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Sample records for oral administration

  1. 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

  2. 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. PMID:26424254

  3. Formulation of nimodipine nanocrystals for oral administration.

    PubMed

    Li, Jianwen; Fu, Qiang; Liu, Xiaohong; Li, Mo; Wang, Yongjun

    2016-02-01

    The aim of this paper is to optimize nimodipine (NMD) nanocrystals (NCs) for oral administration. The effects of independent process variables (microprecipitation temperature, shearing speed, shearing time, homogenization pressure and number of cycles) on the particle size have been studied. Experiments were conducted to optimize the formulation composition. A single factor exploration was used to screen the primary stabilizers. Then, the selected polymers/surfactants were further optimized using an L9 (3(4)) orthogonal design. The optimal formulation was composed of NMD (0.7 %, w/v), F127 (0.4 %, w/v), HPMC-E5 (0.1 %, w/v), and sodium deoxycholate (0.05 %, w/v) and was rod-shaped as shown by SEM observations, and it had a particle size of 833.3 ± 20.6 nm, determined by laser diffraction. These aqueous NCs were physically stable for 15 days. To further improve the stability, the NCs were freeze-dried. The powder obtained exhibited acceptable flowability and was physically stable for at least 24 months. Additionally, the NMD NCs displayed much higher dissolution profiles than the bulk drug. The pharmacokinetic results showed that the relative bioavailability was 397 % in comparison with Nimotop(®), suggesting that NCs are an efficient strategy for improving the oral bioavailability of poorly water-soluble drugs. PMID:26584914

  4. 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.

  5. Methylprednisolone pharmacokinetics after intravenous and oral administration.

    PubMed Central

    Al-Habet, S M; Rogers, H J

    1989-01-01

    1. The pharmacokinetics of methylprednisolone (MP) were studied in five normal subjects following intravenous doses of 20, 40 and 80 mg methylprednisolone sodium succinate (MPSS) and an oral dose of 20 mg methylprednisolone as 4 x 5 mg tablets. Plasma concentrations of MP and MPSS were measured by both high performance thin layer (h.p.t.l.c.) and high pressure liquid chromatography (h.p.l.c.). 2. The mean values (+/- s.d.) of half-life, mean residence time (MRT), systemic clearance (CL) and volume of distribution at steady state (Vss) of MP following intravenous administration were 1.93 +/- 0.35 h, 3.50 +/- 1.01 h, 0.45 +/- 0.12 lh-1 kg-1 and 1.5 +/- 0.63 1 kg-1, respectively. There was no evidence of dose-related changes in these values. The plasma MP concentration-time curves were superimposable when normalized for dose. 3. The bioavailability of methylprednisolone from the 20 mg tablet was 0.82 +/- 0.11 (s.d.). 4. In vivo hydrolysis of MPSS was rapid with a half-life of 4.14 +/- 1.62 (s.d.) min, and was independent of dose. In contrast, in vitro hydrolysis in plasma, whole blood and red blood cells was slow; the process continuing for more than 7 days. Sodium fluoride did not prevent the hydrolysis of MPSS. PMID:2655680

  6. Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration.

    PubMed

    Rawlins, M D; Henderson, D B; Hijab, A R

    1977-04-20

    Plasma paracetamol concentrations were measured in 6 volunteers after single intravenous (1000 mg) and oral (500 mg, 1000 mg and 2000 mg) doses of the drug. Paracetamol levels declined multiphasically with a mean clearance after intravenous administration of 352 +/- 40 ml/min. A two-compartment open model appeared to describe the decline adequately. Comparison of the areas under the plasma concentration-time curves (AUC) indicated that oral bioavailability increased from 0.63 +/- 0.02 after 500 mg, to 0.89 +/- 0.04 and 0.87 +/- 0.08 after 1000 mg and 2000 mg, respectively. As a consequence of the incomplete bioavailability of paracetamol, as well as its multicompartmental distribution, accurate estimates of its distribution volume and clearance cannot be obtained if the drug is given orally. However, an estimate of its total plasma clearance may be derived from the AUC after a 500 mg oral dose. PMID:862649

  7. 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. PMID:23923400

  8. 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

  9. 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. PMID:20185867

  10. Induction of Oral Tolerance by Gamma-Irradiated Ovalbumin Administration

    PubMed Central

    Yang, Hui; Lee, Junglim; Seo, Ji Hyun; Oh, Kwang Hoon; Cho, Young Ho; Yoo, Yung Choon

    2016-01-01

    Oral administration of soluble antigen can induce peripheral tolerance to the antigen. This study was conducted to evaluate whether gamma-irradiated ovalbumin (OVA) can induce oral tolerance. To investigate this, we administrated intact or irradiated OVA to mice, induced allergic response using intact OVA and alum, then compared humoral and cellular immune responses. Mice treated with gammairradiated OVA had less OVA-specific IgE compared with those who were administered intact OVA. There was no difference in levels of OVA-specific IgG+A+M, IgG1, and IgG2a. Splenocytes of mice administered irradiated OVA showed similar OVA-specific T cell proliferation and secretion of IFN-γ and IL-4. However, there was an increase in IL-2 and a decrease of IL-6 secretion in mice treated with irradiated OVA. These results indicate that gamma-irradiated OVA have similar effects to intact OVA on antigen tolerance. PMID:27499658

  11. The engagement of oral-associated lymphoid tissues during oral versus gastric antigen administration.

    PubMed

    Bankvall, Maria; Östberg, Anna-Karin; Jontell, Mats; Wold, Agnes; Östman, Sofia

    2016-09-01

    The role of oral-associated lymphoid tissues during induction of oral tolerance still remains elusive. Therefore, the aim was to compare T-cell activation and induction of tolerance to ovalbumin (OVA) presented through either of two routes; deposited into the oral cavity, or the stomach, thereby bypassing the oral cavity. OVA was administered by the oral or gastric route to BALB/c mice that had received OVA-specific DO11.10+ CD4(+) T cells, stained with CellTrace(™) Violet dye, through intravenous injection. Proliferating OVA-specific T cells were detected in the nose-associated lymphoid tissues (NALT) and the cervical, mesenteric and peripheral lymph nodes at different time-points following OVA exposure. OVA-specific T-cell proliferation was initially observed in the NALT 1 hr after oral, but not gastric, administration. However, at day 1, proliferation at this site was also detected after gastric administration and profound proliferation was observed at all sites by day 4. For the oral route the degree of proliferation observed was lower in the peripheral lymph nodes by day 4 compared with the other sites. These results demonstrate a similar activation pattern achieved by the two routes. However, the NALT distinguishes itself as a site of rapid T-cell activation towards fed antigens irrespective of feeding regimen. To evaluate induction of tolerance a semi-effective OVA dose was used, to detect differences in the degree of tolerance achieved. This was performed in a model of OVA-induced airway hypersensitivity. No differences in tolerance induction were observed between the two administration routes. PMID:27288650

  12. 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. PMID:26000370

  13. Enhanced bioavailability after oral and pulmonary administration of baicalein nanocrystal.

    PubMed

    Zhang, Jianjun; Lv, Huixia; Jiang, Kun; Gao, Yuan

    2011-11-25

    The aim of the study was to investigate the potential of oral and pulmonary nanocrystal to enhance the bioavailability of baicalein, a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi. So far, the nano-sized delivery system of baicalein and its pulmonary delivery have received no exploration. In the present investigation, the baicalein nanocrystal was prepared by anti-solvent recrystallization followed by high pressure homogenization. In vitro characterization was performed including particle size and distribution, Zeta potential, dissolution, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffractometry. It was indicated that no crystalline change was observed after nanocrystal preparation. The baicalein nanocrystal containing only trace of stabilizer exhibited a significantly enhanced dissolution of baicalein. In vivo test was also carried out in rats and pharmacokinetic parameters of the baicalein crystal and the baicalein nanocrystal after gavage and pulmonary administration were compared, based on the simultaneous determination of baicalein and baicalin by high performance liquid chromatography. The mean relative bioavailability of oral baicalein nanocrystal was 1.67-fold that of oral baicalein crystal. The pulmonary baicalein nanocrystal had rapid and extensive absorption and had almost identical pharmacokinetic parameters to intravenous baicalein injection. PMID:21878378

  14. 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

  15. 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

  16. 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

    2015-01-01

    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

  17. Pharmacokinetics of ibuprofen enantiomers in rats after intravenous and oral administration of ibuprofen arginate.

    PubMed

    Wang, Xiao-Lin; Han, Jing; Zhang, Dan; Liu, Hui-Chen

    2012-01-01

    The pharmacokinetics of ibuprofen enantiomers were studied in rats after intravenous and oral administration of ibuprofen arginate by means of a chiral HPLC method. The pharmacokinetics of ibuprofen was stereoselective after intravenous and oral administration of ibuprofen arginate. The pharmacokinetic stereoselectivity was higher after oral administration than that after intravenous administration. The systematic (R)-(-)-to-(S)-(+) inversion might be more important than the presystematic one in the stereoselective pharmacokinetics after oral administration. Oral administration of ibuprofen arginate resulted in a very rapid absorption of (S)-(+)-ibuprofen (eutomer), and the absolute bioavailabilities of (S)-(+)-ibuprofen and (R)-(-)-ibuprofen were about 100% and 80%, respectively. Based on the systemic exposure of (S)-(+)-ibuprofen, it could be concluded that the pharmacological actions might be similar when ibuprofen arginate was given orally and intravenously, except some differences in the onset of action. PMID:22493811

  18. Metabolites of isocorynoxeine in rats after its oral administration.

    PubMed

    Chen, Ya-Ping; Lu, Min-Nan; Hao, Jing-Chao; Li, Mei-Hong; Hattori, Masao; Wang, Wei

    2015-01-01

    This work presents the metabolites of isocorynoxeine (ICOR), which is one of four bioactive tetracyclic oxindole alkaloids isolated from Uncaria hooks used commonly in the traditional Chinese medicines and Kampo medicines. After oral administration of 40 mg kg(-1) ICOR to rats, bile was drained and analyzed by LC-MS. Two phase I metabolites, namely 11-hydroxyisocorynoxeine (M1) and 10-hydroxyisocorynoxeine (M2), and two phase II metabolites, namely 11-hydroxyisocorynoxeine 11-O-β-D-glucuronide (M3) and 10-hydroxyisocorynoxeine 10-O-β-D-glucuronide (M4), were isolated from rat excreta and bile, respectively, whose structures were elucidated on the basis of CD, NMR, and MS. PMID:25633191

  19. Coated hydralazine hydrochloride beads for sustained release after oral administration.

    PubMed

    Mughal, M Akhlaq; Saripella, Kalyan K; Kouba, Chahinaz; Iqbal, Zafar; Neau, Steven H

    2013-09-01

    Hydralazine hydrochloride is an antihypertensive used alone or in combination with isosorbide nitrate for the treatment of congestive heart failure. Since control of blood pressure should be continuous, sustained release delivery of this drug is considered therapeutically beneficial. Core beads for oral administration of this drug were prepared by extrusion-spheronization. Using experimental design to define the coat that was applied, the core beads were coated using a fluid bed coater to different coat thickness with combinations of two commercially available products dissolved in a hydroalcoholic solvent. The coat is a film with a combination of ethylcellulose and hydroxypropylcellulose that can provide desirable release profiles. Visually spherical and rugged bead products were obtained. Two products were identified that exhibited essentially a zero order release profile following a 2-h lag time with release of greater than 70% of the drug over the next 10 h in simulated intestinal fluid. PMID:23057650

  20. Thermal antinociception after dexmedetomidine administration in cats: a comparison between intramuscular and oral transmucosal administration.

    PubMed

    Slingsby, Louisa S; Taylor, Polly M; Monroe, Taylor

    2009-10-01

    Dexmedetomidine 40microg/kg was administered either intramuscularly (IM) or oral transmucosally (OTM) to 12 cats in a randomised cross-over study. Thermal nociceptive thresholds and visual analogue scale (VAS) sedation scores were obtained before and at regular intervals up to 24h after test drug administration. The summary measures of overall mean threshold, overall mean VAS sedation plus onset, offset and duration of analgesia were investigated using a univariate general linear model. There were no significant differences between treatment groups. Data are presented as mean+/-standard deviation: delta T mean increase over time (IM 6 degrees C+/-3 degrees C, OTM 6 degrees C+/-2 degrees C); overall mean VAS (IM 43+/-9 OTM 39+/-1); onset (IM 35+/-32 and OTM 30+/-40min); offset (IM 96+/-56 and OTM 138+/-135min); duration (IM 61+/-47 OTM 99+/-124min). Dexmedetomidine is well absorbed through the oral mucosa in cats since OTM and IM administration of dexmedetomidine 40microg/kg produced similar overall sedative and antinociceptive effects. PMID:19577498

  1. 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. PMID:23317423

  2. 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

  3. 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...

  4. Acquired tolerance to dilator action of hydrallazine during oral administration.

    PubMed Central

    Robinson, B F; Collier, J G; Dobbs, R J

    1980-01-01

    1 The effect on forearm blood flow of local intra-arterial infusion of hydrallazine has been studied in twelve patients with essential hypertension and six normal subjects. 2 When the patients with hypertension were not taking hydrallazine by mouth, they responded to intra-arterial infusions with a dose-dependent increase in forearm blood flow that was not significantly different from that in normal subjects. 3 When the patients were taking hydrallazine by mouth, the increase in forearm flow in response to intra-arterial infusions was reduced and forearm vascular resistance did not fall as low as it did in the control study (P less than 0.01). 4 In four patients, the response to intra-arterial hydrallazine was attenuated to a major extent, and in three of these, there was little or no response to oral treatment. In eight patients, the response to intra-arterial hydrallazine did not fall below one half of that in the control study and this minor reduction in sensitivity might be expected to impair, but not abolish, the response to oral treatment. 5 It is concluded that the resistance vessels commonly develop tolerance to the dilator action of hydrallazine during long-term oral therapy. In some patients a high degree of tolerance develops and this is an important cause of failure to respond to oral treatment. PMID:6769454

  5. Comparison of tissue and plasma levels of ibuprofen after oral and topical administration.

    PubMed

    Dominkus, M; Nicolakis, M; Kotz, R; Wilkinson, F E; Kaiser, R R; Chlud, K

    1996-12-01

    The penetration and absorption of ibuprofen (CAS 15687-27-1) from a topical gel and oral tablets were tested in an open study, performed in 17 patients with degenerative knee disorders requiring an operation. Patients administered the topical test preparation (ibugel, 3 x 375 mg ibuprofen daily) or the standard oral preparation (2 x 600 mg ibuprofen daily) for 3 days prior to the operation. Samples of blood, synovial fluid, muscle, fasciae and subcutis were obtained during the operation (15 h after the last administration) and analysed for ibuprofen content using a validated HPLC method. Different absorption profiles were observed for topical and oral administration. Oral administration led to higher concentrations in the plasma, synovial fluid and fasciae, while higher levels in the muscle and subcutis were found after topical administration. After topical application, the concentrations in the fasciae, muscle and subcutis were significantly higher than those in the blood plasma and synovial fluid (p < 0.05). Very low levels of ibuprofen were observed in the subcutis after oral administration. This can be explained by the different pathways. This study demonstrated that concentrations of ibuprofen in the various biological samples were still within therapeutically effective levels 15 h after topical or oral administration. By use of an oral comparison group, it has been possible to show that the concentrations in times directly under the site of topical application lie in the same order of magnitude as those found after preoral treatment. Therapy of intra-articular inflammatory and degenerative joint diseases requires oral administration of non-steroidal anti-inflammatory drugs (NSAIDs). However, based on the results of this study, topical therapy with NSAIDs can be recommended for soft tissue rheumatism and periarticular insertion tendinopathia. PMID:9006788

  6. Oral administration of inosine produces antidepressant-like effects in mice

    PubMed Central

    Muto, Junko; Lee, Hosung; Lee, Hyunjin; Uwaya, Akemi; Park, Jonghyuk; Nakajima, Sanae; Nagata, Kazufumi; Ohno, Makoto; Ohsawa, Ikuroh; Mikami, Toshio

    2014-01-01

    Inosine, a breakdown product of adenosine, has recently been shown to exert immunomodulatory and neuroprotective effects. We show here that the oral administration of inosine has antidepressant-like effects in two animal models. Inosine significantly enhanced neurite outgrowth and viability of primary cultured neocortical neurons, which was suppressed by adenosine A1 and A2A receptor agonists. Oral administration of inosine to mice transiently increased its concentration in the brain and enhanced neuronal proliferation in the dentate gyrus, accompanied by phosphorylation of mitogen-activated protein kinase and increase in transcript level of brain-derived neurotrophic factor. In stress models, oral inosine prevented an increase in immobility time in forced swim test after chronically unexpected stress and mitigated a reduction in sucrose preference after chronic social defeat stress. These results indicate that oral administration of inosine has the potential to prevent depressive disorder via adenosine receptors. PMID:24569499

  7. Apixaban metabolism and pharmacokinetics after oral administration to humans.

    PubMed

    Raghavan, Nirmala; Frost, Charles E; Yu, Zhigang; He, Kan; Zhang, Haiying; Humphreys, W Griffith; Pinto, Donald; Chen, Shiangyuan; Bonacorsi, Samuel; Wong, Pancras C; Zhang, Donglu

    2009-01-01

    The metabolism and disposition of [(14)C]apixaban, an orally bioavailable, highly selective, and direct acting/reversible factor Xa inhibitor, was investigated in 10 healthy male subjects without (group 1, n=6) and with bile collection (group 2, n=4) after a single 20-mg oral dose. Urine, blood, and feces samples were collected from all subjects. Bile samples were also collected for 3 to 8 h after dosing from group 2 subjects. There were no serious adverse events or discontinuations due to adverse effects. In plasma, apixaban was the major circulating component and O-demethyl apixaban sulfate, a stable and water-soluble metabolite, was the significant metabolite. The exposure of apixaban (C(max) and area under the plasma concentration versus time curve) in subjects with bile collection was generally similar to that in subjects without bile collection. The administered dose was recovered in feces (group 1, 56.0%; group 2, 46.7%) and urine (group 1, 24.5%; group 2, 28.8%), with the parent drug representing approximately half of the recovered dose. Biliary excretion represented a minor elimination pathway (2.44% of the administered dose) from group 2 subjects within the limited collection period. Metabolic pathways identified for apixaban included O-demethylation, hydroxylation, and sulfation of hydroxylated O-demethyl apixaban. Thus, apixaban is an orally bioavailable inhibitor of factor Xa with elimination pathways that include metabolism and renal excretion. PMID:18832478

  8. Oral administration and younger age decrease plasma concentrations of voriconazole in pediatric patients.

    PubMed

    Kato, Karin; Nagao, Miki; Yamamoto, Masaki; Matsumura, Yasufumi; Takakura, Shunji; Fukuda, Kazuhiko; Ichiyama, Satoshi

    2016-01-01

    Voriconazole is used for treating or preventing invasive aspergillosis and other invasive fungal infections. To minimize adverse reactions and to maximize treatment effects, therapeutic drug monitoring should be performed. However, it is challenging to optimize daily voriconazole dosing because limited data have been published so far on pediatric patients. We retrospectively analyzed voriconazole concentrations in patients aged 0-18 years. In addition, a literature review was conducted. In our study cohort, younger age and oral administration were significantly associated with lower plasma voriconazole concentrations (P < 0.01). An unfavorable outcome was associated with low concentrations of voriconazole (P = 0.01). Reports of voriconazole administration in pediatric patients show that higher doses are required in younger children and in patients receiving oral administration. Hence, the current data suggest that we should escalate both initial and maintenance doses of voriconazole in pediatric patients, particularly in patients of younger age receiving an oral administration of voriconazole. PMID:26538245

  9. 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

  10. 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. PMID:26538668

  11. Pharmacokinetics of cefadroxil after oral administration in humans.

    PubMed

    La Rosa, F; Ripa, S; Prenna, M; Ghezzi, A; Pfeffer, M

    1982-02-01

    The human oral pharmacokinetics of cefadroxil were studied in parallel at doses of 250, 500, and 1,000 mg in three groups of 10 healthy young male volunteers. Renal excretion of intact cefadroxil, accounted for 82, 79, and 77% of the above doses. Mean peak serum levels were dose linear: 9, 18, and 35 microgram/ml at 250, 500, and 1,000 mg, respectively. However, overall pharmacokinetics were linear only in the 250- to 500-mg dose range; apparent serum clearances were 10 liters/h, and true renal clearances were 9 and 8 liters/h at 250 and 500 mg. At 1,000 mg, apparent serum clearance dropped to about 7 liters/h, true renal clearance, dropped to 6 liters/h, and the area under the curve increased disproportionately. At 250 and 500 mg, mean half-life was about 1.2 h; at 1,000 mg, however, it was 1.6h. The nonlinear decrease in clearance could be related to saturation of active renal tubular secretion of cefadroxil between the 500- and 1,000-mg doses. Previous results indicating that cefadroxil has greater persistence than other oral cephalosporins such as cephalexin, cephradine, cefaclor were confirmed. PMID:7073267

  12. 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

  13. Pharmacokinetics of (-)-folinic acid after oral and intravenous administration of the racemate.

    PubMed Central

    Greiner, P O; Zittoun, J; Marquet, J; Cheron, J M

    1989-01-01

    1. A pharmacokinetic study of the natural (-)-isomer of folinic acid ((-)-5 CHOTHF) and of total (-)-folates was performed in 12 healthy subjects after i.v. and oral administration of the racemic form of folinic acid. 2. After a 25 mg i.v. injection, (-)-5 CHOTHF kinetics were described by a biexponential function. The mean steady state volume of distribution (Vss) was 161; systemic and renal clearances averaged 335 and 53 ml min-1, respectively. After the same oral dose, (-)-5 CHOTHF was rapidly absorbed. Plasma concentrations of unchanged drug were much lower than those achieved after i.v. administration but in nine subjects, the disposition kinetics were also biexponential. Absolute bioavailability was only 4% as a consequence of a significant intestinal first pass effect. 3. AUC and t1/2Z values for total (-)-folates were similar after both routes of administration, indicating that the drug was fully absorbed. However the AUC of the active metabolite after i.v. dosage was only half that after oral dosage. 4. The amounts of total (-)-folates excreted in urine after both routes of administration were not significantly different and averaged one third of the dose after 24 h, whereas excretion of (-)-5 CHOTHF was three times less after oral treatment than after parenteral treatment. 5. Oral administration is a more suitable route for folinic acid therapy because more of the active metabolite is produced than after parenteral injection. PMID:2789922

  14. Pharmacokinetics of moxidectin in alpacas following administration of an oral or subcutaneous formulation.

    PubMed

    Cocquyt, Christine M; Van Amstel, Sarel; Cox, Sherry; Rohrbach, Barton; Martín-Jiménez, Tomás

    2016-04-01

    The purpose of this study was to evaluate the pharmacokinetics of moxidectin in alpacas after single subcutaneous injection of a non-aqueous formulation or oral administration of an aqueous drench at 0.2 mg∗kg(-1). Plasma moxidectin concentrations were measured with reverse phase HPLC, and data analyzed using non-compartmental methods. Half-life was longer (p=0.02) after subcutaneous administration than oral (292+/-170 vs 33+/-39 h). The area under the concentration-time curve was greater (p=0.04) following subcutaneous administration (1484.8+/-1049.5 h∗ng∗ml(-1)) than oral (157.6+/-85.9 h∗ng∗ml(-1)). The peak concentration (Cmax) was higher and the after subcutaneous administration, but the difference was not statistically significant (p=0.18). The relative bioavailability of the oral moxidectin to the subcutaneous moxidectin was 11%. The data suggest a higher relative bioavailability following subcutaneous compared to oral administration. Further studies are needed to determine the therapeutic concentrations of moxidectin in alpacas. PMID:27033926

  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. Clinical systemic lupeol administration for canine oral malignant melanoma

    PubMed Central

    YOKOE, INORU; AZUMA, KAZUO; HATA, KEISHI; MUKAIYAMA, TOSHIYUKI; GOTO, TAKAHIRO; TSUKA, TAKESHI; IMAGAWA, TOMOHIRO; ITOH, NORIHIKO; MURAHATA, YUSUKE; OSAKI, TOMOHIRO; MINAMI, SABURO; OKAMOTO, YOSHIHARU

    2015-01-01

    Canine oral malignant melanoma (COMM) is the most aggressive malignant tumor in dogs. Lupeol is a triterpene extracted from various fruits and vegetables that reportedly inhibits melanoma cell proliferation in vitro and in vivo. In this study, the efficacy of subcutaneous lupeol for spontaneous COMM was evaluated. A total of 11 dogs (3, 5 and 3 dogs diagnosed with clinical stage I, II and III melanoma, respectively) were evaluated. Subcutaneous lupeol (10 mg/kg) was administered postoperatively at various time points to treat these 11 COMM cases. Of the 11 subjects, 7 exhibited no local recurrence 180 days postoperatively and no severe adverse effects were observed in any of the cases. Furthermore, no distant metastasis was observed during the experimental period. Therefore, systemic lupeol may prevent local tumor progression and distant metastasis and may be a novel adjuvant treatment for the treatment of COMM. PMID:25469276

  17. [Sudden death following a single oral administration of haloperidol].

    PubMed

    Remijnse, P L; Eeckhout, A M; van Guldener, C

    2002-04-20

    A 39-year-old man was admitted with myasthenia, alcoholic hepatitis and electrolyte abnormalities due to an inadequate nutritional state. On admission the ECG showed a prolonged QTc interval (0.46 s). The patient was treated with intravenous fluid and supplementary vitamins and minerals. On the third day of admission the patient developed a delirium, partly due to alcohol withdrawal, and was therefore treated with oxazepam 50 mg 3 times daily and a single dose of haloperidol 5 mg. One hour after ingesting haloperidol, the patient suddenly succumbed and resuscitation was not successful. The autopsy revealed a cardiomyopathy but no explanation for the sudden death. Due to the temporal relationship between the ingestion of haloperidol and this sudden death, we assume that haloperidol induced a fatal arrhythmia in the presence of a preexisting prolonged repolarisation time. To the best of our knowledge, sudden death after a single oral therapeutic dose of haloperidol has not previously been described. PMID:11998355

  18. A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer

    PubMed Central

    Veltkamp, S A; Thijssen, B; Garrigue, J S; Lambert, G; Lallemand, F; Binlich, F; Huitema, A D R; Nuijen, B; Nol, A; Beijnen, J H; Schellens, J H M

    2006-01-01

    To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160 mg+CsA 700 mg on day 1, followed by oral paclitaxel (Taxol®) 160 mg+CsA 700 mg on day 8 (group I) or vice versa (group II). Patients received paclitaxel (Taxol®) 160 mg as 3-h infusion on day 15. The median (range) area under the plasma concentration–time curve of paclitaxel was 2.06 (1.15–3.47) μg h ml−1 and 1.97 (0.58–3.22) μg h ml−1 after oral administration of SMEOF#3 and Taxol®, respectively, and 4.69 (3.90–6.09) μg h ml−1 after intravenous Taxol®. Oral SMEOF#3 resulted in a lower median Tmax of 2.0 (0.5–2.0) h than orally applied Taxol® (Tmax=4.0 (0.8–6.1) h, P=0.02). The median apparent bioavailability of paclitaxel was 40 (19–83)% and 55 (9–70)% for the oral SMEOF#3 and oral Taxol® formulation, respectively. Oral paclitaxel administered as SMEOF#3 or Taxol® was safe and well tolerated by the patients. Remarkably, the SMEOF#3 formulation resulted in a significantly lower Tmax than orally applied Taxol®, probably due to the excipients in the SMEOF#3 formulation resulting in a higher absorption rate of paclitaxel. PMID:16926835

  19. Inhibition of the neutrophil oxidative response induced by the oral administration of nimesulide in normal volunteers.

    PubMed

    Ottonello, L; Dapino, P; Pastorino, G; Dallegri, F

    1992-01-01

    The superoxide (O2) production by phagocytes (neutrophils plus monocytes) and the lactoferrin release by neutrophils were measured in normal volunteers before and after the oral administration of the anti-inflammatory drug nimesulide. The chemotactic factor N-formylmethionyl-leucyl-phenylalanine (FMLP) and opsonized zymosan particles (OPZ) were used as activating stimuli. The oral administration of nimesulide lowered the phagocyte ability to generate O2- in response to both FMLP (percent inhibition = 67.62) and OPZ (percent inhibition = 36.75). The lactoferrin release by neutrophils was unaffected, proving that the drug does not affect the exocytosis of specific granules. The results provide direct evidence that the oral administration of nimesulide efficiently reduces the oxidative potential of phagocytes, particularly neutrophils, without interfering with mechanisms related to exocytosis of specific granules and involved in the amplification of the cell responses to inflammatory mediators. PMID:1340506

  20. 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. PMID:26536331

  1. 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

  2. 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. PMID:26748256

  3. Pharmacokinetics of cefatrizine after oral administration in human volunteers.

    PubMed

    Mastrandrea, V; Ripa, S; La Rosa, F; Ghezzi, A

    1985-01-01

    The oral bioavailability of cefatrizine was studied in four groups, each of ten healthy young male volunteers. Capsules and suspension formulations were each administered at doses of 250 and 500 mg. Both the capsules and suspensions had mean peak plasma levels at 1.6 h at both dose levels. Mean peak plasma levels were 4.1 and 4.3 micrograms/ml for the 250 mg capsule and suspension doses respectively and 7.1 and 7.5 micrograms/ml for the 500 mg capsules and suspension doses respectively. The overall mean half-life was 1.7 h. For both types of formulations and at both dose levels 63-65% of the doses were excreted in the urine as intact cefatrizine, 85% of this amount within 8 h. The overall mean renal clearance was 157 ml/min. The cefatrizine capsule and suspension formulations were completely bioequivalent in regard to both rate and extent of bioavailability. Plasma concentrations and urinary recoveries of cefatrizine were higher than those previously reported, due to precautions taken in sample collection and storage. PMID:4066082

  4. Pharmacokinetics of voriconazole after intravenous and oral administration to healthy cats.

    PubMed

    Vishkautsan, Polina; Papich, Mark G; Thompson, George R; Sykes, Jane E

    2016-09-01

    OBJECTIVE To determine pharmacokinetics and adverse effects after voriconazole administration to cats and identify an oral dose of voriconazole for cats that maintains plasma drug concentrations within a safe and effective range. ANIMALS 6 healthy cats. PROCEDURES Voriconazole (1 mg/kg, IV) was administered to each cat (phase 1). Serial plasma voriconazole concentrations were measured for 24 hours after administration. Voriconazole suspension or tablets were administered orally at 4, 5, or 6 mg/kg (phase 2). Plasma voriconazole concentrations were measured for 24 hours after administration. Pharmacokinetics of tablet and suspension preparations was compared. Finally, an induction dose of 25 mg/cat (4.1 to 5.4 mg/kg, tablet formulation), PO, was administered followed by 12.5 mg/cat (2.05 to 2.7 mg/kg), PO, every 48 hours for 14 days (phase 3). Plasma voriconazole concentration was measured on days 2, 4, 8, and 15. RESULTS Voriconazole half-life after IV administration was approximately 12 hours. Maximal plasma concentration was reached within 60 minutes after oral administration. A dose of 4 mg/kg resulted in plasma concentrations within the target range (1 to 4 μg/mL). Adverse effects included hypersalivation and miosis. During long-term administration, plasma concentrations remained in the target range but increased, which suggested drug accumulation. CONCLUSIONS AND CLINICAL RELEVANCE Voriconazole had excellent oral bioavailability and a long half-life in cats. Oral administration of a dose of 12.5 mg/cat every 72 hours should be investigated. Miosis occurred when plasma concentrations reached the high end of the target range. Therefore, therapeutic drug monitoring should be considered to minimize adverse effects. PMID:27580104

  5. 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. PMID:11782792

  6. Pharmacokinetics of doxycycline in pigs following oral administration in feed.

    PubMed

    Bousquet, E; Nouws, J; Terlouw, P; de Kleyne, S

    1998-01-01

    Doxycycline medicated feed was administered to healthy fattening pigs for an 8-day period either for 1 h every 12 h or ad libitum. The average dosage regimen ranged between 11.8 and 13.3 mg/kg/day. Doxycycline concentrations were determined in plasma, lung and nasal mucosa using a high performance liquid chromatography assay (HPLC). The agreement between the doxycycline HPLC assay and a bioassay was also assessed in plasma. Following the multiple medicated feed administration every 12 h, the plasma concentrations were best described by a one-compartmental model with first-order absorption. Steady-state plasma concentrations ranged between 0.7 and 1 microgram/mL. The mean accumulation factor and elimination half-life were, respectively, 1.8 +/- 0.4 and 5.9 +/- 1.0 h. Following ad libitum administration of medicated feed, steady-state plasma concentrations ranged between 0.9 and 1.5 micrograms/mL. At the end of the treatment, the doxycycline lung and nasal mucosa concentrations were 1.7 +/- 0.4 micrograms/g and 2.9 +/- 0.6 micrograms/g, respectively. These data validate the dosage regimen tested in order to control pig respiratory infections, provided that controlled clinical studies are confirmatory. PMID:9779560

  7. 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

    2015-12-01

    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. PMID:26387441

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

    PubMed

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

    2015-08-01

    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

  9. 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

  10. Absorption kinetics and bioavailability of cephalexin in the dog after oral and intramuscular administration.

    PubMed

    Carli, S; Anfossi, P; Villa, R; Castellani, G; Mengozzi, G; Montesissa, C

    1999-10-01

    The pharmacokinetics of cephalexin, a first generation cephalosporin, were investigated in dogs using two formulations marketed for humans, but also often employed by practitioners for pet therapy. Cephalexin was administered to five dogs intravenously and intramuscularly as a sodium salt and by the oral route as a monohydrate. The dosage was always 20 mg/kg of active ingredient. A microbiological assay with Sarcina lutea as the test organism was adopted to measure cephalexin concentrations in serum. The mean residence time (MRT) median values after intravenous (i.v.), intramuscular (i.m.) and oral administration (p.o.) were 86 min, 200 min, and 279 min, respectively. After i.m. and oral dosing the peak serum concentrations (24.2 +/- 1.8 micrograms/mL and 20.3 +/- 1.7 micrograms/mL, respectively) were attained at 90 min in all dogs and bioavailabilities were 63 +/- 10% and 57 +/- 5%, respectively. The time course of the cephalexin serum concentrations after oral administration was best described by a model incorporating saturable absorption kinetics of the Michaelis-Menten type: thus in the gastrointestinal tract of dogs a carrier mediated transport for cephalexin similar to that reported in humans, may exist. The predicted average serum concentrations of cephalexin after repeated i.m. and oral administration indicated that, in order to maintain the therapeutic concentrations, the 20 mg/kg b.w. dosage should be administered every 6-8 h. PMID:10597534

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

    PubMed

    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

  12. 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.

  13. Bioequivalence of oral and intravenous ofloxacin after multiple-dose administration to healthy male volunteers.

    PubMed Central

    Flor, S C; Rogge, M C; Chow, A T

    1993-01-01

    The bioequivalence of oral and intravenous ofloxacin was investigated after the administration of multiple doses of 400 mg every 12 h to 20 healthy male volunteers in a randomized, crossover, open-label study. Ofloxacin concentrations in plasma were evaluated after 4 days of oral or intravenous (1-h infusion) dosing with a 3-day wash-out period between regimens. As expected, delivery to the systemic circulation took slightly longer after the oral dosing (time to maximum concentration of drug in serum of 1.7 h) relative to the 1-h intravenous infusion, but the systemic availabilities of ofloxacin by the two routes of administration were equivalent (area under the concentration-time curve from 0 to 12 h ratio of 95%). Since previous studies have not demonstrated any change in the bioavailability of ofloxacin in infectious disease patients, this study supports the interchangeability of these dosing regimens. PMID:8363378

  14. Safety of fluralaner, a novel systemic antiparasitic drug, in MDR1(-/-) Collies after oral administration

    PubMed Central

    2014-01-01

    Background Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. This study investigated the safety of oral administration of fluralaner at 3 times the highest expected clinical dose to Multi Drug Resistance Protein 1 (MDR1(-/-)) gene defect Collies. Methods Sixteen Collies homozygous for the MDR1 deletion mutation were included in the study. Eight Collies received fluralaner chewable tablets once at a dose of 168 mg/kg; eight sham dosed Collies served as controls. All Collies were clinically observed until 28 days following treatment. Results No adverse events were observed subsequent to fluralaner treatment of MDR1(-/-) Collies at three times the highest expected clinical dose. Conclusions Fluralaner chewable tablets are well tolerated in MDR1(-/-) Collies following oral administration. PMID:24602342

  15. 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. PMID:23831756

  16. Azimilide pharmacokinetics following intravenous and oral administration of a solution and capsule formulation.

    PubMed

    Corey, A E; Agnew, J R; Valentine, S N; Nesbitt, J D; Wagner, D L; Powell, J H; Thompson, G A

    1999-12-01

    Azimilide dihydrochloride (NE-10064) is a novel class III anti-arrhythmic agent that blocks both the slowly and rapidly acting components of the delayed rectifier potassium current of human atrial and ventricular myocytes. In clinical studies, azimilide reduced the frequency of symptomatic episodes of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. This study was conducted to characterize azimilide pharmacokinetics following single-dose administration of a 1 mg/kg intravenous infusion (18 min), 2 mg/kg oral solution, and a 150 mg orally administered capsule. This was a three-period, randomized, crossover study in 27 healthy, drug-free (including caffeine and alcohol), non-smoking male volunteers (mean [SD]; age, 25.9 [1.0] years; weight 74.3 [0.7] kg; 23 Caucasians and 4 Hispanics). Blood and urine samples were collected for 27 days and analyzed for azimilide using HPLC with UV detection. Subjects were monitored for adverse events and abnormalities in clinical laboratory tests, vital signs, and electrocardiography (including Holter monitoring). Mean (%CV) azimilide parameters were total clearance = 0.143 L/h/kg (38%), renal clearance = 0.014 L/h/kg (35%), steady-state volume of distribution = 13.2 L/kg (23%), and terminal exponential half-life = 78.8 h (44%). Similar parameter estimates were obtained following oral administration. Both the oral solution and capsule formulations were completely absorbed. In addition, the rate (Cmax) and extent of absorption (AUC) following oral administration of the capsule dosage form were bioequivalent to the oral solution with means for times of maximum blood concentration of 7.08 and 7.18 hours for the oral solution and capsule, respectively. Azimilide dihydrochloride was generally well tolerated in all subjects. PMID:10586393

  17. 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. PMID:27324760

  18. Oral administration of active vitamin D metabolites to low birthweight infants.

    PubMed Central

    Kovar, I Z; Mayne, P D; James, J J; Barnes, I C

    1986-01-01

    The active vitamin D metabolites 1 alpha, 25-dihydroxycholecalciferol (Rocaltrol) and the analogue 1 alpha-hydroxycholecalciferol (One-Alpha) are adequately absorbed after oral administration in the preterm infant. The absorption pattern is similar to that seen in adults. PMID:3755581

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

    PubMed

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

    2012-07-01

    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

  1. 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...

  2. 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...

  3. 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

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

    PubMed Central

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

    2013-01-01

    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 Δ9-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. PMID:21637933

  5. Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration.

    PubMed

    Sundlof, S F; Whitlock, T W

    1992-09-01

    Clorsulon was measured in plasma and urine of sheep and goats after administration of a single intravenous (i.v.) and after a single oral dose of 7 mg/kg. A three-compartment model with elimination occurring from the central compartment was determined to best describe the i.v. data, whereas a one-compartment model with a single exponential absorption phase best described the oral plasma data. The bioavailability of orally administered clorsulon was approximately 55% in goats and 60% in sheep. Peak plasma concentrations occurred at 14 h and 15 h after oral administration in goats and sheep, respectively. Absorption from the gastro-intestinal tract effectively prolonged the elimination of clorsulon by increasing the elimination half-life from 17 to 28 h in sheep and from 12 to 23 h in goats for the i.v. and oral routes, respectively. In both goats and sheep, approximately 50% of the i.v. dose was recovered in urine as parent drug at 48 h after administration, whereas 41% and 30% of the dose was recovered after oral administration for goats and sheep, respectively. The elimination rate constant (kel) in goats was nearly twice as large as the value determined in sheep, and the urea under the i.v. plasma curve in goats was only 63% of the value in sheep indicating that goats are more effective in their capacity to eliminate clorsulon than are sheep. These differences in drug disposition between sheep and goats may account for the reduced efficacy of clorsulon reported in goats. PMID:1433492

  6. Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration

    PubMed Central

    Juma, F. D.; Rogers, H. J.; Trounce, J. R.

    1979-01-01

    1 Plasma cyclophosphamide levels were estimated by gas-chromatography in seven patients following intravenous and oral cyclophosphamide administration. Plasma alkylating activity was determined by the nitrobenzyl pyridine (NBP) reaction. 2 The plasma T½ after intravenous administration ranged from 5.97 to 12.37 h but after oral administration was shorter, 1.32-6.8 h. The mean total body clearance was 66.6 ml kg-1 h-1 after intravenous dosing and 93.1 ml kg-1 h-1 following oral dosing. Vdβ was 0.71 (0.10 s.d.) 1 kg-1 suggesting that cyclophosphamide is distributed largely in body water. 3 The mean hepatic extraction ratio was 0.25, indicating a modest first pass metabolism. The metabolic clearance was 3.72 1 kg-1 and the intrinsic hepatic clearance 5.17 1 kg-1. 4 The mean renal clearance was 4.8 ml kg-1 h-1 with 6.5% of the administered dose excreted unchanged in the urine suggesting tubular reabsorption of cyclophosphamide. 5 The mean T½ of plasma alkylating activity was 8.82 h, there being no significant difference following oral and intravenous administration. On average, 3.5 times the alkylating activity was produced by an oral dose of cyclophosphamide as compared to an intravenous dose. It is possible that this may reflect production of a different pattern of alkylating metabolites following cyclophosphamide administration by different routes. The clinical significance of these observations is unknown. PMID:497087

  7. 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.

  8. 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.

  9. Tissue concentrations of coenzyme Q10 in the rat following its oral and intraperitoneal administration.

    PubMed

    Reahal, S; Wrigglesworth, J

    1992-01-01

    Daily oral or ip administration of coenzyme Q10 to rats for time periods of 2 to 10 weeks leads to its accumulation in liver, concentrating in the soluble fraction of the liver cells. No uptake of coenzyme Q10 can be detected in the heart or kidney. Intraperitoneal administration also results in the accumulation of coenzyme Q10 in the spleen. It is concluded that the normal endogenous levels of quinone in the rat heart and kidney cannot be supplemented over the long term by administration of exogenous quinone. PMID:1355718

  10. Ronidazole pharmacokinetics after intravenous and oral immediate-release capsule administration in healthy cats.

    PubMed

    LeVine, Dana N; Papich, Mark G; Gookin, Jody L; Davidson, Gigi S; Davis, Jennifer L; Hayes, Rebecca B

    2011-04-01

    Ronidazole (RDZ) is an effective treatment for feline Tritrichomonas foetus infection, but has produced neurotoxicity in some cats. An understanding of the disposition of RDZ in cats is needed in order to make precise dosing recommendations. Single-dose pharmacokinetics of intravenous (IV) RDZ and immediate-release RDZ capsules were evaluated. A single dose of IV RDZ (mean 9.2mg/kg) and a 95mg immediate-release RDZ capsule (mean 28.2mg/kg) were administered to six healthy cats in a randomized crossover design. Plasma samples were collected for 48 h and assayed for RDZ using high pressure liquid chromatography (HPLC). Systemic absorption of oral RDZ was rapid and complete, with detection in the plasma of all cats by 10 min after dosing and a bioavailability of 99.64 (±16.54)%. The clearance of RDZ following IV administration was 0.82 (±0.07) ml/kg/min. The terminal half-life was 9.80 (±0.35) and 10.50 (±0.82) h after IV and oral administration, respectively, with drug detectable in all cats 48h after both administrations. The high oral bioavailability of RDZ and slow elimination may predispose cats to neurotoxicity with twice-daily administration. Less frequent administration should be considered for further study of effective treatment of T foetus-infected cats. PMID:21239199

  11. Role of neutrophils in hepatotoxicity induced by oral acetaminophen administration in rats.

    PubMed

    Smith, G S; Nadig, D E; Kokoska, E R; Solomon, H; Tiniakos, D G; Miller, T A

    1998-12-01

    Acetaminophen (APAP) is a common analgesic and antipyretic compound which, when administered in high doses, has been associated with significant morbidity and mortality, secondary to hepatic toxicity. To date, the mechanism(s) whereby APAP induces liver injury remains to be delineated. This study investigated the potential role of neutrophils as contributors to liver injury in rats administered sublethal doses of APAP. Oral APAP administration (650 mg/kg) was associated with increases in serum alanine transaminase (ALT) levels indicating biochemical evidence of significant liver damage. Furthermore, histological analyses verified significant hepatocellular necrosis as well as enhanced myeloperoxidase staining in these liver specimens. However, if animals were pretreated with antineutrophil sera prior to APAP administration, neutrophil counts remained depressed, ALT levels were significantly decreased, and the degree of liver injury was attenuated on a histological level. Taken together these data suggest that neutrophils mediate, at least in part, the hepatotoxic effects of oral acetaminophen administration in rats. PMID:9878321

  12. Pharmacokinetics of tramadol in horses after intravenous, intramuscular and oral administration.

    PubMed

    Shilo, Y; Britzi, M; Eytan, B; Lifschitz, T; Soback, S; Steinman, A

    2008-02-01

    Tramadol is a centrally acting analgesic drug that has been used clinically for the last two decades to treat moderate to moderately severe pain in humans. The present study investigated tramadol administration in horses by intravenous, intramuscular, oral as immediate-release and oral as sustained-release dosage-form routes. Seven horses were used in a four-way crossover study design in which racemic tramadol was administered at 2 mg/kg by each route of administration. Altogether, 23 blood samples were collected between 0 and 2880 min. The concentration of tramadol and its M1 metabolite were determined in the obtained plasma samples by use of an LC/MS/MS method and were used for pharmacokinetic calculations. Tramadol clearance, apparent volume of distribution at steady-state, mean residence time (MRT) and half-life after intravenous administration were 26+/-3 mL/min/kg, 2.17+/-0.52 L/kg, 83+/-10 min, and 82+/-10 min, respectively. The MRT and half-life after intramuscular administration were 155+/-23 and 92+/-14 min. The mean absorption time was 72+/-22 min and the bioavailability 111+/-39%. Tramadol was poorly absorbed after oral administration and only 3% of the administered dose was found in systemic circulation. The fate of the tramadol M1 metabolite was also investigated. M1 appeared to be a minor metabolite in horses, which could hardly be detected in plasma samples. The poor bioavailability after oral administration and the short half-life of tramadol may restrict its usefulness in clinical applications. PMID:18177320

  13. Systemic administration of RANKL overcomes the bottleneck of oral vaccine delivery through microfold cells in ileum.

    PubMed

    Maharjan, Sushila; Singh, Bijay; Jiang, Tao; Yoon, So-Yeon; Li, Hui-Shan; Kim, Girak; Gu, Min Jeong; Kim, Soo Ji; Park, Ok-Jin; Han, Seung Hyun; Kang, Sang-Kee; Yun, Cheol-Heui; Choi, Yun-Jaie; Cho, Chong-Su

    2016-04-01

    A successful delivery of antigen through oral route requires to overcome several barriers, such as enzymatic barrier of gastrointestinal tract and epithelial barrier that constitutes of microfold cells (M cells) for antigen uptake. Although each barrier represents a critical step in determining the final efficiency of antigen delivery, the transcytosis of antigen by M cells in the follicle-associated epithelium (FAE) to Peyer's patches appears to be a major bottleneck. Considering the systemic administration of receptor activator of nuclear factor (NF)-ĸB ligand (RANKL) induces differentiation of receptor activator of nuclear factor (NF)-ĸB (RANK)-expressing enterocytes into M cells, here, we illustrated a promising approach of antigen delivery using full length transmembrane RANKL (mRANKL). The results showed that the intraperitoneal injection of mRANKL increased the population of dendritic cells and macrophages in mesenteric lymph nodes and spleen. Subsequently, systemic administration of mRANKL resulted in significantly higher number of functional GP2(+) M cells leading higher transcytosis of fluorescent beads through them. To corroborate the effect of mRANKL in antigen delivery through M cells, we orally delivered microparticulate antigen to mice treated with mRANKL. Oral immunization induced strong protective IgA and systemic IgG antibody responses against orally delivered antigen in mRANKL-treated mice. The higher antibody responses are attributed to the higher transcytosis of antigens through M cells. Ultimately, the higher memory B cells and effector memory CD4 T cells after oral immunization in RANKL-treated mice confirmed potency of RANKL-mediated antigen delivery. To the best of our knowledge, this is the first study to demonstrate significant induction of mucosal and humoral immune responses to M cell targeted oral vaccines after the systemic administration of RANKL. PMID:26851393

  14. Transcytosis, Antitumor Activity and Toxicity of Staphylococcal Enterotoxin C2 as an Oral Administration Protein Drug

    PubMed Central

    Zhao, Wenbin; Li, Yangyang; Liu, Wenhui; Ding, Ding; Xu, Yingchun; Pan, Liqiang; Chen, Shuqing

    2016-01-01

    Staphylococcal enterotoxin C2 (SEC2) is a classical superantigen (SAg), which can tremendously activate T lymphocytes at very low dosage, thus exerting its powerful antitumor activity. As an intravenous protein drug and a bacterial toxin, SEC2 has some limitations including poor patient compliance and toxic side effects. In this research, we devoted our attention to studying the antitumor activity and toxicity of SEC2 as a potential oral administration protein drug. We proved that His-tagged SEC2 (SEC2-His) could undergo facilitated transcytosis on human colon adenocarcinoma (Caco-2) cells and SEC2-His was detected in the blood of rats after oral administration. Furthermore, oral SEC2-His caused massive cytokine release and immune cell enrichment around tumor tissue, leading to inhibition of tumor growth in vivo. Meanwhile, although SEC2-His was dosed up to 32 mg/kg in mice, no significant toxicity was observed. These data showed that SEC2 can cross the intestinal epithelium in an immunologically integral form, maintaining antitumor activity but with reduced systemic toxicity. Therefore, these results may have implications for developing SEC2 as an oral administration protein drug. PMID:27322320

  15. Transcytosis, Antitumor Activity and Toxicity of Staphylococcal Enterotoxin C2 as an Oral Administration Protein Drug.

    PubMed

    Zhao, Wenbin; Li, Yangyang; Liu, Wenhui; Ding, Ding; Xu, Yingchun; Pan, Liqiang; Chen, Shuqing

    2016-01-01

    Staphylococcal enterotoxin C2 (SEC2) is a classical superantigen (SAg), which can tremendously activate T lymphocytes at very low dosage, thus exerting its powerful antitumor activity. As an intravenous protein drug and a bacterial toxin, SEC2 has some limitations including poor patient compliance and toxic side effects. In this research, we devoted our attention to studying the antitumor activity and toxicity of SEC2 as a potential oral administration protein drug. We proved that His-tagged SEC2 (SEC2-His) could undergo facilitated transcytosis on human colon adenocarcinoma (Caco-2) cells and SEC2-His was detected in the blood of rats after oral administration. Furthermore, oral SEC2-His caused massive cytokine release and immune cell enrichment around tumor tissue, leading to inhibition of tumor growth in vivo. Meanwhile, although SEC2-His was dosed up to 32 mg/kg in mice, no significant toxicity was observed. These data showed that SEC2 can cross the intestinal epithelium in an immunologically integral form, maintaining antitumor activity but with reduced systemic toxicity. Therefore, these results may have implications for developing SEC2 as an oral administration protein drug. PMID:27322320

  16. Addressing Concerns about Changing the Route of Antimicrobial Administration from Intravenous to Oral in Adult Inpatients

    PubMed Central

    Béïque, Lizanne; Zvonar, Rosemary

    2015-01-01

    Background: Many health care institutions are in the process of establishing antimicrobial stewardship programs. Changing the route of administration of antimicrobial agents from intravenous to oral (IV to PO) is a simple, well-recognized intervention that is often part of an antimicrobial stewardship program. However, the attending health care team may have concerns about making this switch. Objectives: To provide insights into common concerns related to IV to PO conversion, with the aim of helping antimicrobial stewardship teams to address them. Data Sources: Published clinical trials and reviews were identified from a literature search of Ovid MEDLINE with the keywords (step down or switch or conversion or transition or sequential) and (antibiotics or antibacterial agents or antimicrobial or anti-infective agents). Data Synthesis: The following issues are addressed in this review: benefits of the oral route, serum concentrations yielded by the oral formulation, source of pharmacokinetic data, clinical outcomes, provision of care in the intensive care unit, fear of therapeutic failure, and administration of antimicrobials via feeding tube. Conclusions: When considering a change to oral therapy, it is important to have a thorough understanding of key aspects of the antimicrobial agent, the patient, and the disease being treated. The antimicrobial stewardship team has an important role in facilitating IV to PO conversion, educating prescribers, and addressing any concerns or reservations that may interfere with timely transition from IV to PO administration. PMID:26327706

  17. 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

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

    PubMed

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

    2014-11-28

    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 50mg/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

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

    PubMed

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

    2007-12-01

    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. PMID:17632188

  20. 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. PMID:24221354

  1. Oral administration of myostatin-specific recombinant Saccharomyces cerevisiae vaccine in rabbit.

    PubMed

    Liu, Zhongtian; Zhou, Gang; Ren, Chonghua; Xu, Kun; Yan, Qiang; Li, Xinyi; Zhang, Tingting; Zhang, Zhiying

    2016-04-29

    Yeast is considered as a simple and cost-effective host for protein expression, and our previous studies have proved that Saccharomyces cerevisiae can deliver recombinant protein and DNA into mouse dendritic cells and can further induce immune responses as novel vaccines. In order to know whether similar immune responses can be induced in rabbit by oral administration of such recombinant S. cerevisiae vaccine, we orally fed the rabbits with heat-inactivated myostatin-recombinant S. cerevisiae for 5 weeks, and then myostatin-specific antibody in serum was detected successfully by western blotting and ELISA assay. The rabbits treated with myostatin-recombinant S. cerevisiae vaccine grew faster and their muscles were much heavier than that of the control group. As a common experimental animal and a meat livestock with great economic value, rabbit was proved to be the second animal species that have been successfully orally immunized by recombinant S. cerevisiae vaccine after mice. PMID:27005809

  2. Neonatal plasma vitamin K1 levels following oral and intramuscular administration of vitamin K1.

    PubMed

    Gupta, J M; Salonikas, C; Naidoo, D

    1994-02-01

    Vitamin K1 levels were measured by high performance liquid chromatography in cord blood (n = 33) and at the age of 97-120 h after administration of 2 mg of vitamin K1 orally (n = 88) or 1 mg of vitamin K1 by im injection (n = 88). Vitamin K1 levels were less than 0.05 micrograms/l in cord blood. The mean (range), SEM, mode and median values (micrograms/l) for the infants given oral vitamin K1 were 17.99 (1-56), 1.25, 8 and 15.5 and those for the infants given im vitamin K1 15.83 (2-57), 1.01, 11 and 14, respectively. The t-test showed no significant difference in the mean values (p = 0.09) in the infants given oral or im vitamin K. PMID:8193487

  3. 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

  4. Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion.

    PubMed

    Mizokami, Akiko; Yasutake, Yu; Higashi, Sen; Kawakubo-Yasukochi, Tomoyo; Chishaki, Sakura; Takahashi, Ichiro; Takeuchi, Hiroshi; Hirata, Masato

    2014-12-01

    Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion and pancreatic β-cell proliferation. We previously showed that the effect of GluOC on insulin secretion is mediated largely by glucagon-like peptide-1 (GLP-1) secreted from the intestine in response to GluOC exposure. We have now examined the effect of oral administration of GluOC on glucose utilization as well as the fate of such administered GluOC in mice. Long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level and improved glucose tolerance in mice without affecting insulin sensitivity. It also increased the fasting serum insulin concentration as well as the β-cell area in the pancreas. A small proportion of orally administered GluOC reached the small intestine and remained there for at least 24h. GluOC also entered the general circulation, and the serum GLP-1 concentration was increased in association with the presence of GluOC in the intestine and systemic circulation. The putative GluOC receptor, GPRC6A was detected in intestinal cells, and was colocalized with GLP-1 in some of these cells. Our results suggest that orally administered GluOC improved glucose handling likely by acting from both the intestinal lumen and the general circulation, with this effect being mediated in part by stimulation of GLP-1 secretion. Oral administration of GluOC warrants further study as a safe and convenient option for the treatment or prevention of metabolic disorders. PMID:25230237

  5. Pharmacokinetics of homoplantaginin in rats following intravenous, peritoneal injection and oral administration.

    PubMed

    Cong, Youquan; Wu, Song; Han, Jingjing; Chen, Jun; Liu, Hang; Sun, Qiwen; Wu, Yu; Fang, Yun

    2016-09-10

    The purpose of the present paper was to study the pharmacokinetic characteristics of homoplantaginin, a major active ingredient of Salvia plebeia R.Br. In this study, the effective partition coefficient, in situ absorption in rat intestinal segments and in vitro biotransformation of homoplantaginin by rat intestinal bacteria were determined. In addition, homoplantaginin was administered to rats by intravenous, peritoneal injection and oral administration. The concentrations of homoplantaginin and hispidulin, a metabolite of homoplantaginin, were determined by a validated highperformance liquid chromatographic (HPLC) assay. After intravenous, peritoneal injection, the concentration of hispidulin could not be determined. In contrast, after oral administration, hispidulin and homoplantaginin were simultaneous quantified, homoplantaginin was rapidly absorbed (Tmax=16.00±8.94min), reaching a mean Cmax between 0.77 and 1.27nmol/mL. The absolute oral bioavailability was calculated to be only 0.75%, and the area under curve (AUC) of hispidulin was about 5.4 times than that of homoplantaginin. The poor oral bioavailability may be attributed to the biotransformation of homoplantaginin by rat intestinal bacteria. PMID:27474945

  6. 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. PMID:21402156

  7. 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. PMID:26199634

  8. 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; 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. PMID:26199634

  9. Activation of immune responses in mice by an oral administration of bunching onion (Allium fistulosum) mucus.

    PubMed

    Ueda, Hiroshi; Takeuchi, Atsuko; Wako, Tadayuki

    2013-01-01

    Bunching onion [Allium fistulosum L. (Liliaceae)] secretes mucus in the cavities of its green leaves. The effects of the mucus, which is consumed as food, were examined. The mucus augmented the production of tumor necrosis factor (TNF)-α and monocyte chemotactic protein (MCP)-1 from RAW 264 cells and of interleukin (IL)-12 from J774.1 cells; however, extracts from green leaves and white sheaths did not. An oral administration of this mucus to mice augmented the immune functions of peritoneal cells by increasing TNF-α and IL-12 production and phagocytosis. It also augmented interferon (IFN)-γ production from spleen cells and natural killer (NK) activity. These results suggest that an oral administration of the A. fistulosum mucus can enhance natural immunity. PMID:24018671

  10. Oral drug self-administration: an overview of laboratory animal studies.

    PubMed

    Meisch, R A

    2001-06-01

    Many abused drugs can be established as orally delivered reinforcers for rhesus monkeys and other animals. Benzodiazepines, barbiturates, opioids, psychomotor stimulants, dissociative anesthetics, and ethanol can come to serve as reinforcers when taken by mouth. The principal problems in establishing drugs as reinforcers by the oral route of administration are (1) aversive taste, (2) delay in onset of central nervous system effects, and (3) consumption of low volumes of drug solution. Strategies have been devised to successfully overcome these problems, and orally delivered drugs can be established as effective reinforcers. Reinforcing actions are demonstrated by consumption of greater volumes of drug solution than volumes of the water vehicle, and supporting evidence for reinforcing effects consists of the maintenance of behavior under intermittent schedules of reinforcement and the generation of orderly dose-response functions. This article presents an overview of studies of behavior reinforced by oral drug reinforcement. Factors that control oral drug intake include dose, schedule of reinforcement, food restriction, and alternative reinforcers. Many drugs, administered by the experimenter, can alter oral drug reinforcement. Relative reinforcing effects can be assessed by choice procedures and by persistence of behavior across increases in schedule size. In general, reinforcing effects increase directly with dose. Rhesus monkeys prefer combinations of reinforcing drugs to the component drugs. The taste of drug solutions may act as a conditioned reinforcer and a discriminative stimulus. Consequences of drug intake include tolerance and physiological dependence. Findings with orally self-administered drugs are similar to many findings with other positive reinforcers, including intravenously self-administered drugs. PMID:11522433

  11. 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. PMID:21381650

  12. 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.

  13. 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

  14. Oral Administration of Recombinant Lactococcus lactis Expressing the Cellulase Gene Increases Digestibility of Fiber in Geese.

    PubMed

    Zhou, Haizhu; Gao, Yunhang; Gao, Guang; Lou, Yujie

    2015-12-01

    Enhancing cellulose digestibility in animals is important for improving the utilization of forage, which can decrease the amount of food used in animal production. The aim of the present study was to achieve recombinant expression of the cellulase gene in Lactococcus lactis and evaluate the effects of oral administration of the recombinant L. lactis on fiber digestibility in geese. Cellulase (Cell) and green fluorescent protein (GFP) genes were cloned into a L. lactis expression vector (pNZ8149) to construct the recombinant expression plasmid (pNZ8149-GFP-Cell). Then, the recombinant expression plasmid was transformed into L. lactis (NZ3900) competent cells by electroporation to obtain recombinant L. lactis (pNZ8149-GFP-Cell/NZ3900) in which protein expression was induced by Nisin. Expression of GFP and Cell by the recombinant L. lactis was confirmed using SDS-PAGE, fluorescence detection, and Congo red assays. A feeding experiment showed that oral administration of pNZ8149-GFP-Cell/NZ3900 significantly increased the digestibility of dietary fiber in geese fed either a maize stalk diet or a rice chaff diet. Therefore, oral administration of recombinant L. lactis cells expressing the cellulase gene increases fiber digestibility in geese, offering a way to increase the utilization of dietary fiber in geese. PMID:26341925

  15. 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.

  16. 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

  17. Pharmacokinetics of (/sup 3/H)levamisole in pigs after oral and intramuscular administration

    SciTech Connect

    Galtier, P.; Escoula, L.; Alvinerie, M.

    1983-04-01

    A single oral (10 mg/kg of body weight) or IM (7.5 mg/kg) dose of (/sup 3/H)levamisole was administered to pigs. Liquid scintillation counting and high performance liquid chromatography were used to determine total radioactivity and drug levels in plasma, duodenal and cecal contents, bile, and urine for 24 and 72 hours after dosing. Pharmacokinetic analysis indicated a 1-compartment open model with higher plasma bioavailability of levamisole after IM injection. Biological half-lives for elimination of the drug were 9.3 and 6.9 hours after oral and IM administration, respectively. Anthelmintic concentrations were higher in intestinal contents after oral gavage than after IM injection. The drug appeared extensively metabolized in all body fluids and particularly in bile, regardless of the route of administration. Biliary excretion of radioactivity and unchanged levamisole represented only slight percentages of the administered dose (approx 0.4% and 4.2%, respectively, in 72 hours). In contrast, about 60% and 20% of the dose were eliminated via urine as tritiated materials and unchanged drug. The choice of the most efficacious route of administration is discussed in regard to localization of helminthic disease.

  18. 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. PMID:20851527

  19. 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

    2014-04-23

    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. PMID:24759572

  20. Combined Oral Administration of Bovine Collagen Peptides with Calcium Citrate Inhibits Bone Loss in Ovariectomized Rats

    PubMed Central

    Liu, JunLi; Wang, YiHu; Song, ShuJun; Wang, XiJie; Qin, YaYa; Si, ShaoYan; Guo, YanChuan

    2015-01-01

    Purpose Collagen peptides (CPs) and calcium citrate are commonly used as bone health supplements for treating osteoporosis. However, it remains unknown whether the combination of oral bovine CPs with calcium citrate is more effective than administration of either agent alone. Methods Forty 12-week-old Sprague-Dawley rats were randomly divided into five groups (n = 8) for once-daily intragastric administration of different treatments for 3 months at 3 months after ovariectomy (OVX) as follows: sham + vehicle; OVX + vehicle; OVX + 750 mg/kg CP; OVX + CP-calcium citrate (75 mg/kg); OVX + calcium citrate (75 mg/kg). After euthanasia, the femurs were removed and analyzed by dual energy X-ray absorptiometry and micro-computed tomography, and serum samples were analyzed for bone metabolic markers. Results OVX rats supplemented with CPs or CP-calcium citrate showed osteoprotective effects, with reductions in the OVX-induced decreases in their femoral bone mineral density. Moreover, CP-calcium citrate prevented trabecular bone loss, improved the microarchitecture of the distal femur, and significantly inhibited bone loss with increased bone volume, connectivity density, and trabecular number compared with OVX control rats. CP or CP-calcium citrate administration significantly increased serum procollagen type I N-terminal propeptide levels and reduced serum bone-specific alkaline phosphatase, osteocalcin, and C-telopeptide of type I collagen levels. Conclusions Our data indicate that combined oral administration of bovine CPs with calcium citrate inhibits bone loss in OVX rats. The present findings suggest that combined oral administration of bovine CPs with calcium citrate is a promising alternative for reducing bone loss in osteopenic postmenopausal women. PMID:26258559

  1. Changes of phylloquinone and menaquinone-4 concentrations in rat liver after oral, intravenous and intraperitoneal administration.

    PubMed

    Sakamoto, N; Kimura, M; Hiraike, H; Itokawa, Y

    1996-01-01

    To study the metabolism of K Vitamins (VK) in the liver, two types of natural VK, phylloquinone (K1) and menaquinone-4 (MK-4), were administered to male Wistar rats orally (P.O.), intravenously (I.V.) and intraperitoneally (I.P.). Blood and a small portion of the liver (and ascites by I.P.) were collected 8 times up to 72 h (P.O.) or 24 h (I.V. and I.P.). A modified assay procedure followed by high performance liquid chromatography (HPLC) was developed to detect VK from small amounts of liver tissue. After oral administration of both K1 and MK-4 (10 mumol/kg-P.O.), their concentrations in the liver increased from 1 h then reached a maximum at 6 h (10 nmol/g v.s. 0.35 nmol/g). After intravenous or intraperitoneal administration of K1 and MK-4 (0.5 mumol/kg-I.V. and I.P.), MK-4 concentrations in the liver reached a maximum faster than those of K1 (1.2 nmol/g -3 h vs. 1.3 nmol/g -0.5 h I.V. and 0.97 nmol/g -6 h vs. 0.47 nmol/g -1 h I.P.). MK-4 also increased in the liver from 6 h to 12 h (0.11 nmol/g -12 h) after oral administration of K1 (P.O.). These results indicate that K1 stays in plasma and liver longer than MK-4 and orally administered K1 might be transformed partially into MK-4 in the liver. PMID:8979160

  2. Effect of oral administration of sulfadiazine and trimethoprim in combination on thyroid function in dogs.

    PubMed Central

    Panciera, D L; Post, K

    1992-01-01

    The effect of oral administration of sulfadiazine and trimethoprim in combination on serum concentrations of thyroxine (T4), triiodothyronine (T3) and free thyroxine (fT4) and the thyroid hormone response to thyrotropin administration was assessed. Six dogs were administered sulfadiazine (12.5 mg/kg) and trimethoprim (2.5 mg/kg) orally for 28 days; six untreated dogs acted as controls. Serum T4, T3 and fT4 were determined weekly during and for four weeks after treatment. Thyrotropin response tests were performed prior to treatment, after four weeks of treatment and three weeks after stopping treatment. There were no significant differences in mean serum T4, T3 or fT4 concentrations between treated and control groups at any time during the study. Mean concentration of serum T4 over time did not differ significantly from baseline concentration in either group. Significant differences in the mean serum T3 and fT4 concentrations occurred at several time points in treatment and control groups, and were apparently unrelated to treatment. Significant differences in the T4 or T3 response to thyrotropin administration within or between groups were not present. Serum T3 and fT4 concentrations fluctuate in normal dogs. Administration of sulfadiazine and trimethoprim in combination does not affect tests of thyroid function in the dog. PMID:1477803

  3. Ganciclovir population pharmacokinetics in neonates following intravenous administration of ganciclovir and oral administration of a liquid valganciclovir formulation.

    PubMed

    Acosta, E P; Brundage, R C; King, J R; Sánchez, P J; Sood, S; Agrawal, V; Homans, J; Jacobs, R F; Lang, D; Romero, J R; Griffin, J; Cloud, G; Whitley, R; Kimberlin, D W

    2007-06-01

    Cytomegalovirus (CMV) is the most common viral congenital infection, producing both sensorineural hearing loss and mental retardation. Our objective was to assess the population pharmacokinetics of a research-grade oral valganciclovir solution in neonates with symptomatic congenital CMV disease. Twenty-four neonates received 6 weeks of antiviral therapy. Ganciclovir and valganciclovir were measured by liquid chromatography/tandem mass spectroscopy. NONMEM version VI beta was used for population analyses. All profiles were consistent with a one-compartment model. Postnatal age, body surface area, and gender did not improve the model fit after body weight was taken into account. The typical value of clearance (l/h), distribution volume (l), and bioavailability of ganciclovir were 0.146 x body weight (WT)(1.68), 1.15 x WT, and 53.6%, respectively. Although these results cannot be extrapolated to extemporaneously compounded valganciclovir preparations, they provide the foundation on which a commercial-grade valganciclovir oral solution may be a viable option for administration to neonates. PMID:17392728

  4. Oral administration of IL-12 suppresses anaphylactic reactions in a murine model of peanut hypersensitivity.

    PubMed

    Lee, S Y; Huang, C K; Zhang, T F; Schofield, B H; Burks, A W; Bannon, G A; Sampson, H A; Li, X M

    2001-11-01

    There is no satisfactory therapeutic intervention for peanut allergy, which accounts for most life-threatening food allergic reactions. Since IL-12 has been found to inhibit allergic airway responses in a mouse model of asthma and to cure Th2 cytokine-mediated murine schistosomiasis, we hypothesized that IL-12 treatment might also inhibit peanut allergic reactions. Consequently, we investigated the effects of oral IL-12 treatment in a murine model of peanut allergy and found that oral administration of liposome encapsulated rIL-12 could both prevent and reverse peanut hypersensitivity and could reduce histamine release, peanut-specific serum IgE and IgG1, and fecal IgA levels. Oral IL-12 treatment also increased IFN-gamma but did not decrease IL-4 or IL-5 levels. We conclude that oral rIL-12 treatment has therapeutic as well as preventive effects on peanut allergy, which are associated with increased IFN-gamma production. PMID:11683581

  5. The pharmacokinetics of orbifloxacin in the horse following oral and intravenous administration.

    PubMed

    Davis, J L; Papich, M G; Weingarten, A

    2006-06-01

    The purpose of this study was to determine the pharmacokinetics and physicochemical characteristics of orbifloxacin in the horse. Six healthy adult horses were administered oral and intravenous orbifloxacin at a dose of 2.5 mg/kg. Plasma samples were collected and analyzed by high-pressure liquid chromatography with ultraviolet detection. Plasma protein binding and lipophilicity were determined in vitro. Following i.v. administration, orbifloxacin had a terminal half-life (t1/2) of 5.08 h and a volume of distribution (V(d(SS))) of 1.58 L/kg. Following oral administration, the average maximum plasma concentration (Cmax) was 1.25 microg/mL with a t1/2 of 3.42 h. Systemic bioavailability was 68.35%. Plasma protein binding was 20.64%. The octanol:water partition coefficient (pH 7.4) was 0.2 +/- 0.11. No adverse reactions were noted during this study. Dosage regimens were determined from the pharmacokinetic-pharmacodynamic parameters established for fluoroquinolone antibiotics. For susceptible bacteria, an oral dose of approximately 5 mg/kg once daily will produce plasma concentrations within the suggested range. This dose is suggested for further studies on the clinical efficacy of orbifloxacin for treatment of susceptible bacterial infections in the horse. PMID:16669863

  6. Pharmacokinetics of phenobarbital in the cat following intravenous and oral administration.

    PubMed Central

    Cochrane, S M; Black, W D; Parent, J M; Allen, D G; Lumsden, J H

    1990-01-01

    Phenobarbital was administered to eight healthy cats as a single intravenous dose of 10 mg/kg. Serum phenobarbital concentrations were determined using an immunoassay technique. The intravenous data were fitted to one-, two- and three-compartment models. After statistical comparison of the three models, a two-compartment model was selected. Following intravenous administration, the drug was rapidly distributed (distribution half-life = 0.046 +/- 0.007 h) with a large apparent volume of distribution (931 +/- 44.8 mL/kg). Subsequent elimination of phenobarbital from the body was slow (elimination half-life = 58.8 +/- 4.21 h). Three weeks later, a single oral dose of phenobarbital (10 mg/kg) was administered to the same group of cats. A one-compartment model with an input component was used to describe the results. After oral administration, the initial rapid absorption phase (absorption half-life = 0.382 +/- 0.099 h) was followed by a plateau in the serum concentration (13.5 +/- 0.148 micrograms/mL) for approximately 10 h. The half-life of the terminal elimination phase (76.1 +/- 6.96 h) was not significantly different from the half-life determined for the intravenous route. Bioavailability of the oral drug was high (F = 1.20 +/- 0.120). Based on the pharmacokinetic parameters determined in this study, phenobarbital appears to be a suitable drug for use as an anticonvulsant in the cat. PMID:2306662

  7. 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. PMID:25622984

  8. Glossitis and tongue trauma subsequent to administration of an oral medication, using an udder infusion cannula, in a horse.

    PubMed

    Fuller, Mark C; Abutarbush, Sameeh M

    2007-08-01

    A 10-year-old gelding was presented with a tongue that had swelled immediately after oral administration of oxfendazole, using an udder infusion cannula. The tongue appeared to have been punctured inadvertently. The horse recovered after treatment with intravenous fluid, antibiotics, and anti-inflammatory drugs. Administering oral medication by this method should be discouraged. PMID:17824329

  9. 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. PMID:26429629

  10. 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

  11. 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. PMID:25530452

  12. 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. PMID:2123064

  13. 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. PMID:26102179

  14. 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. PMID:21349314

  15. 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. PMID:21913939

  16. 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

  17. 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. PMID:22181663

  18. Safety, tolerability, and pharmacokinetics of oral and intravenous administration of GSK1322322, a peptide deformylase inhibitor.

    PubMed

    Naderer, Odin J; Jones, Lori S; Zhu, John; Kurtinecz, Milena; Dumont, Etienne

    2013-11-01

    GSK1322322 is the first in a new class of antibiotics that targets peptide deformylase (PDF), an essential bacterial enzyme required for protein maturation. This randomized, double-blind, placebo-controlled, eight-cohort phase I trial enrolled 62 healthy volunteers to assess safety, tolerability, and pharmacokinetic profiles of GSK1322322. GSK1322322 was administered as a single oral or intravenous (IV) dose, escalating from 500 to 3,000 mg or repeat IV doses escalating from 500 to 1,500 mg twice daily. Upon repeat IV administration, GSK1322322 exhibits linear pharmacokinetics over time upon repeat doses as shown by time-invariant pharmacokinetics. A dose-proportional increase in area under concentration-time curve was observed after single or repeat IV dosing, whereas clearance at steady state remained generally unchanged across doses. There was minimal accumulation of GSK1322322 after repeat IV twice-daily administration. After oral tablet doses of GSK1322322 1,000 and 1,500 mg, absolute bioavailability was 69% and 56%, respectively. GSK1322322 administration at single and repeat IV doses and at supratherapeutic single IV doses of 2,000 and 3,000 mg was associated with mild-to-moderate drug-related adverse events. On the basis of the pharmacokinetics and tolerability demonstrated in this study, GSK1322322 has the potential to become the first-in-class PDF inhibitor for clinical use. PMID:23907665

  19. Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats.

    PubMed

    Jeong, Dong Won; Kim, Young Hoon; Kim, Hui Hyun; Ji, Hye Young; Yoo, Sun Dong; Choi, Won Rack; Lee, Soo Min; Han, Chang-Kyun; Lee, Hye Suk

    2007-03-01

    The pharmacokinetics of oleanolic acid was evaluated in vitro and in vivo. From Caco-2 cell permeation studies, oleanolic acid was a low permeability compound with no directional effects, suggesting a low in vivo absorption mediated by a passive diffusion. Oleanolic acid was metabolically unstable following incubation with rat liver microsomes in the presence of NADPH. After intravenous injection at doses of 0.5, 1 and 2 mg/kg doses, oleanolic acid showed dose-linear pharmacokinetics as evidenced by unaltered CL (28.6-33.0 ml/min/kg), Vss (437-583 ml/kg), dose-normalized AUC (16.0-17.9 microg min/ml based on 1 mg/kg) and t1/2 (41.9-52.7 min). Following oral administration of oleanolic acid at doses of 10, 25 and 50 mg/kg, Tmax, t1/2, dose-normalized Cmax (66-74 ng/ml based on 25 mg/kg) and dose-normalized AUC (5.4-5.9 microg min/ml based on 25 mg/kg) were comparable between 25 and 50 mg/kg dose, but the plasma concentrations at 10 mg/kg dose were not measurable as they were below the limit of quantitation (2 ng/ml). The absolute oral bioavailability was 0.7% for oral doses of 25 and 50 mg/kg. The extent of urinary excretion was minimal for both i.v. and oral doses. The very low oral bioavailability of oleanolic acid could be due to a poor absorption and extensive metabolic clearance. PMID:17163409

  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. PMID:25433717

  1. Pharmacokinetics of Uridine Following Ocular, Oral and Intravenous Administration in Rabbits

    PubMed Central

    Kim, Eunyoung; Kang, Wonku

    2013-01-01

    The pyrimidine nucleoside uridine has recently been reported to have a protective effect on cultured human corneal epithelial cells, in an animal model of dry eye and in patients. In this study, we investigate the pharmacokinetic profile of uridine in rabbits, following topical ocular (8 mg/eye), oral (450 mg/kg) and intravenous (100 mg/kg) administration. Blood and urine samples were serially taken, and uridine was measured by high-performance liquid chromatography-tandem mass spectrometry. No symptoms were noted in the animals after uridine treatment. Uridine was not detected in either plasma or urine after topical ocular administration, indicating no systemic exposure to uridine with this treatment route. Following a single intravenous dose, the plasma concentration of uridine showed a bi-exponential decay, with a rapid decline over 10 min, followed by a slow decay with a terminal half-life of 0.36 ± 0.05 h. Clearance and volume of distribution were 1.8 ± 0.6 L/h/kg and 0.58 ± 0.32 L/kg, respectively. The area under the plasma concentration-time curves (AUC) was 59.7 ± 18.2 μg·hr/ml, and urinary excretion up to 12 hr was ~7.7% of the dose. Plasma uridine reached a peak of 25.8 ± 4.1 μg/ml at 2.3 ± 0.8 hr after oral administration. The AUC was 79.0 ± 13.9 μg·hr/ml, representing ~29.4% of absolute bioavailability. About 1% of the oral dose was excreted in the urine. These results should prove useful in the design of future clinical and nonclinical studies conducted with uridine. PMID:24009876

  2. Pharmacokinetics of vitamin C: insights into the oral and intravenous administration of ascorbate.

    PubMed

    Duconge, Jorge; Miranda-Massari, Jorge R; Gonzalez, Michael J; Jackson, James A; Warnock, William; Riordan, Neil H

    2008-03-01

    There is a strong advocacy movement for large doses of vitamin C. Some authors argue that the biological half-life for vitamin C at high plasma levels is about 30 minutes, but these reports are the subject of some controversy. NIH researchers established the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. The dynamic flow model refutes the current low-dose recommendations for dietary intakes and links Pauling's mega-dose suggestions with other reported effects of massive doses of ascorbate for the treatment of disease. Although, a couple of controlled clinical studies conducted at The Mayo Clinic did not support a significant benefit for terminal cancer patients after 10 grams of once-a-day oral vitamin C, other clinical trials have demonstrated that ascorbate may indeed be effective against tumors when administered intravenously. Recent studies confirmed that plasma vitamin C concentrations vary substantially with the route of administration. Only by intravenous administration, the necessary ascorbate levels to kill cancer cells are reached in both plasma and urine. Because the efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated. One limitation of current studies is that pharmacokinetic data at high intravenous doses of vitamin C are sparse, particularly in cancer patients. This fact needs prompt attention to understand the significance of intravenous vitamin C administration. This review describes the current state-of-the-art in oral and intravenous vitamin C pharmacokinetics. In addition, the governmental recommendations of dose and frequency of vitamin C intake will also be addressed. PMID:18450228

  3. [Development of semisolid dosage form of clonazepam for oral cavity administration].

    PubMed

    Sakata, Osamu; Onishi, Hiraku; Machida, Yoshiharu

    2010-01-01

    A semisolid dosage form of clonazepam (CZP), administered to the oral cavity between the lower gum and bottom lip with small volume of saline, was developed to obtain the stable dosage which can replace the injection dosage form. Semisolid dosage forms were prepared using a mixture of CZP/(polyethylene glycol 1500 (PEG))/(oleic acid (OA)) at the ratios of 1/39/0, 1/37/2 and 2/36/2 (w/w), named CZP1-PEG, CZP1-PEG-OA and CZP2-PEG-OA, respectively, and were evaluated in vitro and in vivo. No crystal of CZP was observed in CZP1-PEG-OA for at least 8 days, while CZP crystal appeared before administration for CZP2-PEG-OA. When a small volume of saline was added to CZP1-PEG-OA just before the oral cavity administration, more than 80% (w/w) was found to exist in the soluble form. Each semisolid dosage form (40 mg) was administered to the oral cavity in rats, and CZP 1 mg suspension in 0.5% (w/v) sodium carboxymethylcellulose aqueous solution was administered into rat stomach as a control. CZP1-PEG-OA gave the plasma concentrations of more than 5 ng/ml and 12 ng/ml at 30 min and 1 h after administration, respectively, which might be near the plasma levels effective for the suppression of epileptic seizures in human, while the plasma concentration was less than 5 ng/ml at 30 min or did not reach 10 ng/ml at 1 h for the other formulations. It is proposed that the semisolid dosage form CZP1-PEG-OA should be a possibly useful preparation for the antiepileptic or sedative medication. PMID:20046075

  4. 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

    2016-06-01

    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. PMID:26964683

  5. Medroxyprogesterone acetate plasma levels after a single oral administration of two drug formulations.

    PubMed

    Pannuti, F; Strocchi, E; Longhi, A; Comparsi, R; Camaggi, C M

    1986-08-01

    A comparison has been made between the absorption of oral medroxyprogesterone acetate (MPA) in an aqueous suspension preparation and in syrup form. Plasma drug profiles were measured after a single administration of the two formulations in 17 advanced cancer patients. On average the standard form (aqueous suspension) gave peak levels which were lower than the syrup mixture. However, the wide intersubject spread in MPA plasma levels observed in both groups did not allow any statistical significance to be assigned to this difference. PMID:2945648

  6. Prevention of Osteoporosis by Oral Administration of Phytate-Removed and Deamidated Soybean β-Conglycinin

    PubMed Central

    Akao, Makoto; Abe, Ryusuke; Sato, Noriko; Hasegawa-Tanigome, Atsuko; Kumagai, Hitoshi; Kumagai, Hitomi

    2015-01-01

    Phytate-removed and deamidated soybean β-conglycinin (PrDS) prepared by ion-exchange resins was supplemented to be 4% in the diet administered to ovariectomized rats to investigate its preventive effect on osteoporosis. The apparent calcium absorption rate decreased following ovariectomy and was not replenished by oral administration of phytate-removed soybean β-conglycinin (PrS) or casein. On the other hand, administration of PrDS restored the calcium absorption rate to the same level as the sham group. Markers of bone resorption, such as serum parathyroid hormone (PTH) and urinary deoxypyridinoline (DPD), increased, and the bone mineral density and breaking stress decreased following ovariectomy. However, PrDS supplementation suppressed the changes caused by the decrease in calcium absorption from the small intestine. Therefore, PrDS supplementation shows promise for the prevention of postmenopausal osteoporosis. PMID:25607735

  7. 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

  8. 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

  9. Effect of oral administration of carprofen on intraocular pressure in normal dogs.

    PubMed

    Meekins, J M; Overton, T L; Rankin, A J; Roush, J K

    2016-08-01

    The aim of this study was to determine the effect of oral administration of carprofen on intraocular pressure in normal dogs. Twelve young adult beagle dogs were randomly assigned to treatment (n = 6) or control (n = 6) groups. After an 11-day acclimation period, the treatment group received approximately 2.2 mg/kg carprofen per os every 12 h for 7 days, and the control group received a placebo gel capsule containing no drug per os every 12 h for 7 days. Intraocular pressure (IOP) was measured by a rebound tonometer at three time points per day (8 am, 2 pm, and 8 pm) during the acclimation (days 1-11) and treatment (days 12-18) phases and for 48 h (days 19-20) after the completion of treatment. There was no statistically significant change in IOP for either eye in the dogs receiving oral carprofen during the treatment phase (days 12-18). After day 4, no significant daily IOP changes were seen in control group dogs. Carprofen administered orally every 12 h for 7 days had no effect on IOP in normal beagle dogs. An acclimation period to frequent IOP measurements of at least 5 days is necessary to establish baseline IOP values and minimize possible anxiety-related effects on IOP measurements. PMID:26923773

  10. An interim safety analysis of hepatocellular carcinoma patients administrating oral vitamin K with or without sorafenib

    PubMed Central

    Jung, Dong-Hwan; Song, Gi-Won; Ryoo, Baek-Yeol; Kim, Nayoung; Tak, Eunyoung; Hong, Hea-Nam

    2015-01-01

    Backgrounds/Aims Vitamin K may plays a role in controlling hepatocellular carcinoma (HCC) cell growth. In this study, we intended to present 5-year experience of 72 patients receiving oral vitamin K with or without sorafenib. Its end-point was to evaluate the safety of combination therapy using sorafenib and vitamin K. Methods An interim analysis was performed as a single-arm cross-sectional study, including 72 HCC patients who underwent liver resection or transplantation and administered oral vitamin K2 alone (n=47) or with sorafenib (n=25). Results In all patients, administration of vitamin K2 analog 45 mg/day did not show any noticeable adverse side-effect during vitamin K therapy of 23.3±10.6 months, except for one patient who experienced skin rash at the third day of vitamin K therapy. In 25 patients receiving sorafenib and vitamin K for 6 months or longer, any noticeable adverse side-effect suspected of vitamin K origin was not identified yet. A small proportion of patients showed unexpectedly favorable anti-tumor effects after use of vitamin K with or without sorafenib. Conclusions Because add-on of oral vitamin K did not increase the adverse side-effects of sorafenib, a combination therapy with these two agents appears to be worthy of further clinical trial with an expectation of synergistic therapeutic effects. PMID:26155269

  11. Pharmacokinetic Alteration of Baclofen by Multiple Oral Administration of Herbal Medicines in Rats

    PubMed Central

    Kim, Tae Hwan; Park, Gi-Young; Shin, Soyoung; Seo, Won Sik; Shin, Jeong Cheol; Choi, Jin Ho; Weon, Kwon-Yeon; Min, Byung Sun; Upadhyay, Mahesh; Zhao, Bing Tian; Woo, Mi Hee; Kwon, So Hee

    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 (Cmax) and longer time to reach Cmax (Tmax) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (Furine). The absorption rate (Ka) 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. PMID:25530781

  12. Usefulness of oral administration of lipopolysaccharide for disease prevention through the induction of priming in macrophages.

    PubMed

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

    2014-08-01

    Many publications show that macrophages are closely involved in etiology of diseases, such as cancer, diabetes, arteriosclerosis, and Alzheimer's disease. Recent studies show that waste products (e.g. dead cells, denatured proteins, oxidized lipids, and advanced glycation end-products) are the real causative agents of lifestyle-associated diseases. From the standpoint of health maintenance, macrophages eliminate foreign objects and waste products from an animal's body and appear to be quite important for maintaining homeostasis. There are two stages of activation of macrophages: one is priming and the other is the triggering stage with cytokine secretion. The priming stage of macrophages is an ostensibly functional stage without characteristic morphological changes and secretion of cytokines, but it functionally promotes clearance of waste products. In this review, we discuss the usefulness of oral administration of lipopolysaccharide (LPS) as a macrophage-priming agent for prevention/treatment of several diseases, including cancer. Moreover, the oral administration of LPS is safe. These observations suggest that LPS may be considered a vitamin-like substance with therapeutic properties. PMID:25075092

  13. Localization of chyle leakage site in postoperative chylothorax by oral administration of I-123 BMIPP.

    PubMed

    Sugiura, Kimihiko; Tanabe, Yoshio; Ogawa, Toshihide; Tokushima, Takeshi

    2005-10-01

    The authors present a 71-year-old woman who had a right chylothorax after right upper lobectomy for lung cancer. As the chylothorax was considered to be due to thoracic duct injury at the time of operation, lymphoscintigraphy was performed by oral administration of I-123 beta-methyl-iodophenyl pentadecanoic acid (BMIPP). After visualization of the stomach and intestine, abnormal accumulation of the radiotracer was found initially around the right pulmonary hilum and then spread laterally in the upper pleural cavity, indicating chyle leakage in the region of the right pulmonary hilum. Scintigraphic finding was well correlated with the subsequent thoracoscopic observation, showing chyle leakage from a lymphatic tributary near its confluence to the thoracic duct at the level of the azygos continuation. The disruption site was ligated by video-assisted-thoracoscopic-surgery procedure with successful termination of the chyle leakage. Lymphoscintigraphy by oral administration of I-123 BMIPP is thought to be a useful method for localization of chyle leakage in patients with chylothorax induced by thoracic surgery. PMID:16363625

  14. Analytical determination and pharmacokinetics of major metabolites of carbasalate calcium in broilers following oral administration.

    PubMed

    Wang, X; Huang, L-L; Chen, D-M; Ihsan, A; Yuan, Z-H

    2011-08-01

    As a newer anti-inflammatory agent, carbasalate calcium is used in various animal species. In this study, the pharmacokinetics of carbasalate calcium was investigated in broilers. Broilers, with body weight of 2.0 ± 0.3 kg, were administrated carbasalate calcium soluble powder at a single dose of 40 mg/kg body weight orally. The plasma concentrations of its metabolites, aspirin (ASA), salicylic acid (SA) and gentisic acid (GA) were determined by LC-MS/MS method and the pharmacokinetic parameters were calculated by noncompartmental analysis. After oral administration of carbasalate calcium, the plasma drug concentration for ASA, SA and GA reached a peak (C(max) ) of 8.88 ± 1.31, 42.6 ± 4.62 and 10.1 ± 2.16 μg/mL at 0.170, 2.00 and 2.00 h, respectively. The terminal half-life (t(1/2λz) ) of ASA, SA and GA was 11.2 ± 8.04, 23.7 ± 17.1 and 28.6 ± 4.90 h, respectively. In conclusion, analytical method for the quantification of ASA, SA and GA in plasma in the broilers was developed and validated. In broilers, carbasalate calcium is quickly metabolized in ASA and ASA is rapidly converted to SA and one of the metabolites of SA is GA. PMID:21091728

  15. 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. PMID:19000263

  16. Pharmacokinetics of sulfamonomethoxine in tongue sole (Cynoglossus semilaevis) after intravenous and oral administration.

    PubMed

    Chang, Zhi-Qiang; Li, Zhao-Xin; Li, Jing-Bao; Wang, Ying-Zi; Li, Jian

    2014-08-01

    The pharmacokinetic profiles of sulfamonomethoxine (SMM) were investigated in flatfish tongue soles in the present study. After a single injection of SMM (40 mg/kg BW) to caudal vein of tongue sole at 20 °C, plasma drug concentration versus time data were best fitted to a three-compartment model, characterized with 0.2, 5.7, and 80.4 h for the half-life (t 1/2) of fast distribution, slow distribution, and elimination, respectively. The apparent volume of distribution was 0.1 L/kg, and the body clearance was 0.03 L/h/kg. After oral administration of SMM (200 mg/kg BW) to tongue soles at 20 °C, plasma drug concentrations were best fitted to a two-compartment model, of which the mean half-life of absorption (t 1/2ka) and elimination (t 1/2β ) were 1.7 and 95.7 h, respectively. The maximal absorption concentration (C max) was estimated as 58 mg/L at 2.5 h, and the mean systemic bioavailability (F) was 39.5 % in tongue soles after oral administration. PMID:24577641

  17. Toxicity and inflammatory response in Swiss albino mice after intraperitoneal and oral administration of polyurethane nanoparticles.

    PubMed

    Silva, Adny H; Locatelli, Claudriana; Filippin-Monteiro, Fabíola B; Martin, Philip; Liptrott, Neill J; Zanetti-Ramos, Betina G; Benetti, Luana C; Nazari, Evelize M; Albuquerque, Cláudia A C; Pasa, André A; Owen, Andrew; Creczynski-Pasa, Tânia B

    2016-03-30

    In this work in vivo experiments were conducted in order to characterize the biocompatibility of polyurethane nanoparticles (PU-NPs) after intraperitoneal (i.p.) and oral administration. Additionally, ex vivo assays were performed to assess human blood compatibility as well as in vitro assays to assess protein binding. Our results indicated that administration of three different concentrations of PU-NPs induced a significant increase in visceral fat accumulation after oral dosing. In addition, fat tissue of mice intraperitoneally treated with the highest concentration of nanoparticles showed diffuse mononuclear inflammatory infiltrate in the fat tissue. Histopathological assessment showed inflammatory infiltrate and hepatocyte vacuolization in the liver, inflammatory infiltration and vascular congestion in the lung and glomerular necrosis in the kidney. Hepatic enzymes related with liver function were significantly increased in both groups of mice treated with PU-NPs. The PU-NPs did not affect the human blood cells number as well as coagulation time but showed a susceptibility to bind in proteins commonly found in the blood stream. In addition, increased amounts of pro inflammatory cytokines in vivo, as well as ex vivo in human cells were observed. Further studies to establish the consequences of long-term exposure to PU-NPs are warranted. PMID:26820842

  18. 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. PMID:23321424

  19. Absorptive interactions of concurrent oral administration of (+)-catechin and puerarin in rats and the underlying mechanisms

    PubMed Central

    Su, Hui-fang; Lin, Qing; Wang, Xin-yi; Fu, Yao; Gong, Tao; Sun, Xun; Zhang, Zhi-rong

    2016-01-01

    Aim: (+)-Catechin and puerarin are polyphenol and flavonoid, respectively, in green tea and foodstuffs. They exhibit potent antioxidant activity and are widely used for treating cardiocerebrovascular diseases. The aim of this work was to investigate the potential interactions between (+)-catechin and puerarin following concurrent oral administration in rats, and their absorption mechanisms in Caco-2 cell monolayers. Methods: Pharmacokinetic studies were conducted in male rats received (+)-catechin (140 mg/kg, po) and/or puerarin (200 mg/kg, po). The cell uptake and transport behavior in Caco-2 cell monolayers and the interactions of the two compounds were analyzed. Results: When (+)-catechin and puerarin were administered concurrently, the AUC0-12 h and Cmax values of puerarin were 2.48-fold and 3.91-fold, respectively, as large as those of puerarin alone; the AUC0-12 h and Cmax values of (+)-catechin were decreased to 57.62% and 77.55%, respectively, compared with those of (+)-catechin alone. In Caco-2 cell monolayers, (+)-catechin (300 and 600 μmol/L) significantly increased the cell uptake and transport of puerarin, whereas puerarin (300 and 600 μmol/L) significantly decreased the cellular uptake and transport of (+)-catechin. Furthermore, both cyclosporine A (P-glycoprotein inhibitor) and MK-571 (MRP-2 inhibitor) significantly increased the cellular uptake and transport of (+)-catechin and puerarin. Conclusion: Concurrent oral administration of (+)-catechin and puerarin significantly increased the absolute oral bioavailability of puerarin, but decreasing that of (+)-catechin. The competitive efflux of (+)-catechin and puerarin by P-glycoprotein and MRP-2 might lead to this interaction during their absorption process in the small intestine. PMID:26972494

  20. Acute supra-therapeutic oral terbutaline administration has no ergogenic effect in non-asthmatic athletes.

    PubMed

    Sanchez, Anthony M J; Borrani, Fabio; Le Fur, Marie Amélie; Le Mieux, Anais; Lecoultre, Virgile; Py, Guillaume; Gernigon, Christophe; Collomp, Katia; Candau, Robin

    2013-02-01

    This study aimed to investigate the effects on a possible improvement in aerobic and anaerobic performance of oral terbutaline (TER) at a supra-therapeutic dose in 7 healthy competitive male athletes. On day 1, ventilatory threshold, maximum oxygen uptake [Formula: see text] and corresponding power output were measured and used to determine the exercise load on days 2 and 3. On days 2 and 3, 8 mg of TER or placebo were orally administered in a double-blind process to athletes who rested for 3 h, and then performed a battery of tests including a force-velocity exercise test, running sprint and a maximal endurance cycling test at Δ50 % (50 % between VT and [Formula: see text]). Lactatemia, anaerobic parameters and endurance performance ([Formula: see text] and time until exhaustion) were raised during the corresponding tests. We found that TER administration did not improve any of the parameters of aerobic performance (p > 0.05). In addition, no change in [Formula: see text] kinetic parameters was found with TER compared to placebo (p > 0.05). Moreover, no enhancement of the force-velocity relationship was observed during sprint exercises after TER intake (p > 0.05) and, on the contrary, maximal strength decreased significantly after TER intake (p < 0.05) but maximal power remained unchanged (p > 0.05). In conclusion, oral acute administration of TER at a supra-therapeutic dose seems to be without any relevant ergogenic effect on anaerobic and aerobic performances in healthy athletes. However, all participants experienced adverse side effects such as tremors. PMID:22767151

  1. Effects of orally vs. parenterally administrated trimebutine on gastrointestinal and colonic motility in dogs.

    PubMed

    Buéno, L; Hondé, C; Pascaud, X; Junien, J L

    1987-01-01

    The influence of oral administration and intravenous infusion of trimebutine maleate (TMB) and N-desmethyl TMB (NDTMB), its main metabolite, was investigated in conscious dogs equipped with chronically implanted strain-gauges. In fasted dogs, TMB (10 to 20 mg/kg per os) delayed the occurrence of the next activity front on both stomach and duodenum by reinforcing the duration of the intestinal phase II. It also induced the occurrence of an additional migrating phase III. These effects were associated with a colonic stimulation generally followed by an inhibition. Comparatively NDTMB at similar dosages disrupted the antral cyclic phases which were replaced by continuous low amplitude contractions during 5-7 h. The MMC pattern persisted with a significant increase in the duration of phase II, and the colonic motility was inhibited during 4.3 to 6.7 h. Infused intravenously at a dose of 3 mg X kg-1 X h-1, TMB immediately inhibited the gastric cyclic contractions in fasted dogs. As for the oral route, the small bowel exhibited an increase in the duration of phase II frequently associated with the occurrence of an additional phase III. Furthermore an inhibition of the colonic motility was observed only at the end of the infusion and lasted at least 4 h. At similar dosage NDTMB had less pronounced inhibitory effects on gastric activity fronts and in contrast with TMB, the inhibitory effect on the colonic motility was observed as soon as the infusion of NDTMB started. These data demonstrate that orally administered TMB stimulates intestinal motility as previously described for i.v. route but in contrast to parenteral administration also stimulates antral and colonic motility.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3609630

  2. 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. PMID:25488714

  3. 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

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

    PubMed Central

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

    2014-01-01

    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. PMID:24717726

  5. “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

  6. Methotrexate efficacy and tolerability after switching from oral to subcutaneous route of administration in juvenile idiopathic arthritis

    PubMed Central

    Turowska-Heydel, Dorota; Sobczyk, Małgorzata; Banach-Górnicka, Marta; Rusnak, Katarzyna; Piszczek, Anna; Mężyk, Elżbieta

    2016-01-01

    Objectives 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. Material and methods 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. Results 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. Conclusions 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. PMID:27407272

  7. 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. PMID:27007995

  8. Tissue distribution of berberine and its metabolites after oral administration in rats.

    PubMed

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

    2013-01-01

    Berberine (BBR) has been confirmed to have multiple bioactivities in clinic, such as cholesterol-lowering, anti-diabetes, cardiovascular protection and anti- inflammation. However, BBR's plasma level is very low; it cannot explain its pharmacological effects in patients. We consider that the in vivo distribution of BBR as well as of its bioactive metabolites might provide part of the explanation for this question. In this study, liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC/MS(n)-IT-TOF) as well as liquid chromatography that coupled with tandem mass spectrometry (LC-MS/MS) was used for the study of tissue distribution and pharmacokinetics of BBR in rats after oral administration (200 mg/kg). The results indicated that BBR was quickly distributed in the liver, kidneys, muscle, lungs, brain, heart, pancreas and fat in a descending order of its amount. The pharmacokinetic profile indicated that BBR's level in most of studied tissues was higher (or much higher) than that in plasma 4 h after administration. BBR remained relatively stable in the tissues like liver, heart, brain, muscle, pancreas etc. Organ distribution of BBR's metabolites was also investigated paralleled with that of BBR. Thalifendine (M1), berberrubine (M2) and jatrorrhizine (M4), which the metabolites with moderate bioactivity, were easily detected in organs like the liver and kidney. For instance, M1, M2 and M4 were the major metabolites in the liver, among which the percentage of M2 was up to 65.1%; the level of AUC (0-t) (area under the concentration-time curve) for BBR or the metabolites in the liver was 10-fold or 30-fold higher than that in plasma, respectively. In summary, the organ concentration of BBR (as well as its bioactive metabolites) was higher than its concentration in the blood after oral administration. It might explain BBR's pharmacological effects on human diseases in clinic. PMID:24205048

  9. 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 (t1/2(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 (Cmax) was higher in renal damaged than in healthy ducks and was achieved at maximum time (tmax) of 2.47 and 2.05 h, respectively. The drug was eliminated (t1/2(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 Cmax/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

  10. 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. PMID:26851651

  11. Pharmacokinetics and tissue disposition of meloxicam in beef calves after repeated oral administration.

    PubMed

    Coetzee, J F; Mosher, R A; Griffith, G R; Gehring, R; Anderson, D E; KuKanich, B; Miesner, M

    2015-12-01

    The objective of this study was to investigate the pharmacokinetics and tissue disposition of meloxicam after repeated oral administration in calves. Thirteen male British × Continental beef calves aged 4 to 6 months and weighing 297-392 kg received 0.5 mg/kg meloxicam per os once daily for 4 days. Plasma meloxicam concentrations were determined in 8 calves over 6 days after first treatment. Calves were randomly assigned to be euthanized at 5, 10, 15 (n = 3/timepoint), and 19 days (n = 4) after final administration. Meloxicam concentrations were determined in plasma (LOQ= 0.025 μg/mL) and muscle, liver, kidney, and fat samples (LOQ = 2 ng/g) after extraction using validated LC-MS-MS methods. The mean (± SD) Cmax , Cmin , and Caverage plasma meloxicam concentrations were 4.52 ± 0.87 μg/mL, 2.95 ± 0.77 μg/mL, and 3.84 ± 0.81 μg/mL, respectively. Mean (± SD) tissue meloxicam concentrations were highest in liver (226.67 ± 118.16 ng/g) and kidney samples (52.73 ± 39.01 ng/g) at 5 days after final treatment. Meloxicam concentrations were below the LOQ in all tissues at 15 days after treatment. These findings suggest that tissue from meloxicam-treated calves will have low residue concentrations by 21 days after repeated oral administration. PMID:25708937

  12. 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

  13. Toxicokinetics and biotransformation of 3-(4-methylbenzylidene)camphor in rats after oral administration.

    PubMed

    Völkel, Wolfgang; Colnot, Thomas; Schauer, Ute M D; Broschard, Thomas H; Dekant, Wolfgang

    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 (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

  14. 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

  15. 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. PMID:27463556

  16. 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. PMID:26416348

  17. 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). PMID:25580397

  18. A Single Oral Administration of Theaflavins Increases Energy Expenditure and the Expression of Metabolic Genes

    PubMed Central

    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. PMID:26375960

  19. 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. PMID:26689227

  20. 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. PMID:23643702

  1. 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. PMID:26375960

  2. Absorption and induction of micronucleated peripheral reticulocytes in mice after oral administration of fragrant hydroxyfuranones generated in the Maillard reaction.

    PubMed

    Hiramoto, K; Kato, T; Takahashi, Y; Yugi, K; Kikugawa, K

    1998-07-01

    Fragrant hydroxyfuranone and dihydroxypyranone derivatives generated in the Maillard reaction of sugars and amino acids are detected in various processed foods and have been shown active to break DNA single-strand in the in vitro studies. In the present study, absorption of 2,5-dimethyl-4-hydroxy-3(2 H)-furanone (DMHF) and 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2 H)-furanone (HEMF), both found in soy sauce, into plasma after a single intraperitoneal or oral administration at doses of 0.5-1.0 gkg-1 to mice was examined. Both compounds appeared in plasma 15 min after intraperitoneal administration and disappeared 2 h after the administration. They appeared in plasma 5 min after oral administration, reached maximum after 15-45 min, and gradually disappeared after 2 h, indicating that they are absorbed by the digestive tract. Both DMHF and HEMF induced micronucleated reticulocytes (MNRETs) in mouse peripheral blood in a dose-dependent manner after oral administration. The results indicate that DMHF and HEMF can cause genetic damage after oral administration. PMID:9711264

  3. A novel, ecologically relevant, highly preferred, and non-invasive means of oral substance administration for rodents.

    PubMed

    Sobolewski, Marissa; Allen, Joshua L; Morris-Schaffer, Keith; Klocke, Carolyn; Conrad, Katherine; Cory-Slechta, Deborah A

    2016-01-01

    Prenatal stress and nutrition are well-known to alter a broad range of physiological systems, notably metabolic, endocrine and neurobehavioral function. Commonly used methods for oral administration of xenobiotics can, by acting as a stressor or altering normal nutrition intake, alter these physiological systems as well. Taken together, oral administration methods may unintentionally introduce confounding physiological effects that can mask or enhance toxicity of xenobiotics, particularly if they share biological targets. Consequently, it should be preferable to develop alternative methods without these potential confounds. The aim of this study was to determine the suitability of mealworms as an alternative treat-based method to deliver xenobiotics via the orogastric route. Accurate oral administration is contingent on motivation and preference; mice reliably preferred mealworms over wafer cookie treats. Further, ingestion of wafer cookies significantly increased mouse blood glucose levels, whereas unaltered mealworms produced no such change. Mealworms functioned effectively to orally administer glucose, as glucose-spiked mealworms produced a rise in blood glucose equivalent to the ingestion of the wafer cookie. Mealworms did not interfere with the physiological function of orally administered d-amphetamine, as both mealworm and oral gavage administered d-amphetamine showed similar alterations in locomotor behavior (mice did not fully consume d-amphetamine-dosed cookies and thus could not be compared). Collectively, the findings indicate that mealworms are a preferred and readily consumed treat, which importantly mimics environmental-relevant nutritional intake, and mealworms per se do not alter glucose metabolic pathways. Additionally, mealworms accurately delivered xenobiotics into blood circulation and did not interfere with the physiological function of administered xenobiotics. Thus mealworm-based oral administration may be a preferable and accurate route of

  4. 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

  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. PMID:26667113

  6. 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

  7. Long-term bone retention of C-14 following oral administration of C-14-xylose

    SciTech Connect

    Knight, L.C.; Siegel, J.; Fisher, R.S.; Malmud, L.S.

    1984-01-01

    Oral administration of C-14-labeled xylose followed by measurement of C-14 activity in the breath has become a clinically useful test for diagnosis of small bowel bacterial overgrowth. However, accurate biodistribution and radiation dosimetry information was not available in the literature, so the true radiation exposure of the human subjects was not known. The purpose of this study was to determine the actual biodistribution data for orally administered C-14-xylose. A series of rats were given the material orally and sacrificed at various ages, up to 1 month after dosing. Tissues and fluids were solubilized and counted by liquid scintillation counting. Exhaled C-14-carbon dioxide was measured by trapping the gas in ethanolamine. Approximately two-thirds of the administered dose was absorbed from the GI tract and eventually appeared in the breath and urine. Much of the dose was not found in the major organs within the first day; it was presumed to be in the fatty tissue or muscle, which were not sampled. After most of the C-14 had disappeared from the GI and urinary tract, however, the bone retained a significant amount of radioactivity: approximately 5-6% of the administered dose was found in bone at one week, and remained at one month. These findings suggest that radiation exposure to the skeleton is long-term, much greater in magnitude than previously estimated, and suggests that the value of the test should be reevaluated in the light of the long-term radiation burden to the skeleton, especially in young patients.

  8. 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. PMID:26892718

  9. Residual veterinary antibiotics in pig excreta after oral administration of sulfonamides.

    PubMed

    Qiu, Jinrong; Zhao, Tao; Liu, Qingyun; He, Jinhua; He, Dechun; Wu, Genyi; Li, Yongtao; Jiang, Chengai; Xu, Zhencheng

    2016-04-01

    Sulfonamides (SAs) are applied widely as feed additives in the farming of livestock and poultry. It can lead to the excretion of large amounts of SAs in manure and result in persistent environmental pollution. We evaluated the fate of four SAs, sulfamerazine (SM1), sulfachloropyridazine (SCP), sulfadimoxine (SDM') and sulfaquinoxaline (SQ), from oral administration to excretion in urine and feces in pigs. The four SAs were added to homemade feed to make them reach the required concentration gradient, which were 0, 50 and 100 mg/kg (low, normal and high concentrations, respectively). In different treatments, excretions of the four SAs were 35.68-86.88 %. With regard to total excretion, the order was SQ > SCP > SM1 > SDM' for all treatments. The concentration of SAs in the feed had significant effects on the amount of the four SAs excreted every day. The concentration of SAs in feces and in the urine for different treatments was 15.03-26.55 and 14.54-69.22 %, respectively. In each treatment, excretions of SCP, SDM' and SQ in feces were lower than that in urine. The four SAs remained longer in urine than in feces. Excretions in urine and feces were lower if SAs were administered orally rather than by injection. PMID:26164467

  10. 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. PMID:9125637

  11. Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats.

    PubMed

    Groenen-van Dooren, M M; Ronden, J E; Soute, B A; Vermeer, C

    1995-09-01

    Rats were made vitamin K-deficient by feeding them a diet devoid of vitamin K and by rigorously preventing coprophagy. After one week, circulating prothrombin concentrations were between 5 and 10% of initial values, and various amounts of phylloquinone, menaquinone-4, and menaquinone-9 were given in a single dose either subcutaneously, orally, or colorectally. The relative 'vitamin K activities' of these compounds were assessed by comparing their ability to support prothrombin synthesis after subcutaneous injection. Intestinal and colonic absorption were deduced from the difference between subcutaneous and either oral or colorectal administration of the vitamers. It is concluded that the colonic absorption of all three forms of vitamin K is extremely poor, suggesting that physiological menaquinones in the colon do not contribute substantially to vitamin K status in rats. Furthermore, the stimulation of prothrombin synthesis by menaquinone-9 lasted much longer than that by the two other K-vitamers, resulting in a substantially higher 'vitamin K activity' of menaquinone-9. PMID:7575640

  12. Pharmacokinetic profiles of meloxicam in turtles (Trachemys scripta scripta) after single oral, intracoelomic and intramuscular administrations.

    PubMed

    Di Salvo, A; Giorgi, M; Catanzaro, A; Deli, G; della Rocca, G

    2016-02-01

    Meloxicam is an anti-inflammatory and analgesic drug used to treat many pathological conditions in turtles. With the aim to fill the lack of data about its pharmacokinetic in this species, eighteen turtles (Trachemys scripta scripta) were divided in three groups and treated with a single dose of meloxicam (0.2 mg/kg) by intramuscular, intracoelomic and oral route, respectively. At scheduled time points, blood samples were collected and meloxicam concentrations were determined by HPLC. Pharmacokinetic parameters were calculated from the obtained concentration-time curves. After intramuscular treatment, a plasma peak of meloxicam equal to 1590.03 ± 1845.32 ng/mL (mean ± SD) and a Tmax of 1.17 ± 0.45 h were reached, indicating a quick absorption of the drug. The intracoelomic administration brought to the largest AUC (12621.04 ± 6203.79 h*ng/mL) and to a Cmax and a Tmax equal to 1154.52 ± 662.78 ng/mL and 2.82 ± 1.39 h, respectively. Following oral treatment, the plasma concentrations of meloxicam were very low indicating a scarce absorption. Further studies are warranted to determine the effective plasma concentration of meloxicam in turtles and, consequently, the dosage regimen. PMID:26789011

  13. 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). PMID:24254959

  14. Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats.

    PubMed

    Peng, Xiao-Qing; Li, Jie; Gardner, Eliot L; Ashby, Charles R; Thomas, Ajit; Wozniak, Krystyna; Slusher, Barbara S; Xi, Zheng-Xiong

    2010-02-10

    We have recently reported that the endogenous mGlu2/3 agonist N-acetylaspartylglutamate (NAAG) and the N-acetylated-alpha-linked-acidic dipeptidase (NAALADase, a NAAG degradation enzyme) inhibitor 2-PMPA significantly inhibit cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior by attenuating cocaine-enhanced extracellular dopamine and glutamate in the nucleus accumbens. However, the poor oral bioavailability of NAAG and 2-PMPA limits their practical use in humans. In the present study, we investigated the effects of the orally active NAALADase inhibitor GPI-5693 and its enantiomers on cocaine-taking and cocaine-seeking behaviours. We found that oral administration of GPI-5693 (15, 30, 60 mg/kg, p.o.) did not significantly alter intravenous cocaine self-administration under fixed-ratio (FR2) reinforcement, but significantly inhibited cocaine-induced reinstatement of the extinguished drug-seeking behavior. This inhibition was blocked by pretreatment with LY341495, a selective mGlu2/3 receptor antagonist. Pretreatment with the same doses (15, 30, 60 mg/kg, p.o.) of GPI-16476 or GPI-16477, two enantiomers of GPI-5693, also inhibited cocaine-induced reinstatement similar to GPI-5693. In contrast, GPI-5693 altered neither oral sucrose self-administration nor sucrose-triggered reinstatement of sucrose-seeking behavior. These data suggest that orally effective NAAG peptidase inhibitors deserve further study as potential agents for the treatment of cocaine addiction. PMID:19887067

  15. Hematological and Immunological Changes Due to Short-term Oral Administration of Acephate.

    PubMed

    Sankhala, Laxmi N; Tripathi, Syamantak M; Bhavsar, S K; Thaker, Aswin M; Sharma, Pramod

    2012-05-01

    To evaluate immunotoxicological effects of environmental chemical, subacute toxicity of repeated (28 day) oral administration of acephate (Ace) in BALB/c mice was assessed. Thirty two (sixteen male and sixteen female) mice were divided into four different groups with each group containing eight (four male and four female) mice. Mice of Group C1 were administered normal saline only and served as control. Group T1 was given 1/40(th) of apparent LD(50) (ALD(50)) (8.78 mg/kg), and group T2 was put on 1/30(th) of ALD(50) [11.7 mg/kg], while group T3 received 1/20(th) of ALD(50) [17.55 mg/kg] of Ace suspended in normal saline. The blood samples were collected from mice after 28 days of oral administration and analyzed for hematological, biochemical, and immunological parameters. The study showed that hematological parameters (monocytes and granulocytes) remained unaffected except total leukocyte count and lymphocyte which were decreased highly significantly [P≤0.01] in mice of group T3 on the 28(th) day of experiment. Serum total protein (TP) and serum globulin decreased significantly in mice of treatment groups dose dependently; however, no significant change was seen in serum albumin. Progressive increase in live body weight of mice decreased significantly in extremely toxic group only while spleen:body weight ratio decreased significantly in dose-dependent manner. Furthermore, Ace produced suppressed humoral immune response and the delayed-type hypersensitivity response to Sheep red blood cells (SRBCs) was altered nonsignificantly. The results of this study describe the suppression of immune responses following exposure to Ace at low concentrations in experimental mice. PMID:22778515

  16. 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

  17. 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. PMID:24489866

  18. Oral administration of polyamines ameliorates liver ischemia/reperfusion injury and promotes liver regeneration in rats.

    PubMed

    Okumura, Shinya; Teratani, Takumi; Fujimoto, Yasuhiro; Zhao, Xiangdong; Tsuruyama, Tatsuaki; Masano, Yuki; Kasahara, Naoya; Iida, Taku; Yagi, Shintaro; Uemura, Tadahiro; Kaido, Toshimi; Uemoto, Shinji

    2016-09-01

    Polyamines are essential for cell growth and differentiation. They play important roles in protection from liver damage and promotion of liver regeneration. However, little is known about the effect of oral exogenous polyamine administration on liver damage and regeneration. This study investigated the impact of polyamines (spermidine and spermine) on ischemia/reperfusion injury (IRI) and liver regeneration. We used a rat model in which a 70% hepatectomy after 40 minutes of ischemia was performed to mimic the clinical condition of living donor partial liver transplantation (LT). Male Lewis rats were separated into 2 groups: a polyamine group given polyamines before and after operation as treatment and a vehicle group given distilled water as placebo. The levels of serum aspartate aminotransferase and alanine aminotransferase at 6, 24, and 48 hours after reperfusion were significantly lower in the polyamine group compared with those in the vehicle group. Polyamine treatment reduced the expression of several proinflammatory cytokines and chemokines at 6 hours after reperfusion. Histological analysis showed significantly less necrosis and apoptosis in the polyamine group at 6 hours after reperfusion. Sinusoidal endothelial cells were also well preserved in the polyamine group. In addition, the regeneration of the remnant liver at 24, 48, and 168 hours after reperfusion was significantly accelerated, and the Ki-67 labeling index and the expressions of proliferating cell nuclear antigen and phosphorylated retinoblastoma protein at 24 hours after reperfusion were significantly higher in the polyamine group compared with those in the vehicle group. In conclusion, perioperative oral polyamine administration attenuates liver IRI and promotes liver regeneration. It might be a new therapeutic option to improve the outcomes of partial LT. Liver Transplantation 22 1231-1244 2016 AASLD. PMID:27102080

  19. 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. PMID:27556265

  20. In vivo distribution of lead in male and female rats after intraperitoneal and oral administration.

    PubMed

    Nwokocha, C R; Ufearo, C S; Owu, D U; Idemudo, N C; Ojukwu, L C

    2012-03-01

    The resultant effects of lead exposure are seen in almost all the systems of the body and results in toxicity to many organs. Since toxicity depends on its degree of uptake, distribution and metabolism, the authors investigated the differential uptake, accumulation and distribution of lead in organs of males and female Wistar rats following various routes of administration. Group 1 served as control male and control female; group 2 males and females received 5 mg/kg body weight of lead intraperitoneally for 8 days while group 3 males and female rats were administered drinking water containing 100 ppm of lead acetate for 18 days. Tissues were collected for analysis of the lead content using atomic absorption spectroscopy. The relative retention of lead by the tissues was greater in rats exposed to lead by the i.p. route varying in the order of accumulation / uptake in males as lungs > spleen > stomach > kidney > blood > heart and in females as spleen > stomach > heart > kidney > blood > lungs (i.p. route) and (oral route) as for males kidney > lungs > stomach > blood > heart > spleen, and females as kidney > lungs > stomach > blood > heart > spleen. Male Wistar rats showed more accumulation with oral exposure in lungs, spleen and blood with values for kidney and stomach being significantly (p < 0.05) higher when compared with females. Female Wistar rats showed more accumulation with i.p. exposure for spleen and stomach tissues while values for the heart was significantly (p < 0.05) higher than the males. Our findings suggest that lead retention and the organ distribution varied depending upon the sex and route of lead administration. PMID:21622679

  1. 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

  2. A comparison of bolus injection of landiolol versus oral administration of propranolol before cardiac computed tomography.

    PubMed

    Nakamura, Yoshitaka; Yamaji, Kyohei; Saho, Tatsunori; Matsuzaki, Zyousin; Yuda, Itsuo; Soga, Yoshimitsu; Shirai, Shinichi; Ando, Kenji; Nobuyoshi, Masakiyo

    2014-01-01

    Heart rate (HR) reduction is essential to achieve good image quality for cardiac computed tomography (CCT). We evaluated the efficacy of a bolus injection of landiolol, an ultra-short acting β-blocker, without the administration of oral β-blocker to reduce HR prior to CCT. We enrolled 678 consecutive patients who underwent CCT from December 2011 to March 2012 and divided them into three groups, which were a propranolol group (n = 277), a low-dose landiolol group (n = 188), and a high-dose landiolol group (n = 213). Patients in the propranolol group received oral propranolol (10-20 mg) prior to CCT. Patients in the low-dose and high-dose landiolol groups were administered a bolus injection of landiolol (0.125 mg/kg), while the high-dose group received an additional 3.75 mg of landiolol if the baseline HR was ≥75/min. Although the average HR was significantly lower in the propranolol group (61.6 ± 8.0/min) than in the low-dose landiolol group (64.1 ± 7.4/min, P < 0.001), there was no significant difference in the image quality (P = 0.91). Among patients with baseline HR ≥75/min, the average HR tended to be lower in the high-dose landiolol group (67.2 ± 6.9/min) compared with the low-dose landiolol group (69.0 ± 6.9/min, P = 0.10), and there was a corresponding difference in image quality between these two groups (P = 0.02). In conclusion, Although the decrease of HR was significantly larger in the propranolol group than in the landiolol groups, the image quality was similar. Among the patients who received landiolol, a higher dose was associated with a lower HR and better image quality. Further investigation to assess higher-dose bolus injection of landiolol or bolus injection following oral administration of a β-blocker would be needed. PMID:24634807

  3. Evaluation of the safety of a combination of oral administration of phenylbutazone and firocoxib in horses.

    PubMed

    Kivett, L; Taintor, J; Wright, J

    2014-08-01

    Simultaneous administration of a nonselective COX inhibitor and a COX-2 specific NSAID has not been previously reported in horses. The goal of this study was to determine the safety of a 10-day dosage regimen of phenylbutazone and firocoxib, both at their standard dosages, in horses. Six horses were administered 2.2 mg/kg of phenylbutazone and 0.1 mg/kg of firocoxib by mouth, daily for 10 days. Horses were assessed daily for changes in behavior, appetite, fecal consistency, signs of abdominal pain, and oral mucous membrane ulceration. Horses were assessed prior to and on the last day of treatment for changes in serum creatinine, albumin, total protein, and urine-specific gravity. Horses underwent endoscopic examination of the esophagus, stomach, and pylorus prior to and 24 hours after the last treatment. A significant change in serum creatinine and total protein was observed on day 10 of treatment. No other significant findings were noted during the experiment. Results indicated that co-administration of phenylbutazone and firocoxib may cause renal disease. PMID:24354928

  4. Oral administration of levan polysaccharide reduces the alloxan-induced oxidative stress in rats.

    PubMed

    Dahech, Imen; Belghith, Karima Srih; Hamden, Khaled; Feki, Abdelfattah; Belghith, Hafedh; Mejdoub, Hafedh

    2011-12-01

    This study aimed to evaluate the effect of a polysaccharide named levan, which was produced by new isolated bacteria, on oxidative stress and hyperglycemia in alloxan-induced diabetic rats. Levan polysaccharide was given in drinking water for 60 days at a daily dose equivalent to 2%. The oral administration of levan in diabetic rats caused a decrease in glucose level in plasma and an increase of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities in both pancreas and liver. Furthermore, a protective action against hepatic and pancreatic toxicity in diabetic rats was clearly observed. Furthermore, a significant decrease in hepatic and pancreatic indices toxicity was observed, i.e., alkalines phosphatases (ALP), aspartate and lactate transaminases (AST and ALT), lactate deshydrogenases (LDH) activities and the thiobarbituric acid-reactive substances (TBARs). These beneficial effects of levan were confirmed by histological findings in hepatic and pancreatic tissues of diabetic rats. This study demonstrates for the first time that levan is efficient in inhibiting hyperglycemia and oxidative stress induced by diabetes and suggests that administration of levan may be helpful in the prevention of diabetic complications associated with oxidative stress. PMID:21925206

  5. Apoptotic and proliferative activity of mouse gastric mucosa following oral administration of fumonisin B1

    PubMed Central

    Alizadeh, Ali Mohammad; Mohammadghasemi, Fahimeh; Zendehdel, Kazem; Kamyabi-moghaddam, Zahra; Tavassoli, Abbas; Amini-najafi, Fatemeh; Khosravi, Alireza

    2015-01-01

    Objective(s): Fumonisins are a group of toxic and carcinogenic mycotoxins, which contaminate the grains and their products. The aim of this study was to examine the apoptotic and proliferative activity of mouse gastric mucosa following administration of fumonisin B1 (FB1). Materials and Methods: Twenty-nine female mice divided into treatment (n=15) and control (n=14) groups. The treatment group received FB1 (150 mg/kg diet) for 16 weeks. The gastric atrophy was allocated using grading criteria modeled on the updated Sydney System. Immunohistochemistry studies were performed for evaluation of apoptosis and proliferative activity in gastric mucosa. Results: Mild to moderate gastric atrophy were observed in microscopic findings of the gastric mucosa in treated animals (P<0.05). Number of parietal cells significantly decreased in the treatment group in comparison with the control (P<0.05). Treatment with FB1 for 16 weeks significantly reduced both gastric mucosa height and mitotic index in the gastric glands (P<0.05). TUNEL- and Bax-labeled positive cell numbers significantly increased in the FB1-treated group compared to the control (P<0.05). In addition, proliferative activity of gastric glands in the treated group was significantly lower than the control (P<0.05). Conclusion: Oral administration of FB1 caused atrophy in gastric mucosa both via increasing of apoptosis and suppressing the mitotic activity of these cells. PMID:25810870

  6. Experimental peritonitis induced by oral administration of indomethacin in Mongolian gerbils

    PubMed Central

    Lee, Jin-Uk

    2006-01-01

    The possibility of inducing peritoneal inflammation in three murine species (gerbils, rats and mice) via the oral administration of indomethacin was investigated with the overall aim of developing an experimental animal model for human peritonitis. Gerbils given high doses of indomethacin at a rate of 30 mg and 40 mg/kg body weight showed swelling of the abdomen, depression and dyspnea within 4 days after the treatment. The severity of the clinical symptoms increased with time. The animals were confirmed as having developed peritonitis based on the pathological features including inflammation of the peritoneum, and fibrinous adhesion of the abdominal organs in the abdominal cavity. The severity of peritonitis increased with increasing dose of indomethacin, and was not related to the gender of the animal. On the other hand, peritoneal inflammation did not develop in the rats and mice even at high doses. Therefore, the administration of 30 mg/kg body weight of indomethacin is an effective and simple method of inducing peritonitis in 5-week-old Mongolian gerbils. The animal peritonitis model used in this study can be used as an effective tool for examining potential therapeutic compounds for preventing peritoneal damage during peritonitis, and provide insight into the pathophysiology of peritonitis. PMID:16645338

  7. 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. PMID:27216768

  8. Detection of marijuana use by oral fluid and urine analysis following single-dose administration of smoked and oral marijuana.

    PubMed

    Niedbala, R S; Kardos, K W; Fritch, D F; Kardos, S; Fries, T; Waga, J; Robb, J; Cone, E J

    2001-01-01

    We compared oral fluid testing to urine testing in subjects who were administered single doses of marijuana by smoked and oral routes. Oral fluid specimens were collected with the Intercept DOA Oral Specimen Collection Device, screened for THC with the Cannabinoids Intercept MICRO-PLATE Enzyme Immunoassay (EIA) utilizing a 1.0-ng/mL cutoff concentration, and confirmed for THC by gas chromatography-tandem mass spectrometry (GC-MS-MS) with a 0.5-ng/mL cutoff concentration. Urine specimens were screened for 11-nor-carboxy-delta9-tetrahydrocannabinol (THCCOOH) by immunoassay utilizing a 50-ng/mL cutoff concentration and confirmed for THCCOOH by GC-MS with a 15-ng/mL cutoff concentration. Oral fluid specimens tested positive following smoked marijuana (N = 10) consecutively for average periods (+/-SEM; range) of 15 (+/-2; 1-24) and 13 h (+/-3; 1-24) by EIA and GC-MS-MS, respectively. The average THC detection times of the last oral fluid positive specimen following smoked marijuana by EIA and GC-MS-MS were 31 (+/-9; 1-72) and 34 h (+/-11; 1-72), respectively. In comparison to oral fluid, urine specimens generally tested negative for THCCOOH immediately after marijuana use. The average times to detection of the first urine specimen positive for THCCOOH by EIA and GC-MS were 6 (+/-2; 1-16) and 4 h (+/-1; 2-8), respectively. Urine specimens tested positive consecutively for average periods of 26 (+/-9; 2-72) and 33 h (+/-10; 4-72) for EIA and GC-MS, respectively. The average THCCOOH detection times of the last specimen by EIA and GC-MS were 42 (+/-10; 2-72) and 58 h (+/-6; 16-72), respectively. Considering the noninvasive nature of oral fluid collection and improved detection of recent marijuana use compared to urine testing, it was concluded that oral fluid testing for THC offers specific advantages over other means of marijuana testing when used in safety-sensitive testing programs. PMID:11499881

  9. 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...

  10. Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy

    PubMed Central

    van Putten, Maaike; Young, Courtney; van den Berg, Sjoerd; Pronk, Amanda; Hulsker, Margriet; Karnaoukh, Tatyana G; Vermue, Rick; van Dijk, Ko Willems; de Kimpe, Sjef; Aartsma-Rus, Annemieke

    2014-01-01

    Antisense oligonucleotides (AONs) used to reframe dystrophin mRNA transcripts for Duchenne muscular dystrophy (DMD) patients are tested in clinical trials. Here, AONs are administered subcutaneously and intravenously, while the less invasive oral route would be preferred. Oral delivery of encapsulated AONs supplemented with a permeation enhancer, sodium caprate, has been successfully used to target tumor necrosis factor (TNF)-α expression in liver. To test the feasibility of orally delivered AONs for DMD, we applied 2′-O-methyl phosphorothioate AONs (with or without sodium caprate supplementation) directly to the intestine of mdx mice and compared pharmacokinetics and -dynamics with intravenous, intraperitoneal, and subcutaneous delivery. Intestinally infused AONs were taken up, but resulted in lower plasma levels compared to other delivery routes, although bioavailability could be largely improved by supplementation of sodium caprate. After intestinal infusion, AON levels in all tissues were lower than for other administration routes, as were the ratios of target versus nontarget organ levels, except for diaphragm and heart where comparable levels and ratios were observed. For each administration route, low levels of exon skipping in triceps was observed 3 hours post-AON administration. These data suggest that oral administration of naked 2′-O-methyl phosphorothioate AONs may be feasible, but only when high AON concentrations are used in combination with sodium caprate. PMID:25405468

  11. 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

    ... 10 Energy 1 2011-01-01 2011-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities greater than 1.22 gigabecquerels (33 millicuries). 35.394 Section 35.394 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required...

  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

    ... 10 Energy 1 2013-01-01 2013-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities less than or equal to 1.22 gigabecquerels (33 millicuries). 35.392 Section 35.392 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written...

  13. 10 CFR 35.392 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities less than or equal to 1.22 gigabecquerels (33 millicuries). 35.392 Section 35.392 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written...

  14. 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

    ... 10 Energy 1 2011-01-01 2011-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities less than or equal to 1.22 gigabecquerels (33 millicuries). 35.392 Section 35.392 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written...

  15. 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

    ... 10 Energy 1 2014-01-01 2014-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities greater than 1.22 gigabecquerels (33 millicuries). 35.394 Section 35.394 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required...

  16. 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

    ... 10 Energy 1 2014-01-01 2014-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities less than or equal to 1.22 gigabecquerels (33 millicuries). 35.392 Section 35.392 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written...

  17. 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

    ... 10 Energy 1 2012-01-01 2012-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities less than or equal to 1.22 gigabecquerels (33 millicuries). 35.392 Section 35.392 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written...

  18. 10 CFR 35.394 - Training for the oral administration of sodium iodide I-131 requiring a written directive in...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities greater than 1.22 gigabecquerels (33 millicuries). 35.394 Section 35.394 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required...

  19. 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

    ... 10 Energy 1 2012-01-01 2012-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities greater than 1.22 gigabecquerels (33 millicuries). 35.394 Section 35.394 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required...

  20. 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

    ... 10 Energy 1 2013-01-01 2013-01-01 false Training for the oral administration of sodium iodide I-131 requiring a written directive in quantities greater than 1.22 gigabecquerels (33 millicuries). 35.394 Section 35.394 Energy NUCLEAR REGULATORY COMMISSION MEDICAL USE OF BYPRODUCT MATERIAL Unsealed Byproduct Material-Written Directive Required...

  1. Effect of castration timing and oral meloxicam administration on growth performance, inflammation, behavior and carcass quality of beef calves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  2. 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. PMID:25131428

  3. 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

    2015-01-01

    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. PMID:26561795

  4. 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. PMID:22514127

  5. 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

  6. Formation of Epichlorohydrin, a Known Rodent Carcinogen, Following Oral Administration of 1,3-Dichloro-2-propanol in Rats

    PubMed Central

    2015-01-01

    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. PMID:25254956

  7. 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.

  8. 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

  9. 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

  10. 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%. PMID:11308331

  11. [Pharmacokinetics after oral and intravenous administration of d,l-monolysine acetylsalicylate and an oral dose of acetylsalicylic acid in healthy volunteers].

    PubMed

    Raschka, C; Koch, H J

    2001-01-01

    We studied the ASA pharmacokinetics of single doses of 500 mg and 1000 mg of D,L-lysine-monoacetylsalicylate (Lys-ASA) administered both orally (Delgesic) and 500 mg parenterally (Aspisol) as well as 500 mg acetylsalicylate (ASA, Aspirin) in 13 healthy volunteers. Blood samples were taken before and at defined times up to 48 h after application of Lys-ASA and ASA. Analysis for ASA and its metabolite salicylic acid were performed by HPLC. All concentration versus time data were presented descriptively. As far as ASA was concerned, differences were assessed by means of ANOVA according to Friedman including post hoc Wilcoxon tests for each time point. Pharmacokinetic parameters were calculated based on a one-compartment model. The concentration vs. time curves after oral intake of 500 mg of ASA and Lys-ASA differed significantly (p < 0.001). Peak serum ASA concentrations (Cmax) were 6.8 mg/l for oral Lys-ASA and 2.7 mg/l for ASA per os. The corresponding tmax-values were 14.2 and 38.0 min. Absolute bioavailabilities for 500 mg doses were 75.4 and 63.4 pour cent, respectively. After intake of 100 mg and 1000 mg oral doses of Lys-ASA Cmax was 2.7 mg/l and 15.9 mg/l, tmax being 14.2 min for the 1000 mg dose. The shortest half-life was found after i.v. injection with 7.5 min. Metabolism was fast with maximum rise of salicylic acid concentration after injection of Lys-ASS. We conclude that concerning time dimension oral administration of Lys-ASA is almost equivalent to i.v. Lys-ASA and may be an alternative for i.v. administration in cases of acute heart attacks. PMID:11878089

  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. Polyphenol extract from evening primrose pomace alleviates experimental colitis after intracolonic and oral administration in mice.

    PubMed

    Sałaga, M; Lewandowska, U; Sosnowska, D; Zakrzewski, P K; Cygankiewicz, A I; Piechota-Polańczyk, A; Sobczak, M; Mosinska, P; Chen, Chunqiu; Krajewska, W M; Fichna, J

    2014-11-01

    Oenothera paradoxa (EP) preparations are commonly used in folk medicine to treat skin diseases, neuralgia, and gastrointestinal (GI) disorders. Several reports suggested that EP preparations exhibit potent anti-inflammatory and antioxidant activities both in vitro and in vivo. Here, we aimed to characterize the action of EP pomace polyphenol extract in mouse model of colitis. We analyzed the composition of EP pomace polyphenol extract using reversed phase HPLC system and ultra-performance liquid chromatography (UPLC) system coupled with a quadrupole-time of flight (Q-TOF) MS instrument. Then, we used a well-established animal model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis to determine the anti-inflammatory action of EP pomace polyphenol extract. We also investigated the effect of the EP pomace polyphenol extract on pro-inflammatory (IL-1β and TNF-α) cytokine mRNA levels and hydrogen peroxide concentration in the inflamed colon. Administration of EP pomace polyphenol extract significantly improved macroscopic and microscopic damage scores, as well as myeloperoxidase (MPO) activity in TNBS-treated mice. The anti-inflammatory effect of the extract was observed after intracolonic and oral administration and was dose-dependent. Significant reduction of tissue hydrogen peroxide level after treatment with EP pomace polyphenol extract suggests that its therapeutic effect is a result of free radical scavenging. This novel finding indicates that the application of the EP pomace polyphenol extract in patients with inflammatory bowel diseases (IBDs) may become an attractive supplementary treatment for conventional anti-inflammatory therapy. PMID:25079872

  14. 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. PMID:24919144

  15. Application properties of oral gels as media for administration of minitablets and pellets to paediatric patients.

    PubMed

    Kluk, Anna; Sznitowska, Malgorzata

    2014-01-01

    Modern solid multiparticulate drug forms (minitablets, pellets, granules) can provide the possibility of precise dosing or modified drug release or taste masking for medicines used in children. However, these solid particles require an adequate medium to ease swallowing. The aim of the research was to design a universal semisolid dispersing medium for administration of minitablets and pellets. High viscosity sodium carmellose and carbomer were considered as gelling agents. The hydrogels were prepared with sucrose, glycerol, and potassium sorbate or parabens. Preliminary studies were undertaken to estimate the application properties of the gels under conditions where a medicine is administered to a child. Besides standard tests (viscosity, sedimentation) the following measurements were conducted: gel ductility, mass of the gel removed from a spoon under shaking, ability of the gels to disperse solid particles, and disintegration of minitablets in the gels. The oral hydrogels prepared either with 1.0% and 1.5% carmellose or 0.25% and 0.5% (w/w) carbomer were suitable for dispersing and delivery of minitablets or pellets. Not only viscosity but also ductility was an essential criterion in selecting the best vehicle. The in vivo perceptibility test for pellets and minitablets did not confirm that gels are more advantageous than syrups. PMID:24216119

  16. 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. PMID:9748710

  17. Fialuridine accumulates in DNA of dogs, monkeys, and rats following long-term oral administration.

    PubMed Central

    Richardson, F C; Engelhardt, J A; Bowsher, R R

    1994-01-01

    Accumulation of the antiviral nucleoside analogue fialuridine (FIAU; 1-(2'-deoxy-2'-fluoro-beta-D-arab-inofuranosyl-5-iodouracil) in genomic DNA was examined with a modified version of a recently developed RIA for FIAU. DNA was obtained from tissues of dogs administered FIAU at 0, 1, 2, or 3 mg/kg of body weight per day for 90 days, monkeys administered FIAU at 0 or 25 mg/kg per day for 30 days, and rats administered FIAU at 0, 255, or 510 mg/kg per day for 70 days. FIAU incorporation was observed in all species. In the rat, FIAU was incorporated into DNA of all tissues examined, with highest concentrations in the liver followed by jejunum, spleen, and heart. FIAU was also incorporated into sperm DNA. Incorporation rates were as high as 11,000 pmol of FIAU per mumol of thymidine or 1 FIAU molecule per 90 thymidine molecules. In dogs and rats, the extent of incorporation was dose-dependent. Across species, FIAU concentrations in DNA were not singly dependent on the total dose administered but also may have been dependent on the duration of exposure. These studies show that FIAU accumulates to high concentrations in genomic DNA of liver as well as other tissues during chronic oral administration and suggest that net accumulation of FIAU in DNA may be a critical step in FIAU-induced toxicity. PMID:7991573

  18. Evaluating the effect of oral administration of Echinacea hydroethanolic extract on the immune system in dog.

    PubMed

    Torkan, S; Khamesipour, F; Katsande, S

    2015-07-01

    This study was designed to evaluate the effects of oral administration of Echinacea hydroethanolic extract on the dog's immune system. The study was performed on 14 dogs that were referred to the veterinary clinic. These dogs were randomly allocated to two equal treatment groups. The first group received 1 ml of 5% Echinacea hydroethanolic extract two times a day for 2 months, and the second group received a placebo (water). To do haematology and immunology tests, the dogs were bled on days 0, 30 and 60. Blood tests, including packed cell volume (PCV), haemoglobin (Hb), red blood cell count (RBC), white blood cell count (WBC), counting neutrophils (Nut), lymphocytes (Lym), monocytes (Mon), eosinophils (Eos), basophils (Baso) and B cell, were performed. Furthermore, safety factor IgM and per cent of phagocytosis and phagocyte were measured from the blood sample. The results showed that in the group which received Echinacea PCV, Hb, RBC count, WBC count, Lym, Nut, the per cent of phagocytosis and IgM significantly increased (P < 0.05). Moreover, positive effects of Echinacea plant on the immune system were observed. There was a significant change in HTC, RBC, Hb over time in the group that received Echinacea and the per cent of phagocytosis and IgM (P < 0.05). The study establishes that these extracts might have appreciable immunostimulatory activity. However, further studies are required to confirm these findings. PMID:25832590

  19. Excretion of Morroniside in Rat Urine After Single Oral and Intravenous Administration.

    PubMed

    Xiong, Shan; Li, Jinglai; Zhang, Zhenqing

    2016-07-01

    This study was designed to develop a sensitive, simple and rapid method for the quantitation of morroniside in rat urine using high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS) and to investigate the excretion of morroniside in rat urine. The mobile phase consisted of water-acetonitrile (gradient elution) at a flow rate of 0.4 mL/min. Detection was performed using positive-ion electrospray ionization in multiple reaction monitoring (MRM) modes. And the detection of morroniside in rat urine by the LC-MS-MS was accurate and precise from 1.0 to 2,500 ng/mL (a correlation coefficient of 0.9953). The recoveries and matrix effects were all in line with the biological sample measurement requirements. The intraday accuracy was 88.68-105.78% with precision of 6.50-11.19% and the interday accuracy was 95.77-102.43% with precision of 7.08-10.40%. Excretion data of morroniside in rat urine indicated that 21.43‰ (i.g.) and 100.35% (i.v.) of the dose administered was excreted as unconverted form, respectively. And the maximal excretion rate was 27.57 and 482.42 μg/h after oral and intravenous administration, respectively. These results indicated that the developed method has satisfactory sensitivity, accuracy and precision for the quantification of morroniside in rat urine. PMID:26896349

  20. 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

  1. 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

  2. Oral administration of acarbose ameliorates imiquimod-induced psoriasis-like dermatitis in a mouse model.

    PubMed

    Chen, Hsin-Hua; Chao, Ya-Hsuan; Chen, Der-Yuan; Yang, Deng-Ho; Chung, Ting-Wen; Li, Yi-Rong; Lin, Chi Chen

    2016-04-01

    Psoriasis is a chronic autoimmune disease of undefined etiology that involves dysregulated interplay between immune cells and keratinocytes. Acarbose was found to decrease inflammatory parameters in diabetic patients in addition to its anti-diabetic effects. Here, we report that imiquimod (IMQ)-induced epidermal hyperplasia and psoriasis like-inflammation were significantly inhibited by acarbose treatment. Real-time PCR showed that mRNA levels of the cytokines TNF-α, IL-6, IL-1β IL-17A, and IL-22 in skin were also decreased significantly by acarbose. In addition, we found that acarbose reduced infiltration of CD3(+) T cells and GR-1(+) neutrophils in lesional skin and also reduced the percentage of IL-17-producing CD4(+) T cells (Th17) and IL-17- and IL-22-producing γδ T cells in the spleen. In contrast, acarbose increased the frequency of IL-10-producing CD4(+) regulator Tr1 T cells in the spleen and small intestine. These results indicate that oral administration of acarbose can attenuate the severity of imiquimod-induced psoriasis with local and systemic anti-inflammatory and immune modulation effects, thus suggesting that acarbose is an effective therapeutic strategy for psoriasis regulation. PMID:26874324

  3. The prevalence of trimetazidine use in athletes in Poland: excretion study after oral drug administration.

    PubMed

    Jarek, Anna; Wójtowicz, Marzena; Kwiatkowska, Dorota; Kita, Monika; Turek-Lepa, Ewa; Chajewska, Katarzyna; Lewandowska-Pachecka, Sylwia; Pokrywka, Andrzej

    2014-01-01

    Stimulants, together with anabolic androgenic steroids, are regarded as one of the most popular doping substances in sport. Owing to a great variety of these substances and new designer drugs being introduced to the market, each year the World Anti-Doping Agency (WADA) updates the list of substances and methods prohibited in sport. On 1 January 2014, a new doping agent - trimetazidine (TMZ) - was added to the WADA Prohibited List. TMZ, a substance prohibited in competition, is classified in the S6b Specified Stimulant Group. TMZ is used as a well-known cardiologic drug with confirmed biochemical and clinical activity. According to knowledge of the pharmacology and mechanism of TMZ action, TMZ can be used by athletes to improve physical efficiency, especially in the case of endurance sports. This study presents the phenomena of TMZ use by Polish athletes involved in anti-doping control in the WADA-accredited laboratory in Warsaw (Poland) between 2008 and 2013. Samples were taken from the athletes of such disciplines as cycling, athletics, and triathlon. Moreover, the elimination study of TMZ has been conducted to establish the change of TMZ concentration in urine sample after oral administration of a single or double (during the long-term therapy) dose. TMZ was monitored in urine samples by gas chromatography-mass spectrometry-nitrogen phosphorus detection (GC-MS-NPD). PMID:25421604

  4. Oral administration of Cimicifuga racemosa extract attenuates immobilization stress-induced reactions.

    PubMed

    Nadaoka, Isao; Watanabe, Kazuki; Yasue, Masaaki; Sami, Manabu; Kitagawa, Yasushi; Mimaki, Yoshihiro

    2012-01-01

    Dried rhizomes of Cimicifuga racemosa (CR), known as black cohosh, have been widely used as a herbal dietary supplement in the treatment of menopausal symptoms. Here we used experimental mouse stress models to investigate the role of anti-stress food factors, and found that a CR extract had stress-relieving effects. A single oral administration of CR extract (1,000 mg/kg) significantly attenuated plasma corticosterone and aspartate aminotransferase (AST) levels that had increased as a result of enforced immobilization. Bioassay-guided fractionation of the CR extract resulted in the isolation of 10 triterpenes, among which actein, 23-epi-26-deoxyactein, and cimiracemoside F (100 mg/kg, per os) were shown to contribute to the anti-stress effects. Furthermore, the CR extract significantly prevented the development of water immersion stress-induced gastric mucosal ulcers in rats. We propose that the CR extract might be suitable for the prevention and treatment of stress-related disorders. PMID:22428232

  5. 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

  6. Oral Administration of Fermented Soymilk Products Protects the Skin of Hairless Mice against Ultraviolet Damage.

    PubMed

    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

  7. 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. PMID:25112318

  8. 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 were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration. PMID:23859819

  9. Influence of Circulation System on Estimation of Absorption and Elimination Constant after per oral Drug Administration: A Reanalysis.

    PubMed

    Rausova, Z; Chrenova, J; Dedik, L

    2013-03-01

    This study aimed to identify the cause of atypical shape of measured concentration-time profile in the peak area by one compartment open model with a lag time (Bateman function with a lag) after single dose oral administration of drug published in "Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Application" by Gabrielsson and Weiner (1997) and two concentration profiles after frequent sampling oral glucose tolerance test. Following the oral administration of 100 μg of substance A to human volunteer, frequent sampling was carried out and concentration-time profiles were obtained. Our hemodynamic circulatory structural model capable of parameters estimation of circulation and gastrointestinal subsystem to explain the plateau within the interval 40-100 min (substance A) and 15-30 min (glucose) of the measured concentration-time profile was developed. The mean residence time, the rate constants of absorption and elimination parameters of our model were calculated. Comparing to the Bateman function, our results demonstrate better approximation of the substance A and glucose concentration-time profile and estimation of absorption rate constant by our structural model. Obtained model results indicate that the atypical shape of measured concentration-time profile of single dose oral administration of drug was probably caused by the gastrointestinal and circulation system with deep compartment. This applies to the substances with high coefficient of absorption. PMID:24019565

  10. Co-administration of CD40 agonistic antibody and antigen fails to overcome the induction of oral tolerance.

    PubMed

    Chung, Yeonseok; Kim, Dong-Hyeon; Lee, Seung-Ho; Kang, Chang-Yuil

    2004-01-01

    T-cell stimulation in the absence of a second, costimulatory signal can lead to anergy or deletion. There is growing evidence that peripheral tolerance to an exogenous antigen might be caused by the lack of costimulatory molecules on antigen-presenting cells (APCs). In the present study, we examined whether tolerance against orally administered antigen could be reversed by maturation of APCs via CD40 signalling. Monoclonal antibody (mAb) to CD40 efficiently induced costimulatory molecules on APCs. Treatment with anti-CD40 mAb potentiated the division of ovalbumin-specific T cells in response to oral ovalbumin in secondary lymphoid organs. However, such treatment did not prolong the presentation of oral ovalbumin on APCs. Surprisingly, treatment of anti-CD40 mAb at the time of oral administration of ovalbumin did not reverse the induction of tolerance to ovalbumin in either the high- or low-dose regimens. Furthermore, the induction of oral tolerance in our model is not the result of negative signalling by cytotoxic T-lymphocyte antigen-4. These results indicate that tolerance for oral antigen could be established regardless of APC maturation by a CD40-specific mAb, suggesting that there could be a unique mechanism to regulate immunity versus tolerance to encountered antigen in the gut-associated lymphoid tissue. PMID:14678195

  11. Pharmacokinetics of Cocaine and Metabolites in Human Oral Fluid and Correlation with Plasma Concentrations following Controlled Administration

    PubMed Central

    Scheidweiler, Karl B.; Kolbrich Spargo, Erin A.; Kelly, Tamsin L.; Cone, Edward J.; Barnes, Allan J.; Huestis, Marilyn A.

    2011-01-01

    Oral fluid is an attractive alternative matrix for drug testing, with a non-invasive and directly observed collection, but there are few controlled cocaine administration studies to guide interpretation. Materials and Methods While residing on a closed research unit for up to 10 weeks under constant medical supervision, 19 participants were administered 75 mg/70 kg subcutaneous cocaine and 14 received 150mg/70 kg. The disposition of cocaine, benzoylecgonine (BE) and ecgonine methyl ester (EME) into oral fluid was determined by gas chromatography-mass spectrometry for 0.08–48h after administration. Results In oral fluid collected by citric acid candy stimulated expectoration, cocaine first appeared in oral fluid 0.08–0.32h after dosing and was rapidly eliminated with half-lives of 1.1–3.8h. BE and EME were first detected 0.08–1.0h after dosing, with longer half-lives of 3.4–13.8 (BE) and 2.4–15.5h (EME) (p<0.05). Oral fluid and plasma concentrations were significantly correlated for cocaine, BE and EME (p<0.0001). There were no significant differences (p>0.05) in first and last detection times with the 8 μg/L cutoff proposed by the Substance Abuse and Mental Health Services Administration or the 10 μg/L cutoff from the European initiative, Driving Under the Influence of Drugs, Alcohol and Medicines. Metabolite:cocaine ratios increased after cocaine administration, potentially helpful for interpreting time of last use. Comparison of oral fluid collection via citric acid candy stimulated expectoration, citric acid treated Salivette® and neutral cotton Salivette® devices did not reveal significant differences between devices for areas under the curve for cocaine, BE or EME (p>0.05). Discussion and Conclusion These results provide additional evidence for interpreting cocaine and metabolite concentrations in oral fluid and oral fluid’s usefulness as an alternative matrix for drug testing. PMID:20814350

  12. Oral administration of lactulose: a novel therapy for acute carbon monoxide poisoning via increasing intestinal hydrogen production.

    PubMed

    Fan, Dan-Feng; Hu, Hui-Jun; Sun, Xue-Jun; Meng, Xiang-En; Zhang, Yu; Pan, Shu-Yi

    2016-01-01

    It has been known that the pathophysiology of carbon monoxide (CO) poisoning is related to hypoxia, the increased production of reactive oxygen species (ROS) and oxidative stress. Studies have shown that the novel, safe and effective free radical scavenger, hydrogen, has neuroprotective effects in both acute CO poisoning and delayed neuropsychological sequelae in CO poisoning. Orally administered lactulose, which may be used by some intestinal bacteria as a food source to produce endogenous hydrogen, can ameliorate oxidative stress. Based on the available findings, we hypothesize that oral administration of lactulose may be a novel therapy for acute CO poisoning via increasing intestinal hydrogen production. PMID:27000012

  13. CARCINOGENIC POTENTIAL OF ROTENONE: SUBCHRONIC ORAL AND PERITONEAL ADMINISTRATION TO RATS AND CHRONIC DIETARY ADMINISTRATION TO SYRIAN GOLDEN HAMSTERS

    EPA Science Inventory

    Three long-term studies were performed to evaluate the carcinogenic potential of the pesticide rotenone in hamsters and rats. Rotenone was administered orally to Wistar rats and by intraperitoneal injection to Sprague-Dawley rats, which were maintained and observed for 14 and 18 ...

  14. Extensive metabolism and route-dependent pharmacokinetics of bisphenol A (BPA) in neonatal mice following oral or subcutaneous administration.

    PubMed

    Draganov, Dragomir I; Markham, Dan A; Beyer, Dieter; Waechter, John M; Dimond, Stephen S; Budinsky, Robert A; Shiotsuka, Ronald N; Snyder, Stephanie A; Ehman, Kimberly D; Hentges, Steven G

    2015-07-01

    Orally administered bisphenol A (BPA) undergoes efficient first-pass metabolism to produce the inactive conjugates BPA-glucuronide (BPA-G) and BPA-sulfate (BPA-S). This study was conducted to evaluate the pharmacokinetics of BPA, BPA-G and BPA-S in neonatal mice following the administration of a single oral or subcutaneous (SC) dose. This study consisted of 3 phases: (1) mass-balance phase in which effective dose delivery procedures for oral or SC administration of (3)H-BPA to postnatal day three (PND3) mice were developed; (2) pharmacokinetic phase during which systemic exposure to total (3)H-BPA-derived radioactivity in female PND3 mice was established; and (3) metabolite profiling phase in which 50 female PND3 pups received either a single oral or SC dose of (3)H-BPA. Blood was collected from 5 pups/route/time-point at various times post-dosing, the blood plasma samples were pooled by group, and time-point and samples were profiled by HPLC with fraction collection. Fractions were analyzed for total radioactivity and data used to reconstruct radiochromatograms and to integrate individual peaks. The identity of the BPA, BPA-G, and BPA-S peaks was confirmed using authentic standards and LC-MS/MS analysis. The result of this study revealed that female PND3 mice have the capacity to metabolize BPA to BPA-G, BPA-S and other metabolites after both routes of administration. Systemic exposure to free BPA is route-dependent as the plasma concentrations were lower following oral administration compared to SC injection. PMID:25929835

  15. Effect of oral administration of kefir on serum proinflammatory cytokines on 5-FU induced oral mucositis in patients with colorectal cancer.

    PubMed

    Topuz, E; Derin, D; Can, G; Kürklü, E; Cinar, S; Aykan, F; Cevikbaş, A; Dişçi, R; Durna, Z; Sakar, B; Saglam, S; Tanyeri, H; Deniz, G; Gürer, U; Taş, F; Guney, N; Aydiner, A

    2008-12-01

    In order to investigate the effect of kefir consumption on mucositis induced by 5-FU based chemotherapy (CT), we monitored the systemic immune response by measurement of the serum proinflammatory cytokine levels and we evaluated the anti-microbial effect of kefir with an agar diffusion method. Forty patients with colorectal cancer were included in this randomized prospective study. On the first 5 days of each CT cycle, the study group received oral lavage with kefir and then swallowed 250 ml of kefir while control group received oral lavage with 0.09% NaCl twice a day. Before and after every cycle of CT, the oral mucosa was assessed. Serum proinflammatory cytokine levels were evaluated before the initiation and after the third and the sixth cycle. Kefir was administered in 99 out of 205 courses. Mucositis developed in 27.3% of the courses given with kefir administration and in 21.7% of the courses given with 0.9% NaCl oral rinses. The difference between the two groups was not statistically significant (p > 0.05). When we compared the serum proinflammatory cytokine levels of the two groups at the baseline and following the third and the sixth cycles, we again found no statistically significant difference (p > 0.05). Kefir consumption at the mentioned doses made no statistically significant effect on serum proinflammatory cytokine levels and on the incidence of mucositis development in cancer patients. Under in vitro conditions, kefir inhibits only Staphylococcus epidermidis. PMID:18762864

  16. Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration.

    PubMed

    Bollard, M; Caldwell, J; Taylor, G W; Strolin-Benedetti, M; Semeraro, C

    2000-10-01

    1. Z-7760 (S(-)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. 3H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 microCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total 3H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma 3H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma 3H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given 3H-Z-7760 p.o. (0.4 mg and 40 microCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with 3H-Z-7760 (0.4 mg and 400 microCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% 3H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100 mg/kg, 40 microCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces

  17. Morphine and codeine in oral fluid after controlled poppy seed administration.

    PubMed

    Concheiro, Marta; Newmeyer, Matthew N; da Costa, Jose Luiz; Flegel, Ron; Gorelick, David A; Huestis, Marilyn A

    2015-07-01

    Opiates are an important drug class in drug testing programmes. 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 two addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45 g raw poppy seed doses, each containing 15.7 mg morphine and 3.1 mg codeine, 8 h 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 (1 µg/L morphine and codeine limits of quantification). Specimens (n = 459) were collected before and up to 32 h after the first dose. All specimens screened positive 0.5 h after dosing and remained positive for 0.5-13 h at Draeger 20 µg/L morphine cut-off. Maximum OF morphine and codeine concentrations (Cmax ) were 177 and 32.6 µg/L, with times to Cmax (Tmax ) of 0.5-1 h and 0.5-2.5 h post-dose, respectively. Windows of detection after the second dose extended at least 24 h for morphine and to 18 h for codeine. After both doses, the last morphine positive OF result was 1 h with 40 µg/L 2004 proposed US Substance Abuse and Mental Health Services Administration cut-off, and 0.5 h with 95 µg/L cut-off, recently recommended by the Driving under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1 h after ingestion of 15.7 mg of morphine in raw poppy seeds, depending on the cut-off employed. PMID:25345619

  18. Benefits of oral and topical administration of ROQUETTE Chlorella sp. on skin inflammation and wound healing in mice.

    PubMed

    Hidalgo-Lucas, Sophie; Bisson, Jean-Francois; Duffaud, Anais; Nejdi, Amine; Guerin-Deremaux, Laetitia; Baert, Blandine; Saniez-Degrave, Marie-Helene; Rozan, Pascale

    2014-01-01

    The human body is constantly exposed to the risk of traumatic lesions. Chlorella is a green microalgae enriched with nutrients, vitamins, minerals and chlorophyll. In some communities, Chlorella is a traditional medicinal plant used for the management of inflammation-related diseases. ROQUETTE Chlorella sp. (RCs) was investigated by oral administration (125, 250 and 500 mg/kg) and cutaneous application (2.5, 5.0 and 10.0%) to evaluate its impact in two dermatological disorder models in mice: skin inflammation and wound healing. For skin inflammation, it was administered during 14 days starting one week before the induction of chronic skin inflammation by repeated cutaneous application of 12-Otetradecanoylphorbol 13-acetate (TPA). For wound healing the microalgae was administered by topical application after scarification of the skin until complete wound healing. Results indicated that oral and topical administrations of the two higher doses of RCs had significant effects on macroscopic score of skin inflammation with an efficient effect on microscopic score with cutaneous application. The microalgae had also efficient effect on healing process and duration of wound healing for both administration routes and particularly at the two highest doses of RCs. These findings suggest that administration of RCs by both oral and topical routes appeared to have beneficial effects on skin lesions. PMID:24965517

  19. Augmentation of natural killer cell activity in mice by oral administration of transforming growth factor-beta.

    PubMed Central

    Ishizaka, S; Kimoto, M; Kanda, S; Saito, S

    1998-01-01

    The latent form of transforming growth factor-beta (TGF-beta) in human milk and platelets was converted to the active form when conscious, pylorus-ligated mice were given human milk and platelets by intragastric intubation. Oral administration of TGF-beta exerted enhancing effects on the natural killer (NK)-cell activities in spleen and liver. Augmentation of NK-cell activities in spleen was observed for 7 days after oral administration of TGF-beta. TGF-beta at concentrations of 5 and 20 ng produced the greatest augmentation of NK-cell activities in spleen. However, NK-cell activities in spleen were unaffected when TGF-beta was given intravenously. Interleukin (IL)-12 production in spleen was enhanced by oral administration of TGF-beta, but not by intravenous administration of TGF-beta. These findings suggest that large amounts of TGF-beta in human milk are involved in early antiviral protection through the augmentation of NK-cell activities. PMID:9824511

  20. Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector.

    PubMed

    Huang, Wei; McMurphy, Travis; Liu, Xianglan; Wang, Chuansong; Cao, Lei

    2016-06-01

    Recombinant adeno-associated virus (rAAV) vectors are attractive vehicles for gene therapy. Gene delivery to the adipose tissue using naturally occurring AAV serotypes is less successful compared to liver and muscle. Here, we demonstrate that oral administration of an engineered serotype Rec2 led to preferential transduction of brown fat with absence of transduction in the gastrointestinal track. Among the six natural and engineered serotypes being compared, Rec2 was the most efficient serotype achieving high level transduction at a dose 1~2 orders lower than reported doses for systemic administration. Overexpressing vascular endothelial growth factor (VEGF) in brown fat via oral administration of Rec2-VEGF vector increased the brown fat mass and enhanced thermogenesis. In contrast, knockdown VEGF in brown fat of VEGF (loxP) mice via Rec2-Cre vector hampered cold response and decreased brown fat mass. Oral administration of Rec2 vector provides a novel tool to genetically manipulate brown fat for research and therapeutic applications. PMID:26857843

  1. Stimulatory effect of oral administration of green tea and caffeine on locomotor activity in SKH-1 mice.

    PubMed

    Michna, Laura; Lu, Yao-Ping; Lou, You-Rong; Wagner, George C; Conney, Allan H

    2003-08-01

    Administration of green tea or caffeine was shown previously to inhibit ultraviolet B light-induced carcinogenesis in SKH-1 mice, and this effect was associated with a reduction in dermal fat. In the present study, oral administration of 0.6% green tea (6 mg tea solids/ml) or 0.04% caffeine (0.4 mg/ml; equivalent to the amount of caffeine in 0.6% green tea) as the sole source of drinking fluid to SKH-1 mice for 15 weeks increased total 24 hr locomotor activity by 47 and 24%, respectively (p<0.0001). Oral administration of 0.6% decaffeinated green tea (6 mg tea solids/ml) for 15 weeks increased locomotor activity by 9% (p<0.05). The small increase in locomotor activity observed in mice treated with decaffeinated green tea may have resulted from the small amounts of caffeine still remaining in decaffeinated green tea solutions (0.047 mg/ml). The stimulatory effects of orally administered green tea and caffeine on locomotor activity were paralleled by a 38 and 23% increase, respectively, in the dermal muscle layer thickness. In addition, treatment of the mice with 0.6% green tea or 0.04% caffeine for 15 weeks decreased the weight of the parametrial fat pad by 29 and 43%, respectively, and the thickness of the dermal fat layer was decreased by 51 and 47%, respectively. These results indicate that oral administration of green tea or caffeine to SKH-1 mice increases locomotor activity and muscle mass and decreases fat stores. The stimulatory effect of green tea and caffeine administration on locomotor activity described here may contribute to the effects of green tea and caffeine to decrease fat stores and to inhibit carcinogenesis induced by UVB in SKH-1 mice. PMID:12850499

  2. Intratablet S-nitrosation: A New Approach for the Oral Administration of S-nitrosothiols as Nitric Oxide Donors.

    PubMed

    de Souza, Gabriela Freitas Pereira; de Oliveira, Marcelo Ganzarolli

    2016-01-01

    The primary S-nitrosothiol, S-nitroso-N-acetylcysteine (SNAC) is a nitric oxide donor with potential pharmaceutical applications for the oral treatment of hepatic steatosis and cirrhosis and for protection against gastric acid-peptic disorders. However, its low thermal stability precludes the preparation of stable dosage forms based on presynthesized SNAC. In this study, we describe an innovative strategy for the oral administration of SNAC based on its intratablet formation via the S-nitrosation reaction of its parent stable thiol, N-acetyl-L-cysteine by nitrous acid during the absorption of water by the tablet. The proposed strategy allows for the manufacturing of thermally stable oral dosage forms for the controlled release of SNAC in the enteric medium. PMID:26852866

  3. Oral administration of quercetin inhibits bone loss in rat model of diabetic osteopenia.

    PubMed

    Liang, Wei; Luo, Zhonghua; Ge, Shuhua; Li, Mo; Du, Junjie; Yang, Min; Yan, Ming; Ye, Zhengxu; Luo, Zhuojing

    2011-11-16

    Diabetic osteopenia can result in an increased incidence of bone fracture and a delay in fracture healing. Quercetin, one of the most widely distributed flavonoids in plants, possesses antioxidant property and beneficial effect on osteoporosis in ovariectomized mice. All these properties make quercetin a potential candidate for controlling the development of diabetic osteopenia. Therefore, the present study was designed to investigate the putative beneficial effect of quercetin on diabetic osteopenia in rats. Diabetes mellitus was induced by streptozotocin. The diabetic rats received daily oral administration of quercetin (5mg/kg, 30 mg/kg and 50mg/kg) for 8 weeks, which was started at 4 weeks after streptozotocin injection. Quercetin at 5mg/kg showed little effect on diabetic osteopenia, while quercetin at 30 mg/kg and 50mg/kg could increase the decreased serum osteocalcin, serum alkaline phosphatase activity, and urinary deoxypyridinoline in diabetic rats. In addition, quercetin (30 mg/kg and 50mg/kg) could partially reverse the decreased biomechanical quality and the impaired micro-architecture of the femurs in diabetic rats. Histomorphometric analysis showed that both decreased bone formation and resorption were observed in diabetic rats, which was partially restored by quercetin (30 mg/kg and 50mg/kg). Further investigations showed that quercetin significantly lowered the oxidative DNA damage level, up-regulated the total serum antioxidant capability and the activity of serum antioxidants in diabetic rats. All those findings indicate the beneficial effect of quercetin on diabetic osteopenia in rats, and raise the possibility of developing quercetin as potential drugs or an ingredient in diet for controlling diabetic osteopenia. PMID:21914440

  4. Pharmacokinetic and toxicological data of spirolides after oral and intraperitoneal administration.

    PubMed

    Otero, Paz; Alfonso, Amparo; Rodríguez, Paula; Rubiolo, Juan A; Cifuentes, José Manuel; Bermúdez, Roberto; Vieytes, Mercedes R; Botana, Luis M

    2012-02-01

    Spirolides are a kind of marine toxins included in the cyclic imine toxin group and produced by the dinoflagellate Alexandrium ostenfeldii. This study shows for the first time a complete and detailed description about the symptoms observed in mice when these toxins were intraperitoneal (i.p.) administered. It is also compared the i.p. toxicity of 13-desmethyl spirolide C (13-desMeC), 13,19-didesMeC (13,19-didesMeC) and 20-methyl spirolide G (20-Me-G) in experiments performed with highly purified toxins. The bioassay indicates that 13-desMeC and 13,19-didesMeC are extremely toxic compounds which have a LD(50) of 27.9μg/kg and 32.2μg/kg, respectively. However, when 20-MeG was i.p administrated with dose up 63.5μg/kg, no deaths were recorded. In order to evaluate the oral toxicity, spirolides were administered by gastric intubation into mice. Then, samples of blood, urine and faeces were collected and analyzed by liquid chromatography-mass spectrometry tandem (LC-MS/MS) technique. Spirolides appear in blood at 15min and in urine after 1h of being toxin administered. In summary, in this paper, it is provided new data about the toxicity, absorption, and excretion of spirolides in mouse. So far, little information is available on this item but necessary for spirolide regulation in the European Union (EU). PMID:22100396

  5. Pharmacokinetics and metabolism study of veratramine in mice after oral administration using LC-MS/MS.

    PubMed

    Cong, Yue; Zhang, Jun-Li; Li, Sha-Sha; Shen, Shan; Wang, Jiang-Ying; Cai, Zongwei

    2016-09-01

    A simple and sensitive high-performance liquid chromatography coupled with hybrid triple quadrupole-linear ion trap mass spectrometry (Q-trap-MS) method was developed and validated for the determination of veratramine, the major bioactive and neurotoxic component in Veratrum nigrum L. Veratramine and the internal standard (IS) were separated with a Waters Symmetry C18 column and eluted with a gradient mobile phase system containing acetonitrile and 0.1% aqueous formic acid. The analysis was performed by using positive electrospray ionization mode with multiple reaction monitoring (MRM). Transition ions of m/z 410.2 → 295.2 for veratramine and m/z 426.1 → 113.8 for the IS were monitored. The method was validated with a good linearity in the range of 1-1000 ng/mL and lower limit of quantification of 1 ng/mL. The precision (CV) of intra- and inter-day ranged from 3.92 to 7.29%, while the accuracy (bias) intra- and inter-day were between -4.78 and 1.65%. The recovery, stability and matrix effect were within the acceptable ranges. Five metabolites of veratramine, including four hydroxylated and one sulfated metabolites, were tentatively identified using predictive MRM-information dependent acquisition-enhanced product ion mode (predictive MRM-IDA-EPI). The developed method was successfully applied to the pharmacokinetic and metabolic study of veratramine in mice after oral administration of veratramine. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26972867

  6. Carnitine status and safety after administration of S-1108, a new oral cephem, to patients.

    PubMed Central

    Shimizu, K; Saito, A; Shimada, J; Ohmichi, M; Hiraga, Y; Inamatsu, T; Shimada, K; Tanimura, M; Fujita, Y; Nishikawa, T

    1993-01-01

    The metabolism and clinical safety of the pivalic acid-containing antibiotic S-1108, an orally active pro-drug cephalosporin, were investigated to assess the clinical effects, with special emphasis on the influence of carnitine consumption in 15 patients with various infectious diseases receiving S-1108 three times a day at a 300- or 600-mg total daily dose for 3 to 7 days. The free carnitine concentrations in plasma were greatly reduced to approximately 65% of pretreatment levels, and the plasma pivaloylcarnitine (the main metabolite of pivaloyloxymethyl ester) concentrations were increased during the 200-mg (three times a day) regimens but returned to the pretreatment levels within 3 to 5 days after the cessation of treatment. In three elderly patients with declining renal function (creatinine clearance rate, 31 to 50 ml/min), the acylcarnitine/free carnitine ratio increased from 0.1 to 0.4 up to 0.7 to 1.5 at day 5 during the 7-day treatment, showed a tendency to decrease, and then returned to the pretreatment ratio 4 days after discontinuation of the drug. The degree of free carnitine reduction and increase of the acylcarnitine/free carnitine ratio depended mostly on the dose and the duration of S-1108 treatment. The increased acylcarnitine/free carnitine ratio in elderly patients was due to reduction of the free carnitine concentration in plasma and mainly to the retardation of nontoxic pivaloylcarnitine excretion. This study indicated that there was a decrease in free carnitine levels in plasma, but there were no clinical symptoms or adverse effects associated with carnitine reduction in patients during the 7-day multiple administration of S-1108. PMID:8517691

  7. Antihypertensive effects of continuous oral administration of nattokinase and its fragments in spontaneously hypertensive rats.

    PubMed

    Fujita, Mitsugu; Ohnishi, Katsunori; Takaoka, Shinsaku; Ogasawara, Kazuya; Fukuyama, Ryo; Nakamuta, Hiromichi

    2011-01-01

    To determine whether the antihypertensive effect of nattokinase is associated with the protease activity of this enzyme, we compared nattokinase with the fragments derived from nattokinase, which possessed no protease activity, in terms of the effect on hypertension in spontaneously hypertensive rats (SHR). In the continuous oral administration test, the groups were given a basic diet alone (control), the basic diet containing nattokinase (0.2, 2.6 mg/g diet) or the basic diet containing the fragments derived from nattokinase (0.2, 0.6 mg/g diet). The group fed the basic diet containing high-dosage nattokinase (2.6 mg/g diet) showed significant reductions in systolic blood pressure (SBP), diastolic blood pressure (DBP) and plasma fibrinogen level, compared with control group and no influence on activities of renin and angiotensin-converting enzyme (ACE, EC 3.4.15.1), and plasma angiotensin II level in the renin-angiotensin system. The treatment of the basic diet containing high-dosage fragments (0.6 mg/g diet) significantly decreased SBP, DBP and plasma angiotensin II level in plasma but the treatment did not influence on plasma fibrinogen level. These results suggest that nattokinase and its fragments are different from each other in the mechanism to reduce hypertension. Nattokinase, retained its protease activity after absorbance across the intestines, may decrease blood pressure through cleavage of fibrinogen in plasma. The fragments, which absorbed as nattokinase-degradation products, prevents the elevation of plasma angiotensin II level to suppress hypertension. PMID:22040882

  8. Tissue dosimetry, metabolism and excretion of pentavalent and trivalent dimethylated arsenic in mice after oral administration

    SciTech Connect

    Hughes, Michael F. Devesa, Vicenta; Adair, Blakely M.; Conklin, Sean D.; Creed, John T.; Styblo, Miroslav; Kenyon, Elaina M.; Thomas, David J.

    2008-02-15

    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 in mice after acute oral administration. Adult female mice were administered [{sup 14}C]-DMA(V) (0.6 or 60 mg As/kg) and sacrificed serially over 24 h. Tissues and excreta were collected for analysis of radioactivity. Other mice were administered unlabeled DMA(V) (0.6 or 60 mg As/kg) or dimethylarsinous acid (DMA(III)) (0.6 mg As/kg) and sacrificed at 2 or 24 h. Tissues (2 h) and urine (24 h) were collected and analyzed for arsenicals. Absorption, distribution and excretion of [{sup 14}C]-DMA(V) were rapid, as radioactivity was detected in tissues and urine at 0.25 h. For low dose DMA(V) mice, there was a greater fractional absorption of DMA(V) and significantly greater tissue concentrations of radioactivity at several time points. Radioactivity distributed greatest to the liver (1-2% of dose) and declined to less than 0.05% in all tissues examined at 24 h. Urinary excretion of radioactivity was significantly greater in the 0.6 mg As/kg DMA(V) group. Conversely, fecal excretion of radioactivity was significantly greater in the high dose group. Urinary metabolites of DMA(V) included DMA(III), trimethylarsine oxide (TMAO), dimethylthioarsinic acid and trimethylarsine sulfide. Urinary metabolites of DMA(III) included TMAO, dimethylthioarsinic acid and trimethylarsine sulfide. DMA(V) was also excreted by DMA(III)-treated mice, showing its sensitivity to oxidation. TMAO was detected in tissues of the high dose DMA(V) group. The low acute toxicity of DMA(V) in the mouse appears to be due in part to its minimal retention and rapid elimination.

  9. Behavioral thermoregulation in the rat following the oral administration of ethanol.

    PubMed

    Gordon, C J; Fogelson, L; Mohler, F; Stead, A G; Rezvani, A H

    1988-01-01

    To assess if ethyl alcohol (ethanol) causes a reduction in the set-point for control of body temperature, behavioral thermoregulatory responses in the Fischer rat were measured following a single oral administration of ethanol. In a preliminary study, five rats were given 3.0 g/kg ethanol dissolved in saline (20%; v/v) by gavage and placed in a longitudinal temperature gradient for 2 hr. The temperature gradient permitted the rats to behaviorally thermoregulate (i.e. select a thermal preferendum). The selected ambient temperature (Ta) in the temperature gradient was notably lower during the initial and final stages of the test period when compared to the response of rats administered similar volumes of saline. Colonic temperature upon removal from the gradient was approximately 1.0 degree C below that of the saline-treated animals. In a follow-up study, rats were placed in the temperature gradient for 1 hr for accommodation purposes. The rats were then gavaged with 0, 1.0 or 3.0 g/kg ethanol and placed back in the gradient for another 2 hr. Selected Ta was significantly reduced in the 3.0 g/kg group during the second hour post-ethanol exposure. The 1.0 g/kg dosage had little effect on selected Ta. As in the preliminary study, the colonic temperature of the rats in the follow up study given 3.0 g/kg was 1.0 degree C below that of the control at 2 hr post-injection. Because the 3.0 g/kg treated animals were significantly hypothermic and selected cooler Tas in the temperature gradient, it was concluded that ethanol exerted a lowering of the set-point for control of body temperature. PMID:3228459

  10. Pharmacokinetics and metabolism of benzene in Zymbal gland and other key target tissues after oral administration in rats.

    PubMed Central

    Low, L K; Meeks, J R; Norris, K J; Mehlman, M A; Mackerer, C R

    1989-01-01

    Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, and mammary gland of Sprague-Dawley rats following chronic oral administration of benzene. The cause for the specificity of such lesions remains unclear, but it is possible that tissue-specific metabolism or pharmacokinetics of benzene is responsible. Metabolism and pharmacokinetic studies were carried out in our laboratory with 14C-benzene at oral doses of 0.15 to 500 mg/kg to ascertain tissue retention, metabolite profile, and elimination kinetics in target and nontarget organs and in blood. Findings from those studies indicate the following: a) the Zymbal gland is not a sink or a site of accumulation for benzene or its metabolites even after a single high dose (500 mg/kg) or after repeated oral administration; b) the metabolite profile is quantitatively different in target tissues (e.g., Zymbal gland, nasal cavity), nontarget tissues and blood; and (c) pharmacokinetic studies show that the elimination of radioactivity from the Zymbal gland is biphasic. PMID:2792043