturtium intake resulted in an increased release of PYY over a time period of 6 h whereas circulating levels of other hormones were not changed. Given the finding that nasturtium consumption enhances secretion of PYY, a key hormone involved in energy regulation, special diets containing nasturtium, or supplementation with nasturtium or BITC might be considered in the treatment of obesity. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Pharmacokinetics of repeated oral administration of tramadol hydrochloride in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Souza, Marcy J; Gerhardt, Lillian; Cox, Sherry

    2013-07-01

    To determine the pharmacokinetics of tramadol hydrochloride (30 mg/kg) following twice-daily oral administration in Hispaniolan Amazon parrots (Amazona ventralis). 9 healthy adult Hispaniolan Amazon parrots. Tramadol hydrochloride was administered to each parrot at a dosage of 30 mg/kg, PO, every 12 hours for 5 days. Blood samples were collected just prior to dose 2 on the first day of administration (day 1) and 5 minutes before and 10, 20, 30, 60, 90, 180, 360, and 720 minutes after the morning dose was given on day 5. Plasma was harvested from blood samples and analyzed by high-performance liquid chromatography. Degree of sedation was evaluated in each parrot throughout the study. No changes in the parrots' behavior were observed. Twelve hours after the first dose was administered, mean ± SD concentrations of tramadol and its only active metabolite M1 (O-desmethyltramadol) were 53 ± 57 ng/mL and 6 ± 6 ng/mL, respectively. At steady state following 4.5 days of twice-daily administration, the mean half-lives for plasma tramadol and M1 concentrations were 2.92 ± 0.78 hours and 2.14 ± 0.07 hours, respectively. On day 5 of tramadol administration, plasma concentrations remained in the therapeutic range for approximately 6 hours. Other tramadol metabolites (M2, M4, and M5) were also present. On the basis of these results and modeling of the data, tramadol at a dosage of 30 mg/kg, PO, will likely need to be administered every 6 to 8 hours to maintain therapeutic plasma concentrations in Hispaniolan Amazon parrots.

  11. Tear film concentrations of doxycycline following oral administration in ophthalmologically normal dogs.

    PubMed

    Collins, Sean P; Labelle, Amber L; Dirikolu, Levent; Li, Zhong; Mitchell, Mark A; Hamor, Ralph E

    2016-09-01

    OBJECTIVE To determine tear film concentrations of doxycycline in ophthalmologically normal dogs following oral doxycycline administration. DESIGN Crossover study. ANIMALS 10 privately owned dolichocephalic or mesaticephalic dogs free of ophthalmic disease. PROCEDURES Dogs were randomly assigned to receive doxycycline hyclate first at 5 mg/kg (2.3 mg/lb) or 10 mg/kg (4.5 mg/lb), PO, every 12 hours for 5 days, beginning on day 1. Doxycycline was administered 1 hour prior to feeding. Tear samples were collected from days 1 through 10 approximately 3 hours after the morning dose was administered. Following a 3-week washout period, dogs received the alternative dose in the same conditions. Doxycycline concentration in tear samples from 1 eye (same eye used for both sessions) was measured via liquid chromatography-mass spectrometry and compared between the 2 doxycycline doses. RESULTS Doxycycline was detected in tear samples of all dogs from days 1 through 10 for both doxycycline doses. Median peak doxycycline concentrations for the 5 mg/kg and 10 mg/kg doses were 2.19 ng/mL on day 3 and 4.32 ng/mL on day 4, respectively. Concentrations differed significantly with time, but this difference was not influenced by dose, dose order, or eye. A significant positive correlation was identified between doxycycline concentration and body weight (r = 0.22). CONCLUSIONS AND CLINICAL RELEVANCE Detectable doxycycline concentrations were achieved in the tear film of ophthalmologically normal dogs following oral administration of doxycycline at 5 or 10 mg/kg, every 12 hours. Dose had no significant effect on tear film concentration of the drug.

  12. Oral Administration of Lipopolysaccharide of Acetic Acid Bacteria Protects Pollen Allergy in a Murine Model.

    PubMed

    Amano, Satoko; Inagawa, Hiroyuki; Nakata, Yoko; Ohmori, Masaki; Kohchi, Chie; Soma, Gen-Ichiro

    2015-08-01

    Lipopolysaccharide (LPS), a major component of the cell wall of Gram-negative bacteria, is known to possess strong immune-regulatory activity. We have found and reported the existence of biologically-active LPS in acetic acid bacteria. The LPS shows Limulus-positive activity and activation of macrophages to produce nitric oxide and tumor necrosis factor. In this study, we investigated the anti-allergic effect of an orally-administrated acetic acid bacteria extract containing LPS; the cedar pollinosis model was used. Acetic acid bacteria were isolated from various fruits by Nodai kaihen medium. Then, the anti-allergic effect of acetic acid bacteria extracts was investigated. BALB/c mice were immunized with a mixture of cedar pollen and alum into their peritoneal cavity; they also received additional immunizations of pollen to nasal cavity. After immunizing the mice with pollen into their nasal cavity to trigger an allergic reaction, the frequency of nose scratching was counted for 5 min. The bacteria were cultured and prepared and the water-extract contained about 1-10 mg/ml of Limulus positive substances. The extract of acetic acid bacteria induced higher levels of interleukin (IL)-10 and FOXP3 mRNA expression in macrophages (RAW246.7 cell), as assessed by DNA microarray analysis. Oral administration of the acetic acid bacteria extract demonstrated significantly less scratching numbers than control water group with pollen immunization. These results showed that LPS in acetic acid bacteria has the potential to protect from an allergic reaction, especially from cedar pollinosis. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  13. Long-Term Oral Administration of Hop Flower Extracts Mitigates Alzheimer Phenotypes in Mice

    PubMed Central

    Sasaoka, Norio; Sakamoto, Megumi; Kanemori, Shoko; Kan, Michiru; Tsukano, Chihiro; Takemoto, Yoshiji; Kakizuka, Akira

    2014-01-01

    Coincident with the expanding population of aged people, the incidence of Alzheimer disease (AD) is rapidly increasing in most advanced countries. At present, no effective prophylactics are available. Among several pathological mechanisms proposed for AD, the “amyloid hypothesis” has been most widely accepted, in which accumulation or deposition of Aβ is considered to be the initial event. Thus, prevention of Aβ production would be an ideal strategy for the treatment or prevention of AD. Aβ is produced via the proteolytic cleavage of its precursor protein, APP (amyloid precursor protein), by two different enzymes, β and γ-secretases. Indeed, inhibitors against either or both enzymes have been developed and tested for clinical efficacy. Based on the “amyloid hypothesis”, we developed a luciferase-based screening method to monitor γ-secretase activity, screened more than 1,600 plant extracts, most of which have long been used in Chinese medicine, and observed that Hop extracts significantly inhibit Aβ production in cultured cells. A major component of the inhibitory activity was purified, and its chemical identity was determined by NMR to be Garcinielliptone HC. In vivo, oral administration of Hop extracts to AD model mice decreased Aβ depositions in the cerebral cortex of the parietal lobe, hippocampus, and artery walls (amyloid angiopathy) in the brains. In a Morris water maze test, AD model mice that had daily consumed Hop extracts in their drinking water showed significant mitigation of memory impairment at ages of 9 and 12 months. Moreover, in the open field test oral administration of Hop extracts also prevented an emotional disturbance that appeared in the AD mice at 18 months. Despite lifelong consumption of Hop extracts, no deleterious side effects were observed at any age. These results support the “amyloid hypothesis”, and indicate that Hop extract is a promising candidate for an effective prophylactic for AD. PMID:24489866

  14. Long-term oral administration of hop flower extracts mitigates Alzheimer phenotypes in mice.

    PubMed

    Sasaoka, Norio; Sakamoto, Megumi; Kanemori, Shoko; Kan, Michiru; Tsukano, Chihiro; Takemoto, Yoshiji; Kakizuka, Akira

    2014-01-01

    Coincident with the expanding population of aged people, the incidence of Alzheimer disease (AD) is rapidly increasing in most advanced countries. At present, no effective prophylactics are available. Among several pathological mechanisms proposed for AD, the "amyloid hypothesis" has been most widely accepted, in which accumulation or deposition of Aβ is considered to be the initial event. Thus, prevention of Aβ production would be an ideal strategy for the treatment or prevention of AD. Aβ is produced via the proteolytic cleavage of its precursor protein, APP (amyloid precursor protein), by two different enzymes, β and γ-secretases. Indeed, inhibitors against either or both enzymes have been developed and tested for clinical efficacy. Based on the "amyloid hypothesis", we developed a luciferase-based screening method to monitor γ-secretase activity, screened more than 1,600 plant extracts, most of which have long been used in Chinese medicine, and observed that Hop extracts significantly inhibit Aβ production in cultured cells. A major component of the inhibitory activity was purified, and its chemical identity was determined by NMR to be Garcinielliptone HC. In vivo, oral administration of Hop extracts to AD model mice decreased Aβ depositions in the cerebral cortex of the parietal lobe, hippocampus, and artery walls (amyloid angiopathy) in the brains. In a Morris water maze test, AD model mice that had daily consumed Hop extracts in their drinking water showed significant mitigation of memory impairment at ages of 9 and 12 months. Moreover, in the open field test oral administration of Hop extracts also prevented an emotional disturbance that appeared in the AD mice at 18 months. Despite lifelong consumption of Hop extracts, no deleterious side effects were observed at any age. These results support the "amyloid hypothesis", and indicate that Hop extract is a promising candidate for an effective prophylactic for AD.

  15. Histological effects of oral administration of nutmeg on the kidneys of adult Wister rats

    PubMed Central

    Eweka, Andrew Osayame; Eweka, Abieyuwa

    2010-01-01

    Aims: The effects of oral administration of nutmeg commonly used as spice in various dishes, as components of teas and soft drinks or mixed in milk and alcohol on the kidneys of adult Wistar rats were carefully studied. Material and Methods: Rats of both sexes (n = 24), with average weight of 220g were randomly assigned into two treatments (A & B) of (n=16) and Control (c) (n=8) groups. The rats in the treatment groups (A & B) received 0.1g (500mg/kg body weight) and 0.2g (1000mg/kg body weight) of nutmeg thoroughly mixed with the feeds respectively on a daily basis for forty-two days. The control group (c) received equal amount of feeds daily without nutmeg added for forty-two days. The growers’ mash feeds was obtained from Edo Feeds and Flour Mill Limited, Ewu, Edo state, Nigeria and the rats were given water liberally. The rats were sacrificed by cervical dislocation on the forty-third day of the experiment. The kidneys were carefully dissected out and quickly fixed in 10% buffered formaldehyde for routine histological study after hematoxylin and eosin method. Result: The histological findings in the treated sections of the kidneys showed distortion of the renal cortical structures, vacuolations appearing in the stroma and some degree of cellular necrosis, with degenerative and atrophic changes when compared to the control group. Conclusion: These findings indicate that oral administration of nutmeg may have some deleterious effects on the kidneys of adult Wistar rats at higher doses and by extension may affect its excretory and other metabolic functions. It is recommended that caution should therefore be advocated in the intake of this product and further studies be carried out to examine these findings. PMID:22624138

  16. Effects of oral administration of trimethoprim-sulfamethoxazole on tear production in clinically normal guinea pigs.

    PubMed

    Asadi, Faezeh; Rajaei, Seyed Mehdi; Golabdar, Salar

    2016-09-01

    To determine the effects of short-term oral administration of trimethoprim-sulfamethoxazole on tear production in clinically normal guinea pigs. Thirty-two healthy adult Abyssinian guinea pigs were used in this study. One day before the start of the trial, the pretreatment baseline phenol red thread test (PRTT) values were recorded. Sixteen guinea pigs in the treated group received 25 mg/kg trimethoprim-sulfamethoxazole orally twice a day for 14 days. The other sixteen guinea pigs were used as untreated controls and received a placebo during the study. All the ophthalmic tests were performed without chemical restraint. PRTT values were evaluated in both eyes of all the guinea pigs using a commercial PRTT strip of a single lot number on days 0 (baseline), 15, and 21 after starting the trial. The pretreatment baseline mean ± SD PRTT values for the treatment and control groups were 11.12 ± 3.82 mm/15 s and 11.93 ± 2.73 mm/15 s, respectively. After 14 days of drug administration, the mean ± SD PRTT values for the treatment and control groups were 10.87 ± 3.11 mm/15 s and 13.00 ± 2.47 mm/15 s, respectively. On Day 21, the mean ± SD PRTT values for the treatment and control groups were 12.62 ± 4.05 mm/15 s and 12.87 ± 2.99 mm/15 s, respectively. Significant decreases in the PRTT values, compared with the pretreatment baseline values, were not observed in the treatment group on Day 15 (P = 0.14) and Day 21 (P = 0.31). Trimethoprim-sulfamethoxazole did not decrease tear production in the guinea pigs in this study. © 2015 American College of Veterinary Ophthalmologists.

  17. Pharmacokinetic study of salvianolic acid D after oral and intravenous administration in rats

    PubMed Central

    Song, Junke; Zhang, Wen; Sun, Jialin; Xu, Xiaona; Zhang, Xue; Zhang, Li; Feng, Zhangying; Du, Guan-hua

    2015-01-01

    A sensitive, specific and rapid LC-MS method was developed and validated for the determination of salvianolic acid D (SalD) in rat plasma. This method used a single quadrupole mass spectrometer with an electrospray ionization (ESI) source. A single ion monitoring scanning (SIM) mode was employed. It showed good linearity over the concentration range from 3.3 to 666.7 ng/mL for the determination of SalD. The R.S.D.% of intra-day and inter-day precision values were no more than 7.69%, and the accuracy was within 91%−104% at all quality control levels. This LC-MS method was applied to the pharmacokinetic study of SalD in rats. A two-compartmental model analysis was employed. The plasma concentrations at 2 min (C2min) were 5756.06±719.61, 11,073.01±1783.46 and 21,077.58±5581.97 μg/L for 0.25, 0.5 and 1 mg/kg intravenous injection, respectively. The peak plasma concentration (Cmax) was 333.08±61.21 μg/L for 4 mg/kg oral administration. The area under curve (AUC0−t) was 14,384.379±8443.184, 22,813.369±11,860.823, 46,406.122±27,592.645 and 8201.740±4711.961 μg/L·h for intravenous injection (0.25, 0.5 and 1 mg/kg) and oral administration (4 mg/kg), respectively. The bioavailability of SalD was calculated to be 4.159%±0.517%. PMID:26579453

  18. Effect of oral administration of cyclosporine on Toxoplasma gondii infection status of cats.

    PubMed

    Lappin, Michael R; VanLare, Karen A; Seewald, Wolfgang; Roycroft, Linda M; Scorza, Andrea V; King, Stephen; Roberts, Elizabeth S

    2015-04-01

    To evaluate whether anti-inflammatory doses of cyclosporine activate Toxoplasma gondii in chronically infected cats or potentiate infection in cats exposed for the first time. 30 T gondii-negative cats. Cats were assigned to 1 of 3 groups (10 cats/group). Group 1 (control) cats were administered a placebo for 126 days; group 2 cats were administered a placebo for 84 days, followed by cyclosporine at 7.5 mg/kg/d, PO, for 42 days; and group 3 cats were administered cyclosporine at 7.5 mg/kg/d, PO, for 126 days. Cats were orally inoculated with T gondii on day 42. Results for fecal flotations, PCR assays, and histologic examinations and IgM and IgG titers were analyzed. Cyclosporine concentrations were measured on selected days. All cats were infected by T gondii and developed signs of self-limiting gastrointestinal tract infection. Group 3 had the highest incidence and severity of CNS and pulmonary histopathologic findings typical of toxoplasmosis. One cat in group 3 died of systemic toxoplasmosis; that cat had a cyclosporine concentration of 1,690 ng/mL. Group 2 cats infected with T gondii before cyclosporine administration did not have repeated oocyst shedding. Group 3 cats shed fewer oocysts for a shorter time than did control cats of group 1. Oral administration of cyclosporine in accordance with the protocol for this study did not potentiate the enteroepithelial phase of T gondii infection. Cats with high cyclosporine blood concentrations at the time of primary T gondii infection may be at risk of developing systemic toxoplasmosis.

  19. Pharmacokinetic study of salvianolic acid D after oral and intravenous administration in rats.

    PubMed

    Song, Junke; Zhang, Wen; Sun, Jialin; Xu, Xiaona; Zhang, Xue; Zhang, Li; Feng, Zhangying; Du, Guan-Hua

    2015-05-01

    A sensitive, specific and rapid LC-MS method was developed and validated for the determination of salvianolic acid D (SalD) in rat plasma. This method used a single quadrupole mass spectrometer with an electrospray ionization (ESI) source. A single ion monitoring scanning (SIM) mode was employed. It showed good linearity over the concentration range from 3.3 to 666.7 ng/mL for the determination of SalD. The R.S.D.% of intra-day and inter-day precision values were no more than 7.69%, and the accuracy was within 91%-104% at all quality control levels. This LC-MS method was applied to the pharmacokinetic study of SalD in rats. A two-compartmental model analysis was employed. The plasma concentrations at 2 min (C 2min) were 5756.06±719.61, 11,073.01±1783.46 and 21,077.58±5581.97 μg/L for 0.25, 0.5 and 1 mg/kg intravenous injection, respectively. The peak plasma concentration (C max) was 333.08±61.21 μg/L for 4 mg/kg oral administration. The area under curve (AUC0-t ) was 14,384.379±8443.184, 22,813.369±11,860.823, 46,406.122±27,592.645 and 8201.740±4711.961 μg/L·h for intravenous injection (0.25, 0.5 and 1 mg/kg) and oral administration (4 mg/kg), respectively. The bioavailability of SalD was calculated to be 4.159%±0.517%.

  20. Extemporaneous procedures for dissolving risedronate tablets for oral administration and for feeding tubes.

    PubMed

    Dansereau, Richard J; Crail, Debbie J

    2005-01-01

    Risedronate (Actonel, Procter & Gamble Pharmaceuticals) is commercially available only as film-coated tablets. Extemporaneous procedures for dissolving tablets for feeding tubes and for preparation of an oral liquid have not previously been evaluated. To evaluate procedures for dissolving risedronate sodium tablets for administration in liquid form and drug recovery following dissolution in cups and following passage through different types of feeding tubes. Tablets (5 and 35 mg) were individually dispersed in 2 oz of water. After 2 minutes, the solution was stirred for 30 seconds, dispensed, and rinsed with an additional 4 oz of water. The sample was filtered and analyzed by HPLC. Ten replicates were performed using the various cups. Gastrostomy and nasoenteric tubes were flushed with 1 oz of water. Individual tablets were dispersed in 2 oz of water; after 2 minutes, the solution was stirred for 30 seconds and poured through the tube and flushed with 1 oz of water. Samples were filtered and analyzed by HPLC. Ten replicates were performed for each type of feeding tube. For cups, the mean amount of drug recovered ranged from 95.7% to 100.5% of the label claim, with a relative standard deviation (RSD) range of 1.1-6.3%. For gastrostomy and nasoenteric tubes, the mean amount of drug recovered ranged from 98.3% to 101.9% of label claim, with an RSD range of 0.9-3.3%. A simple and accurate procedure was developed for dissolving risedronate tablets in water to prepare a liquid formulation for administration orally or through feeding tubes.

  1. Pharmacokinetics, metabolism, and saliva output during transdermal and extended-release oral oxybutynin administration in healthy subjects.

    PubMed

    Appell, Rodney A; Chancellor, Michael B; Zobrist, R Howard; Thomas, Heather; Sanders, Steven W

    2003-06-01

    To compare the pharmacokinetics and adverse effect dynamics of 2 modified-release oxybutynin treatments. Between October 15 and November 6, 2001, 13 healthy subjects (7 men and 6 women) participated in a randomized, 2-way crossover study of transdermal (Oxytrol, 3.9 mg/d) and extended-release oral (Ditropan XL, 10 mg) oxybutynin. Multiple blood and saliva samples were collected. Pharmacokinetic parameters and total salivary output were assessed. Statistical analyses included 95% confidence intervals, paired t test, analysis of variance, and linear regression. Steady-state plasma concentrations were achieved after the first transdermal application and after the second extended-release oral dose. Mean +/- SD 24-hour oxybutynin areas under the concentration-time curve were comparable during transdermal and oral extended-release treatments, 10.8 +/- 24 vs 9.2 +/- 33 ng x h(-1) x mL(-1), respectively. However, the ratio of area under the curve (N-desethyloxybutynin/oxybutynin) after transdermal administration (1.2 +/- 03) was significantly lower (P < .001) than after extended-release oral administration (4.1 +/- 0.9). Mean plasma concentrations were less variable during transdermal compared with extended-release oral administration. Mean +/- SD saliva output was greater during transdermal than extended-release oral treatment (15.7 +/- 93 vs 12.2 +/- 6.8 g, respectively; P = .02). Lower N-desethyloxybutynin during transdermal application was associated with greater saliva output (r = -059, P = .04). No clinically important treatment-related adverse effects were observed. Transdermal oxybutynin administration results in greater systemic availability and minimizes metabolism to N-desethyloxybutynin compared with extended-release oral administration. Lower N-desethyloxybutynin plasma concentration and greater saliva output during transdermal treatment correspond to the reported low incidence of dry mouth in patients with overactive bladder.

  2. Patient-reported preferences for oral versus intravenous administration for the treatment of cancer: a review of the literature

    PubMed Central

    Eek, Daniel; Krohe, Meaghan; Mazar, Iyar; Horsfield, Alison; Pompilus, Farrah; Friebe, Rachel; Shields, Alan L

    2016-01-01

    Objective The emergence of various modes of administration for cancer treatment, including oral administration, brings into focus the importance of patient preference for administration. The purpose of this research was to evaluate the administration preferences of cancer patients, specifically between oral and intravenous (IV) treatment, as well as the factors contributing to preference. Methods A literature search was conducted in OvidSP to identify research in which the preferences of cancer patients for oral or IV treatment have been evaluated. Data were analyzed in two stages: 1) those articles that directly compared preference between modes of administration were tallied to determine explicit preference for oral or IV treatment; and 2) all attributes associated with patient preference were documented. Results Of the 48 abstracts identified as part of the initial OvidSP search, eight articles were selected for full-text review. One article was removed following full-text review, and seven additional articles were identified through a gray literature search, yielding a total of 14 articles for evaluation. In Stage 1, 13 of the 14 articles compared preference, of which eleven articles (84.6%) reported that patients preferred oral treatment over IV, while two (15.4%) stated that cancer patients preferred IV treatment over oral. In Stage 2, the most frequently reported attributes contributing to preference included convenience, ability to receive treatment at home, treatment schedule, and side effects. Discussion Evidence suggests that oncology patients prefer oral treatment to IV. Rationale for preference was due to a number of factors, including convenience, perception of efficacy, and past experience. Further evaluation should be conducted, given the limited data on patient preference in oncology. PMID:27601886

  3. Patient-reported preferences for oral versus intravenous administration for the treatment of cancer: a review of the literature.

    PubMed

    Eek, Daniel; Krohe, Meaghan; Mazar, Iyar; Horsfield, Alison; Pompilus, Farrah; Friebe, Rachel; Shields, Alan L

    2016-01-01

    The emergence of various modes of administration for cancer treatment, including oral administration, brings into focus the importance of patient preference for administration. The purpose of this research was to evaluate the administration preferences of cancer patients, specifically between oral and intravenous (IV) treatment, as well as the factors contributing to preference. A literature search was conducted in OvidSP to identify research in which the preferences of cancer patients for oral or IV treatment have been evaluated. Data were analyzed in two stages: 1) those articles that directly compared preference between modes of administration were tallied to determine explicit preference for oral or IV treatment; and 2) all attributes associated with patient preference were documented. Of the 48 abstracts identified as part of the initial OvidSP search, eight articles were selected for full-text review. One article was removed following full-text review, and seven additional articles were identified through a gray literature search, yielding a total of 14 articles for evaluation. In Stage 1, 13 of the 14 articles compared preference, of which eleven articles (84.6%) reported that patients preferred oral treatment over IV, while two (15.4%) stated that cancer patients preferred IV treatment over oral. In Stage 2, the most frequently reported attributes contributing to preference included convenience, ability to receive treatment at home, treatment schedule, and side effects. Evidence suggests that oncology patients prefer oral treatment to IV. Rationale for preference was due to a number of factors, including convenience, perception of efficacy, and past experience. Further evaluation should be conducted, given the limited data on patient preference in oncology.

  4. CHILDREN WITH CYSTIC FIBROSIS: UNDERSTANDING ISSUES RELATED TO ORAL ADMINISTRATION OF LIQUID FLUCLOXACILLIN.

    PubMed

    Batchelor, Hannah; Rayner, Oli; Nickless, Jessica; Wan, Mandy; Southern, Kevin; Rose, Claudia

    2016-09-01

    Palatability of flucloxacillin is poor, yet is used long-term in the management of children with cystic fibrosis (CF). Strategies to aid administration of unpalatable medicines have been reported, however there has never been a systematic approach to gathering views of many parents/carers all administering the same medication to the same population of children. This study aimed to quantify the extent of flucloxacillin palatability issues for parents/cares of children with CF and identify parent/carer and healthcare professional (HCP) reported age-specific strategies to aid administration of flucloxacillin to children with CF. Passive analysis reviews of public online forums were conducted using search terms including, 'flucloxacillin' and 'taste' or 'palatability' or 'child' to identify evidence of tactics used by parents to aid administration of flucloxacillin to children, not only those with CF (strategies were only included if the age of the child was disclosed). A bespoke online questionnaire was developed and partially validated for parents/carers of children with CF to identify age-specific strategies to aid administration of flucloxacillin. Healthcare professionals (HCPs) were purposively selected for semi-structured interviews to further explore age-specific strategies to aid administration of flucloxacillin. 18 individual strategies were identified on 10 different public online forums to aid the administration of flucloxacillin to children. These included mixing with food/drink: milk was commonly used for children aged 6-20 months; honey, Nutella, jam, ice cream and squash for those aged 21-36 months. The use of an oral syringe to direct the medicine slowly into the back/side of the mouth, and pinching a child's nose was reported.253 parents/carers of children with CF completed the online survey and 11 HCPs were involved in the semi-structured interviews. 50.2% of parents/carers reported that administration of flucloxacillin was problematic, yet 89

  5. Oral administration of Enterococcus faecalis FK-23 suppresses Th17 cell development and attenuates allergic airway responses in mice.

    PubMed

    Zhang, Bei; An, Jun; Shimada, Takashi; Liu, Shuang; Maeyama, Kazutaka

    2012-08-01

    Evidence is increasing that oral administration of probiotics can attenuate asthmatic responses both in murine models and clinical trials. T-helper 17 (Th17) cells, a subset of CD4+ T cells have been implicated as having an important role in the development of several allergic disorders, but the relationship between oral administration of probiotics and Th17 development has not been well studied. BALB/c mice were given lysed Enterococcus faecalis FK-23 (LFK) orally for 28 days. After sensitization by subcutaneous injection of ovalbumin (OVA) on Days 14 and 21 and 1% OVA inhalation on Days 25, 26 and 27, they were challenged with a 5% OVA aerosol on Day 28. Twenty-four hours later, airway resistance and accumulation of inflammatory cells in bronchoalveolar lavage fluid (BALF) and lung tissues were determined. Ιnterleukin (IL)-17-expressing CD4+ lymphocytes isolated from lung, spleen and lamina propria of the intestine were detected by flow cytometry. The expression of IL-6 and TGF-β mRNA was assessed by real-time PCR. Increases in airway hyperresponsiveness, and numbers of total leukocytes and mast cells in BALF induced by OVA challenge were significantly suppressed by oral administration of LFK. The increased percentage of IL-17-expressing CD4+ cells from lung, spleen and intestine in OVA-challenged mice was reduced following LFK treatment. We conclude that the oral administration of LFK suppresses the asthmatic response and that this is associated with attenuation of Th17 cell development.

  6. Acute oral Bryostatin-1 administration improves learning deficits in the APP/PS1 transgenic mouse model of Alzheimer's disease.

    PubMed

    Schrott, L M; Jackson, K; Yi, P; Dietz, F; Johnson, G S; Basting, T F; Purdum, G; Tyler, T; Rios, J D; Castor, T P; Alexander, J S

    2015-01-01

    Previous studies showed that Bryostatin-1, a potent PKC modulator and alphasecretase activator, can improve cognition in models of Alzheimer's disease (AD) with chronic (>10 weeks), intraperitoneal (i.p.) administration of the drug. We compared learning and spatial memory in the APPswe, PSEN1dE985Dbo (APP/PS1) mouse model of AD and studied the ability of acute intraperitoneal and oral Bryostatin-1 to reverse cognitive deficits in this model. Compared to wild-type (WT) mice, APP/PS1 mice showed significant delays in learning the location of a submerged platform in the Morris water maze. Bryostatin-1 was administered over a 2-week course prior to and during water maze testing. Acute i.p. Bryostatin-1 administration did not improve latency to escape but oral Bryostatin-1 significantly improved memory (measured by a reduction in latency to escape). This benefit of oral Bryostatin-1 administration was most apparent during the first 3 days of testing. These findings show that: 1) Bryostatin-1 is orally active in models of learning and memory, 2) this effect can be produced in less than 2 weeks and 3) this effect is not seen with i.p. administration. We conclude that oral Bryostatin-1 represents a novel, potent and long-acting memory enhancer with future clinical applications in the treatment of human AD.

  7. Pharmacokinetics of idarubicin (4-demethoxydaunorubicin; IMI-30; NSC 256439) following intravenous and oral administration in patients with advanced cancer.

    PubMed Central

    Gillies, H C; Herriott, D; Liang, R; Ohashi, K; Rogers, H J; Harper, P G

    1987-01-01

    The plasma pharmacokinetics of idarubicin (4-demethoxydaunorubicin) were studied in 20 patients with advanced malignant disease after intravenous (21 occasions) and oral (14 occasions) administration. Idarubicin plasma concentrations were measured by high performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters calculated for the intravenous plasma drug concentration, time data revealed a terminal half-life of 12.9 +/- 6.0 h (mean +/- s.d.), clearance 98.7 +/- 47.3 1 h-1 m-2 and volume of distribution 1533 +/- 536 1 m-2. A bi-exponential equation corresponding to a two compartment open model best fitted the data. Half-life and clearance were not significantly different following oral administration. Bioavailability of oral idarubicin was 0.29 +/- 0.20 (mean +/- s.d.). There was a wide range of bioavailability between and within subjects. Plasma concentrations of idarubicinol (the only metabolite detected) rapidly exceeded those of the parent drug, and exposure to this metabolite was greater than to the parent drug. The mean half-life of idarubicinol was not significantly different after i.v. (63.1 +/- 28.2 h) and oral (45.8 +/- 16.0 h) administration. Much larger amounts of this metabolite were formed following the oral route of administration. This may have implications for the clinical use of this drug as idarubicinol may have appreciable cytotoxic activity. PMID:3471265

  8. Oral administration of haloperidol at clinically recommended doses elicits smaller parkinsonian effects but more tardive dyskinesia in rats.

    PubMed

    Shireen, Erum; Naeem, Sadaf; Inam, Qurrat-ul-Aen; Haleem, Darakhshan Jabeen

    2013-03-01

    The present study was designed to monitor extrapyramidal symptoms (EPS) elicited by the oral administration of haloperidol at clinically recommended doses and to compare it with EPS produced when the drug is injected intraperitoneally at doses used in animal research. Rats injected with haloperidol at a dose of 1 mg/kg daily for 5 weeks exhibited akinesia in an open field and impaired motor coordination. Effects of the drug on motor coordination but not on open field akinesia were attenuated gradually from 2-5 weeks of treatment. Oral administration of haloperidol in drinking water at clinically recommended dose exhibited decreased exploratory activity without producing akinesia. Motor coordination was impaired maximally after 3 weeks and tolerance was developed in the drug induced motor impairment after 5 weeks of treatment. Intensity of vacuous chewing movements (VCMs) and tardive VCMs was greater by oral administration than intraperitoneal injections of haloperidol. The present results showed that oral administration of haloperidol expected to produce sustained effect may result in tolerance in acute parkinsonian like effects but more intensity of tardive dyskinesia. We suggest that drugs which may helpful in alleviating tardive dyskinesia may be more useful if person is on oral drug therapy.

  9. Evaluation of analgesic effect and absorption of buprenorphine after buccal administration in cats with oral disease.

    PubMed

    Stathopoulou, Thaleia-Rengina; Kouki, Maria; Pypendop, Bruno H; Johnston, Atholl; Papadimitriou, Serafeim; Pelligand, Ludovic

    2017-09-01

    Objectives The objective of this study was to evaluate the analgesic effect and absorption of buprenorphine after buccal administration in cats with oral disease. Methods Six adult client-owned cats with chronic gingivostomatitis (weighing 5.1 ± 1.1 kg) were recruited for a randomised, prospective, blinded, saline-controlled, crossover study. Pain scores, dental examination, stomatitis score and buccal pH measurement were conducted on day 1 under sedation in all cats. On day 2, animals were randomised into two groups and administered one of the two treatments buccally (group A received buprenorphine 0.02 mg/kg and group B received 0.9% saline) and vice versa on day 3. Pain scores and food consumption were measured at 30, 90 and 360 mins after the administration of buprenorphine. Blood samples were taken at the same time and plasma buprenorphine concentration was measured by liquid chromatography-mass spectrometry. Data were statistically analysed as non-parametric and the level of significance was set as P <0.05. Results There were no major side effects after buprenorphine administration. Buccal pH values ranged between 8.5 and 9.1 and the stomatitis disease activity index between 10 and 22 (17.8 ± 4.5) with the scale ranging from 0-30. The maximum buprenorphine plasma concentration (14.8 ng/ml) was observed 30 mins after administration and there was low inter-individual variability. There was a significant difference between baseline pain scores compared with pain scores after buprenorphine ( P <0.05 ) and between the saline and buprenorphine group at 30 mins ( P = 0.04) and 90 mins ( P = 0.04). There was also a significant effect of the stomatitis index on the pain score. Regarding the pharmacokinetic parameters, cats with stomatitis showed lower bioavailability and shorter absorption half-life after buccal administration of buprenorphine compared with normal cats in previous studies. Conclusions and relevance Buccal administration of buprenorphine in cats with

  10. Plasma disposition and faecal excretion of oxfendazole, fenbendazole and albendazole following oral administration to donkeys.

    PubMed

    Gokbulut, Cengiz; Akar, Ferda; McKellar, Quintin A

    2006-07-01

    Fenbendazole (FBZ), oxfendazole (fenbendazole sulphoxide, FBZSO), and albendazole (ABZ) were administered orally to donkeys at 10mg/kg bodyweight. Blood and faecal samples were collected from 1 to 120 h post-treatment. The plasma and faecal samples were analysed by high performance liquid chromatography (HPLC). The parent molecule and its sulphoxide and sulphone (FBZSO(2)) metabolites did not reach detectable concentrations in any plasma samples following FBZ administration. ABZ was also not detected in any plasma samples, but its sulphoxide and sulphone metabolites were detected, demonstrating that ABZ was completely metabolised by first-pass mechanisms in donkeys. Maximum plasma concentrations (C(max)) of FBZSO (0.49microg/mL) and FBZSO(2) (0.60microg/mL) were detected at (t(max)) 5.67 and 8.00h, respectively, following administration of FBZSO. The area under the curve (AUC) of the sulphone metabolite (10.33microg h/mL) was significantly higher than that of the parent drug FBZSO (5.17microg h/mL). C(max) of albendazole sulphoxide (ABZSO) (0.08g/mL) and albendazole sulphone (ABZSO(2)) (0.04microg/mL) were obtained at 5.71 and 8.00h, respectively, following ABZ administration. The AUC of the sulphoxide metabolite (0.84microg h/mL) of ABZ was significantly higher than that of the sulphone metabolite (0.50microg h/mL). The highest dry-faecal concentrations of parent molecules were detected at 32, 34 and 30h for FBZSO, FBZ and ABZ, respectively. The sulphide metabolite was significantly higher than the parent molecule after FBZSO administration. The parent molecule was predominant in the faecal samples following FBZ administration. After ABZ administration, the parent molecule was significantly metabolised, probably by gastrointestinal microflora, to its sulphoxide metabolite (ABZSO) that showed a similar excretion profile to the parent molecule in the faecal samples. The AUC of the parent FBZ was significantly higher than that of FBZSO and ABZ in faeces. It is

  11. Brain and blood levels of bismuth after oral or parenteral administration of tripotassium-dicitrato bismuthate to rats.

    PubMed

    Abbracchio, M P; Balduini, W; Cavallaro, A; Adamoli, P; Fittipaldi, M; Muzio, F; Malandrino, S; Cattabeni, F

    1985-01-01

    Bismuth levels in blood and brain of rats have been measured following acute or subchronic administration of tri-potassium-dicitrato bismuthate (TDB) by intraperitoneal injection or by gavage. After parenteral administration, the presence of bismuth in blood was associated with appreciable bismuth concentrations in brain of treated animals (approximately equal to 10-30% of blood levels). In contrast, following oral treatment, no bismuth was detected in brain of animals, even at doses of TDB able to produce blood bismuth concentrations comparable with those obtained after intraperitoneal administration. The formation of different bismuth species in blood of treated animals depending upon the route of administration of TDB is suggested.

  12. Growth characteristics of rats receiving ractopamine hydrochloride and the metabolic disposition of ractopamine hydrochloride after oral or intraperitoneal administration.

    PubMed

    Smith, D J; Paulson, G D

    1994-02-01

    Objectives of this study were 1) to measure the effect of oral or i.p. administration of ractopamine HCl on growth and feed utilization in rats, 2) to determine the total absorption of [14C]ractopamine HCl after oral administration, and 3) to determine the disposition of radioactivity and the urinary elimination of unchanged [14C]ractopamine in rats after oral or i.p. administration of [14C]ractopamine. Twenty-seven female Sprague-Dawley rats (164.6 +/- 5.7 g) were randomly assigned to control (CONT), oral (ORAL), and i.p. (IP) treatments. Control and ORAL rats were implanted i.p with sham pumps, and IP rats were implanted i.p. with osmotic pumps primed to deliver 312 micrograms of ractopamine HCl per 24 h. Control and IP rats received no dietary ractopamine, but ORAL rats received 20 mg of ractopamine HCl/kg of diet. The IP rats had greater cumulative net weight gains and ADG on d 2, 6, 8, 10, and 12 than CONT rats. The ADFI was greater for ORAL rats on d 2 and 4 than for CONT rats, and the gain:feed ratio was greater on d 2, 6, 8, 10, and 12 for IP rats than for CONT rats. Net weight gain, ADG, and gain:feed ratio did not differ between ORAL and CONT rats. Absorption of radioactivity administered orally as [14C]ractopamine (2.9 mg) was 87.9% during a 24-h experimental period; biliary, urinary, and fecal excretion of radioactivity was 58.5%, 28.7%, and 1.4% of that administered, respectively. Urine from rats dosed orally with [14C]ractopamine contained 1.9% of the radioactivity as the parent compound, and urine from rats dosed i.p. contained 22.6% of the radioactivity as parent ractopamine. Ractopamine HCl increased weight gain and efficiency of feed utilization when administered i.p. to rats, but not when administered orally. The ineffectiveness of oral ractopamine for stimulating the growth of rats was probably due to extensive presystemic metabolism of ractopamine.

  13. Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats

    PubMed Central

    2014-01-01

    Objective The aim of this study was to obtain kinetic data that can be used in human risk assessment of titanium dioxide nanomaterials. Methods Tissue distribution and blood kinetics of various titanium dioxide nanoparticles (NM-100, NM-101, NM-102, NM-103, and NM-104), which differ with respect to primary particle size, crystalline form and hydrophobicity, were investigated in rats up to 90 days post-exposure after oral and intravenous administration of a single or five repeated doses. Results For the oral study, liver, spleen and mesenteric lymph nodes were selected as target tissues for titanium (Ti) analysis. Ti-levels in liver and spleen were above the detection limit only in some rats. Titanium could be detected at low levels in mesenteric lymph nodes. These results indicate that some minor absorption occurs in the gastrointestinal tract, but to a very limited extent. Both after single and repeated intravenous (IV) exposure, titanium rapidly distributed from the systemic circulation to all tissues evaluated (i.e. liver, spleen, kidney, lung, heart, brain, thymus, reproductive organs). Liver was identified as the main target tissue, followed by spleen and lung. Total recovery (expressed as % of nominal dose) for all four tested nanomaterials measured 24 h after single or repeated exposure ranged from 64-95% or 59-108% for male or female animals, respectively. During the 90 days post-exposure period, some decrease in Ti-levels was observed (mainly for NM-100 and NM-102) with a maximum relative decrease of 26%. This was also confirmed by the results of the kinetic analysis which revealed that for each of the investigated tissues the half-lifes were considerable (range 28–650 days, depending on the TiO2-particle and tissue investigated). Minor differences in kinetic profile were observed between the various particles, though these could not be clearly related to differences in primary particle size or hydrophobicity. Some indications were observed for an

  14. Challenges in oral administration of metronidazole dissolved in drinking water to rhesus monkeys (Macaca mulatta).

    PubMed

    Labberton, Linda; Bakker, Jaco; Klomp, Rianne; Langermans, Jan A M; van Geijlswijk, Ingeborg M

    2013-06-01

    Intestinal pathogens such as Entamoeba spp. and Giardia spp. protozoans are not uncommon among rhesus macaques (Macaca mulatta) in research facilities. These infections affect the health of the macaques, potentially causing severe diarrhea, and also pose a risk of zoonotic transmission to human caretakers. Infections must therefore be treated, but no standard treatment for intestinal protozoans in macaques has been developed. Metronidazole is commonly used to treat infections with Giardia spp. and Entamoeba spp. in veterinary medicine, but evidence-based information on effectiveness and dosages for nonhuman primates is lacking, and administration of drugs to nonhuman primates is challenging. The authors designed a study to determine whether oral administration of metronidazole dissolved in drinking water would be successful in rhesus macaques. They monitored daily fluid intake of macaques given water with or without metronidazole and with or without flavored syrup. Metronidazole addition, with or without flavored syrup, resulted in a decrease in fluid intake. Although it was possible to administer metronidazole in drinking water to some macaques, the authors conclude that this strategy is not a practical clinical method because of variation in the amount of water and metronidazole ingested by the macaques.

  15. The relationship between glucuronide conjugate levels and hepatotoxicity after oral administration of valproic acid.

    PubMed

    Lee, Min Sun; Lee, Young-Joo; Kim, Bo Joon; Shin, Kye Jung; Chung, Bong Chul; Baek, Du-Jong; Jung, Byung Hwa

    2009-07-01

    The aim of this study was to investigate the relationship between hepatotoxicity, levels of glucuronide conjugates of valproic acid (VPA), and the toxic metabolites of VPA (4-ene VPA and 2,4-diene VPA). We also examined whether hepatotoxicity could be predicted by the urinary excretion levels of VPA and its toxic metabolites. VPA was administrated orally in rats in amounts ranging from 20 mg/kg to 500 mg/kg. Free and total (free plus glucuronide conjugated) VPA, 4-ene VPA, and 2,4-diene VPA were quantified in urine and liver using gas chromatography-mass spectrometry. Serum levels of aspartate aminotransferase, alanine aminotransferase, and alpha-glutathione S-transferase (alpha-GST) were also determined to measure the level of hepatotoxicity. The serum alpha-GST level increased slightly at the 20 mg/kg dose, and substantially increased at the 100 and 500 mg/kg dose; aspartate aminotransferase and alanine aminotransferase levels did not change with the administration of increasing doses of VPA. The liver concentration of free 4-ene VPA and the urinary excretion of total 4-ene VPA were the only measures that correlated with the increase in the serum alpha-GST level (p < 0.094 and p < 0.023 respectively). From these results, we conclude that hepatotoxicity of VPA correlates with liver concentration of 4-ene VPA and can be predicted by the urinary excretion of total 4-ene VPA.

  16. Effects of 3 weeks GMP oral administration on glutamatergic parameters in mice neocortex.

    PubMed

    Ganzella, Marcelo; Moreira, Julia Dubois; Almeida, Roberto Farina; Böhmer, Ana Elisa; Saute, Jonas Alex Morales; Holmseth, Silvia; Souza, Diogo Onofre

    2012-03-01

    Overstimulation of the glutamatergic system (excitotoxicity) is involved in various acute and chronic brain diseases. Several studies support the hypothesis that guanosine-5'-monophosphate (GMP) can modulate glutamatergic neurotransmission. The aim of this study was to evaluate the effects of chronically administered GMP on brain cortical glutamatergic parameters in mice. Additionally, we investigated the neuroprotective potential of the GMP treatment submitting cortical brain slices to oxygen and glucose deprivation (OGD). Moreover, measurements of the cerebrospinal fluid (CSF) purine levels were performed after the treatment. Mice received an oral administration of saline or GMP during 3 weeks. GMP significantly decreases the cortical brain glutamate binding and uptake. Accordingly, GMP reduced the immunocontent of the glutamate receptors subunits, NR2A/B and GluR1 (NMDA and AMPA receptors, respectively) and glutamate transporters EAAC1 and GLT1. GMP treatment significantly reduced the immunocontent of PSD-95 while did not affect the content of Snap 25, GLAST and GFAP. Moreover, GMP treatment increased the resistance of neocortex to OGD insult. The chronic GMP administration increased the CSF levels of GMP and its metabolites. Altogether, these findings suggest a potential modulatory role of GMP on neocortex glutamatergic system by promoting functional and plastic changes associated to more resistance of mice neocortex against an in vitro excitotoxicity event.

  17. No carcinogenicity of ethyl tertiary-butyl ether by 2-year oral administration in rats.

    PubMed

    Suzuki, Masaaki; Yamazaki, Kazunori; Kano, Hirokazu; Aiso, Shigetoshi; Nagano, Kasuke; Fukushima, Shoji

    2012-01-01

    The carcinogenicity of ethyl tertiary-butyl ether (ETBE) was examined by oral administration using F344/DuCrlCrlj rats. Groups of 50 male and 50 female rats were given drinking water containing ETBE at doses of 0, 625, 2,500 or 10,000 ppm (w/w) for 104 weeks. No significant increase in the incidence of tumors was detected in any organ of either sex. Rat-specific non-neoplastic lesions were observed in the kidney: An increase in the severity of chronic progressive nephropathy was observed in the male and female 10,000 ppm groups, and increased incidences of urothelial hyperplasia of the pelvis and mineral deposition in the renal papilla were observed in the male 2,500 and 10,000 ppm groups. Besides these lesions, no treatment-related histopathological changes were observed in any organ or tissue in either sex. Thus, the present study demonstrated that a two year administration ETBE in the drinking water did not exert any carcinogenic effects in either male or female rats.

  18. Dramatic Inhibition of Retinal and Choroidal Neovascularization by Oral Administration of a Kinase Inhibitor

    PubMed Central

    Seo, Man Seong; Kwak, Nohoon; Ozaki, Hiroaki; Yamada, Haruhiko; Okamoto, Naoyuki; Yamada, Eri; Fabbro, Doriano; Hofmann, Francesco; Wood, Jeanette M.; Campochiaro, Peter A.

    1999-01-01

    The most common cause of new blindness in young patients is retinal neovascularization, and in the elderly is choroidal neovascularization. Therefore, there has been a great deal of attention focused on the development of new treatments for these disease processes. Previous studies have demonstrated partial inhibition of retinal neovascularization in animal models using antagonists of vascular endothelial growth factor or other signaling molecules implicated in the angiogenesis cascade. These studies have indicated potential for drug treatment, but have left many questions unanswered. Is it possible to completely inhibit retinal neovascularization using drug treatment with a mode of administration that is feasible to use in patients? Do agents that inhibit retinal neovascularization have any effect on choroidal neovascularization? In this study, we demonstrate complete inhibition of retinal neovascularization in mice with oxygen-induced ischemic retinopathy by oral administration of a partially selective kinase inhibitor that blocks several members of the protein kinase C family, along with vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases. The drug also blocks normal vascularization of the retina during development but has no identifiable adverse effects on mature retinal vessels. In addition, the kinase inhibitor causes dramatic inhibition of choroidal neovascularization in a laser-induced murine model. These data provide proof of concept that pharmacological treatment is a viable approach for therapy of both retinal and choroidal neovascularization. PMID:10362799

  19. Clinical and biochemical findings in bovine cerebrocortical necrosis produced by oral administration of amprolium.

    PubMed

    Kasahara, T; Ichijo, S; Osame, S; Sarashina, T

    1989-02-01

    Purposing to get some hints on cause and early diagnosis for cerebrocortical necrosis (CCN), CCN was produced in three healthy calves by the oral administration of amprolium. All three calves showed central nervous signs characterized by ataxic gait, clonic spasm, astasia and opisthotonus, from 24 to 49 days after the start of daily administration of 321-418 mg/kg amprolium. They showed bradycardia from about 20 days before the appearance of the nervous signs, which was supposed to be a finding of primary change and to be useful for early diagnosis of CCN. At necropsy of the two calves, large necrotic lesion was found in the cerebral cortex, and tissue thiamine levels decreased significantly, especially in cerebrum and cerebellum. In the other calf, injection with 25 mg thiamine tetrahydrofurfuryl disulfide (TTFD) was proved to be effective for the recovery of clinical signs. No significant changes in thiamine level were recorded in the whole blood, but those in erythrocytes decreased slightly at about a week before the appearance of the clinical signs. No significant alteration of thiamine excretion was observed in urine. Those findings suggest that CCN in calves is caused by thiamine deficiency and that the blood thiamine levels cannot be used for diagnosis of CCN.

  20. Effects of oral administration of caffeine and D-ribose on mental fatigue.

    PubMed

    Ataka, Suzuka; Tanaka, Masaaki; Nozaki, Satoshi; Mizuma, Hiroshi; Mizuno, Kei; Tahara, Tsuyoshi; Sugino, Tomohiro; Shirai, Tomoko; Kajimoto, Yoshitaka; Kuratsune, Hirohiko; Kajimoto, Osami; Watanabe, Yasuyoshi

    2008-03-01

    We examined the effects of administering two different candidate antifatigue substances, caffeine and D-ribose, on mental fatigue. In a double-blinded, placebo-controlled, three-way crossover design, 17 healthy volunteers were randomized to oral caffeine (200 mg/d), D-ribose (2000 mg/d), or placebo for 8 d. As fatigue-inducing mental tasks, subjects performed a 30-min Uchida-Kraepelin psychodiagnostic test and a 30-min advanced trail-making test on four occasions. During the tasks, the task performance of the caffeine group was better than that of the placebo group. However, after the fatigue-inducing tasks, although subjective perception of fatigue, motivation, or sleepiness was not significantly different, plasma branched-chain amino acid levels in the caffeine group were lower than those of the placebo group. Administration of D-ribose had no effect. Because plasma branched-chain amino acid levels are decreased by mental fatigue, these results suggest that administration of caffeine improved task performance through the enhancement of central nervous system activity without increasing the sensation of fatigue. However, further decreases in branched-chain amino acid levels indicate that caffeine might promote deeper fatigue than placebo. Unfortunately, research subsequent to our study design has shown that D-ribose dosing higher than we used is needed to see a clinical effect and therefore no conclusions can be made from this study as to the efficacy of D-ribose.

  1. Protective effect of oral L-arginine administration on gentamicin-induced renal failure in rats.

    PubMed

    Can, C; Sen, S; Boztok, N; Tuglular, I

    2000-03-03

    We investigated the effects of orally supplemented L-arginine, the substrate of nitric oxide (NO) and N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide-synthase inhibitor in gentamicin-induced renal failure. Rats were given gentamicin (100 mg/kg/day s.c.), gentamicin and L-arginine (2 g/l, drinking water), gentamicin and L-NAME (100 mg/l, drinking water) or gentamicin plus L-arginine and L-NAME. After 8 days, the gentamicin group developed marked renal failure, characterized by a significantly decreased creatinine clearance and increased blood creatinine, fractional excretion of sodium, fractional excretion of lithium, urine gamma glutamyl transferase, systolic blood pressure and daily urine volume when compared to controls. Renal histological analysis confirmed tubular necrosis. L-arginine administration caused normalization of these parameters, whereas L-NAME led to aggravation of the failure. Concomitant administration of L-NAME and L-arginine to gentamicin-treated rats caused no significant changes when compared to the rats receiving gentamicin alone. We conclude that L-arginine supplementation has beneficial effects in gentamicin-induced renal failure in rats and that these effects are reversed by the NO-synthase inhibitor, L-NAME.

  2. Changes in the concentrations of vitamin E analogs and their metabolites in rat liver and kidney after oral administration

    PubMed Central

    Kiyose, Chikako; Saito, Kazuki; Yachi, Rieko; Muto, Chie; Igarashi, Osamu

    2015-01-01

    Vitamin E analog, such as α- and γ-tocopherol, can undergo ω-oxidation without cleavage of the chroman ring, and this pathway is responsible for generation of the major urinary vitamin E metabolite, carboxyethyl hydroxychroman. However, it is still unclear how carboxyethyl hydroxychroman is changed in various tissues after vitamin E intake. We therefore investigated changes in the concentrations of α- and γ-tocopherol and their metabolites in rat liver and kidney. The concentration of α-tocopherol in rat liver increased until 6 h after oral administration, and then decreased. The change in the concentration of α-carboxyethyl hydroxychroman in rat liver in the α-Toc group slowly increased until 12 h after oral administration. Cytochrome P450 3A1 mRNA expression significantly increased from 12 h after the start of α-tocopherol administration. The change in the concentration of γ-carboxyethyl hydroxychroman in rat liver in the γ-Toc group markedly increased until 12 h after oral administration. On the other hand, γ-carboxyethyl hydroxychroman in rat kidney showed greater accumulation than α-carboxyethyl hydroxychroman from 3 h to 24 h after oral administration. From these results, we considered that γ-carboxyethyl hydroxychroman formed in the liver continues to be released into the bloodstream and is transported to the kidney rapidly. PMID:25759520

  3. Pharmacokinetic of 5 components after oral administration of Fructus Forsythiae by HPLC-MS/MS and the effects of harvest time and administration times.

    PubMed

    Bai, Yang; Li, Jin; Liu, Wei; Jiao, Xiu-cheng; He, Jun; Liu, Jiao; Ma, Lin; Gao, Xiu-mei; Chang, Yan-xu

    2015-07-01

    The unripe Fructus Forsythiae (Qingqiao) and ripe Fructus Forsythiae (Laoqiao) are two types of the clinical forms of commercial fructus of Forsythia suspensa(Thunb.) Vahl. There is limited information available for differences in pharmacokinetic properties of active components between unripe and ripe Fructus Forsythiae in vivo. A rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the simultaneous determination of 9 typical components in rat plasma. The separation of nine analytes was performed on an Eclipse plus C18 (4.6mm×100mm, 1.8μm) column with the mobile phases consisted of a mixture of 0.1% formic acid in water and acetonitrile. Method validation indicated that the developed method was rapid, specific and sensitive. It was found that the AUC(0-24h) of 5 ingredients (forsythoside A, rutin, phillyrin, isorhamnetin and quercetin) in rats after single orally administrated unripe Fructus Forsythiae also had significant differences compared with those after single dose oral administration of ripe Fructus Forsythiae extract. The systemic exposure of 5 ingredients after multiple oral administration of Fructus Forsythiae extract had significantly increased than those after single oral administration. The results indicated that harvest time is not only effects the contents but the bioavailability of active components of Fructus Forsythiae, which suggests that the rate and extent of drug metabolism were altered when the clinical forms of commercial Fructus Forsythiae with different harvest time. The administration times could influence the bioavailability of active components of Fructus Forsythiae.

  4. Can oral fluid cannabinoid testing monitor medication compliance and/or cannabis smoking during oral THC and oromucosal Sativex administration?

    PubMed Central

    Lee, Dayong; Karschner, Erin L.; Milman, Garry; Barnes, Allan J.; Goodwin, Robert S.; Huestis, Marilyn A.

    2012-01-01

    OBJECTIVES We characterize cannabinoid disposition in oral fluid (OF) after Dronabinol, synthetic oral Δ9-tetrahydrocannabinol (THC), and Sativex, a cannabis-extract oromucosal spray, and evaluate whether smoked cannabis relapse or Sativex compliance can be identified with OF cannabinoid monitoring. METHODS 5 and 15 mg synthetic oral THC, low (5.4 mg THC, 5.0 mg cannabidiol (CBD)) and high (16.2 mg THC, 15.0 mg CBD) dose Sativex, and placebo were administered in random order (n=14). Oral fluid specimens were collected for 10.5h after dosing and analyzed for THC, CBD, cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH). RESULTS After oral THC, OF THC concentrations decreased over time from baseline, reflecting residual THC excretion from previously self-administered smoked cannabis. CBD and CBN also were rarely detected. After Sativex, THC, CBD and CBN increased greatly, peaking at 0.25–1h. Median CBD/THC and CBN/THC ratios were 0.82–1.34 and 0.04–0.06, respectively, reflecting cannabinoids’ composition in Sativex. THCCOOH/THC ratios within 4.5h post Sativex were ≤1.6 pg/ng, always lower than after oral THC and placebo. THCCOOH/THC ratios increased throughout each dosing session. CONCLUSIONS Lack of measurable THC, CBD and CBN in OF following oral THC, and high OF CBD/THC ratios after Sativex distinguish oral and sublingual drug delivery routes from cannabis smoking. Low THCCOOH/THC ratios suggest recent Sativex and smoked cannabis exposure. These data indicate that OF cannabinoid monitoring can document compliance with Sativex pharmacotherapy, and identify relapse to smoked cannabis during oral THC medication but not Sativex treatment, unless samples were collected shortly after smoking. PMID:23146820

  5. Excretion of methamphetamine and amphetamine in human sweat following controlled oral methamphetamine administration.

    PubMed

    Barnes, Allan J; Smith, Michael L; Kacinko, Sherri L; Schwilke, Eugene W; Cone, Edward J; Moolchan, Eric T; Huestis, Marilyn A

    2008-01-01

    Understanding methamphetamine (MAMP) and amphetamine (AMP) excretion in sweat is important for interpreting sweat and hair testing results in judicial, workplace, and drug treatment settings. Participants (n = 8) received 4 10-mg (low) oral doses of sustained-release S-(+)-MAMP HCl (d-MAMP HCl) within 1 week in a double-blind, institutional review board-approved study. Five participants also received 4 20-mg (high) doses 3 weeks later. PharmChek sweat patches (n = 682) were worn for periods of 2 h to 1 week during and up to 3 weeks after dosing. The mass of MAMP and AMP in each patch was measured by GC-MS, with a limit of quantification of 2.5 ng/patch. MAMP was measurable in sweat within 2 h of dosing. After low and high doses, 92.9% and 62.5% of weekly sweat patches were positive, with a median (range) MAMP of 63.0 (16.8-175) and 307 (199-607) ng MAMP/patch, respectively; AMP values were 15.5 (6.5-40.5) and 53.8 (34.0-83.4) ng AMP/patch. Patches applied 2 weeks after the drug administration week had no measurable MAMP following the low doses, and only 1 positive result following the high doses. Using criteria proposed by the Substance Abuse Mental Health Services Administration, 85.7% (low) and 62.5% (high) weekly sweat patches from the dosing week were positive for MAMP, and all patches applied after the dosing week were negative. These data characterize the excretion of MAMP and AMP after controlled MAMP administration and provide a framework for interpretation of MAMP sweat test results in clinical and forensic settings.

  6. Excretion of Methamphetamine and Amphetamine in Human Sweat Following Controlled Oral Methamphetamine Administration

    PubMed Central

    Barnes, Allan J.; Smith, Michael L.; Kacinko, Sherri L.; Schwilke, Eugene W.; Cone, Edward J.; Moolchan, Eric T.; Huestis, Marilyn A.

    2009-01-01

    BACKGROUND Understanding methamphetamine (MAMP) and amphetamine (AMP) excretion in sweat is important for interpreting sweat and hair testing results in judicial, workplace, and drug treatment settings. METHODS Participants (n = 8) received 4 10-mg (low) oral doses of sustained-release S-(+)-MAMP HCl (d-MAMP HCl) within 1 week in a double-blind, institutional review board–approved study. Five participants also received 4 20-mg (high) doses 3 weeks later. PharmChek sweat patches (n = 682) were worn for periods of 2 h to 1 week during and up to 3 weeks after dosing. The mass of MAMP and AMP in each patch was measured by GC-MS, with a limit of quantification of 2.5 ng/patch. RESULTS MAMP was measurable in sweat within 2 h of dosing. After low and high doses, 92.9% and 62.5% of weekly sweat patches were positive, with a median (range) MAMP of 63.0 (16.8 – 175) and 307 (199 – 607) ng MAMP/patch, respectively; AMP values were 15.5 (6.5 – 40.5) and 53.8 (34.0 – 83.4) ng AMP/patch. Patches applied 2 weeks after the drug administration week had no measurable MAMP following the low doses, and only 1 positive result following the high doses. Using criteria proposed by the Substance Abuse Mental Health Services Administration, 85.7% (low) and 62.5% (high) weekly sweat patches from the dosing week were positive for MAMP, and all patches applied after the dosing week were negative. CONCLUSIONS These data characterize the excretion of MAMP and AMP after controlled MAMP administration and provide a framework for interpretation of MAMP sweat test results in clinical and forensic settings. PMID:17981924

  7. The effects of oral magnesium hydroxide administration on rumen fluid in cattle.

    PubMed

    Smith, Geoffrey W; Correa, Maria T

    2004-01-01

    This study was conducted to determine the effects of oral magnesium hydroxide administration on rumen fluid in cattle. Six lactating Holstein cows (4-7 years of age) with rumen fistulas were studied. Cattle were randomly assigned to receive boluses of magnesium hydroxide (162 g) or a powdered form (450 g dissolved in 3.5 L of water) PO daily for 3 days. Analysis of rumen fluid, blood gas tensions, and pH and measurement of serum magnesium concentrations were conducted daily. The study was discontinued after 72 hours, or sooner if rumen pH exceeded 8.0. After at least 3 weeks, the study was repeated with each cow receiving the other form of magnesium hydroxide (powder or bolus). Compared with baseline rumen pH (mean +/- SD: 6.22 +/- 0.28), magnesium hydroxide boluses caused a significant increase (P < .05) in rumen pH after 48 (7.27 +/- 0.11) and 72 (8.01 +/- 0.16) hours of administration, whereas the powdered form caused a significant increase (P < .05) in rumen pH after 24 (7.54 +/- 0.19) and 48 (8.43 +/- 0.22) hours of administration. Both the powdered and bolus forms of magnesium hydroxide decreased rumen protozoal numbers and increased methylene blue reduction times compared with baseline values. There was no change in blood pH, bicarbonate, or base excess values. Serum magnesium concentrations were significantly increased (P < .05) in cows that received the magnesium hydroxide powder. The results of this study indicate that magnesium hydroxide has a potent alkalinizing effect on rumen pH and significantly decreases rumen microbial activity.

  8. Acute and residual interactive effects of repeated administrations of oral methamphetamine and alcohol in humans

    PubMed Central

    Kirkpatrick, Matthew G.; Gunderson, Erik W.; Levin, Frances R.; Foltin, Richard W.; Hart, Carl L.

    2011-01-01

    Although methamphetamine and alcohol are commonly used together in a binge-like pattern, there is a dearth of empirical data investigating the repeated effects of this drug combination. The current study examined acute and residual mood, performance, and physiological effects of methamphetamine alone, alcohol alone, and the combination. Nine adult male volunteers completed this 20-day within-participant, residential laboratory study. During four 5-day blocks of sessions, participants were administered oral methamphetamine (0, 10 mg) combined with alcohol (0, 0.375, 0.75 g/kg) three times (day 2: AM, day 2: PM, and day 3: PM). Breath alcohol concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and repeatedly thereafter. Subjective and objective sleep measures were also assessed; residual effects were assessed on days 3–5 of each block. Following the first drug administration, the methamphetamine–alcohol combination produced greater elevations of heart rate and ratings of “good drug effect” compared to either drug alone. Methamphetamine attenuated alcohol-related performance decrements and feelings of intoxication, whereas alcohol attenuated methamphetamine-related sleep disruptions. By the third administration, many of these effects were significantly diminished, suggesting that participants developed tolerance. Few residual effects were observed. These data show that methamphetamine combined with alcohol produced a profile of effects that was different from the effects of either drug alone. The largely positive effects of the drug combination (i.e., greater euphoria, and fewer performance and sleep disruptions) might explain why these drugs are often used in combination. PMID:21748253

  9. Intravenous ethanol infusions can mimic the time course of breath alcohol concentrations following oral alcohol administration in healthy volunteers.

    PubMed

    Ramchandani, Vijay A; Plawecki, Martin; Li, Ting-Kai; O'Connor, Sean

    2009-05-01

    Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA-related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3- to 4-fold variance, between- and within-subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between-subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC-time course attained following oral alcohol in the same subject. This was a 2-session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion-rate profile was precomputed using a physiologically-based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individual's physiology. The peak BrACs (C(max)), times of peak BrAC (T(max)), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol. The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean C

  10. Effects of oral loperamide on efficacy of naltrexone, baclofen and AM-251 in blocking ethanol self-administration in rats.

    PubMed

    Dean, Reginald L; Eyerman, David; Todtenkopf, Mark S; Turncliff, Ryan Z; Bidlack, Jean M; Deaver, Daniel R

    2012-01-01

    Naltrexone is a μ-opioid receptor antagonist that has been extensively studied for its ability to block the rewarding effects of ethanol. Opioid receptors are widely distributed within the gastrointestinal tract (GIT). Typically, naltrexone is administered by parenteral routes in nonclinical studies. We initially tested if opioid receptors within the GIT would influence the ability of oral naltrexone to inhibit ethanol oral self-administration in rats using the co-administration of oral loperamide, a peripherally restricted opioid agonist. As expected, oral naltrexone only had modest effects on ethanol intake, and the response was not dose-dependent. However in rats, treatment with loperamide prior to the administration of naltrexone resulted in a suppression of ethanol intake which approached that observed with naltrexone given by the subcutaneous (SC) route. Importantly, administration of loperamide prior to administration of naltrexone did not alter blood concentrations of naltrexone. We then evaluated if oral loperamide would enhance effects of baclofen (a GABA(B) receptor agonist) and AM-251 (a CB-1 receptor antagonist) and found that pre-treatment with loperamide did potentiate the action of both drugs to reduce ethanol self-administration. Finally, the specific opioid receptor type involved was investigated using selective μ- and κ-receptor antagonists to determine if these would affect the ability of the AM-251 and loperamide combination to block ethanol drinking behavior. The effect of loperamide was blocked by ALKS 37, a peripherally restricted μ-receptor antagonist. These data suggest an important role for opioid receptors within the GIT in modulating central reward pathways and may provide new insights into strategies for treating reward disorders, including drug dependency.

  11. Enhanced immune response to foot-and-mouth disease vaccine by oral administration of ginseng stem-leaf saponins.

    PubMed

    Li, Renjun; Ma, Yanfen; Zhai, Lijuan; Lu, Yisong; Chi, Xiaoqing; Wu, Jiusheng; Hu, Songhua

    2016-08-01

    Vaccination is an important approach to the control of foot-and-mouth disease (FMD). This study evaluated the effect of oral administration of ginseng stem-leaf saponins (GSLS) on the immune response to FMD vaccine and the gut mucosal immunity in mice. In experiment 1, mice were orally administered GSLS or not treated as a control. The animals were then immunized twice with FMD vaccine. Blood was sampled weekly within five weeks after the boost immunization for measurement of serum IgG and the isotypes. In experiment 2, mice were orally administrated GSLS or not treated as a control. After that, splenocytes were prepared from sacrificed mice for lymphocyte proliferation assay and intestinal tissues were sampled for immunohistochemistry and histological examination. The results showed that oral administration of GSLS significantly enhanced serum IgG and the isotype responses to FMD vaccine as well as the number of intestinal intraepithelial lymphocytes (IELs) and immunoglobulin A (IgA)+ cells. Therefore, GSLS may be a potent oral adjuvant and deserve further study to improve vaccination in susceptible animals.

  12. 2013 Updated American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards Including Standards for the Safe Administration and Management of Oral Chemotherapy

    PubMed Central

    Neuss, Michael N.; Polovich, Martha; McNiff, Kristen; Esper, Peg; Gilmore, Terry R.; LeFebvre, Kristine B.; Schulmeister, Lisa; Jacobson, Joseph O.

    2013-01-01

    In 2009, ASCO and the Oncology Nursing Society (ONS) published standards for the safe use of parenteral chemotherapy in the outpatient setting, including issues of practitioner orders, preparation, and administration of medication. In 2011, these were updated to include inpatient facilities. In December 2011, a multistakeholder workgroup met to address the issues associated with orally administered antineoplastics, under the leadership of ASCO and ONS. The workgroup participants developed recommended standards, which were presented for public comment. Public comments informed final edits, and the final standards were reviewed and approved by the ASCO and ONS Boards of Directors. Significant newly identified recommendations include those associated with drug prescription and the necessity of ascertaining that prescriptions are filled. In addition, the importance of patient and family education regarding administration schedules, exception procedures, disposal of unused oral medication, and aspects of continuity of care across settings were identified. This article presents the newly developed standards. PMID:23914148

  13. Effect of age on the pharmacokinetics of polymorphic nimodipine in rats after oral administration.

    PubMed

    Liu, Wenli; Wang, Xiaona; Chen, Ruilian; Zhang, Kaixuan; Li, Yao; Li, Yi; Si, Duanyun; Gong, Junbo; Yin, Dianshu; Wang, Yongli; Wei, Zhenping; Yang, Mingshi

    2016-09-01

    The previous investigation has proved that their existed pharmacokinetic difference between the different crystal forms of the polymorphic drugs after oral administration. However, no systemic investigations have been made on the change of this pharmacokinetic difference, resulted either from the physiological or from the pathological factors. In this paper, we used polymorphic nimodipine (Nim) as a model drug and investigated the effect of age difference (2- and 9-month old) on the pharmacokinetics after oral delivery in rats. As the results shown, for L-form of Nim (L-Nim), the AUC0-24 h in 2-month-old rats was 343.68±47.15 ng·h/mL, which is 23.36% higher than that in 9-month-old rats. For H-form of Nim (H-Nim), the AUC0-24 h in 2-month-old rats was 140.91±19.47 ng·h/mL, which is 54.64% higher than that in 9-month-old rats. The AUC0-24 h ratio between H-Nim and L-Nim was 2.44 in 2-month-old rats and 3.06 in 9-month-old rats. Since age difference could result in unparallelled change of the absorption and bioavailability of the polymorphic drugs, the results in this experiment are of value for further investigation of crystal form selection in clinical trials and rational clinical application of the polymorphic drugs.

  14. [Problems with oral administration of antimicrobially effective substances in animals--the situation with poultry].

    PubMed

    Löhren, U

    2008-08-01

    The most prevalent method of application of drugs under veterinary prescription including antimicrobials is the oral administration. This paper describes the three possible and legal ways of applying veterinary drugs to animals: --as feed medication in a specialized feed mill which must be registered according to Section 13 of our national medicinal act; --as powder for oral application and medication with the feed on the premises of the farm; --dissolved in the drinking water for the relevant flock. Drinking water application is by far the most relevant method of applying antimicrobials to poultry flocks, if medication is needed. The most prevalent systems for drinking water application in poultry flocks are technically described: header tanks or dose pumps. As far as dose pumps are concerned both systems: proportional dose pumps as well as electronic dose pumps are in use. With poultry the use of antimicrobials is based on clinical judgement of the flock, laboratory diagnosis, including bacterial isolation and sensitivity testing (wherever possible), medical knowledge and experience of the involved veterinarian, economic considerations, epidemiological background and information at the flock level. Responsible use of antimicrobials is a major topic which discriminates German poultry meat producers (e.g. Wiesenhof) from third world meat producers. One reason for the uncritical use of Antimicrobials can be the so called "vet hopping" which is practised with some other meat delivering animals. This is ruled out by the guidelines of the major German Poultry Meat producers. These companies organise regular meetings with their caretaking vets to find out if there is still use of antimicrobials with some of their contractors as alternative to good Hygiene and Biosecurity. Some Poultry Integrations have additional restrictions on the use of some critical antimicrobials like Fluorquinolones and Tetracyclines.

  15. Enhancement of mucosal immune responses in chickens by oral administration of cysteamine.

    PubMed

    Yang, Q; Lian, G; Gong, X

    2007-07-01

    Somatostatin, a tetradecapeptide originally isolated from the hypothalamus, can exert an inhibitory effect on the secretion of growth hormone by the anterior pituitary gland. In addition to endocrine organs, somatostatin is also present in the digestive tract and immune organs. In lymphoid tissues, somatostatin appears to play a role in the modulation of the immune response. Cysteamine (CS) is a sulfhydryl reducing agent that is known as a depletory agent of somatostatin. To evaluate its effects on chicken mucosal immune responses, CS was administrated orally to 1-wk-old broilers (40 mg/kg) that were immunized orally with Newcastle disease attenuated vaccine (NDV). The number of IgA-positive cells and intestinal intraepithelial lymphocytes (iIEL) in duodenum and jejunum were examined at 3-, 5-, and 7-wk posttreatment and immunization. The number of somatostatin-positive cells and relative amounts of somatostatin mRNA were also examined in the duodenum. The number of somatostatin-positive cells in the duodenum was reduced (P < 0.05) after CS treatment. In broilers receiving CS and NDV treatment (CS+NDV) the level of IgA-positive cells and iIEL in the duodenum and jejunum was increased (P < 0.05) at 3 and 5 wk posttreatment. The expression of somatostatin mRNA increased (P < 0.05) compared with that of the control group at 5 wk after immunization in broilers receiving CS+NDV or NDV alone. The results suggest that CS can induce proliferation and differentiation of IgA-positive cells and iIEL in the intestinal mucosa of chickens by reducing the number of somatostatin-positive cells.

  16. Intraocular ciprofloxacin levels after oral administration in silicone oil-filled eyes.

    PubMed

    Talwar, Dinesh; Kulkarni, Amol; Azad, RajVardhan; Gupta, Suresh K; Velpandian, T; Sharma, YogRaj; Rajpal; Biswas, Nihar R

    2003-02-01

    To evaluate penetration of oral ciprofloxacin in the retro-silicone oil space fluid (RSOF) in silicone oil (SO)-filled eyes. One dose of 750 mg ciprofloxacin was given to two groups of five patients with vitrectomized eyes with SO endotamponade, 4 hours (group I) and 8 hours (group II) before SO removal. In 10 vitrectomized eyes with SO endotamponade (group III) and another 10 patients scheduled for vitrectomy for the first time (group IV), two 750-mg doses every 12 hours, with the last dose 12 hours before surgery, were given. Blood samples were taken at the time of collection of RSOF samples in groups I, II, and III and of the vitreous in group IV. All samples were assayed for ciprofloxacin by high-performance liquid chromatography. The mean drug concentration in the RSOF was 0.34 +/- 0.09, 0.37 +/- 0.04, 0.84 +/- 0.29, and 0.44 +/- 0.11 micro g/mL in groups I, II, III, and IV respectively. The mean serum concentration was 1.29 +/- 0.63, 1.08 +/- 0.14, 1.93 +/- 0.84, and 1.34 +/- 0.55 micro g/mL in groups I, II, III, and IV respectively with no statistically significant difference between groups III and IV (P = 0.081). Antibiotic levels in the RSOF in SO-filled eyes after oral administration of ciprofloxacin in two 750-mg doses exceeded the minimal inhibitory concentration for 90% of isolates (MIC(90)) for most bacterial species and was higher than levels reached in the vitreous in nonvitrectomized eyes (P = 0.001).

  17. Pharmacokinetics of Ginkgolide B after Oral Administration of Three Different Ginkgolide B Formulations in Beagle Dogs.

    PubMed

    Zhao, Jie; Geng, Ting; Wang, Qi; Si, Haihong; Sun, Xiaoping; Guo, Qingming; Li, Yanjing; Huang, Wenzhe; Ding, Gang; Xiao, Wei

    2015-11-06

    Ginkgolide B (GB), an important active constituent of Ginkgo biloba extract, has been used in clinical applications for the treatment of dementia, cerebral insufficiency or related cognitive decline. To investigate the main pharmacokinetic characteristics of three different GB formulations in beagle dogs, a simple, specific and sensitive LC-MS/MS method was established and validated. The separation of the analytes was achieved on an Agilent Eclipse Plus C18 column (1.8 μm, 2.1×50 mm) with a mobile phase consisting of water and acetonitrile. The flow rate was set at 0.4 mL/min. Quantitation was performed using multiple reaction monitoring (MRM) in negative ion mode, with the transitions at m/z (Q1/Q3) 423.1/367.1 for GB and m/z 269.3/170.0 for IS. The linear calibration curve of GB was obtained over the concentration range of 2-200 ng/mL. The intra- and inter-day precisions were <15% and the accuracies were within ±12.7%. The validated method was applied to compare the pharmacokinetic characteristics of GB in healthy beagle dogs after oral administration of three formulations (HME08, GB capsule prepared by hot-melt extrusion technology; LL06, GB pellet prepared by liquid layer technology; conventional GB tablet). The Cmax values of GB from different formulations in beagle dog plasma were 309.2, 192.4 and 66.6 µg/L, and the AUC values were 606.7, 419.1 and 236.2 µg/L·h, respectively. The data suggested that the exposure level of GB from HME08 and LL06 in beagle dog plasma was greatly improved compared with conventional tablets. This study should be helpful for the design and development of oral GB preparations.

  18. Pharmacokinetic modeling and Monte Carlo simulation of ondansetron following oral administration in dogs.

    PubMed

    Baek, I-H; Lee, B-Y; Kang, J; Kwon, K-I

    2015-04-01

    Ondansetron is a potent antiemetic drug that has been commonly used to treat acute and chemotherapy-induced nausea and vomiting (CINV) in dogs. The aim of this study was to perform a pharmacokinetic analysis of ondansetron in dogs following oral administration of a single dose. A single 8-mg oral dose of ondansetron (Zofran(®) ) was administered to beagles (n = 18), and the plasma concentrations of ondansetron were measured by liquid chromatography-tandem mass spectrometry. The data were analyzed by modeling approaches using ADAPT5, and model discrimination was determined by the likelihood-ratio test. The peak plasma concentration (Cmax ) was 11.5 ± 10.0 ng/mL at 1.1 ± 0.8 h. The area under the plasma concentration vs. time curve from time zero to the last measurable concentration was 15.9 ± 14.7 ng·h/mL, and the half-life calculated from the terminal phase was 1.3 ± 0.7 h. The interindividual variability of the pharmacokinetic parameters was high (coefficient of variation > 44.1%), and the one-compartment model described the pharmacokinetics of ondansetron well. The estimated plasma concentration range of the usual empirical dose from the Monte Carlo simulation was 0.1-13.2 ng/mL. These findings will facilitate determination of the optimal dose regimen for dogs with CINV.

  19. Morphine and Codeine in Oral Fluid after Controlled Poppy Seed Administration

    PubMed Central

    Concheiro, Marta; Newmeyer, Matthew N.; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A.; Huestis, Marilyn A.

    2014-01-01

    Opiates are an important drug class in drug testing programs. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only 2 addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45g raw poppy seed doses, each containing 15.7mg morphine and 3.1mg codeine, 8h apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze® device and quantified by liquid chromatography tandem mass spectrometry (1μg/L morphine and codeine limits of quantification). Specimens (n=459) were collected before and up to 32h after the first dose. All specimens screened positive 0.5h after dosing and remained positive for 0.5-13h at Draeger 20μg/L morphine cutoff. Maximum OF morphine and codeine concentrations (Cmax) were 177 and 32.6μg/L, with times to Cmax (Tmax) of 0.5-1h and 0.5-2.5h post-dose, respectively. Windows of detection after the second dose extended at least 24h for morphine and to 18h for codeine. After both doses, the last morphine positive OF result was 1h with 40μg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cutoff, and 0.5h with 95μg/L cutoff, recently recommended by the Driving Under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1h after ingestion of 15.7mg of morphine in raw poppy seeds, depending upon the cutoff employed. PMID:25345619

  20. Continuous oral administration of atorvastatin ameliorates brain damage after transient focal ischemia in rats.

    PubMed

    Saito, Tomonari; Nito, Chikako; Ueda, Masayuki; Inaba, Toshiki; Kamiya, Fumio; Muraga, Kanako; Katsura, Ken-Ichiro; Katayama, Yasuo

    2014-01-17

    Pre-treatment with statins is known to ameliorate ischemic brain damage after experimental stroke, and is independent of cholesterol levels. We undertook pre- vs post-ischemic treatment with atorvastatin after focal cerebral ischemia in rats. Male Sprague-Dawley rats underwent transient 90-min middle cerebral artery occlusion (MCAO). Atorvastatin (20mg/kg/day) or vehicle was administered orally. Rats were divided into vehicle-treated, atorvastatin pre-treatment, atorvastatin post-treatment, and atorvastatin continuous-treatment groups. In the pre-treatment, rats were given atorvastatin or vehicle for 7 days before MCAO. In the post-treatment, rats received atorvastatin or vehicle for 7 days after MCAO. Measurement of infarct volume, as well as neurological and immunohistochemical assessments, were done 24h and 7 days after reperfusion. Each atorvastatin-treated group demonstrated significant reductions in infarct and edema volumes compared with the vehicle-treated group 24h after reperfusion. Seven days after reperfusion, infarct volumes in the post-treatment group and continuous-treatment group (but not the pre-treatment group) were significantly smaller than in the vehicle-treated group. Only the continuous-treatment group had significantly improved neurological scores 7 days after reperfusion compared with the vehicle group. Post-treatment and continuous-treatment groups had significantly decreased lipid peroxidation, oxidative DNA damage, microglial activation, expression of tumor necrosis factor-alpha, and neuronal damage in the cortical ischemic boundary area after 7 days of reperfusion. These results suggest that continuous oral administration (avoiding withdrawal) with statins after stroke may reduce the extent of post-ischemic brain damage and improve neurological outcome by inhibiting oxidative stress and inflammatory responses. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Pharmacokinetic study of furosemide incorporated PLGA microspheres after oral administration to rat

    PubMed Central

    Derakhshandeh, Katayoun; Karimi, Moin; Azandaryani, Abbas Hemati; Bahrami, Gholamreza; Ghanbari, Kiumras

    2016-01-01

    Objective(s): The purpose of the current study was to assess the feasibility of microspheres from biocompatible polymer for oral bioavailability (BA) enhancement of potent sulfonamide- type loop diuretic- Furosemide - which used in the treatment of congestive heart failure, caused edema, cirrhosis, renal disease and as an adjunct in acute pulmonary edema. The comparatively poor and inconstant BA of furosemide, which occurs site-specifically in the stomach and upper small intestine, has been ascribed to the poor dissolution of furosemide. Materials and Methods: In attempt to enhance the drug BA, poly (dl-lactic-co-glycolic acid) (PLGA) microspheres of furosemide were obtained using solvent-evaporation method and the carrier characteristics were investigated subsequently. Results: The in vivo performance of optimum formulation was assessed by pharmacokinetic evaluation of drug after orally administration of free and loaded in microspheres to rats (4 mg/Kg). For this reason, the concentration of drug in plasma was measured by a new developed and sensitive method of HPLC. Acceptable drug loading and encapsulation efficiency of microspheres were obtained to be 70.43 and 85.21 %, respectively. Microspheres provided improved pharmacokinetic parameters (Cmax = 147.94 ng/ml, Tmax = 1.92 hr) in rats as compared with pure drug (Cmax = 75.69 ng/ml, Tmax = 1.5 hr). The obtained AUC of drug in microsphere was 10 fold higher than of the free drug. Conclusion: The results showed that the prepared microspheres successfully improved BA of the poorly water-soluble drug effectively. PMID:27872700

  2. Pharmacokinetics of fluconazole following intravenous and oral administration to koalas (Phascolarctos cinereus).

    PubMed

    Black, L A; Krockenberger, M B; Kimble, B; Govendir, M

    2014-02-01

    Clinically normal koalas (n = 12) received a single dose of 10 mg/kg fluconazole orally (p.o.; n = 6) or intravenously (i.v.; n = 6). Serial plasma samples were collected over 24 h, and fluconazole concentrations were determined using a validated HPLC assay. A noncompartmental pharmacokinetic analysis was performed. Following i.v. administration, median (range) plasma clearance (CL) and steady-state volume of distribution (Vss ) were 0.31 (0.11-0.55) L/h/kg and 0.92 (0.38-1.40) L/kg, respectively. The elimination half-life (t1/2 ) was much shorter than in many species (i.v.: median 2.25, range 0.98-6.51 h; p.o.: 4.69, range 2.47-8.01 h), and oral bioavailability was low and variable (median 0.53, range 0.20-0.97). Absorption rate-limited disposition was evident. Plasma protein binding was 39.5 ± 3.5%. Although fluconazole volume of distribution (Varea ) displayed an allometric relationship with other mammals, CL and t1/2 did not. Allometrically scaled values were approximately sevenfold lower (CL) and sixfold higher (t1/2 ) than observed values, highlighting flaws associated with this technique in physiologically distinct species. On the basis of fAUC/MIC pharmacodynamic targets, fluconazole is predicted to be ineffective against Cryptococcus gattii in the koala as a sole therapeutic agent administered at 10 mg/kg p.o. every 12 h. © 2013 John Wiley & Sons Ltd.

  3. Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca.

    PubMed

    Riba, Jordi; McIlhenny, Ethan H; Valle, Marta; Bouso, José Carlos; Barker, Steven A

    2012-01-01

    Ayahuasca is an Amazonian psychotropic plant tea obtained from Banisteriopsis caapi, which contains β-carboline alkaloids, chiefly harmine, harmaline and tetrahydroharmine. The tea usually incorporates the leaves of Psychotria viridis or Diplopterys cabrerana, which are rich in N,N-dimethyltryptamine (DMT), a psychedelic 5-HT(2A/1A/2C) agonist. The β-carbolines reversibly inhibit monoamine-oxidase (MAO), effectively preventing oxidative deamination of the orally labile DMT and allowing its absorption and access to the central nervous system. Despite increased use of the tea worldwide, the metabolism and excretion of DMT and the β-carbolines has not been studied systematically in humans following ingestion of ayahuasca. In the present work, we used an analytical method involving high performance liquid chromatography (HPLC)/electrospray ionization (ESI)/selected reaction monitoring (SRM)/tandem mass spectrometry(MS/MS) to characterize the metabolism and disposition of ayahuasca alkaloids in humans. Twenty-four-hour urine samples were obtained from 10 healthy male volunteers following administration of an oral dose of encapsulated freeze-dried ayahuasca (1.0 mg DMT/kg body weight). Results showed that less than 1% of the administered DMT dose was excreted unchanged. Around 50% was recovered as indole-3-acetic acid but also as DMT-N-oxide (10%) and other MAO-independent compounds. Recovery of DMT plus metabolites reached 68%. Harmol, harmalol, and tetrahydroharmol conjugates were abundant in urine. However, recoveries of each harmala alkaloid plus its O-demethylated metabolite varied greatly between 9 and 65%. The present results show the existence in humans of alternative metabolic routes for DMT other than biotransformation by MAO. Also that O-demethylation plus conjugation is an important but probably not the only metabolic route for the harmala alkaloids in humans.

  4. Pharmacokinetics of doxycycline in laying hens after intravenous and oral administration.

    PubMed

    Yang, F; Si, H B; Wang, Y Q; Zhao, Z S; Zhou, B H; Hao, X Q

    2016-08-01

    The pharmacokinetics of doxycycline in laying hens was investigated after a single intravenous (IV) or an oral (PO) dose at 20 mg/kg body weight. The concentrations of doxycycline in plasma samples were determined by high-performance liquid chromatography with an ultraviolet detector, and pharmacokinetic parameters were calculated using a compartmental model method. The disposition of doxycycline after one single IV injection was best described by a two-compartment open model and the main pharmacokinetic parameters were as follows: volume of distribution (Vd) was 865.15 ± 127.64 ml/kg, distribution rate constant (α) was (2.28 ± 0.38) 1/h, elimination rate constant (β) was 0.08 ± 0.02 1/h and total body clearance (Cl) was104.11 ± 18.32 ml/h/kg, while after PO administration, the concentration versus time curve was best described by a one-compartment open model and absorption rate constant (Ka), peak concentration (Cmax), time to reach Cmax (tmax) and absolute bioavailability (F) were 2.55 ± 1.40 1/h, 5.88 ± 0.70 μg/ml, 1.73 ± 0.75 h and 52.33%, respectively. The profile of doxycycline exhibited favourable pharmacokinetic characteristics in laying hens, such as quick absorption and slow distribution and elimination, though oral bioavailability was relatively low. A multiple-dosing regimen (a dose of 20 mg/kg/d for 3 consecutive days) of doxycycline was recommended to treat infections in laying hens. But a further study should be conducted to determine the withdrawal time of doxycycline in eggs.

  5. Effects of dopamine transporter selective 3-phenyltropane analogs on locomotor activity, drug discrimination, and cocaine self-administration after oral administration.

    PubMed

    Carroll, F Ivy; Fox, Barbara S; Kuhar, Michael J; Howard, James L; Pollard, Gerald T; Schenk, Susan

    2006-12-28

    Several studies suggest that a dopamine transporter uptake inhibitor that has a slower onset and longer duration of action than cocaine in animal behavioral measures and decreases cocaine self-administration would be useful as an indirect dopamine agonist pharmacotherapy to treat cocaine addiction. In the present study, we compared five 3-phenyltropane analogs administered orally in locomotor activity in mice and drug discrimination in rats to gain information concerning relative potency, onset, and duration of action. The compounds were also evaluated for reduction of cocaine self-administration in rats after oral administration. In general, the compounds had a slower onset of action than cocaine and reduced cocaine self-administration. 3beta-(4-Chlorophenyl)-2beta-(3-(4'-methylphenyl)-isoxazol-5-yl)tropane (RTI-336) was the most potent in locomotor activity and drug discrimination; it was less stimulatory than cocaine in the first hour and had the slowest onset and longest duration of action. It also reduced self-administration of two infusion doses of cocaine in the rat.

  6. Performance of Students with Disabilities under Regular and Oral Administrations of a High-Stakes Reading Examination

    ERIC Educational Resources Information Center

    Huynh, Huynh; Barton, Karen E.

    2006-01-01

    This study examined the effect of oral administration accommodations on test structure and student performance on the Reading test of the South Carolina High School Exit Examination (HSEE). The examination was given at Grade 10 and was untimed; hence, students were permitted as much time as they needed to answer all the questions. Three groups of…

  7. TISSUE DISTRIBUTION OF INORGANIC ARSENIC (AS) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (ASV)

    EPA Science Inventory

    TISSUE DISTRIBUTION OF INORGANIC ARSENIC (iAs) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (AsV). E M Kenyon1, L M Del Razo2, and M F Hughes1. 1NHEERL, ORD, US EPA, RTP, NC, USA; 2CINVESTAV-IPN, Mexico City, Mexico.

    The relationship o...

  8. Effect of castration timing and oral meloxicam administration on growth performance, inflammation, behavior and carcass quality of beef calves

    USDA-ARS?s Scientific Manuscript database

    Beef bull calves (n = 62) were assigned randomly, within sire breed, to 1 of 4 treatments at birth. Treatments were: 1) surgical castration near birth, 2) surgical castration near birth with oral administration of meloxicam (1 milligram/kilogram of body weight), 3) surgical castration at weaning (WN...

  9. 10 CFR 35.394 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ....394 Section 35.394 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required § 35.394 Training for the oral administration of sodium iodide... include— (i) Radiation physics and instrumentation; (ii) Radiation protection; (iii) Mathematics...

  10. 10 CFR 35.392 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... millicuries). 35.392 Section 35.392 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required § 35.392 Training for the oral administration of... requiring a written directive. The training must include— (i) Radiation physics and instrumentation; (ii...

  11. 10 CFR 35.392 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... millicuries). 35.392 Section 35.392 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required § 35.392 Training for the oral administration of... requiring a written directive. The training must include— (i) Radiation physics and instrumentation; (ii...

  12. 10 CFR 35.392 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... millicuries). 35.392 Section 35.392 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required § 35.392 Training for the oral administration of... requiring a written directive. The training must include— (i) Radiation physics and instrumentation; (ii...

  13. 10 CFR 35.394 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ....394 Section 35.394 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required § 35.394 Training for the oral administration of sodium iodide... include— (i) Radiation physics and instrumentation; (ii) Radiation protection; (iii) Mathematics...

  14. 10 CFR 35.394 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ....394 Section 35.394 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required § 35.394 Training for the oral administration of sodium iodide... include— (i) Radiation physics and instrumentation; (ii) Radiation protection; (iii) Mathematics...

  15. 10 CFR 35.392 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... millicuries). 35.392 Section 35.392 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required § 35.392 Training for the oral administration of... requiring a written directive. The training must include— (i) Radiation physics and instrumentation; (ii...

  16. 10 CFR 35.394 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ....394 Section 35.394 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required § 35.394 Training for the oral administration of sodium iodide... include— (i) Radiation physics and instrumentation; (ii) Radiation protection; (iii) Mathematics...

  17. TISSUE DISTRIBUTION OF INORGANIC ARSENIC (AS) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (ASV)

    EPA Science Inventory

    TISSUE DISTRIBUTION OF INORGANIC ARSENIC (iAs) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (AsV). E M Kenyon1, L M Del Razo2, and M F Hughes1. 1NHEERL, ORD, US EPA, RTP, NC, USA; 2CINVESTAV-IPN, Mexico City, Mexico.

    The relationship o...

  18. Nanotamoxifen Delivery System: Toxicity Assessment After Oral Administration and Biodistribution Study After Intravenous Delivery of Radiolabeled Nanotamoxifen

    PubMed Central

    Shukla, Jaya; Dinda, Amit Kumar; Srivastava, Abhay Krishna; Srivastava, Kamna; Mittal, Bhagwant Rai; Bandopadhyaya, Guru Pad

    2016-01-01

    Tamoxifen is the most prescribed anticancer oral drug for increasing overall survival and decreasing recurrence and the risk of contralateral disease. However, some side effects, such as endometrial and liver tumors, thromboembolic disorders, and drug resistance, are associated with long-term tamoxifen treatment. We assessed the hematologic and organ toxicity after oral administration of three different doses of nanotamoxifen formulations. We also performed biodistribution studies of Technetium-99m (99mTc)-nanotamoxifen after intravenous administration. The results demonstrated that nanotamoxifen was well-tolerated, with no adverse effect on biochemical parameters of blood and at the cellular level. Nitric oxide (NO) levels indicated no free radical formation. Oral nanotamoxifen is well-tolerated, with no hepatic or renal toxicity. Intravenous nanotamoxifen has potential to escape the liver, and is known for producing the harmful metabolite 4-hydroxytamoxifen (4OH-tamoxifen), which can cause uterine cancer. PMID:26912972

  19. Toxicokinetics of acrylamide in rats and humans following single oral administration of low doses

    SciTech Connect

    Kopp, Eva Katharina; Dekant, Wolfgang

    2009-03-01

    The rodent carcinogen acrylamide (AA) is formed during preparation of starch-containing foods. AA is partly metabolized to the genotoxic epoxide glycidamide (GA). After metabolic processing, the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), rac-N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) and rac-N-acetyl-S-(1-carbamoyl-moyl-2-hydroxyethyl)-L-cysteine (iso-GAMA) are excreted with urine. In humans, AAMA can be sulfoxidized to AAMA-sulfoxide. The aim of this study was to assess potential species-differences in AA-toxicokinetics in rats and humans after single oral administration of doses similar to the daily human dietary exposure. Male Fischer 344 rats (n = 5/dose group) were administered 20 and 100 {mu}g/kg b.w. {sup 13}C{sub 3}-AA in deionized water via oral gavage. Human subjects (n = 3/gender) were orally administered 0.5 and 20 {mu}g/kg b.w. {sup 13}C{sub 3}-AA with drinking water. Urine samples were collected in intervals for 96 and 94 h, respectively. Urinary concentrations of {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide were monitored by liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 66.3% and 70.5% of the 20 and 100 {mu}g/kg b.w. doses in rats and for 71.3% and 70.0% of the 0.5 and 20 {mu}g/kg b.w. doses in humans. In rats, {sup 13}C{sub 3}-AAMA accounted for 33.6% and 38.8% of dose and 32.7% and 31.7% of dose was recovered as {sup 13}C{sub 3}-GAMA; {sup 13}C{sub 3}-AAMA-sulfoxide was not detected in rat urine. In humans, {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide accounted for 51.7% and 49.2%, 6.3% and 6.4% and 13.2% and 14.5% of the applied dose, respectively. The obtained results suggest that the extent of AA bioactivation to GA in humans is lower than in rodents.

  20. Oral administration of bovine whey proteins to mice elicits opposing immunoregulatory responses and is adjuvant dependent

    PubMed Central

    AFUWAPE, A O; TURNER, M W; STROBEL, S

    2004-01-01

    Most studies investigating the induction of oral tolerance (OT) use purified proteins such as ovalbumin (OVA), bovine serum albumin (BSA) and beta-lactoglobulin (β-LG). Little information is available regarding the induction of OT to a protein mixture, e.g. cow's milk. In this study we compared the regulatory mechanisms induced after the oral administration of a whey protein concentrate (WP) derived from cow's milk following immunization with two different adjuvants, complete Freund's adjuvant (CFA) and alum. OVA was used as a control antigen. Animals were given a single feed of these proteins at an equivalent dose of 1 mg/g body weight before they were immunized seven days later with the antigen in Freund's adjuvant or alum. Delayed type hypersensitivity (DTH) responses were suppressed by both a feed of WP and OVA after immunization with CFA. However, only OVA feeding suppressed antigen specific IgG responses. In an attempt to investigate whether WP would tolerize the more susceptible IgE responses, alum immunization replaced CFA as the adjuvant used for systemic immunizations. WP, after a single feed, significantly primed for DTH and IgE responses indicating oral sensitization to WP. In contrast, OVA suppressed DTH, IgE and IgG responses. Antigen specific proliferation of mononuclear cells was suppressed in mice fed OVA, but primed in those fed with WP. In addition cells taken from sensitized mice fed WP up-regulated levels of specific interleukin (IL) -4, -10 and -12 in vitro whereas these cytokines were suppressed in cultures from tolerant WP fed mice. Global suppression was obtained in cultures from tolerant OVA fed mice. TGF-β was not detected in draining PLN cell cultures of either tolerant or sensitized mice. These data suggest that a whey protein mixture induces divergent responses following immunization with either CFA or alum despite being fed at an identical dose. We suggest that that the choice of the adjuvant may determine the immunoregulatory

  1. Bioavailability of the flavonol quercetin in neonatal calves after oral administration of quercetin aglycone or rutin.

    PubMed

    Maciej, J; Schäff, C T; Kanitz, E; Tuchscherer, A; Bruckmaier, R M; Wolffram, S; Hammon, H M

    2015-06-01

    Polyphenols, such as flavonoids, are secondary plant metabolites with potentially health-promoting properties. In newborn calves flavonoids may improve health status, but little is known about the systemically availability of flavonoids in calves to exert biological effects. The aim of this study was to investigate the oral bioavailability of the flavonol quercetin, applied either as quercetin aglycone (QA) or as its glucorhamnoside rutin (RU), in newborn dairy calves. Twenty-one male newborn German Holstein calves were fed equal amounts of colostrum and milk replacer according to body weight. On d 2 and 29 of life, 9 mg of quercetin equivalents/kg of body weight, either fed as QA or as RU, or no quercetin (control group) were fed together with the morning meal. Blood samples were taken before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 12, 24, and 48 h after feed intake. Quercetin and quercetin metabolites with an intact flavonol structure (isorhamnetin, tamarixetin, and kaempferol) were analyzed in blood plasma after treatment with glucuronidase or sulfatase by HPLC with fluorescence detection. Maximum individual plasma concentration was depicted from the concentration-time-curve on d 2 and 29, respectively. Additional blood samples were taken to measure basal plasma concentrations of total protein, albumin, urea, and lactate as well as pre- and postprandial plasma concentrations of glucose, nonesterified fatty acids, insulin, and cortisol. Plasma concentrations of quercetin and its metabolites were significantly higher on d 2 than on d 29 of life, and administration of QA resulted in higher plasma concentrations of quercetin and its metabolites than RU. The relative bioavailability of total flavonols (sum of quercetin and its metabolites isorhamnetin, tamarixetin, and kaempferol) from RU was 72.5% on d 2 and 49.6% on d 29 when compared with QA (100%). Calves fed QA reached maximum plasma concentrations of total flavonols much earlier than did RU-fed calves. Plasma

  2. Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer

    SciTech Connect

    Hao, Hui-fang; Takaoka, Munenori; Bao, Xiao-hong; Wang, Zhi-gang; Tomono, Yasuko; Sakurama, Kazufumi; Ohara, Toshiaki; Fukazawa, Takuya; Yamatsuji, Tomoki; Fujiwara, Toshiyoshi; Naomoto, Yoshio

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer A novel FAK inhibitor TAE226 suppressed FAK activity in HCT116 colon cancer cells. Black-Right-Pointing-Pointer TAE226 suppressed proliferation and migration, with a modest effect on adhesion. Black-Right-Pointing-Pointer Silencing of FAK by siRNA made no obvious difference on cancer cell attachment. Black-Right-Pointing-Pointer TAE226 treatment suppressed the progression of peritoneal dissemination. Black-Right-Pointing-Pointer Oral administration of TAE226 prolonged the survival of tumor-bearing mice. -- Abstract: Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken

  3. The vaginal isolate Lactobacillus paracasei LPC-S01 (DSM 26760) is suitable for oral administration

    PubMed Central

    Balzaretti, Silvia; Taverniti, Valentina; Rondini, Greta; Marcolegio, Giorgio; Minuzzo, Mario; Remagni, Maria C.; Fiore, Walter; Arioli, Stefania; Guglielmetti, Simone

    2015-01-01

    Bacterial vaginosis is one of the most common urogenital diseases affecting women in reproductive age. The administration of probiotics as vaginal suppository has been proposed as a strategy to cure this condition and reduce its recurrence. Nonetheless, also oral consumption of probiotics, which is a more practical route of administration, proved to be an efficient strategy. In this perspective, we studied Lactobacillus paracasei LPC-S01 (DSM 26760), a human vaginal isolate included in commercial probiotic preparations for topical use, in order to assess if this bacterium can also perform as gastrointestinal probiotic. Comparative genomics revealed the presence of several accessory genes suggesting that LPC-S01 is a niche-generalist member of its species. According to a procedure conventionally used to predict the probiotic potential, we demonstrated that the probiotic properties of strain LPC-S01, with respect to those of the well-known probiotic references L. paracasei Shirota and DG, are equal for the bile tolerance and the reduction of NF-κB activation in Caco-2 cells, or superior for the tolerance to gastric juice and the adhesion to Caco-2 epithelial cells. We then demonstrated that LPC-S01 is susceptible to antibiotics indicated by EFSA and does not produce biogenic amines. Finally, a double-blind cross-over pilot intervention trial on healthy human volunteers showed that, after a 7-days oral consumption of capsules containing about 24 billion live cells, the fecal cell concentrations of strains LPC-S01 and DG (evaluated by qPCR) were not dissimilar. Specifically, both probiotics' cell concentrations were above the detection limit for an average of 5 days from the end of the treatment, corresponding to a mean number of evacuations of 7 ± 2. Taken together, these data demonstrate that the vaginal isolate L. paracasei LPC-S01 possesses safety and functional properties that may support its use as probiotic to be administered per os for potential intestinal as

  4. Formation of epichlorohydrin, a known rodent carcinogen, following oral administration of 1,3-dichloro-2-propanol in rats.

    PubMed

    Waidyanatha, Suramya; Gaudette, Norman F; Hong, Yan; Fennell, Timothy R

    2014-10-20

    The observed toxicity and carcinogenicity of 1,3-dichloro-2-propanol (DCP) in rodents is thought to be due to the formation of reactive metabolites, epichlorohydrin (ECH) and dichloroacetone (DCA). However, there is no direct evidence for the formation of these metabolites from exposure to DCP in rodents due to the challenges of measuring these reactive intermediates directly in vivo. The objective of this work was to investigate the metabolism of DCP to ECH and DCA in vivo by first developing a sensitive analytical method in a suitable biological matrix and analyzing samples from rats administered DCP. DCA reacted rapidly in vitro in rat blood, plasma, and liver homogenate, precluding its detection. Because ECH rapidly disappeared in liver homogenate, but was relatively long-lived in plasma and blood in vitro, blood was selected for analysis of this metabolite. Following a single oral dose of 50 mg/kg DCP in male or female Harlan Sprague-Dawley rats, ECH was detected in blood with a maximum concentration reached at ≤13.7 min. ECH was cleared rapidly with a half-life of ca. 33 and 48 min in males and females, respectively. Following a single oral dose of 25 mg/kg ECH in male and female rats, the elimination half-life of ECH was ca. 34 and 20 min, respectively; the oral bioavailability of ECH was low (males, 5.2%; females, 2.1%), suggesting extensive first pass metabolism of ECH following oral administration. The area under the concentration vs time curve for ECH following oral administration of DCP and intravenous administration of ECH was used to estimate the percent of the DCP dose converted to ECH in rats. On the basis of this analysis, we concluded that in male and female rats following oral administration of 50 mg/kg DCP, ≥1.26% or ≥1.78% of the administered dose was metabolized to ECH, respectively.

  5. Bioavailability of a dexlansoprazole delayed-release orally disintegrating tablet: effects of food and mode of administration

    PubMed Central

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

    2017-01-01

    Background Dexlansoprazole is a proton pump inhibitor (PPI) approved for use in dual delayed-release capsule and orally disintegrating tablet (ODT) formulations. Aim To assess effects of food, water, and route of administration on the bioavailability of dexlansoprazole 30-mg ODT. Methods Two separate open-label, phase 1, single-dose crossover studies were conducted in healthy adults. In study 1, pharmacokinetic parameters were analyzed in participants receiving dexlansoprazole ODT in a fed or fasted state with and without water. In study 2, the bioavailability of dexlansoprazole after administration via oral syringe or nasogastric (NG) tube, or after swallowing intact with water was compared to ODT administration in the fasted state, swallowed without water. Blood samples for determining dexlansoprazole plasma concentrations and pharmacokinetic parameter estimates were collected before and after dosing. Results Equivalent values for area under the plasma concentration–time curve (AUC) were observed in the fed and fasted states, but the maximum observed plasma concentration (Cmax) was 38% lower in the fed state; therefore, bioequivalence was not achieved. A water rinse following standard ODT administration decreased dexlansoprazole bioavailability, with lower Cmax and AUC values than when ODT was administered without a water rinse. Bioequivalence was demonstrated when comparing the alternative routes of administration, including via oral syringe or NG tube with standard ODT administration. Unlike with a water rinse, bioequivalence to standard ODT administration (i.e., without water) was demonstrated when swallowing the ODT intact with water. Rates of adverse events were comparable irrespective of administration route in the fasted state (6.7%–9.3%) and were 12% higher in the fed state than in the fasted state. Conclusion The AUC from the dexlansoprazole ODT was equivalent when administered in the fed and fasted states. Equivalent systemic exposure to

  6. Population pharmacokinetics of a single dose of meloxicam after oral and intramuscular administration to captive lesser flamingos (Phoeniconaias minor).

    PubMed

    Zordan, Martín A; Papich, Mark G; Pich, Ashley A; Unger, Katy M; Sánchez, Carlos R

    2016-12-01

    OBJECTIVE To determine the pharmacokinetics of a single dose of meloxicam after IM and oral administration to healthy lesser flamingos (Phoeniconaias minor) by use of a population approach. ANIMALS 16 healthy captive lesser flamingos between 1 and 4 years of age. PROCEDURES A single dose of meloxicam (0.5 mg/kg) was administered IM to each bird, and blood samples were collected from birds at 3 (n = 13 birds), 2 (2), or 1 (1) selected point between 0 and 13 hours after administration, with samples collected from birds at each point. After a 15-day washout period, the same dose of meloxicam was administered PO via a red rubber tube and blood samples were collected as described for IM administration. Pharmacokinetic values were determined from plasma concentrations measured by high-performance liquid chromatography. RESULTS Plasma drug concentrations after IM administration of meloxicam reached a mean ± SD maximum value of 6.01 ± 3.38 μg/mL. Mean area under the concentration-versus-time curve was 17.78 ± 2.79 μg•h/mL, and mean elimination half-life was 1.93 ± 0.32 hours. Plasma concentrations after oral administration reached a mean maximum value of 1.79 ± 0.33 μg/mL. Mean area under the curve was 22.16 ± 7.17 μg•h/mL, and mean elimination half-life was 6.05 ± 3.53 hours. CONCLUSIONS AND CLINICAL RELEVANCE In lesser flamingos, oral administration of meloxicam resulted in higher bioavailability and a longer elimination half-life than did IM administration, but the maximum plasma concentration was low and may be insufficient to provide analgesia in flamingos. Conversely, IM administration achieved the desired plasma concentration but would require more frequent administration.

  7. Bioavailability and pharmacokinetics of the investigational anticancer agent XK469 (NSC 698215) in rats following oral and intravenous administration.

    PubMed

    Boinpally, Ramesh R; Zhou, Sen-Lin; LoRusso, Patricia M; Parchment, Ralph E

    2005-04-01

    To determine the oral bioavailability of R-XK469, a water-soluble investigational anticancer agent undergoing phase I clinical trials as an intravenous product. R-XK469 was administered to two groups of catheterized Sprague-Dawley rats via the oral and IV routes at a dose of 10 mg/kg and blood samples were collected at predetermined times. XK469 in plasma samples was quantified using a HPLC method. The pharmacokinetic parameters were computed using WinNonlin 4.0.1 software. The pharmacokinetic parameters of XK469 following oral and IV administrations, respectively, were (mean+/-SD): C(max) 138+/-64 and 404 +/- 355 microg/ml; AUC(0-infinity) 2381 +/- 773 and 2854 +/- 1924 microg h/ml; and elimination half-life (T(1/2)) 12.9 +/- 5.8 and 13.5 +/- 7.8 h T(max) was 2.92+/-1.92 h following oral dosing. Oral R-XK469 was 83% bioavailable. Together with the antitumor efficacy of oral XK469 shown in preclinical models and its schedule dependency, these results indicate the promise of developing an oral dosage form of R-XK469 for clinical development.

  8. Toxico-kinetics, recovery, and metabolism of napropamide in goats following a single high-dose oral administration.

    PubMed

    Pahari, A K; Majumdar, S; Mandal, T K; Chakraborty, A K; Bhattacharyya, A; Chowdhury, A

    2001-04-01

    Toxicokinetic behavior, recovery and metabolism of napropamide (a pre-emergent herbicide) and its effect on Cytochrome P(450) of liver microsomal pellet were studied following a single high-dose oral administration of 2.5 g kg(-1) and continuous (7 days) oral administration of 500 mg kg(-1) in black Bengal goat. Napropamide was detected in blood at 15 min and the maximum quantity was recovered at 3 h after administration. The absorption rate constant (Ka) value was low indicating poor absorption from the gastrointestinal tract. High elimination half-life (t(1/2) beta) and low body clearance (Cl(B)) values coupled with higher transfer of compound from tissue to central compartment (K(21)) suggest that napropamide persisted in the blood for a long time, i.e., after 72 h of oral administration. The recovery percentage of napropamide, including metabolites, from goats varied from 75.94 to 80.08 and excretion of the parent compound through feces varied from 18.86 to 21.59%, indicating that a major portion of the orally administered napropamide was absorbed from the gastrointestinal tract of goat. Napropamide significantly increased the Cytochrome P(450) content of liver microsomal pellet. The recovery of metabolites from feces, urine, and tissues ranged from 4.2--6.2, 40.81--49.42, and 2.7--11.6%, respectively, during a 4--7 day period. The material balance of napropamide (including metabolites) following a single high-dose oral administration at 2.5 g kg(-1) during 4--7 days after dosing was found to be in the range of 75--80%.

  9. MR cholangiography in potential liver donors: quantitative and qualitative improvement with administration of an oral effervescent agent.

    PubMed

    Kwon, Heon-Ju; Kim, Kyoung Won; Choi, Sang Hyun; Jung, Jin-Hee; Kim, So Yeon; Kim, Se-Young; Lee, Jeongjin; Jung, Dong-Hwan; Ha, Tae-Yong; Song, Gi-Won; Lee, Sung-Gyu

    2017-03-23

    To determine whether an oral effervescent agent improves magnetic resonance cholangiography (MRC) images, both qualitatively and quantitatively, in potential live liver donors. This retrospective study was approved by the Institutional Review Board, and informed consent was waived. Seventy potential liver donors underwent 2D MRC before and after administration of an oral effervescent agent. One radiologist measured relative contrast ratio (rC) and relative signal intensity (rS) for right and left intrahepatic ducts (RHD and LHD), and common hepatic duct (CHD). After assessment of overall image quality, two other radiologists independently scored visualization of five ductal segments (RHD, LHD, CHD, cystic, and common bile duct) and assessed the preferred image set. In consensus, they assessed the biliary anatomy. The data were analyzed using a paired t-test, Wilcoxon's signed-rank test, and chi-square test. Both rC and rS of RHD and CHD were significantly higher on MRC images after administration of an oral effervescent agent than before (P < 0.03). The overall image quality grades and biliary visualization scores for all five duct segments were significantly higher on MRC images after administration of an oral effervescent agent than before (P < 0.0001). Between these images, both readers more often preferred MRC images with an effervescent agent rather than those without this agent (reader 1: 56/70, 80.0%; reader 2: 55/70, 78.6%; P = 0.0003). The readers correctly assessed second-order biliary tract anatomy in two more subjects on MRC after administration of an effervescent agent than before. Oral administration of an effervescent agent improves MRC images, both qualitatively and quantitatively, in live liver donors. 3 J. Magn. Reson. Imaging 2017. © 2017 International Society for Magnetic Resonance in Medicine.

  10. Optimal timing of oral fosfomycin administration for pre-prostate biopsy prophylaxis.

    PubMed

    Rhodes, Nathaniel J; Gardiner, Bradley J; Neely, Michael N; Grayson, M Lindsay; Ellis, Andrew G; Lawrentschuk, Nathan; Frauman, Albert G; Maxwell, Kelly M; Zembower, Teresa R; Scheetz, Marc H

    2015-07-01

    As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis. Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model. Plasma and tissue concentrations were simulated during the first 24 h post-dose, comparing these with EUCAST susceptibility breakpoints for Escherichia coli, a common uropathogen. Non-compartmental-determined pharmacokinetic values in our population were similar to those reported in the package insert. Predicted plasma concentrations rapidly increased after the first hour, giving more than 90% population coverage for organisms with an MIC ≤4 mg/L over the first 12 h post-dose. Organisms with higher MICs fared much worse, with organisms at the EUCAST breakpoint being covered for <10% of the population at any time. Transitional zone prostate concentrations exceeded 4 mg/L for 90% of the population between hours 1 and 9. Peripheral zone prostate concentrations were much lower and only exceeded 4 mg/L for 70% of the population between hours 1 and 4. Until more precise plasma and tissue data are available, we recommend that fosfomycin prophylaxis be given 1-4 h prior to prostate biopsy. We do not recommend fosfomycin prophylaxis for subjects with known organisms with MICs >4 mg/L. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Combined administration of antibiotics and direct oral anticoagulants: a renewed indication for laboratory monitoring?

    PubMed

    Lippi, Giuseppe; Favaloro, Emmanuel J; Mattiuzzi, Camilla

    2014-10-01

    The recent development and marketing of novel direct oral anticoagulants (DOACs) represents a paradigm shift in the management of patients requiring long-term anticoagulation. The advantages of these compounds over traditional therapy with vitamin K antagonists include a reportedly lower risk of severe hemorrhages and the limited need for laboratory measurements. However, there are several scenarios in which testing should be applied. The potential for drug-to-drug interaction is one plausible but currently underrecognized indication for laboratory assessment of the anticoagulant effect of DOACs. In particular, substantial concern has been raised during Phase I studies regarding the potential interaction of these drugs with some antibiotics, especially those that interplay with permeability glycoprotein (P-gp) and cytochrome 3A4 (CYP3A4). A specific electronic search on clinical trials published so far confirms that clarithromycin and rifampicin significantly impair the bioavailability of dabigatran, whereas clarithromycin, erythromycin, fluconazole, and ketoconazole alter the metabolism of rivaroxaban in vivo. Because of their more recent development, no published data were found for apixaban and edoxaban, or for potential interactions of DOACs with other and widely used antibiotics. It is noteworthy, however, that an online resource based on Food and Drug Administration and social media information, reports several hemorrhagic and thrombotic events in patients simultaneously taking dabigatran and some commonly used antibiotics such as amoxicillin, cephalosporin, and metronidazole. According to these reports, the administration of antibiotics in patients undergoing therapy with DOACs would seem to require accurate evaluation as to whether dose adjustments (personalized or antibiotic class driven) of the anticoagulant drug may be advisable. This might be facilitated by direct laboratory assessments of their anticoagulant effect ex vivo. Thieme Medical Publishers

  12. Acute oral administration of low doses of methylphenidate targets calretinin neurons in the rat septal area

    PubMed Central

    García-Avilés, Álvaro; Albert-Gascó, Héctor; Arnal-Vicente, Isabel; Elhajj, Ebtisam; Sanjuan-Arias, Julio; Sanchez-Perez, Ana María; Olucha-Bordonau, Francisco

    2015-01-01

    Methylphenidate (MPD) is a commonly administered drug to treat children suffering from attention deficit hyperactivity disorder (ADHD). Alterations in septal driven hippocampal theta rhythm may underlie attention deficits observed in these patients. Amongst others, the septo-hippocampal connections have long been acknowledged to be important in preserving hippocampal function. Thus, we wanted to ascertain if MPD administration, which improves attention in patients, could affect septal areas connecting with hippocampus. We used low and orally administered MPD doses (1.3, 2.7 and 5 mg/Kg) to rats what mimics the dosage range in humans. In our model, we observed no effect when using 1.3 mg/Kg MPD; whereas 2.7 and 5 mg/Kg induced a significant increase in c-fos expression specifically in the medial septum (MS), an area intimately connected to the hippocampus. We analyzed dopaminergic areas such as nucleus accumbens and striatum, and found that only 5 mg/Kg induced c-fos levels increase. In these areas tyrosine hydroxylase correlated well with c-fos staining, whereas in the MS the sparse tyrosine hydroxylase fibers did not overlap with c-fos positive neurons. Double immunofluorescence of c-fos with neuronal markers in the septal area revealed that co-localization with choline acethyl transferase, parvalbumin, and calbindin with c-fos did not change with MPD treatment; whereas, calretinin and c-fos double labeled neurons increased after MPD administration. Altogether, these results suggest that low and acute doses of methylphenidate primary target specific populations of caltretinin medial septal neurons. PMID:25852493

  13. Doxycycline depletion and residues in eggs after oral administration to laying hens.

    PubMed

    Gajda, Anna; Posyniak, Andrzej

    2015-01-01

    The depletion of doxycycline (DC) residues in eggs was determined after oral drug administration by drinking water to laying hens. The antibiotic was supplied to birds for 5 consecutive days and the eggs were collected during medication and 18 days after withdrawal. DC residues were determined by LC-MS/MS. DC was isolated from eggs with a solution of 0.02 M of oxalic acid (pH 4), 0.1 M Na2EDTA and acetonitrile. The limit of detection (LOD) and limit of quantification (LOQ) of the method were 2 and 5 µg kg(-1), respectively. Analyses were performed on whole egg, egg white and yolk separately. DC was detectable 24 h after the beginning of administration. The concentration of antibiotic increased daily, resulting in the highest DC concentration in whole eggs at the first day of the withdrawal period. Thirteen days after withdrawal, the content of DC in whole eggs was below the LOQ of the method. However, some differences were found in the depletion curve of DC between egg white and yolk. Residues of DC in egg white were much higher during treatment and 1 day after withdrawal, but later the concentration in egg white decreased fairly rapidly and a higher DC content in egg yolk was observed. The depletion period was shorter for egg white than for yolk, and DC was detected in the egg white until 12 days after withdrawal and 2 days more in egg yolk than in white. DC reached a peak faster in egg white, but the residues were detectable for longer period in the yolk.

  14. Pharmacokinetics and metabolism of [14C]-proglumetacin after oral administration in the rat.

    PubMed

    Makovec, F; Chisté, R; Peris, W; Setnikar, I

    1987-07-01

    The pharmacokinetics and metabolism of 1H-indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl 2-[4-[3-[[4-(benzoylamino)-5-(dipropylamino)-1, 5-dioxopentyl]oxy]propyl]-1-piperazinyl]ethyl ester (+/-) (proglumetacin, CR 604), 14C-labelled in position C-2 of the indolic moiety, was studied in male and female rats after oral administration. The radioactivity is slowly absorbed from the gastrointestinal tract and reaches the peak in plasma 6 h after administration. Afterwards the radioactivity is eliminated from plasma according to a bi-exponential equation, with an initial elimination rate having a t1/2 of 4.5 h and a terminal elimination rate having a t1/2 of 16 h. The elimination rate is probably dependent on the slow absorption rate (flip-flop system) and on an entero-hepatic recirculation of the radioactivity. The radioactivity is excreted with the feces (60.8%) and with the urines (33.5%). No radioactivity is eliminated with the expired air. About 13% of the fecal radioactivity is represented by proglumetacin. This fraction or radioactivity (ca. 8% of the administered) represents probably the non-absorbed amount of substance. The parent proglumetacin is not found in blood, urine and organs. Conversely several indolic metabolites are found, with a predomination of indometacin. Proglumetacin is therefore a pro-drug of indometacin and of other indolic metabolites, which are responsible for the antiinflammatory activity of proglumetacin. The radioactivity is distributed in all tissues. The maximum radioactivity is found in liver and kidneys, however, always in a smaller concentration than in plasma. No "deep compartment" was found.

  15. Early effect on intragastric pH of oral administration of rabeprazole with mosapride compared with rabeprazole alone.

    PubMed

    Iida, Hiroshi; Kaai, Megumi; Inoh, Yumi; Kanoshima, Kenji; Ohkuma, Kanji; Nonaka, Takashi; Fujita, Koji; Ida, Tomonori; Kusakabe, Akihiko; Maeda, Shin; Nakajima, Atsushi; Inamori, Masahiko

    2017-01-01

    An ideal medication for acid-related diseases would offer prompt stopping of blood flow as well as efficient symptom resolution. The aim of this study was to investigate the gastric acid suppression potency of a single oral dose of rabeprazole alone, compared with administration of rabeprazole plus mosapride. Twelve male volunteers, Helicobacter pylori (H. pylori)-negative, participated in this randomized, three-way crossover study. After a single oral administration of rabeprazole, rabeprazole with mosapride, or rabeprazole administered 1 h after mosapride, we monitored their intragastric pH constantly for 6 h. A 7-day washout period was allowed between each administration. The median 6-h intragastric pH after the administration of rabeprazole 1 h after mosapride was 4.41±1.22 (mean±s.d.), significantly higher than after rabeprazole alone 3.45±1.33, P=0.0376). There was no significant difference between the median 6-h pH after the administration of rabeprazole plus mosapride and that after rabeprazole alone (3.81±0.98 vs. 3.45±1.33, respectively; P=0.0927). An oral dose of rabeprazole administered 1 h after mosapride increased the intragastric pH more rapidly than rabeprazole alone, in healthy, male, H. pylori-negative volunteers.

  16. Early effect on intragastric pH of oral administration of rabeprazole with mosapride compared with rabeprazole alone

    PubMed Central

    Iida, Hiroshi; Kaai, Megumi; Inoh, Yumi; Kanoshima, Kenji; Ohkuma, Kanji; Nonaka, Takashi; Fujita, Koji; Ida, Tomonori; Kusakabe, Akihiko; Maeda, Shin; Nakajima, Atsushi; Inamori, Masahiko

    2017-01-01

    Background An ideal medication for acid-related diseases would offer prompt stopping of blood flow as well as efficient symptom resolution. The aim of this study was to investigate the gastric acid suppression potency of a single oral dose of rabeprazole alone, compared with administration of rabeprazole plus mosapride. Methods Twelve male volunteers, Helicobacter pylori (H. pylori)-negative, participated in this randomized, three-way crossover study. After a single oral administration of rabeprazole, rabeprazole with mosapride, or rabeprazole administered 1 h after mosapride, we monitored their intragastric pH constantly for 6 h. A 7-day washout period was allowed between each administration. Results The median 6-h intragastric pH after the administration of rabeprazole 1 h after mosapride was 4.41±1.22 (mean±s.d.), significantly higher than after rabeprazole alone 3.45±1.33, P=0.0376). There was no significant difference between the median 6-h pH after the administration of rabeprazole plus mosapride and that after rabeprazole alone (3.81±0.98 vs. 3.45±1.33, respectively; P=0.0927). Conclusion An oral dose of rabeprazole administered 1 h after mosapride increased the intragastric pH more rapidly than rabeprazole alone, in healthy, male, H. pylori-negative volunteers. PMID:28655978

  17. Oral administration of Lactobacillus plantarum HY7714 protects hairless mouse against ultraviolet B-induced photoaging.

    PubMed

    Kim, Hyun Mee; Lee, Dong Eun; Park, Soo Dong; Kim, Yong-Tae; Kim, Yu Jin; Jeong, Ji Woong; Jang, Sung Sik; Ahn, Young-Tae; Sim, Jae-Hun; Huh, Chul-Sung; Chung, Dae Kyun; Lee, Jung-Hee

    2014-11-28

    Ultraviolet (UV) irradiation alters multiple molecular pathways in the skin, thereby inducing skin damage, including photoaging. In recent years, probiotics have gained interest due to their beneficial effects on skin health, such as inhibiting atopic dermatitis and improving skin immunity or inflammation. However, little is known about the effects of probiotics on UVBinduced photoaging. In this study, we evaluated the effect of Lactobacillus plantarum HY7714 against UVB-induced photoaging in human dermal fibroblasts and hairless mice. The results showed that L. plantarum HY7714 treatment effectively rescued UVB-reduced procollagen expression through the inhibition of UVB-induced matrix metalloproteinase (MMP)-1 expression in human dermal fibroblasts. Data from a western blot showed that L. plantarum HY7714 inhibited the phosphorylation of Jun N-terminal kinase, thereby suppressing the UVB-induced phosphorylation and expression of c-Jun. Oral administration of L. plantarum HY7714 clearly inhibited the number, depth, and area of wrinkles in hairless mouse skin. Histological data showed that L. plantarum HY7714 significantly inhibited UVB-induced epidermal thickness in mice. Western blot and zymography data also revealed that L. plantarum HY7714 effectively inhibited MMP-13 expression as well as MMP-2 and -9 activities in dermal tissue. Collectively, these results provide further insight regarding the skin biological actions of L. plantarum HY7714, a potential skin anti-photoaging agent.

  18. Urinary excretion of arbutin metabolites after oral administration of bearberry leaf extracts.

    PubMed

    Quintus, Joachim; Kovar, Karl-Artur; Link, Peter; Hamacher, Harald

    2005-02-01

    An HPLC assay with fluorimetric detection of the arbutin metabolites hydroquinone glucuronide (2) and hydroquinone sulphate (6) in urine was developed and validated. Methylarbutin (4) and 6 were synthesised as reference substances. Compound 2 was prepared enzymatically from hydroquinone and uridine 5'-diphosphoglucuronic acid using the glucosyltransferase system of rat liver microsomes and enriched by two liquid-liquid and an additional solid phase extraction. Compound 2 as the main component of this purified product was identified by UV and fluorescence spectroscopy, by HPLC-MS, and by enzymatic hydrolysis to hydroquinone (5). The assay yields precise and accurate urine levels of 2, 5 and 6 in the concentration range expected after oral administration of recommended therapeutic doses of bearberry leaf extract. In a preliminary pharmacokinetic study on 3 volunteers the time-dependent renal excretion of arbutin metabolites 2, 5 and 6 was investigated after ingestion of an aqueous bearberry leaf extract containing an arbutin dose recommended by the German Kommission E. More than half of the administered dose of arbutin was excreted within 4 hours mainly in form of the metabolites 2 and 6 and more than 75 % of the total applied arbutin was excreted within 24 h. The elimination of 5 was negligible in 2 out of 3 volunteers. The excretion of this metabolite in the third test person reached 5.6 % of the total administered arbutin dose. The preliminary pharmacokinetic results confirm that renal elimination of toxicologically critical concentrations of the metabolite 5 will not be expected.

  19. Intermittent oral administration of potassium iodide solution for the correction of iodine deficiency.

    PubMed

    Todd, C H; Dunn, J T

    1998-06-01

    Iodized salt and iodized oil are the main methods used to prevent iodine deficiency, but sometimes alternative approaches are needed. We tested the efficacy of various regimens for the intermittent administration of potassium iodide in Hwedza, Zimbabwe, an area of known severe iodine deficiency. We divided 304 schoolchildren aged 7-13 y into five equal groups that received iodine as a 10% solution of potassium iodide as follows: 8.7 mg every 2 wk (group A), 29.7 mg every month (group B), 148.2 mg every 3 mo (group C), 382 mg every 6 mo (group D), or 993 mg once (group E). The follow-up period was 13 mo. No adverse effects were encountered with any of these doses. After 6 mo, the median blood spot thyroglobulin concentration had decreased in all groups and had normalized in groups A and B to values found in iodine-sufficient populations. The number of children with elevated thyroid-stimulating hormone concentrations decreased in groups A-C, but the changes were not significant. Urine iodine concentration generally remained low in all groups but increased in group A. After 13 mo, mean thyroid volume measured by ultrasound had decreased in groups A and B to values comparable with those in iodine-sufficient areas, and was unchanged in the other groups. We conclude that oral potassium iodide is effective for the prophylaxis of iodine deficiency if given as a dose of 30 mg I monthly or 8 mg biweekly.

  20. Oral administration of diluted nasal desmopressin in managing neonatal central diabetes insipidus.

    PubMed

    Mavinkurve, Meenal; McGrath, Niamh; Johnston, Niall; Moloney, Sinead; Murphy, Nuala P; Hawkes, Colin P

    2017-05-23

    Neonatal central diabetes insipidus (NCDI) remains a therapeutic challenge, as extremely low doses of enteral desmopressin cannot be titrated with current preparations. The aim of this study was to describe the use of orally administered dilute desmopressin in NCDI. Nasal desmopressin (100 μg/mL) was diluted in 0.9% saline to 10 μg/mL. Infants were treated with 1-5 μg and doses were titrated to a twice-daily regimen. The feed volume was 150 mL/kg/day and titrated according to weight gain. Five infants aged 6-105 days were included. Stabilizing treatment doses ranged from 2 to 5 μg twice daily in neonates, and 12 μg twice daily in the older infant who was diagnosed at 105 days. Dilution of nasal desmopressin with saline facilitates safe administration and dose titration in NCDI. We recommend considering this therapeutic approach to NCDI, particularly in small infants or where alternative treatment regimens have been unsuccessful.

  1. Pharmacokinetics and pharmacodynamics of d-chlorpheniramine following intravenous and oral administration in healthy Thoroughbred horses.

    PubMed

    Kuroda, Taisuke; Nagata, Shun-ichi; Takizawa, Yoshimasa; Tamura, Norihisa; Kusano, Kanichi; Mizobe, Fumiaki; Hariu, Kazuhisa

    2013-08-01

    The pharmacokinetics of d-chlorpheniramine (CPM), a histamine H1-receptor antagonist, and its ability to inhibit of histamine-induced cutaneous wheal formation, were studied in healthy Thoroughbred horses (n=5). Following an intravenous (IV) dose of 0.5mg/kg bodyweight (BW), plasma drug disposition was very rapid, with the mean terminal half-life and total body clearance calculated as 2.7h and 0.7 L/h/kg, respectively. The observed maximal inhibition of wheal formation following IV doses of 0.1 and 0.5mg/kg BW were 37.8% and 60.6% at 0.5h, respectively. Oral administration of CPM (0.5mg/kg BW) resulted in a bioavailability of 38%, which induced a peak plasma drug concentration at 1h and a maximal inhibition of wheal formation (39%) at 2h. A pharmacokinetic/pharmacodynamic link model showed that CPM in horses has lower efficacy, much lower potency and slightly lower sensitivity than other reported antihistamines. These results indicated that CPM should be administered at frequent intervals or at large dose rates to maintain therapeutic concentrations in horses.

  2. Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration

    PubMed Central

    Sidenius, Ulrik; Heegaard, Niels H.

    2016-01-01

    Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes. PMID:27795959

  3. [Oral administration of oil bleomycin combined with sodium polyacrylate for the treatment of esophageal cancer].

    PubMed

    Kamano, T; Kishino, H; Mizukami, K; Azuma, N; Kondo, K; Watanabe, Y; Kidokoro, T

    1982-08-01

    With anticipation of potentiation of the regional effect of bleomycin on the lesion of esophageal carcinoma, 12 patients with esophageal carcinoma were medicated orally with 5 ml of a paste-like mixture of 1 g of Sodium polyacrylate (PANA Kayaku) and 30 mg of oil bleomycin every day for 7 to 43 preoperative days. These 12 patients were further medicated with the mixture 1 hour before operation, and in 9 of them, bleomycin levels in the tumor and normal tissue of the resected portion of the esophagus and also in the regional lymph nodes were determined. The level in the normal tissue was on average concentration of 1.2 micrograms/g, while the level in tumor showed a tendency to higher level, being an average concentration of an being 4.4 micrograms/g. Bleomycin was found being efficiently transferred into the regional lymph nodes, where it was detected the average concentration of 1.7 micrograms/g. It may be anticipated that this mixture will be effective against preoperative and inoperable esophageal carcinoma and for ther studies on dosage and administration schedule is desirable.

  4. Oral Administration of Fermented Probiotics Improves the Condition of Feces in Adult Horses

    PubMed Central

    ISHIZAKA, Saori; MATSUDA, Akira; AMAGAI, Yosuke; OIDA, Kumiko; JANG, Hyosun; UEDA, Yuko; TAKAI, Masaki; TANAKA, Akane; MATSUDA, Hiroshi

    2014-01-01

    ABSTRACT The effects of probiotics on horses are still controversial. The present study was a randomized, double-blinded, placebo-controlled crossover study designed to evaluate the ability of probiotics to improve intestinal conditions in adult horses. Fermented probiotics were administered to 10 healthy adult geldings for 28 days. The clinical condition of the horses was monitored daily, and the blood and feces were biochemically analyzed every 14 days. In the probiotic-treated group, the concentration of carboxylic acids in the feces was increased at days 14 and 28. In contrast to the fecal pH in the control group, which increased at days 14 and 28, the fecal pH in the probiotic-treated group did not increase. Additionally, the relative amounts of enteropathogenic bacterial DNA were diminished in the probiotic-treated group. These results suggest that probiotic bacteria proliferated in the equine intestine. No instances of abnormal clinical conditions or abnormal values in blood tests were observed throughout the study. Oral administration of fermented probiotics may have the ability to improve the intestinal environment biochemically and microbiologically without the risk of adverse effects. PMID:25558179

  5. Cytokine synthesis in human peripheral blood mononuclear cells after oral administration of polyenzyme preparations.

    PubMed

    Desser, L; Rehberger, A; Kokron, E; Paukovits, W

    1993-01-01

    Pharmaceutical preparations containing mixtures of various proteolytic and nonproteolytic enzymes have been suggested for use in the treatment of malignant diseases. However, the mode of action of such preparations was not clear. We have shown before that intact bromelain, papain or amylase, which are components of a commercial polyenzyme preparation, induce cytokine production in peripheral blood mononuclear cells in vitro. IFN-alpha and IFN-gamma which had no effect alone, synergistically increased TNF production when applied together with the enzymes. Here we show that trypsin alone had only a small inducing effect. The tryptic but not the autolytic fragments of papain and bromelain have a higher (10- to 40-fold) inducing capacity for TNF production than the untreated enzyme. Additionally we demonstrate that after ingestion of milligram doses of the polyenzyme preparation (as recommended for clinical use), PBMNC of healthy donors acquire the ability to produce TNF-alpha, IL-1 beta and IL-6 when incubated ex vivo with IFN-gamma. Our results indicate that the biological effects observed after oral administration of polyenzyme preparations are related to their ability to induce cytokine production. This may explain the antitumor effects of such enzymes. Our results also suggest that polyenzyme preparations may have a stronger immunomodulary effect when used in combination with IFN-gamma.

  6. Effects of Oral Administration of Silymarin in a Juvenile Murine Model of Non-alcoholic Steatohepatitis.

    PubMed

    Marin, Veronica; Gazzin, Silvia; Gambaro, Sabrina E; Dal Ben, Matteo; Calligaris, Sonia; Anese, Monica; Raseni, Alan; Avellini, Claudio; Giraudi, Pablo J; Tiribelli, Claudio; Rosso, Natalia

    2017-09-12

    The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of silymarin in a juvenile non-alcoholic steatohepatitis (NASH) model and the in vitro effects on fat-laden human hepatocytes. C57Bl/6 mice were exposed to HFHC diet immediately after weaning. After eight weeks, animals showed histological signs of NASH. Silymarin was added to the HFHC diet, the treatment continued for additional 12 weeks and the effects on BMI, hepatomegaly, visceral fat, lipid profile, transaminases, HOMA-IR, steatosis, inflammation, fibrosis, oxidative stress, and apoptosis were determined. The switch from HFHC to control diet was used to mimic life style changes. In vitro experiments were performed in parallel in human hepatocytes. HFHC diet supplemented with silymarin showed a significant improvement in glycemia, visceral fat, lipid profile, and liver fibrosis. Moreover, it reduced (both in vitro and in vivo) ALT, hepatic inflammation, oxidative stress, and apoptosis. Lifestyle changes restored the control group parameters. The data presented show the beneficial effects of the oral administration of silymarin in the absence of changes in the dietary habits in a juvenile model of NASH.

  7. Bioavailability of escin after administration of two oral formulations containing aesculus extract.

    PubMed

    Kunz, K; Lorkowski, G; Petersen, G; Samcova, E; Schaffler, K; Wauschkuhn, C H

    1998-08-01

    In a steady-state cross-over study in 18 healthy volunteers, the relative bioavailability of beta-escin (CAS 11072-93-8) after oral administration of a new immediate release enteric-coated test formulation containing aesculus extract was evaluated in comparison with a prolonged-release reference preparation. The subject received the test and the reference preparation in randomised sequence for 7 days each with no washout period in between. The daily dose was 50 mg escin b.i.d. Blood samples for pharmacokinetic profiling were taken on the 7th treatment day of each period over a full 24-h cycle of two successive dosing intervals. For the determination of beta-escin serum concentrations, a highly specific radioimmunoassay (RIA) was used. Generally, escin serum concentrations were lower during the second dosing interval (night) than during the first interval, probably indicating a drug by food interaction. (The morning dose was given after overnight fasting whereas the evening dose was given between meals). Test and reference demonstrated bioequivalence with regard to the extent of absorption; for the AUC (0-24 h p.a.), the 90% confidence interval ranged from 84% to 114% (point estimate: 98%). The differences observed for rate parameters can be disregarded due to the generally slow elimination and the wide therapeutic concentration range of escin.

  8. Oral administration of grape seed polyphenol extract restores memory deficits in chronic cerebral hypoperfusion rats.

    PubMed

    Chen, Chen; Zheng, Yake; Wu, Tianwen; Wu, Chuanjie; Cheng, Xuan

    2017-04-01

    Chronic cerebral hypoperfusion (CCH) has been recognized as an important cause of both vascular dementia and Alzheimer's disease (AD), the two most prominent neurodegenerative diseases causing memory impairment in the elderly. However, an effective therapy for CCH-induced memory impairment has not yet been established. Grape seed polyphenol extract (GSPE) has powerful antioxidant properties and protects neurons and glia during ischemic injury, but its potential use in the prevention of CCH-induced memory impairment has not yet been investigated. Here, CCH-related memory impairment was modeled in rats using permanent bilateral occlusion of the common carotid artery. A Morris water maze task was used to evaluate memory, the levels of acetylcholinesterase, choline acetyltransferase, acetylcholine were used to evaluate cholinergic function, and oxidative stress was assessed by measuring the enzyme activity of superoxide dismutase, glutathione peroxidase, malonic dialdehyde, and catalase. We found that oral administration of GSPE for 1 month can rescue memory deficits. We also found that GSPE restores cholinergic neuronal function and represses oxidative damage in the hippocampus of CCH rats. We propose that GSPE protects memory in CCH rats by reducing ischemia-induced oxidative stress and cholinergic dysfunction. These findings provide a novel application of GSPE in CCH-related memory impairments.

  9. Effect of Oral Administration of Emtricitabine on Woodchuck Hepatitis Virus Replication in Chronically Infected Woodchucks

    PubMed Central

    Korba, Brent E.; Schinazi, R. F.; Cote, Paul; Tennant, Bud C.; Gerin, John L.

    2000-01-01

    Emtricitabine [(−)FTC] [(−)-β-2′,3′-dideoxy-5-fluoro-3′-thiacytidine] has been shown to be an effective inhibitor of hepatitis B virus (HBV) in cell culture, with a potency and selectivity that are essentially identical to those of lamivudine. The antiviral activity of oral administration of (−)FTC against WHV replication in chronically infected woodchucks, an established and predictive model for antiviral therapy against HBV, was examined in a placebo-controlled study. (−)FTC significantly reduced viremia and intrahepatic WHV replication in a dose-dependent manner that was comparable to the antiviral activity of lamivudine observed in previous studies conducted by our laboratories. No effect on the levels of hepatic WHV RNA or the levels of woodchuck hepatitis surface antigen or anti-woodchuck hepatitis surface and core antibodies in the serum of the treated animals was observed. No evidence of drug-related toxicity was observed in any of the animals treated. PMID:10817750

  10. Oral Administration of Fermented Soymilk Products Protects the Skin of Hairless Mice against Ultraviolet Damage

    PubMed Central

    Kano, Mitsuyoshi; Kubota, Norihiro; Masuoka, Norie; Hori, Tetsuji; Miyazaki, Kouji; Ishikawa, Fumiyasu

    2016-01-01

    The protective effect of isoflavones on skin damage from ultraviolet (UV) radiation and their bioavailability were investigated in ovariectomized hairless mice fed diets composed of fermented soymilk containing aglycone forms of isoflavones or control soymilk containing glucose-conjugated forms of isoflavones. The erythema intensity of dorsal skin was significantly higher in ovariectomized mice than in sham-operated mice (p < 0.05). The erythema intensity and epidermal thickness of dorsal skin were significantly lower in the fermented soymilk diet group than in the control diet group (each p < 0.05). Levels of cyclobutane pyrimidine dimers in dorsal skin were significantly lower in the fermented soymilk diet group than in the control group (p < 0.05). Serum and dorsal skin isoflavone concentrations were significantly higher in the fermented soymilk diet group than in the soymilk diet group (p < 0.05). These results indicate that oral administration of a fermented soymilk diet increases isoflavone concentrations in the blood and skin, effectively scavenging the reactive oxygen species generated by UV irradiation and exerting an estrogen-like activity, with a consequent protective effect on skin photodamage in hairless mice. PMID:27556484

  11. [Research on bioactive ingredients in rat liver after oral administration of different combinations of Wuji pill].

    PubMed

    Zhang, Rui-Jie; Chen, Ying; Gong, Zi-Peng; Dong, Yu; Zhang, Hai-Xian; Yang, Qing; Weng, Xiao-Gang; Li, Yu-Jie; Zhu, Xiao-Xin

    2014-05-01

    A L9 (3(4)) orthogonal design table to be used to get nine combinations of extraction of three herbs of Wuji pill: Coptis chinensis, Tetradium ruticarpum and Paeonia lactiflora Pall., and nine extraction of single herbs correspondingly, altogether eighteen combinations. Quantification of five representative bioactive ingredients: berberine, palmatine, evodiamine, rutaecarpine, paeoniflorin in rat liver by ultra high liquid chromatography-tandem mass spectrometry after oral administration at 2 h time point of eighteen combinations. The result shows the bioactive ingredients have different concentrations betweem different combinations and the single herb with the same dosage significantly as well as the same dose combinations. C. chinensis with evodiamine concentration of low and high dose T. ruticarpum was positively correlated. T. ruticarpum with berberine concentration of low dose C. chinensis was negatively correlated and of meddle dose C. chinensis was correlated positively. T. ruticarpum with paeoniflorin concentration of middle dose P. lactiflora was correlated positively. P. lactiflora with palmatine concentration of middle dose C. chinensis was negatively correlated and with evodiamine and rutaecarpine concentration of middle dose T. ruticarpum was negatively correlated. These shows the three single herbs interactions resulted in the differences of each ingredients concentration in rat liver. The orthogonal analysis indicates the combination 12: 6: 6 make the maximum concentration in rat liver.

  12. Oral administration of live Bifidobacterium substrains isolated from centenarians enhances intestinal function in mice.

    PubMed

    Yang, Haiying; Liu, Aiping; Zhang, Ming; Ibrahim, Salam A; Pang, Zhihua; Leng, Xiaojing; Ren, Fazheng

    2009-10-01

    We studied the effects of two bifidobacteria strains isolated from healthy centenarians on intestinal function in mice. Bifidobacterium adolescentis BBMN23 and Bifidobacterium longum BBMN68 were orally administrated to specific pathogen-free BALB/c mice at different doses (2 x 10(11), 2 x 10(9), or 2 x 10(7) CFU/kg body weight) each day for 4 weeks. Villus height, crypt depth, villus width, and villus/crypt ratio (V/C) were determined. The content of duodenal secreted immunoglobulin A (sIgA) was also evaluated. There were clear increases in height and width of duodenal villi in both treated groups. Crypt depths were deeper in animals treated with BBMN23 than in controls, while depths were reduced in animals receiving BBMN68. The V/C ratio was increased after feeding with BBMN68, while BBMN23 had no significant effect. Both strains improved the sIgA content of the duodenum. These results suggest that BBMN23 and BBMN68 may improve intestinal digestion and ability and enhance immune barrier function in the intestine.

  13. Oral probiotic bacterial administration suppressed allergic responses in an ovalbumin-induced allergy mouse model.

    PubMed

    Kim, Hyeyoung; Kwack, Kubum; Kim, Dae-Young; Ji, Geun Eog

    2005-08-01

    This study investigated whether orally administered probiotic bacteria (Bifidobacterium bifidum and Lactobacillus casei) and a gram-negative bacterium (Escherichia coli) function as allergic immune modulators to prevent food allergy, according to the hygiene hypothesis. C3H/HeJ mice were sensitized with ovalbumin (OVA) and cholera toxin for 5 weeks. After sensitization, the OVA-induced mice that were not treated with bacteria had significantly increased levels of OVA-specific IgE, total IgE, and IgG1 in sera, as well as scab-covered tails. In comparison, groups treated with B. bifidum BGN4 (BGN4), L. casei 911 (L. casei), or Escherichia coli MC4100 (E. coli) had decreased levels of OVA-specific IgE, total IgE, and IgG1, and decreased levels of mast cell degranulation and tail scabs. OVA-specific IgA levels were decreased in BGN4- and L. casei-treated groups. In conclusion, administration of E. coli, BGN4, or L. casei decreased the OVA-induced allergy response. However, a normal increase in body weight was inhibited in the E. coli-treated mice and in the montreated mice groups during allergy sensitization. Thus, BGN4 and L. casei appear to be useful probiotic bacteria for the prevention of allergy.

  14. Accuracy of dispersing tramadol capsules for oral administration in young children.

    PubMed

    Kluger, M; Penrose, S; Bjorksten, A R; Chalkiadis, G

    2016-11-01

    Tramadol is used in children aged <12 years for analgesia, particularly for those at risk of obstructive sleep apnoea undergoing adenotonsillectomy. The Australian Therapeutic Goods Administration have strongly recommended that oral tramadol drops (100 mg/ml) not be used in children <12 years because of the risk of inadvertent overdose. The total mass of drug in a 10 ml bottle is 1000 mg. The only alternative preparation available is a 50 mg capsule that requires dispersion of a capsule's contents should smaller doses be required. The accuracy of this preparation has not been assessed. Twenty surgical ward nurses were asked to prepare a 15 mg dose of tramadol from a 50 mg capsule. The dose was within ±5% of 15 mg in 13 cases (65%) and within ±10% in 19 cases (95%) (range 13.9-17.1 mg). Despite the dose variability of this method of preparing tramadol, we consider it sufficiently accurate for clinical use. We also consider it safe, as even at the highest dose prepared, the variability would be unlikely to contribute to clinically significant side-effects or toxicity. Moreover, the maximal dose that could be administered is limited to the size of the capsule (50 mg).

  15. Distribution of prolylhydroxyproline and its metabolites after oral administration in rats.

    PubMed

    Kawaguchi, Tomoaki; Nanbu, Patricia Naomi; Kurokawa, Mihoko

    2012-01-01

    Prolylhydroxyproline (Pro-Hyp), which is derived from collagen hydrolysate, has been shown to be beneficial for skin and joint health. However, little is known about the distribution of Pro-Hyp in these tissues. In the present study, we investigated the biodistribution of orally administered [(14)C]Pro-Hyp in rats. Whole-body autoradiography at 30 min after administration of [(14)C]Pro-Hyp showed that radioactivity is widely distributed in tissues including skin and articular cartilage, with the highest level of radioactivity observed in the gastric and intestinal walls. Incorporation of radioactivity into cells known to respond to Pro-Hyp such as dermal fibroblasts, synovial cells, chondrocytes, osteoblasts, and osteoclasts was observed. The chemical form of [(14)C]Pro-Hyp-derived radioactivity detected in the tissues was investigated by thin layer chromatography. The radioactive constituents in cartilage extract were two proline-modified peptides (56%), intact Pro-Hyp (5%), and two nonpeptide metabolites (28%). Similar results were obtained for skin and bone marrow. Plasma analysis at 3 to 30 min post-dose suggested that the majority of Pro-Hyp is modified in its proline residue by a first-pass effect without peptide bond hydrolysis. In conclusion, we demonstrated that Pro-Hyp is partly distributed in observed tissues including skin and cartilage in its intact form, which might be responsible for its biological functions.

  16. Small-Scale Assays for Studying Dissolution of Pharmaceutical Cocrystals for Oral Administration.

    PubMed

    Box, Karl J; Comer, John; Taylor, Robert; Karki, Shyam; Ruiz, Rebeca; Price, Robert; Fotaki, Nikoletta

    2016-04-01

    The purpose of this study was to better understand the dissolution properties and precipitation behavior of pharmaceutical cocrystals of poorly soluble drugs for the potential for oral administration based on a small-scale dissolution assay. Carbamazepine and indomethacin cocrystals with saccharin and nicotinamide as coformers were prepared with the sonic slurry method. Dissolution of the poorly soluble drugs indomethacin and carbamazepine and their cocrystals was studied with a small-scale dissolution assay installed on a SiriusT3 instrument. Two methodologies were used: (i) surface dissolution of pressed tablet (3 mm) in 20 mL running for fixed times at four pH stages (pH 1.8, pH 3.9, pH 5.4, pH 7.3) and (ii) powder dissolution (2.6 mg) in 2 mL at a constant pH (pH 2). Improved dissolution and useful insights into precipitation kinetics of poorly soluble compounds from the cocrystal form can be revealed by the small-scale dissolution assay. A clear difference in dissolution/precipitation behaviour can be observed based on the characteristics of the coformer used.

  17. Renal excretion profiles of psilocin following oral administration of psilocybin: a controlled study in man.

    PubMed

    Hasler, Felix; Bourquin, Daniel; Brenneisen, Rudolf; Vollenweider, Franz X

    2002-09-05

    In a clinical study eight volunteers received psilocybin (PY) in psychoactive oral doses of 212+/-25 microg/kg body weight. To investigate the elimination kinetics of psilocin (PI), the first metabolite of PY, urine was collected for 24 h and PI concentrations were determined by high-performance liquid chromatography with column switching and electrochemical detection (HPLC-ECD). Sample workup included protection of the unstable PI with ascorbic acid, freeze-drying, and extraction with methanol. Peak PI concentrations up to 870 microg/l were measured in urine samples from the 2-4 h collection interval. The PI excretion rate in this period was 55.5+/-33.8 microg/h. The limit of quantitation (10 microg/L) was usually reached 24 h after drug administration. Within 24 h, 3.4+/-0.9% of the applied dose of PY was excreted as free PI. Addition of beta-glucuronidase to urine samples and incubation for 5 h at 40 degrees C led to twofold higher PI concentrations, although 18+/-7% of the amount of unconjugated PI was decomposed during incubation. We conclude that in humans PI is partially excreted as PI-O-glucuronide and that enzymatic hydrolysis extends the time of detectability for PI in urine samples.

  18. Study on treatment of bacterial vaginosis with oral administration of metronidazole or cefdinir.

    PubMed

    Mikamo, H; Izumi, K; Ito, K; Katoh, N; Watanabe, K; Ueno, K; Tamaya, T

    1994-01-01

    Bacterial vaginosis (BV) is considered to be one of the most common vaginal infections in women. Fifteen symptomatic women with BV were enrolled in this study. Ten patients with the diagnosis of BV were treated with 10 days oral administration of metronidazole (MTN), 500 mg twice a day, and five patients with cefdinir (CFDN), 300 mg three times a day. In the MTN therapy, the rate of abnormal vaginal discharge subjectively decreased from 100 to 60%, the rate of abnormal vaginal discharges objectively decreased from 100 to 20%, the rate of positive amine tests decreased from 100 to 20%, the rate of genital malodor and abnormal pH of vaginal discharges decreased substantially from 100 to 10%, and the rate of the presence of clue cells also decreased notably from 90 to 10%. However, in the CFDN therapy, none of these factors improved. With respect to susceptibility to CFDN and MTN, CFDN demonstrated good antibacterial activity against almost all bacteria isolated except Gardnerella vaginalis. On the other hand, MTN demonstrated excellent activity against anaerobic bacteria except Peptostreptococcus spp., and had no antibacterial activity against aerobic bacteria. Since the therapeutic effect of MTN in BV appeared to be better than that of CFDN, anaerobes may play a major role in causing clinical symptoms in patients with BV.

  19. Gene Expression in Rat Hearts Following Oral Administration of a Single Hepatotoxic Dose of Acetaminophen

    PubMed Central

    Kil, Hong Ryang; Park, Kwangsik; Noh, Chung Il

    2012-01-01

    Purpose Toxicity caused by acetaminophen and its toxic mechanisms in the liver have been widely studied, including effects involving metabolism and oxidative stress. However, its adverse effects on heart have not been sufficiently investigated. This study evaluated the cardiac influence and molecular events occurring within the myocardium in rats treated with a dose of acetaminophen large enough to induce conventional liver damage. Materials and Methods Male rats were orally administered a single dose of acetaminophen at 1,000 mg/kg-body weight, and subsequently examined for conventional toxicological parameters and for gene expression alterations to both the heart and liver 24 hours after administration. Results Following treatment, serum biochemical parameters including aspartate aminotransferase and alanine aminotransferase were elevated. Histopathological alterations of necrosis were observed in the liver, but not in the heart. However, alterations in gene expression were observed in both the liver and heart 24 hours after dosing. Transcriptional profiling revealed that acetaminophen changed the expression of genes implicated in oxidative stress, inflammatory processes, and apoptosis in the heart as well as in the liver. The numbers of up-regulated and down-regulated genes in the heart were 271 and 81, respectively, based on a two-fold criterion. Conclusion The induced expression of genes implicated in oxidative stress and inflammatory processes in the myocardium reflects molecular levels of injury caused by acetaminophen (APAP), which could not be identified by conventional histopathology. PMID:22187249

  20. Absorption, Distribution, Metabolism and Excretion of 3-MCPD 1-Monopalmitate after Oral Administration in Rats.

    PubMed

    Gao, Boyan; Liu, Man; Huang, Guoren; Zhang, Zhongfei; Zhao, Yue; Wang, Thomas T Y; Zhang, Yaqiong; Liu, Jie; Yu, Liangli

    2017-03-15

    Fatty acid esters of monochloropropane 1,2-diol (3-MCPD) are processing-induced toxicants and have been detected in several food categories. This study investigated the absorption, distribution, metabolism, and excretion of 3-MCPD esters in Sprague-Dawley (SD) rats using 3-MCPD 1-monopalmitate as the probe compound. The kinetics of 3-MCPD 1-monopalmitate in plasma was investigated using SD rats, and the results indicated that 3-MCPD 1-monopalmitate was absorbed directly in vivo and metabolized. Its primary metabolites in the liver, kidney, testis, brain, plasma, and urine were tentatively identified and measured at 6, 12, 24, and 48 h after oral administration. Structures were proposed for eight metabolites. 3-MCPD 1-monopalmitate was converted to free 3-MCPD, which formed the phase II metabolites. All of the metabolites were chlorine-related chemical components; most of them existed in urine, reflecting the excretion pattern of 3-MCPD esters. Understanding the metabolism of 3-MCPD esters in vivo is critical for assessing their toxicities.

  1. Surface display of human growth hormone on Bacillus subtilis spores for oral administration.

    PubMed

    Lian, Chaoqun; Zhou, Yang; Feng, Fan; Chen, Liang; Tang, Qi; Yao, Qin; Chen, Keping

    2014-04-01

    Human growth hormone (hGH) is the major and important hormone component of human being. At present, hGH for clinical uses is mostly produced in Escherichia coli, which requires costly denaturation and refolding to recover functionality. To obtain long-term bioactive hormone, we used hGH as a foreign gene and constructed a recombinant plasmid pJS700-hGH which carries a recombinant gene cotC-hgh with an enterokinase site under the control of cotC promoter. Plasmid pJS700-hGH was transformed into Bacillus subtilis by double crossover and an amylase-inactivated mutant was produced. After spore formation, Western blot and fluorescence immunoassay were used to monitor hGH surface expression on spores. Oral administration to silkworm with spores displaying hGH further showed that the recombinant spores may have potential ability to be digested and absorbed into the silkworm's hemolymph due to both the resistant characters of spores and the addition of enterokinase site.

  2. Ovarian Toxicity in Female Rats after Oral Administration of Melamine or Melamine and Cyanuric Acid.

    PubMed

    Sun, Jiarui; Zhang, Xinchen; Cao, Yinan; Zhao, Qiling; Bao, Endong; Lv, Yingjun

    2016-01-01

    Although the toxicity of melamine to the kidneys and testes is well known, few studies have investigated the effects of melamine on female reproductive organs. Therefore, this study explores the effects of oral administration melamine or melamine and cyanuric acid for 28 days on the ovaries of female rats. Rats that were exposed to the mixture exhibited reduced ovarian and uterine weights, a shorter estrous cycle, and reduced serum estrogen and progesterone levels compared to rats that were exposed to melamine and control rats. Furthermore, morphological analysis revealed pathological changes in the ovaries of rats exposed to melamine or the mixture, such as more atretic follicles and necrosis of oocytes and granulosa cells. TUNEL staining revealed that the exposed groups had a higher proportion of TUNEL-positive granulosa cells than the control group, and the mRNA expressions of SOD1, GPX1, GPX2, P450scc, 17β-HSD I, and 17β-HSD II were reduced in the exposure groups compared with the control group. These results indicated that exposure to melamine alone or to the melamine-cyanuric acid mixture could damage the ovaries in rats.

  3. Ovarian Toxicity in Female Rats after Oral Administration of Melamine or Melamine and Cyanuric Acid

    PubMed Central

    Sun, Jiarui; Zhang, Xinchen; Cao, Yinan; Zhao, Qiling; Bao, Endong; Lv, Yingjun

    2016-01-01

    Although the toxicity of melamine to the kidneys and testes is well known, few studies have investigated the effects of melamine on female reproductive organs. Therefore, this study explores the effects of oral administration melamine or melamine and cyanuric acid for 28 days on the ovaries of female rats. Rats that were exposed to the mixture exhibited reduced ovarian and uterine weights, a shorter estrous cycle, and reduced serum estrogen and progesterone levels compared to rats that were exposed to melamine and control rats. Furthermore, morphological analysis revealed pathological changes in the ovaries of rats exposed to melamine or the mixture, such as more atretic follicles and necrosis of oocytes and granulosa cells. TUNEL staining revealed that the exposed groups had a higher proportion of TUNEL-positive granulosa cells than the control group, and the mRNA expressions of SOD1, GPX1, GPX2, P450scc, 17β-HSD I, and 17β-HSD II were reduced in the exposure groups compared with the control group. These results indicated that exposure to melamine alone or to the melamine-cyanuric acid mixture could damage the ovaries in rats. PMID:26866683

  4. Modification of pharmacokinetics of norfloxacin following oral administration of curcumin in rabbits

    PubMed Central

    Pavithra, B. H.; Jayakumar, K.

    2009-01-01

    Investigation was carried out in adult New Zealand white rabbits to study the influence of curcumin pre-treatment on pharmacokinetic disposition of norfloxacin following single oral administration. Sixteen rabbits were divided into two groups of eight each consisting of either sex. Animals in group-I were administered norfloxacin (100 mg/kg body weight p.o), while animals in group-II received similar dose of norfloxacin after pre-treatment with curcumin (60 mg/kg body weight per day, 3 days, p.o). Blood samples were drawn from the marginal ear vein into heparin-coated vials at 0 (zero time), 5, 10, 15, 30 min and 1, 2, 4, 6, 12 and 24 h post-treatment. Plasma norfloxacin concentrations were determined by high performance liquid chromatography. The plasma concentration-time profile of norfloxacin was adequately described by a one-compartment open model. The pharmacokinetic data revealed that curcumin-treated animals had significantly (p ≤ 0.05) higher area under the plasma concentration-time curve and area under the first moment of plasma drug concentration-time curve. Prior treatment of curcumin significantly (p ≤ 0.05) increased elimination half-life and volume of distribution of norfloxacin. Further treatment with curcumin reduced loading and maintenance doses by 26% and 24% respectively. PMID:19934593

  5. Modification of pharmacokinetics of norfloxacin following oral administration of curcumin in rabbits.

    PubMed

    Pavithra, B H; Prakash, N; Jayakumar, K

    2009-12-01

    Investigation was carried out in adult New Zealand white rabbits to study the influence of curcumin pre-treatment on pharmacokinetic disposition of norfloxacin following single oral administration. Sixteen rabbits were divided into two groups of eight each consisting of either sex. Animals in group-I were administered norfloxacin (100 mg/kg body weight p.o), while animals in group-II received similar dose of norfloxacin after pre-treatment with curcumin (60 mg/kg body weight per day, 3 days, p.o). Blood samples were drawn from the marginal ear vein into heparin-coated vials at 0 (zero time), 5, 10, 15, 30 min and 1, 2, 4, 6, 12 and 24 h post-treatment. Plasma norfloxacin concentrations were determined by high performance liquid chromatography. The plasma concentration-time profile of norfloxacin was adequately described by a one-compartment open model. The pharmacokinetic data revealed that curcumin-treated animals had significantly (p < or = 0.05) higher area under the plasma concentration time curve and area under the first moment of plasma drug concentration-time curve. Prior treatment of curcumin significantly (p < or = 0.05) increased elimination half-life and volume of distribution of norfloxacin. Further treatment with curcumin reduced loading and maintenance doses by 26% and 24% respectively.

  6. Oral Corticosterone Administration Reduces Insulitis but Promotes Insulin Resistance and Hyperglycemia in Male Nonobese Diabetic Mice.

    PubMed

    Burke, Susan J; Batdorf, Heidi M; Eder, Adrianna E; Karlstad, Michael D; Burk, David H; Noland, Robert C; Floyd, Z Elizabeth; Collier, J Jason

    2017-03-01

    Steroid-induced diabetes is the most common form of drug-induced hyperglycemia. Therefore, metabolic and immunological alterations associated with chronic oral corticosterone were investigated using male nonobese diabetic mice. Three weeks after corticosterone delivery, there was reduced sensitivity to insulin action measured by insulin tolerance test. Body composition measurements revealed increased fat mass and decreased lean mass. Overt hyperglycemia (>250 mg/dL) manifested 6 weeks after the start of glucocorticoid administration, whereas 100% of the mice receiving the vehicle control remained normoglycemic. This phenotype was fully reversed during the washout phase and readily reproducible across institutions. Relative to the vehicle control group, mice receiving corticosterone had a significant enhancement in pancreatic insulin-positive area, but a marked decrease in CD3(+) cell infiltration. In addition, there were striking increases in both citrate synthase gene expression and enzymatic activity in skeletal muscle of mice in the corticosterone group relative to vehicle control. Moreover, glycogen synthase expression was greatly enhanced, consistent with elevations in muscle glycogen storage in mice receiving corticosterone. Corticosterone-induced hyperglycemia, insulin resistance, and changes in muscle gene expression were all reversed by the end of the washout phase, indicating that the metabolic alterations were not permanent. Thus, male nonobese diabetic mice allow for translational studies on the metabolic and immunological consequences of glucocorticoid-associated interventions in a mouse model with genetic susceptibility to autoimmune disease.

  7. Oral administration of withaferin A inhibits carcinogenesis of prostate in TRAMP model

    PubMed Central

    Suman, Suman; Das, Trinath P.; Moselhy, Jim; Pal, Deeksha; Kolluru, Venkatesh; Alatassi, Houda; Ankem, Murali K.; Damodaran, Chendil

    2016-01-01

    We previously reported that withaferin A (WA), a natural compound, deters prostate cancer by inhibiting AKT while inducing apoptosis. In the current study, we examined its chemopreventive efficacy against carcinogenesis in the prostate using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Two distinct sets of experiments were conducted. To determine whether WA delays tumor progression, it was given before cancer onset, at week 6, and until week 44. To determine its effect after the onset of prostate cancer, it was given from weeks 12 to 35. In both strategies, oral administration of WA effectively suppressed tumor burden when compared to vehicle-treated animals. No toxicity was seen in treated animals at gross pathological examination. Western blot analysis and immunohistochemistry of tumor sections revealed that in TRAMP controls, AKT and pAKT were highly expressed while nuclear FOXO3a and Par-4 were downregulated. On the contrary, treated mice showed inhibition of AKT signaling and activation of FOX03a-Par-4-induced cell death. They also displayed inhibition of mesenchymal markers such as β-catenin, vimentin, and snail as well as upregulation of E-cadherin. Because expressions of the angiogenic markers factor VIII and retic were downregulated, an anti-angiogenic role of WA is suggested. Overall, our results suggest that WA could be a promising anti-cancer agent that effectively inhibits carcinogenesis of the prostate. PMID:27447565

  8. Repeated oral administration of chitosan/DNA nanoparticles delivers functional FVIII with the absence of antibodies in hemophilia A mice.

    PubMed

    Dhadwar, S S; Kiernan, J; Wen, J; Hortelano, G

    2010-12-01

    Current treatment of hemophilia A is expensive and involves regular infusions of factor (F)VIII concentrates. The supply of functional FVIII is further compromised by the generation of neutralizing antibodies. Thus, the development of an alternative safe, cost effective, non-invasive treatment that circumvents immune response induction is desirable. To evaluate the feasibility of oral administration of chitosan nanoparticles containing FVIII DNA to provide sustainable FVIII activity in hemophilia A mice. Nanoparticles were characterized for morphology, DNA protection and transfection efficiency. Oral administration of nanoparticles containing canine FVIII in C57Bl/6 FVIII(-/-) hemophilia A mice was evaluated for biodistribution, plasma FVIII activity and phenotypic correction. Sustainable FVIII expression was elucidated after repeated nanoparticle administration. Immune responses to repeated oral nanoparticle administration were also investigated. Chitosan nanoparticles had a particle size range of 200-400 nm and protected DNA from endonuclease and pH degradation. In addition, nanoparticles transfected HEK 293 cells resulted in expression of eGFP, luciferase and FVIII. Hemophilia A mice that ingested chitosan nanoparticles demonstrated transient canine FVIII expression reaching > 100 mU 1 day after treatment, together with partial phenotypic correction. The delivered FVIII plasmid DNA was detected in the intestine and, to a lesser extent, in the liver. Importantly, repeated weekly administrations restored FVIII activity. Furthermore, inhibitors and non-neutralizing FVIII antibodies were not detectable. Repeat oral administration of FVIII DNA formulated in chitosan nanoparticles resulted in sustained FVIII activity in hemophilic mice, and thus may provide a non-invasive alternative treatment for hemophilia A. © 2010 International Society on Thrombosis and Haemostasis.

  9. Administrative Challenges to the Integration of Oral Health With Primary Care: A SWOT Analysis of Health Care Executives at Federally Qualified Health Centers.

    PubMed

    Norwood, Connor W; Maxey, Hannah L; Randolph, Courtney; Gano, Laura; Kochhar, Komal

    Inadequate access to preventive oral health services contributes to oral health disparities and is a major public health concern in the United States. Federally Qualified Health Centers play a critical role in improving access to care for populations affected by oral health disparities but face a number of administrative challenges associated with implementation of oral health integration models. We conducted a SWOT (strengths, weaknesses, opportunities, and threats) analysis with health care executives to identify strengths, weaknesses, opportunities, and threats of successful oral health integration in Federally Qualified Health Centers. Four themes were identified: (1) culture of health care organizations; (2) operations and administration; (3) finance; and (4) workforce.

  10. Oral administration of D-aspartate, but not L-aspartate, depresses rectal temperature and alters plasma metabolites in chicks.

    PubMed

    Erwan, Edi; Chowdhury, Vishwajit Sur; Nagasawa, Mao; Goda, Ryosei; Otsuka, Tsuyoshi; Yasuo, Shinobu; Furuse, Mitsuhiro

    2014-07-25

    L-Aspartate (L-Asp) and D-aspartate (D-Asp) are physiologically important amino acids in mammals and birds. However, the functions of these amino acids have not yet been fully understood. In this study, we therefore examined the effects of L-Asp and D-Asp in terms of regulating body temperature, plasma metabolites and catecholamines in chicks. Chicks were first orally administered with different doses (0, 3.75, 7.5 and 15 mmol/kg body weight) of L- or D-Asp to monitor the effects of these amino acids on rectal temperature during 120 min of the experimental period. Oral administration of D-Asp, but not of L-Asp, linearly decreased the rectal temperature in chicks. Importantly, orally administered D-Asp led to a significant reduction in body temperature in chicks even under high ambient temperature (HT) conditions. However, centrally administered D-Asp did not significantly influence the body temperature in chicks. As for plasma metabolites and catecholamines, orally administered D-Asp led to decreased triacylglycerol and uric acid concentrations and increased glucose and chlorine concentrations but did not alter plasma catecholamines. These results suggest that oral administration of D-Asp may play a potent role in reducing body temperature under both normal and HT conditions. The alteration of plasma metabolites further indicates that D-Asp may contribute to the regulation of metabolic activity in chicks. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. The pharmacokinetics of methocarbamol and guaifenesin after single intravenous and multiple-dose oral administration of methocarbamol in the horse.

    PubMed

    Rumpler, M J; Colahan, P; Sams, R A

    2014-02-01

    A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations