Oral administration of yessotoxin stabilizes E-cadherin in mouse colon

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Callegari, Federica; Sosa, Silvio; Ferrari, Sara; Soranzo, Maria Rosa; Pierotti, Silvia; Yasumoto, Takeshi; Tubaro, Aurelia; Rossini, Gian Paolo

2006-01-01

YTX has been shown to disrupt the E-cadherin-catenin system in cultured epithelial cells, raising some concern that ingestion of seafood contaminated by YTX might favour tumour spreading and metastasis formation in vivo. In order to probe whether YTX might affect cadherin systems in vivo, we have set up a study involving repeated oral dosing of the toxin in mice (1 mg/kg/day, for 7 days) and analysis of E-cadherin and N-cadherin in tissue extracts obtained at the end of the dosing scheme, as well as 1 and 3 months after YTX administration. We found that the E-cadherin pools obtained from lung and kidney were not altered by YTX in any of our experimental conditions. Extracts from mouse colon contained intact E-cadherin and an E-cadherin fragment of about 90 kDa (ECRA 9 ), displaying a molecular alteration resembling that caused by YTX in cultured cells. We found that the relative proportion of ECRA 9 , as compared to intact E-cadherin, was higher in colon extracts from control mice than from YTX-treated animals, indicating that oral administration of YTX to mice stabilizes E-cadherin of mouse colon. No significant difference could be detected in samples prepared from colons obtained 30 or 90 days after termination of YTX treatment. Oral administration of YTX to mice did not lead to a significant increase in the fragments of E-cadherin detectable in serum, neither it altered the N-cadherin pool of mouse heart. Electron microscopy analysis showed no substantial ultrastructural differences between controls and YTX-treated mice. Our findings show that ingestion of food contaminated by YTX poses a low risk of disruption of the E-cadherin system in vivo

Oral administration of Aloe vera gel powder prevents UVB-induced decrease in skin elasticity via suppression of overexpression of MMPs in hairless mice.

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Saito, Marie; Tanaka, Miyuki; Misawa, Eriko; Yao, Ruiquing; Nabeshima, Kazumi; Yamauchi, Kouji; Abe, Fumiaki; Yamamoto, Yuki; Furukawa, Fukumi

2016-07-01

This study reports the effects of oral Aloe vera gel powder (AVGP) containing Aloe sterols on skin elasticity and the extracellular matrix in ultraviolet B (UVB)-irradiated hairless mice. Ten-week-old hairless mice were fed diets containing 0.3% AVGP for 8 weeks and irradiated UVB for 6 weeks. Mice treated with AVGP showed significant prevention of the UVB-induced decrease in skin elasticity. To investigate the mechanism underlying this suppression of skin elasticity loss, we measured the expression of matrix metalloproteinase (MMP)-2, -9, and -13. AVGP prevented both the UVB-induced increases in MMPs expressions. Moreover, we investigated hyaluronic acid (HA) content of mice dorsal skin and gene expression of HA synthase-2 (Has2). In the results, AVGP oral administration prevented UVB-induced decreasing in skin HA content and Has2 expression and attenuates the UVB-induced decrease in serum adiponectin, which promotes Has2 expression. These results suggested that AVGP has the ability to prevent the skin photoaging.

Protection from radiation injury through oral administration of PF4 gene carried by attenuated salmonella

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Zhao Lihua; Liu Bin; Yu Xiaofei; Zhang Lei; Han Zhongchao

2005-01-01

Objective: To investigate the in vivo radiation protection effect of PF4 by oral administration of attenuated salmonella as the carrier in mice. Methods: The eukaryotic vector pIRES2-EGFP-carried PF4 gene was transferred into an aroA-autotrophic mutant of salmonella typhimurium (SL3261), which was administered orally to BALBPc mice at 1x10 8 PFu once every interval three days. At 12 hours after the third oral administration the mice were subjected to a total body irradiation (TBI) of 700 cGy by a 60 Co source. The protective effect of SL3261/PF4 was determined by detection GFP ( green fluorescence protein) expression in tissues, peripheral blood count, culture of bone marrow colony-forming cells and survival time of mice. Results: Expression of GFP could be detected in the liver, spleen, intestine, kidney, peripheral blood and bone marrow. On days 7 and 14 after irradiation, Compared to controls, there were obvious differences in number of bone marrow mononuclear cells, CFU-GM (granulocyte-macrophage colony-forming unit ) and HPP-CFC (high proliferating potential-colony-forming cells) of mice treated with SL3261/PF4 (P<0.05) as well as prolongation of the survival time. Conclusion: These data demonstrate for the first time that PF4 protects mice from TBI injury and accelerates recovery of hematopoiesis by oral administration of attenuated salmonella carrying PF4 gene. (authors)

Oral administration of human papillomavirus type 16 E7 displayed on Lactobacillus casei induces E7-specific antitumor effects in C57/BL6 mice.

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Poo, Haryoung; Pyo, Hyun-Mi; Lee, Tae-Young; Yoon, Sun-Woo; Lee, Jong-Soo; Kim, Chul-Joong; Sung, Moon-Hee; Lee, Seung-Hoon

2006-10-01

The mounting of a specific immune response against the human papillomavirus type 16 E7 protein (HPV16 E7) is important for eradication of HPV16 E7-expressing cancer cells from the cervical mucosa. To induce a mucosal immune response by oral delivery of the E7 antigen, we expressed the HPV16 E7 antigen on the surface of Lactobacillus casei by employing a novel display system in which the poly-gamma-glutamic acid (gamma-PGA) synthetase complex A (PgsA) from Bacillus subtilis (chungkookjang) was used as an anchoring motif. After surface expression of the HPV16 E7 protein was confirmed by Western blot, flow cytometry and immunofluorescence microscopy, mice were orally inoculated with L. casei-PgsA-E7. E7-specific serum IgG and mucosal IgA productions were enhanced after oral administration and significantly enhanced after boosting. Systemic and local cellular immunities were significantly increased after boosting, as shown by increased counts of lymphocytes (SI = 9.7 +/- 1.8) and IFN-gamma secreting cells [510 +/- 86 spot-forming cells/10(6)cells] among splenocytes and increased IFN-gamma in supernatants of vaginal lymphocytes. Furthermore, in an E7-based mouse tumor model, animals receiving orally administered L. casei-PgsA-E7 showed reduced tumor size and increased survival rate versus mice receiving control (L. casei-PgsA) immunization. These results collectively indicate that the oral administration of E7 displayed on lactobacillus induces cellular immunity and antitumor effects in mice. Copyright 2006 Wiley-Liss, Inc.

Anti-tumour immune effect of oral administration of Lactobacillus plantarum to CT26 tumour-bearing mice.

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Hu, Jingtao; Wang, Chunfeng; Ye, Liping; Yang, Wentao; Huang, Haibin; Meng, Fei; Shi, Shaohua; Ding, Zhuang

2015-06-01

Colorectal cancer (CRC) is one of the most prevalent forms of cancer that shows a high mortality and increasing incidence. There are numerous successful treatment options for CRC, including surgery, chemotherapy, radiotherapy and immunotherapy; however, their side effects and limitations are considerable. Probiotics may be an effective strategy for preventing and inhibiting tumour growth through stimulation of host innate and adaptive immunity. We investigated and compared potential anti-tumour immune responses induced by two isolated Lactobacillus strains, Lactobacillus plantarum A and Lactobacillus rhamnosus b, by pre-inoculating mice with lactobacilli for 14 days. Subsequently, subcutaneous and orthotopic intestinal tumours were generated in the pre-inoculated mice using CT26 murine adenocarcinoma cells and were assessed for response against the tumour. Our results indicated that oral administration with L. plantarum inhibited CT26 cell growth in BALB/c mice and prolonged the survival time of tumour-bearing mice compared with mice administered L. rhamnosus. L. plantarum produced protective immunity against the challenge with CT26 cells by increasing the effector functions of CD8+ and natural killer (NK) cell infiltration into tumour tissue, up-regulation of IFN-gamma (but not IL-4 or IL-17) production, and promotion of Th1-type CD4+ T differentiation. Consequently, our results suggest that L. plantarum can enhance the anti-tumour immune response and delay tumour formation.

Human papillomavirus type 16 E6-specific antitumor immunity is induced by oral administration of HPV16 E6-expressing Lactobacillus casei in C57BL/6 mice.

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Lee, Tae-Young; Kim, Yang-Hyun; Lee, Kyung-Soon; Kim, Jeong-Ki; Lee, Il-Han; Yang, Jai-Myung; Sung, Moon-Hee; Park, Jong-Sup; Poo, Haryoung

2010-11-01

Given that local cell-mediated immunity (CMI) against the human papillomavirus type 16 E6 (HPV16 E6) protein is important for eradication of HPV16 E6-expressing cancer cells in the cervical mucosa, the HPV16 E6 protein may be a target for the mucosal immunotherapy of cervical cancer. Here, we expressed the HPV16 E6 antigen on Lactobacillus casei (L. casei) and investigated E6-specific CMI following oral administration of the L. casei-PgsA-E6 to mice. Surface expression of HPV16 E6 antigens was confirmed and mice were orally inoculated with the L. casei-PgsA or the L. casei-PgsA-E6. Compared to the L. casei-PgsA-treated mice, significantly higher levels of serum IgG and mucosal IgA were observed in L. casei-PgsA-E6-immunized mice; these differences were significantly enhanced after boost. Consistent with this, systemic and local CMI were significantly increased after the boost, as shown by increased counts of IFN-gamma-secreting cells in splenocytes, mesenteric lymph nodes (MLN), and vaginal samples. Furthermore, in the TC-1 tumor model, animals receiving the orally administered L. casei-PgsA-E6 showed reduced tumor size and increased survival rate versus mice receiving control (L. casei-PgsA) immunization. We also found that L. casei-PgsA-E6-induced antitumor effect was decreased by in vivo depletion of CD4(+) or CD8(+) T cells. Collectively, these results indicate that the oral administration of lactobacilli bearing the surface-displayed E6 protein induces T cell-mediated cellular immunity and antitumor effects in mice.

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

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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. © 2016 John Wiley & Sons Ltd.

[Enhancing effect of Ulex europaeus agglutinin I modified liposomes on oral insulin absorption in mice].

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Zhang, Na; Ping, Qi-neng; Xu, Wen-fang

2004-12-01

To investigate the enhancing effect on insulin absorption through GI. tract in mice by using the Ulex europaeus agglutinin I (UEA1) modified liposomes as the carrier. UEA1 modified phosphatidylethanolamine (PE) was prepared by conjugating method of 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide (EDC), then the modified compound (PE-UEA1) was incorporated into the conventional liposomes of insulin to obtain UEA1 modified liposomes. The agglutination test was performed to examine the UEA1 biological activities after synthesis and modification. When liposomes were applied to healthy mice or diabetic mice at insulin dose of 350 u x kg(-1) orally, the hypoglycemic effect was investigated according to the blood glucose level determination. The blood glucose levels of the healthy mice reduced by UEA1 modified liposomes were (84 +/- 15)% at 4 h, (78 +/- 11)% at 8 h and (90 +/- 12)% at 12 h after oral administration. The conventional liposomes and saline showed no effect. The blood glucose levels of the diabetic mice reduced by UEA1 modified liposomes were (73 +/- 7)% at 4 h, (74 +/- 9)% at 8 h, (86 +/- 9)% at 12 h after oral administration. The UEA1 modified liposomes promote the oral absorption of insulin due to the specific-site combination on M cell membrane.

COMPARATIVE TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC (IAS) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (ASV) AND ARSENITE (ASIII)

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COMPARATIVE TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC (iAs) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (AsV) AND ARSENITE (AsIII). E M Kenyon, L M Del Razo and M F Hughes. U.S. EPA, ORD, NHEERL, ETD, PKB, RTP, NC, USA; ...

Supraspinally-administered agmatine attenuates the development of oral fentanyl self-administration

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Wade, Carrie L.; Schuster, Daniel J.; Domingo, Kristine M.; Kitto, Kelley F.; Fairbanks, Carolyn A.

2009-01-01

The decarboxylation product of arginine, agmatine, has effectively reduced or prevented opioid-induced tolerance and dependence when given either systemically (intraperitoneally or subcutaneously) or centrally (intrathecally or intracerebroventricularly). Systemically administered agmatine also reduces the escalation phase of intravenous fentanyl self-administration in rats. The present study assessed whether centrally (intracerebroventricular, i.c.v.) delivered agmatine could prevent the development of fentanyl self-administration in mice. Mice were trained to respond under a fixed-ratio 1 (FR1) schedule for either fentanyl (0.7 μg/70 μl, p.o.) or food reinforcement. Agmatine (10 nmol/5 μl), injected i.c.v. 12-14h before the first session and every other evening (12-14h before session) for 2 weeks, completely attenuated oral fentanyl self-administration (but not food-maintained responding) compared to saline-injected controls. When agmatine was administered after fentanyl self-administration had been established (day 8) it had no attenuating effects on bar pressing. This dose of agmatine does not decrease locomotor activity as assessed by rotarod. The present findings significantly extend the previous observation that agmatine prevents opioid-maintained behavior to a chronic model of oral fentanyl self-administration as well as identifying a supraspinal site of action for agmatine inhibition of drug addiction. PMID:18495108

Subchronic Oral Bromocriptine Methanesulfonate Enhances Open Field Novelty-Induced Behavior and Spatial Memory in Male Swiss Albino Mice

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Olakunle James Onaolapo

2013-01-01

Full Text Available This study set out to assess the neurobehavioral effects of subchronic, oral bromocriptine methanesulfonate using the open field and the Y-maze in healthy male mice. Sixty adult Swiss albino mice were assigned into three groups. Controls received normal saline, while test groups received bromocriptine methanesulfonate at 2.5 and 5 mg/kg/day, respectively, for a period of 21 days. Neurobehavioral tests were carried out on days 1 and 21 after administration. Open field assessment on day 1 after administration revealed significant increase in grooming at 2.5 and 5 mg/kg, while horizontal and vertical locomotion showed no significant changes. Day 1 also showed no significant changes in Y-maze alternation. On day 21, horizontal locomotion, rearing, and grooming were increased significantly at 2.5 and 5 mg/kg doses after administration; also, spatial memory was significantly enhanced at 2.5 mg/kg. In conclusion, the study demonstrates the ability of oral bromocriptine to affect neurobehavior in normal mice. It also suggests that there is a cumulative effect of oral bromocriptine on the behaviors studied with more changes being seen after subchronic administration rather than after a single oral dose.

Subchronic Oral Bromocriptine Methanesulfonate Enhances Open Field Novelty-Induced Behavior and Spatial Memory in Male Swiss Albino Mice.

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Onaolapo, Olakunle James; Onaolapo, Adejoke Yetunde

2013-01-01

This study set out to assess the neurobehavioral effects of subchronic, oral bromocriptine methanesulfonate using the open field and the Y-maze in healthy male mice. Sixty adult Swiss albino mice were assigned into three groups. Controls received normal saline, while test groups received bromocriptine methanesulfonate at 2.5 and 5 mg/kg/day, respectively, for a period of 21 days. Neurobehavioral tests were carried out on days 1 and 21 after administration. Open field assessment on day 1 after administration revealed significant increase in grooming at 2.5 and 5 mg/kg, while horizontal and vertical locomotion showed no significant changes. Day 1 also showed no significant changes in Y-maze alternation. On day 21, horizontal locomotion, rearing, and grooming were increased significantly at 2.5 and 5 mg/kg doses after administration; also, spatial memory was significantly enhanced at 2.5 mg/kg. In conclusion, the study demonstrates the ability of oral bromocriptine to affect neurobehavior in normal mice. It also suggests that there is a cumulative effect of oral bromocriptine on the behaviors studied with more changes being seen after subchronic administration rather than after a single oral dose.

Evaluation of edaravone against radiation-induced oral mucositis in mice.

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Nakajima, Noriko; Watanabe, Shinichi; Kiyoi, Takeshi; Tanaka, Akihiro; Suemaru, Katsuya; Araki, Hiroaki

2015-03-01

Oral mucositis induced by radiotherapy for cancers of the head and neck reduce the quality of life of patients. However, effective therapeutic agents are lacking. Symptomatic treatment involves local anesthesia and analgesia. We focused on the antioxidant effects of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut(®)). Oral mucositis was induced on the tongue tips of mice using a single dose of X-rays (20 Gy). To evaluate the protective effect of edaravone (30 and 300 mg/kg), administration was carried out 30 min before irradiation. Survival, oral mucositis score, myeloperoxidase activity, and levels of 2-Thiobarbituric acid reactive substances were measured, and all were improved compared with those of control mice. A significant difference was not found in terms of survival due to edaravone. Histopathologic findings also highlighted the beneficial features of edaravone. Edaravone reduced the production of reactive oxygen species. These findings suggest that the protective effect of edaravone against radiation-induced oral mucositis is through an antioxidant effect. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Evaluation of edaravone against radiation-induced oral mucositis in mice

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Noriko Nakajima

2015-03-01

Full Text Available Oral mucositis induced by radiotherapy for cancers of the head and neck reduce the quality of life of patients. However, effective therapeutic agents are lacking. Symptomatic treatment involves local anesthesia and analgesia. We focused on the antioxidant effects of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut®. Oral mucositis was induced on the tongue tips of mice using a single dose of X-rays (20 Gy. To evaluate the protective effect of edaravone (30 and 300 mg/kg, administration was carried out 30 min before irradiation. Survival, oral mucositis score, myeloperoxidase activity, and levels of 2-Thiobarbituric acid reactive substances were measured, and all were improved compared with those of control mice. A significant difference was not found in terms of survival due to edaravone. Histopathologic findings also highlighted the beneficial features of edaravone. Edaravone reduced the production of reactive oxygen species. These findings suggest that the protective effect of edaravone against radiation-induced oral mucositis is through an antioxidant effect.

Orally administered sodium 4-phenylbutyrate suppresses the development of dextran sulfate sodium-induced colitis in mice.

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Ono, Kazuhiko; Nimura, Satoshi; Hideshima, Yuko; Nabeshima, Kazuki; Nakashima, Manabu

2017-12-01

Sodium 4-phenylbutyrate (PBA) exerts therapeutic effects in a wide range of pathologies. A previous study by the present authors revealed that intraperitoneal administration of PBA suppresses the onset of dextran sulfate sodium (DSS)-induced colitis in mice. In the present study, the effects of orally administered PBA are investigated, as this route of administration is more clinically relevant. The therapeutic efficacy of PBA (10 mg/12 h) in mice with experimental colitis was assessed based on the disease activity index, production of inflammatory cytokines, colon length and histopathological investigations. The results of the present study demonstrated a significantly higher survival rate in the PBA-treated group compared with the PBA-untreated (DSS control) group (P=0.0156). PBA treatment improved pathological indices of experimental colitis (P<0.05). Furthermore, the oral administration of PBA significantly inhibited the DSS-induced shortening of the colon (P<0.05) and overproduction of interleukin (IL)-1β and IL-6 (both P<0.05) as measured in colonic lavage fluids. A marked attenuation of the DSS-induced overproduction of tumor necrosis factor was also observed. For histopathological analysis, a marked decrease in mature goblet cells and increase in enlarged nuclei of the absorptive cells was observed in colon lesions of DSS control mice as compared with normal untreated mice. However, in the PBA-treated mice, no such lesions were observed and the mucosa resembled that of DSS-untreated mice. The results of the present study, combined with those results of a previous study, suggest that oral and intraperitoneal administration of PBA have similar preventative effects on DSS-induced colitis, achieved by suppressing its pathogenesis.

Oral lactoferrin protects against experimental candidiasis in mice.

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Velliyagounder, K; Alsaedi, W; Alabdulmohsen, W; Markowitz, K; Fine, D H

2015-01-01

To determine the role of human lactoferrin (hLF) in protecting the oral cavities of mice against Candida albicans infection in lactoferrin knockout (LFKO(-/-)) mice was compared to wild-type (WT) mice. We also aim to determine the protective role of hLF in LFKO(-/-) mice. Antibiotic-treated immunosuppressed mice were inoculated with C. albicans (or sham infection) by oral swab and evaluated for the severity of infection after 7 days of infection. To determine the protective role of hLF, we added 0·3% solution of hLF to the drinking water given to some of the mice. CFU count, scoring of lesions and microscopic observations were carried out to determine the severity of infection. LFKO(-/-) I mice showed a 2 log (P = 0·001) higher CFUs of C. albicans in the oral cavity compared to the WT mice infected with C. albicans (WTI). LFKO(-/-) I mice given hLF had a 3 log (P = 0·001) reduction in CFUs in the oral cavity compared to untreated LFKO(-/-) I mice. The severity of infection, observed by light microscopy, revealed that the tongue of the LFKO(-/-) I mice showed more white patches compared to WTI and LFKO(-/-) I + hLF mice. Scanning electron microscopic observations revealed that more filiform papillae were destroyed in LFKO(-/-) I mice when compared to WTI or LFKO(-/-) I + hLF mice. Human LF is important in protecting mice from oral C. albicans infection. Administered hLF may be used to prevent C. albicans infection. Human LF, a multifunctional iron-binding glycoprotein can be used as a therapeutic active ingredient in oral healthcare products against C. albicans. © 2014 The Society for Applied Microbiology.

Plant-based vaccines for oral delivery of type 1 diabetes-related autoantigens: Evaluating oral tolerance mechanisms and disease prevention in NOD mice.

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Posgai, Amanda L; Wasserfall, Clive H; Kwon, Kwang-Chul; Daniell, Henry; Schatz, Desmond A; Atkinson, Mark A

2017-02-13

Autoantigen-specific immunological tolerance represents a central objective for prevention of type 1 diabetes (T1D). Previous studies demonstrated mucosal antigen administration results in expansion of Foxp3 + and LAP + regulatory T cells (Tregs), suggesting oral delivery of self-antigens might represent an effective means for modulating autoimmune disease. Early preclinical experiments using the non-obese diabetic (NOD) mouse model reported mucosal administration of T1D-related autoantigens [proinsulin or glutamic acid decarboxylase 65 (GAD)] delayed T1D onset, but published data are conflicting regarding dose, treatment duration, requirement for combinatorial agents, and extent of efficacy. Recently, dogma was challenged in a report demonstrating oral insulin does not prevent T1D in NOD mice, possibly due to antigen digestion prior to mucosal immune exposure. We used transplastomic plants expressing proinsulin and GAD to protect the autoantigens from degradation in an oral vaccine and tested the optimal combination, dose, and treatment duration for the prevention of T1D in NOD mice. Our data suggest oral autoantigen therapy alone does not effectively influence disease incidence or result in antigen-specific tolerance assessed by IL-10 measurement and Treg frequency. A more aggressive approach involving tolerogenic cytokine administration and/or lymphocyte depletion prior to oral antigen-specific immunotherapy will likely be required to impart durable therapeutic efficacy.

ACCUMULATION AND METABOLISM OF ARSENIC IN MICE AFTER REPEATED ADMINISTRATION OF ARSENATE

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Accumulation and metabolism of arsenic in mice after repeated oral administration of arsenate, Hughes, M. F., Kenyon, E. M., Edwards, B. C., Mitchell, C. T., Del Razo, L. M., and Thomas, D. J. The human carcinogen inorganic arsenic (iAs) is a pervasive environmental ...

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

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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

Ciguatoxins and Maitotoxins in Extracts of Sixteen Gambierdiscus Isolates and One Fukuyoa Isolate from the South Pacific and Their Toxicity to Mice by Intraperitoneal and Oral Administration

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Rex Munday

2017-06-01

Full Text Available Ciguatoxins (CTXs, and possibly maitotoxins (MTXs, are responsible for Ciguatera Fish Poisoning, an important health problem for consumers of reef fish (such as inhabitants of islands in the South Pacific Ocean. The habitational range of the Gambierdiscus species is expanding, and new species are being discovered. In order to provide information on the potential health risk of the Gambierdiscus species, and one Fukuyoa species (found in the Cook Islands, the Kermadec Islands, mainland New Zealand, and New South Wales, Australia, 17 microalgae isolates were collected from these areas. Unialgal cultures were grown and extracts of the culture isolates were analysed for CTXs and MTXs by liquid chromatography tandem mass spectrometry (LC-MS/MS, and their toxicity to mice was determined by intraperitoneal and oral administration. An isolate of G. carpenteri contained neither CTXs nor MTXs, while 15 other isolates (including G. australes, G. cheloniae, G. pacificus, G. honu, and F. paulensis contained only MTX-1 and/or MTX-3. An isolate of G. polynesiensis contained both CTXs and MTX-3. All the extracts were toxic to mice by intraperitoneal injection, but those containing only MTX-1 and/or -3 were much less toxic by oral administration. The extract of G. polynesiensis was highly toxic by both routes of administration.

Ciguatoxins and Maitotoxins in Extracts of Sixteen Gambierdiscus Isolates and One Fukuyoa Isolate from the South Pacific and Their Toxicity to Mice by Intraperitoneal and Oral Administration

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Munday, Rex; Murray, Sam; Rhodes, Lesley L.; Larsson, Michaela E.; Harwood, D. Tim

2017-01-01

Ciguatoxins (CTXs), and possibly maitotoxins (MTXs), are responsible for Ciguatera Fish Poisoning, an important health problem for consumers of reef fish (such as inhabitants of islands in the South Pacific Ocean). The habitational range of the Gambierdiscus species is expanding, and new species are being discovered. In order to provide information on the potential health risk of the Gambierdiscus species, and one Fukuyoa species (found in the Cook Islands, the Kermadec Islands, mainland New Zealand, and New South Wales, Australia), 17 microalgae isolates were collected from these areas. Unialgal cultures were grown and extracts of the culture isolates were analysed for CTXs and MTXs by liquid chromatography tandem mass spectrometry (LC-MS/MS), and their toxicity to mice was determined by intraperitoneal and oral administration. An isolate of G. carpenteri contained neither CTXs nor MTXs, while 15 other isolates (including G. australes, G. cheloniae, G. pacificus, G. honu, and F. paulensis) contained only MTX-1 and/or MTX-3. An isolate of G. polynesiensis contained both CTXs and MTX-3. All the extracts were toxic to mice by intraperitoneal injection, but those containing only MTX-1 and/or -3 were much less toxic by oral administration. The extract of G. polynesiensis was highly toxic by both routes of administration. PMID:28665362

Ciguatoxins and Maitotoxins in Extracts of Sixteen Gambierdiscus Isolates and One Fukuyoa Isolate from the South Pacific and Their Toxicity to Mice by Intraperitoneal and Oral Administration.

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Munday, Rex; Murray, Sam; Rhodes, Lesley L; Larsson, Michaela E; Harwood, D Tim

2017-06-30

Ciguatoxins (CTXs), and possibly maitotoxins (MTXs), are responsible for Ciguatera Fish Poisoning, an important health problem for consumers of reef fish (such as inhabitants of islands in the South Pacific Ocean). The habitational range of the Gambierdiscus species is expanding, and new species are being discovered. In order to provide information on the potential health risk of the Gambierdiscus species, and one Fukuyoa species (found in the Cook Islands, the Kermadec Islands, mainland New Zealand, and New South Wales, Australia), 17 microalgae isolates were collected from these areas. Unialgal cultures were grown and extracts of the culture isolates were analysed for CTXs and MTXs by liquid chromatography tandem mass spectrometry (LC-MS/MS), and their toxicity to mice was determined by intraperitoneal and oral administration. An isolate of G. carpenteri contained neither CTXs nor MTXs, while 15 other isolates (including G. australes, G. cheloniae , G. pacificus , G. honu , and F. paulensis ) contained only MTX-1 and/or MTX-3. An isolate of G. polynesiensis contained both CTXs and MTX-3. All the extracts were toxic to mice by intraperitoneal injection, but those containing only MTX-1 and/or -3 were much less toxic by oral administration. The extract of G. polynesiensis was highly toxic by both routes of administration.

Oral administration of Lactobacillus plantarum strain AYA enhances IgA secretion and provides survival protection against influenza virus infection in mice.

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Yosuke Kikuchi

Full Text Available The mucosal immune system provides the first line of defense against inhaled and ingested pathogenic microbacteria and viruses. This defense system, to a large extent, is mediated by the actions of secretory IgA. In this study, we screened 140 strains of lactic acid bacteria for induction of IgA production by murine Peyer's patch cells. We selected one strain and named it Lactobacillus plantarum AYA. We found that L. plantarum AYA-induced production of IL-6 in Peyer's patch dendritic cells, with this production promoting IgA(+ B cells to differentiate into IgA-secreting plasma cells. We also observed that oral administration of L. plantarum AYA in mice caused an increase in IgA production in the small intestine and lung. This production of IgA correlated strongly with protective ability, with the treated mice surviving longer than the control mice after lethal influenza virus infection. Our data therefore reveals a novel immunoregulatory role of the L. plantarum AYA strain which enhances mucosal IgA production and provides protection against respiratory influenza virus infection.

Comparison between the Effects of Oral and Intramuscular Administration of Shin’iseihaito (Xinyiqingfeitang in a Streptococcus pyogenes-Induced Murine Sinusitis Model

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Masaaki Minami

2018-01-01

Full Text Available Streptococcus pyogenes (S. pyogenes is a species of Gram-positive coccoid bacteria having many virulence factors. Its capsule and exotoxins can cause upper respiratory tract infections such as sinusitis. The general treatment for S. pyogenes-induced sinusitis is administration of antibiotics such as penicillin and macrolides; however, a serious problem associated with these antibiotics is their attenuated effect. Shin’iseihaito (Xinyiqingfeitang, a formula of Japanese traditional Kampo medicine and traditional Chinese medicine, has been used for the treatment of sinusitis. In general, formulas of Japanese traditional Kampo medicine are orally administered. This is in contrast to certain formulas of traditional Chinese medicine, which are being recently administered intramuscularly or intravenously. Regarding these traditional Chinese medicine formulas, the injection methodology is reported to be more effective than oral intake. In this study, we compared the efficacy between orally and intramuscularly administered Shin’iseihaito against S. pyogenes-induced sinusitis. We evaluated the antibacterial effect of Shin’iseihaito extract (SSHT against S. pyogenes by K-B disk diffusion assay. Furthermore, we investigated the nasal colonization of S. pyogenes, determined cytokine (TNF-α, IL-1β, and IL-6 levels, and conducted a splenocyte proliferative assay in a murine sinusitis model. SSHT displayed direct anti-S. pyogenes activity. Intramuscular administration of SSHT decreased the nasal colonization of S. pyogenes compared with oral administration. Thymidine uptake analysis revealed that the proliferation of splenocytes from S. pyogenes-infected mice under intramuscular SSHT treatment was upregulated compared to that of splenocytes from S. pyogenes-infected mice under oral SSHT treatment. We also found that TNF-α, IL-1β, and IL-6 levels in the nasal discharge from intramuscularly treated S. pyogenes-infected mice were lower than those from

Alteration of intestinal microbiota in mice orally administered with salmon cartilage proteoglycan, a prophylactic agent.

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Krisana Asano

Full Text Available Proteoglycan (PG extracted from salmon nasal cartilage has potential to be a prophylactic agent. Daily oral administration of the PG attenuates systemic inflammatory response in the experimental mouse models. In this study, we applied the culture-independent approach to investigate an alteration of intestinal microbiota composition in PG-administered mice. The results indicated that the population level of bacilli increased in the small and large intestine upon PG administration. On the other hand, the population level of clostridia decreased in the large intestine. The proportion of bacteria that are able to ferment saccharides and produce short-chain fatty acids increased in the small intestine and decreased in the large intestine. Importantly, population level of probiotic lactobacilli and bacteria exhibiting the immunomodulatory effect increased in the PG-administered mice. In addition, several disease-associated bacteria decreased upon PG administration. These results provided an understanding of the specific role of PG involved in host immune modulation and supported our hypothesis that daily oral administration of PG improves the overall balance in composition of the intestinal microbial community.

Identification and Pharmacokinetics of Multiple Potential Bioactive Constituents after Oral Administration of Radix Astragali on Cyclophosphamide-Induced Immunosuppression in Balb/c Mice

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Menghua Liu

2015-03-01

Full Text Available Radix Astragali (RA is one of the commonly-used traditional Chinese medicines (TCMs with an immunomodulatory effect confirmed in the clinic. In order to better understand the material basis for the therapeutic effects, this study was to investigate the absorbed components and their pharmacokinetic profile after oral administration of RA on cyclophosphamide-induced immunosuppression in Balb/c mice. As a result, 51 compounds in RA extract and 31 prototype compounds with nine metabolites were detected in mice plasma by the ultra-fast liquid chromatography (UFLC-DAD-Q-TOF-MS/MS method. The pharmacokinetic parameters of five main constituents, including calycosin-7-O-glucoside, ononin, calycosin, formononetin and astragaloside IV, were obtained using HPLC-MS/MS. These results offered useful information for research on the pharmacological mechanism of RA and for its further development.

Short communication. Enhancement of the immune responses to vaccination against foot-and-mouth disease in mice by oral administration of Quillaja saponaria-A and extracts of Cochinchina momordica seed

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C. W. Xiao

2013-02-01

Full Text Available This study was designed to evaluate the effects of oral administration of extracts from Cochinchina momordica seed (ECMS or Quillaja saponaria-A (Quil-A on the immune responses in mice immunized with foot and mouth disease virus (FMDV-serotype O vaccine. Forty-two imprinting control region (ICR mice were randomly divided into seven groups of 6 animals in each group, and a dose of 400 μg of Quil-A or ECMS was orally administered for 1,, 2 or 3 days. After that, the animals were subcutaneously immunized twice with FMD vaccine at 3-week intervals and blood samples were collected 2-weeks after boosting for measurement of FMDV-specific IgG and its subclasses. Spleens were collected for lymphocytes proliferation assay. Results indicated that serum FMDV-specific IgG and the IgG subclass responses were significantly enhanced in mice orally administered ECMS or Quil-A when compared with the control group (p<0.05. Lymphocytes proliferation response to FMD vaccine was significantly enhanced by ECMS compared with the control (p<0.05. This study illustrates that ECMS induced immunomodulatory effects and performed better than Quil-A.

Evaluation of the antidepressant-like effects of acute and sub-acute administration of crocin and crocetin in mice

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Bahareh Amin

2015-08-01

Full Text Available Objective: The present study was designed to investigate the putative antidepressant effects of crocin and crocetin, two major active ingredients of Crocus sativus L. (saffron using mice in two different regimens of acute and sub-acute administration. Material and Methods: In acute treatment, antidepressant-like activities of crocin and crocetin (10, 20 and 40 mg/kg, i.p. were evaluated using forced swim test (FST. In sub-acute study (21 times with 24-h intervals, antidepressant-like effects of oral administration of drugs were examined using FST and tail suspension test (TST. Locomotor activity and motor coordination were studied using open field and rotarod tests, respectively. Results: Acute treatment with crocin (40 mg/kg and crocetin (20 and 40 mg/kg produced antidepressant-like effect in FST without affecting the baseline locomotion in mice. Sub-acute oral administration of crocin significantly decreased immobility time only at the highest dose (100 mg/kg. Crocetin (12.5, 25 and 50 mg/kg was able to decrease immobility time in FST and TST. Locomotor activity and coordination of mice were not affected by crocin or crocetin. Conclusion: Since higher doses of crocin was required to show antidepressant effects, more efficacy of crocetin may be concluded. This observation provides further support for metabolism of crocin to crocetin following oral administration.

Effect of oral administration of lactobacillus acidophilus on the immune responses and survival of BALB/c mice bearing human breast cancer

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Soltan Dallal MM

2010-02-01

Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: In according to immunomodulatory effect of probiotics and effect of these bacteria on the effectiveness of immune responses, at the present work we proposed the evaluation of oral administration of L.acidophilus on the immune statues in BALB/c mice bearing breast cancer."n"nMethods: A total of 30 In-bred BALB/c mices aged from six to eight weeks weighting 25-30g were randomly enrolled in our study, in two groups each consist of 15 mices. The L.acidophilus ATCC4356 strain used in this study was inoculated in MRS broth and cultivated for a day at 37°C under anaerobic conditions, collected by centrifugation and resuspend in Phosphate Buffer Saline (PBS. After preparation of proper amount of these suspensions it was orally administered to the mice with a gastric feeding, Control mices received an equal volume of PBS in duration of study."n"nResults: Results showed the increase in production of IFnγ (p<0.005, and decrease in production of Th2 cytokines such as IL4 (p=0.347 in the L.acidophilus administered mice in comparison to control group of mice. In addition the proliferation of immune cells in probiotic group was significantly higher than controls, and most importantly probiotic administered mice showed

Oral Administration of Vanillin Improves Imiquimod-Induced Psoriatic Skin Inflammation in Mice.

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Cheng, Hui-Man; Chen, Feng-Yuan; Li, Chia-Cheng; Lo, Hsin-Yi; Liao, Yi-Fang; Ho, Tin-Yun; Hsiang, Chien-Yun

2017-11-29

Vanillin is one of the most widely used flavoring products worldwide. Psoriasis is a chronic inflammatory skin disorder. The interleukin-23 (IL-23)/interleukin-17 (IL-17) axis plays a critical role in psoriasis. Here, we analyzed the effect of vanillin on imiquimod (IMQ)-induced psoriatic skin inflammation in mice. Mice were treated topically with IMQ on the back skin and orally with various amounts of vanillin for 7 consecutive days. Vanillin significantly improved IMQ-induced histopathological changes of skin in a dose-dependent manner. The thickness and number of cell layers of epidermis were reduced by 29 ± 14.4 and 27.8 ± 11%, respectively, in mice given 100 mg/kg of vanillin. A microarray showed that a total of 9042 IMQ-upregulated genes were downregulated by vanillin, and the biological pathways involved in the immune system and metabolism were significantly altered by vanillin. The upregulated expressions of IL-23, IL-17A, and IL-17F genes were suppressed by vanillin, with fold changes of -3.07 ± 0.08, -2.06 ± 0.21, and -1.62 ± 0.21, respectively. Moreover, vanillin significantly decreased both the amounts of IL-17A and IL-23 and the infiltration of immune cells in the skin tissues of IMQ-treated mice. In conclusion, our findings suggested that vanillin was an effective bioactive compound against psoriatic skin inflammation. Moreover, the downregulation of IL-23 and IL-17 expression suggested that vanillin was a novel regulator of the IL-23/IL-17 axis.

Oral administration of Uncariae rhynchophylla inhibits the development of DNFB-induced atopic dermatitis-like skin lesions via IFN-gamma down-regulation in NC/Nga mice.

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Kim, Dong-Young; Jung, Jung-A; Kim, Tae-Ho; Seo, Sang-Wan; Jung, Sung-Ki; Park, Cheung-Seog

2009-04-21

Uncariae rhynchophylla (UR) is an herb which has blood pressure lowering and anti-inflammatory effects and has been prescribed traditionally to treat stroke and vascular dementia. In the present study, we examined whether UR suppress Atopic dermatitis (AD)-like skin lesions in NC/Nga mice treated with 2, 4-dinitrofluorobenzene (DNFB) under SPF conditions. The effect of UR in DNFB- treated NC/Nga mice was determined by measuring the skin symptom severity, levels of serum IgE, and of the amounts of IL-4 and IFN-gamma secreted by activated T cells in draining lymph nodes. Oral administration of UR to DNFB-treated NC/Nga mice was found to inhibit ear thickness increases and the skin lesions induced by DNFB. IFN-gamma production by CD4+ T cells from the lymph nodes of DNFB-treated NC/Nga mice was significantly inhibited by UR treatment, although levels of IL-4 and total IgE in serum were not. UR may suppress the development of AD-like dermatitis in DNFB-treated NC/Nga mice by reducing IFN-gamma production.

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

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

2008-01-01

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

Radioprotection offered by bacterial secondary metabolite RK-IP-006.G to the mice by oral route of administration

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Gupta, Ashutosh K.; Malhotra, Poonam; Singh, Praveen K.; Chhachhia, Neha; Singh, Shravan K.; Kumar, Raj

2014-01-01

Ionizing radiation is known to cause oxidative damage in biological system primarily by generating reactive oxygen species (ROS). Gastrointestinal system is considered one of the most radiosensitive biological systems. The most radiosensitive cells type found in the intestine are continuously proliferative crypt cells. Damage to intestinal crypt cells lead to gastrointestinal functions impairment that contribute to mortality. In the present study, whole body radioprotective efficacy of bacterial secondary metabolite RK-IP-006.G was evaluated in C57BL/6 male mice. To determine free radical scavenging properties of RK-IP-006.G 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) assay was performed. Radiation induced lipid peroxidation and its inhibition by RK-IP-006.G pretreatment was assessed in intestinal tissue homogenate. To find out cellular antioxidant status of the irradiated and RK-IP- 006.G treated mice, SOD, Catalase, and Glutathion-S-Transferase activity were estimated in intestinal tissue homogenate. Anti-apoptotic and mitochondrial membrane hypopolarization effect of the RK-IP-006.G was also analyzed using fluorescent probes Acridine Orange and Rhodamine123 respectively. Results of the study demonstrated that, RK-IP-006.G pretreatment (∼2h; 150 mg/kg.b.wt. oral administration) to the lethally irradiated (9 Gy) C57BL/6 male mice contributes to >83% whole body radioprotection in mice. Significant (P>0.05%) inhibition in lipid peroxidation was observed in intestinal tissue of irradiated mice pretreated with RK-IP-006.G compared to only irradiated controls. Significant (P>0.05%) increase in antioxidant enzyme i.e. Catalase, SOD and GST activities was reported in irradiated mice pretreated with RK-IP-006.G compared to irradiated control groups. RK-IP-006.G pretreatment also found to be instrumental in inhibiting radiation induced apoptosis and mitochondrial membrane hyperpolarization. In conclusion, present study revealed that bacterial secondary

Effect of Yifukang oral liquid on gastric emptying and intestinal peristalsis in mice

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Sun, Jianhua; Li, Jun; Li, Xianyu; Hao, Shaojun; Guo, Junyi; Ma, Zhenzhen; Zhang, Zhengchen

2018-04-01

To observe the effect of Yifukang oral liquid on gastric emptying and intestinal peristalsis in mice. Methods: 60 mice were randomly divided into 5 groups. The suspension of Baohe Pill and the same volume of normal saline group were given once a day for 7 days. After the last administration for 30 minutes, 0.25 ml of 0.04% phenolic red solution was administered by stomach. After 20 minutes, the animals were killed, the stomach was removed, the gastric contents were cleaned, and the lotion 5ml was centrifuged. The absorbance of the supernatant was measured by TU-1901 ultraviolet spectrophotometer at the wavelength of 560nm. The residual rate of gastric phenolic red was calculated. Rate was used to evaluate gastric emptying velocity.60 mice were randomly divided into five groups: group 5, large, medium, small Yifukang oral liquid dosage group, pill suspension and the same volume normal saline. After 20 min after the last dose of carbon powder suspension, the mice were sacrificed, the abdominal cavity was cut open, the intestine of the ileocecum was cut off, the intestinal mesentery was separated, the total length of the small intestine (cm) was measured, and the distance (cm) in the small intestine was measured, and the end-of-carbon propulsion rate was calculated. Compared with the blank group, small dose of Yi Fu Kang group and Baohe Pill group could significantly promote the ability of gastric emptying in mice. Compared with the blank group, small dose group and rehabilitation benefits Baohewan group can significantly promote the gastric emptying ability of mice (Pmice. Yi Fu Kang oral liquid group could significantly increase the percentage of small intestine carbon powder(Pmice (P<0.05). Yi Fukang oral liquid has the effect of promoting gastric emptying and small intestinal peristalsis.

Neurobehavioral and Cardiovascular Effects of Potassium Cyanide Administered Orally to Mice.

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Hawk, Michael A; Ritchie, Glenn D; Henderson, Kim A; Knostman, Katherine A B; Roche, Brian M; Ma, Zhenxu J; Matthews, Claire M; Sabourin, Carol L; Wakayama, Edward J; Sabourin, Patrick J

2016-09-01

The Food and Drug Administration Animal Rule requires evaluation of cardiovascular and central nervous system (CNS) effects of new therapeutics. To characterize an adult and juvenile mouse model, neurobehavioral and cardiovascular effects and pathology of a single sublethal but toxic, 8 mg/kg, oral dose of potassium cyanide (KCN) for up to 41 days postdosing were investigated. This study describes the short- and long-term sensory, motor, cognitive, and behavioral changes associated with oral dosing of a sublethal but toxic dose of KCN utilizing functional observation battery and Tier II CNS testing in adult and juvenile mice of both sexes. Selected tissues (histopathology) were evaluated for changes associated with KCN exposure with special attention to brain regions. Telemetry (adult mice only) was used to evaluate cardiovascular and temperature changes. Neurobehavioral capacity, sensorimotor responsivity or spontaneous locomotor activity, and rectal temperature were significantly reduced in adult and juvenile mice at 30 minutes post-8 mg/kg KCN dose. Immediate effects of cyanide included bradycardia, adverse electrocardiogram arrhythmic events, hypotension, and hypothermia with recovery by approximately 1 hour for blood pressure and heart rate effects and by 2 hours for body temperature. Lesions consistent with hypoxia, such as mild acute tubular necrosis in the kidneys corticomedullary junction, were the only histopathological findings and occurred at a very low incidence. The mouse KCN intoxication model indicates rapid and completely reversible effects in adult and juvenile mice following a single oral 8 mg/kg dose. Neurobehavioral and cardiovascular measurements can be used in this animal model as a trigger for treatment. © The Author(s) 2016.

Orally administered nicotine induces urothelial hyperplasia in rats and mice

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Dodmane, Puttappa R.; Arnold, Lora L.; Pennington, Karen L.; Cohen, Samuel M.

2014-01-01

Highlights: • Rats and mice orally administered with nicotine tartrate for total of 4 weeks. • No treatment-related death or whole body toxicity observed in any of the groups. • Urothelium showed simple hyperplasia in treated rats and mice. • No significant change in BrdU labeling index or SEM classification of urothelium. - Abstract: Tobacco smoking is a major risk factor for multiple human cancers including urinary bladder carcinoma. Tobacco smoke is a complex mixture containing chemicals that are known carcinogens in humans and/or animals. Aromatic amines a major class of DNA-reactive carcinogens in cigarette smoke, are not present at sufficiently high levels to fully explain the incidence of bladder cancer in cigarette smokers. Other agents in tobacco smoke could be excreted in urine and enhance the carcinogenic process by increasing urothelial cell proliferation. Nicotine is one such major component, as it has been shown to induce cell proliferation in multiple cell types in vitro. However, in vivo evidence specifically for the urothelium is lacking. We previously showed that cigarette smoke induces increased urothelial cell proliferation in mice. In the present study, urothelial proliferative and cytotoxic effects were examined after nicotine treatment in mice and rats. Nicotine hydrogen tartrate was administered in drinking water to rats (52 ppm nicotine) and mice (514 ppm nicotine) for 4 weeks and urothelial changes were evaluated. Histopathologically, 7/10 rats and 4/10 mice showed simple hyperplasia following nicotine treatment compared to none in the controls. Rats had an increased mean BrdU labeling index compared to controls, although it was not statistically significantly elevated in either species. Scanning electron microscopic visualization of the urothelium did not reveal significant cytotoxicity. These findings suggest that oral nicotine administration induced urothelial hyperplasia (increased cell proliferation), possibly due to a

Oral or parenteral administration of replication-deficient adenoviruses expressing the measles virus haemagglutinin and fusion proteins: protective immune responses in rodents.

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Fooks, A R; Jeevarajah, D; Lee, J; Warnes, A; Niewiesk, S; ter Meulen, V; Stephenson, J R; Clegg, J C

1998-05-01

The genes encoding the measles virus (MV) haemagglutinin (H) and fusion (F) proteins were placed under the control of the human cytomegalovirus immediate early promoter in a replication-deficient adenovirus vector. Immunofluorescence and radioimmune precipitation demonstrated the synthesis of each protein and biological activity was confirmed by the detection of haemadsorption and fusion activities in infected cells. Oral as well as parenteral administration of the H-expressing recombinant adenovirus elicited a significant protective response in mice challenged with MV. While the F-expressing adenovirus failed to protect mice, cotton rats immunized with either the H- or F-expressing recombinant showed reduced MV replication in the lungs. Antibodies elicited in mice following immunization with either recombinant had no in vitro neutralizing activity, suggesting a protective mechanism involving a cell-mediated immune response. This study demonstrates the feasibility of using oral administration of adenovirus recombinants to induce protective responses to heterologous proteins.

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

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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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Oral Administration of Heat-Killed Mycobacterium manresensis Delays Progression toward Active Tuberculosis in C3HeB/FeJ Mice.

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Cardona, Paula; Marzo-Escartín, Elena; Tapia, Gustavo; Díaz, Jorge; García, Vanessa; Varela, Ismael; Vilaplana, Cristina; Cardona, Pere-Joan

2015-01-01

Low-dose tolerance using heat-killed mycobacteria has been tested as a means of stopping progression toward active tuberculosis (TB) lesions in a human-like murine model using C3HeB/FeJ mice. In the present study, we studied the effect of different treatment schedules with heat-killed non-tuberculous-mycobacteria (NTM) species when given orally, based on the hypothesis of generating oral tolerance. This study included M. manresensis, a new species belonging to the fortuitum group, present in drinking water. Oral treatment with M. manresensis for 2 weeks was able to induce a PPD-specific Tregs population, which has been related to a decrease in the neutrophilic infiltration found in TB lesions. Further mechanistic analysis using PPD-stimulated splenocytes links this 2-week treatment with heat-killed M. manresensis to IL-10 production and memory PPD-specific Tregs, and also to a weak PPD-specific global immune response stimulation, increasing IL-6, TNF, and IFN-γ production. In lungs, this treatment decreased the bacillary load, granulomatous infiltration and pro-inflammatory cytokines (TNF, IFN-γ, IL-6, and IL-17). Oral administration of M. manresensis during standard treatment for TB also significantly reduced the relapse of active TB after ending the treatment. Overall the data suggest that the use of heat-killed M. manresensis could be a new and promising tool for avoiding active TB induction and as adjunctive to TB treatment. This supports the usefulness of generating a new kind of protection based on a complex balanced immune response focused on both destroying the bacilli and including control of an excessive inflammatory response.

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

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

2017-07-01

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

Effects of beer administration in mice on acute toxicities induced by X rays and carbon ions

International Nuclear Information System (INIS)

Monobe, Manami

2003-01-01

We have investigated the tissue specificity of radioprotection by beer, which was previously found for human lymphocytes. C3H/He female mice, aged 14 weeks, received an oral administration of beer, ethanol or saline at a dose of 1 ml/mouse 30 min before whole-body irradiation with 137 Cs γ rays or 50 keV/μm carbon ions. The dicentrics of chromosome aberrations in spleen cells were significantly (p 0 (slope of a dose-survival curve) for γ rays and carbon ions as well. Beer administration significantly (p 50/30 (radiation dose required to kill 50% of mice within 30 days) for γ rays and carbon ions. Ethanol-administration also significantly (p 50/30 value for γ rays, but not for carbon ions. It is concluded that beer administration reduces the radiation injury caused by photons and carbon ions, depending on the tissue type. Radioprotection by beer administration is not solely due to OH radical-scavenging action by the ethanol contained in beer. (author)

Analysis of the toxicity and histopathology induced by the oral administration of Pseudanabaena galeata and Geitlerinema splendidum (cyanobacteria) extracts to mice.

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Rangel, Marisa; Martins, Joyce C G; Garcia, Angélica Nunes; Conserva, Geanne A A; Costa-Neves, Adriana; Sant'Anna, Célia Leite; de Carvalho, Luciana Retz

2014-01-22

Cyanobacteria are common members of the freshwater microbiota in lakes and drinking water reservoirs, and are responsible for several cases of human intoxications in Brazil. Pseudanabaena galeata and Geitlerinema splendidum are examples of the toxic species that are very frequently found in reservoirs in Sao Paulo, which is the most densely populated area in Brazil. In the search for toxic strains collected from water reservoirs and maintained in the Cyanobacterial Culture Collection (CCIBt) of the Institute of Botany of Brazil, the acetic acid extracts (AE) of P. galeata CCIBt 3082 and G. splendidum CCIBt 3223 were analyzed by planar chromatography, which indicated the absence of cyanotoxins. Animal tests were then carried out, and both extracts were found to induce toxic effects in mice when administered intraperitoneally. The present study aimed to investigate whether the oral ingestion of the above mentioned cyanobacteria extracts would also induce toxic effects in mice. Necropsy and histopathological studies were conducted using tissue samples from the animals, which were euthanized one week after the administration of the extracts. The AE of P. galeata did not cause death but did induce transient symptoms, including eyebrow ptosis, straub tail, and pain. The euthanized animals presented hemorrhage in the liver, whereas the histological analysis showed disorganization of the hepatic parenchyma, necrosis, hyperemia, and proximity of the centrilobular vein in the liver. In addition, alterations in the convoluted tubules of the kidneys were observed, and the lungs were unaffected. The AE of G. splendidum caused only one death, and induced transient symptoms, such as dyspnea, paralysis, and pain, in the other mice. The necropsy of the euthanized mice showed hemorrhage in the lungs and liver. The lungs presented hemorrhagic focuses, alveolar collapse, and granulomatous foci. The liver presented hemorrhagic and enlarged sinusoids, hyperemia, proximity of the

Intranasal administration of live Lactobacillus species facilitates protection against influenza virus infection in mice.

Science.gov (United States)

Youn, Ha-Na; Lee, Dong-Hun; Lee, Yu-Na; Park, Jae-Keun; Yuk, Seong-Su; Yang, Si-Yong; Lee, Hyun-Jeong; Woo, Seo-Hyung; Kim, Hyoung-Moon; Lee, Joong-Bok; Park, Seung-Yong; Choi, In-Soo; Song, Chang-Seon

2012-01-01

Influenza virus infections continue to be a significant public health problem. For improved therapies and preventive measures against influenza, there has been an increased tendency in modern medicine involving the use of probiotics. In this study, we compared the protective efficacy of various live and dead Lactobacillus species against challenge with influenza virus in mice according to the administration route and dose. In addition, to understand the underlying mechanism behind this clinical protective effect, we performed immunologic assays including examination of IgA levels and cytokine profiles in the lung. The survival rate of mice receiving intranasal administration of Lactobacillus was higher than after oral administration, and administration of live bacteria was more protective than of dead bacteria. The lung levels of interleukin (IL)-12 and IgA were significantly increased (PLactobacillus strains on influenza virus infection. Therefore, for clinical applications, selection of effective strains could be critical and individually optimized application regimens of the selected strains are required. Copyright © 2011 Elsevier B.V. All rights reserved.

Influence of Vehicles Used for Oral Dosing of Test Molecules on the Progression of Mycobacterium tuberculosis Infection in Mice

OpenAIRE

Singh, Shubhra; Dwivedi, Richa; Chaturvedi, Vinita

2014-01-01

Preclinical evaluation of drug-like molecules requires their oral administration to experimental animals using suitable vehicles. We studied the effect of oral dosing with corn oil, carboxymethyl cellulose, dimethyl sulfoxide, and polysorbate-80 on the progression of Mycobacterium tuberculosis infection in mice. Infection was monitored by physical (survival time and body weight) and bacteriological (viable counts in lungs) parameters. Compared with water, corn oil significantly improved both ...

Improvement of skin condition by oral administration of collagen hydrolysates in chronologically aged mice.

Science.gov (United States)

Wang, Zhenbin; Wang, Qing; Wang, Lin; Xu, Weidong; He, Yuanqing; Li, Yunliang; He, Song; Ma, Haile

2017-07-01

Collagen hydrolysates (CHs) have been demonstrated to have positive effects on skin photoaging by topical application or oral ingestion. However, there has been little research on their influence on skin chronological aging. In this study, 9-month-old female ICR mice were given normal AIN-93M diets containing CHs (2.5, 5 and 10% w/w) from Nile tilapia scale. After 6 months, the collagen content and antioxidant enzyme (superoxide dismutase and glutathione peroxidase) activities increased significantly (P skin did not change (P > 0.05). The color, luster and quantity of hair were obviously ameliorated. Moreover, the structure of epidermis and dermis, the density and distribution of collagen fibers and the ratio of type I to type III collagen were improved in a dose-dependent manner as shown by histochemical staining. Oral ingestion of CHs increased the collagen content and antioxidant enzyme activities and improved the appearance and structure of skin. These results suggest the potential of CHs as an anti-skin-aging ingredient in nutraceuticals or functional foods. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Aqueous stability and oral pharmacokinetics of meloxicam and carprofen in male C57BL/6 mice.

Science.gov (United States)

Ingrao, Joelle C; Johnson, Ron; Tor, Elizabeth; Gu, Yu; Litman, Marcus; Turner, Patricia V

2013-09-01

We found that carprofen and meloxicam under 3 environmental conditions (ambient dark, ambient light, and 4 °C) remained stable for at least 7 d. We then evaluated the oral pharmacokinetics of meloxicam (20 mg/kg) and carprofen (10 mg/kg) in male C57BL/6 mice after oral gavage or administration in the drinking water. Mice did not drink meloxicam-medicated water but readily consumed carprofen-medicated water, consuming an average of 14.19 mL carprofen-medicated water per 100 g body weight daily; mice drank more during the dark phase than during the light phase. Plasma analyzed by HPLC (meloxicam) and tandem mass spectrometry (carprofen) revealed that the peak meloxicam and carprofen concentrations were 16.7 and 20.3 μg/mL and occurred at 4 and 2 h after oral gavage, respectively. Similar blood levels were achieved after 12 h access to the carprofen-medicated water bottle. At 24 h after oral gavage, the drugs were not detectable in plasma. Meloxicam plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.4 mg/L × h, 7.4 h, 0.36 L/kg, and 0.125 mL/h × kg, respectively. Carprofen plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.8 mg/L × h, 7.4 h, 0.42 L/kg, and 0.062 mL/h × kg, respectively. No gross or microscopic evidence of toxicity was seen in any mouse. Our findings indicate that carprofen can be administered in drinking water to mice and that medicated water bottles should be placed 12 to 24 h prior to painful procedures.

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

Science.gov (United States)

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

2017-02-01

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

Intravenous voriconazole after toxic oral administration

NARCIS (Netherlands)

Alffenaar, J.W.C.; Van Assen, S.; De Monchy, J.G.R.; Uges, D.R.A.; Kosterink, J.G.W.; Van Der Werf, T.S.

In a male patient with rhinocerebral invasive aspergillosis, prolonged high-dosage oral administration of voriconazole led to hepatotoxicity combined with a severe cutaneous reaction while intravenous administration in the same patient did not. High concentrations in the portal blood precipitate

Oral cadmium chloride intoxication in mice

DEFF Research Database (Denmark)

Andersen, O; Nielsen, J B; Svendsen, P

1988-01-01

Diethyldithiocarbamate (DDC) is known to alleviate acute toxicity due to injection of cadmium salts. However, when cadmium chloride was administered by the oral route, DDC enhanced rather than alleviated the acute toxicity; both oral and intraperitoneal (i.p.) administration of DDC had this effect...

Oral iron administration in suckling piglets – a review

Directory of Open Access Journals (Sweden)

Martin Svoboda

2018-01-01

Full Text Available Iron deficiency is presently a serious problem in suckling piglets on pig farms. The most often used method of anaemia prevention in piglets is parenteral administration of iron dextran. Oral iron represents an alternative to this method. The goal of this article is to review current knowledge on oral iron administration in suckling piglets. The substances that can be used for this purpose include iron dextran, iron salts, iron chelates, carbonyl iron, an iron polymaltose complex and iron microparticles. The different methods of oral iron administration in piglets are discussed.

Analysis of the Toxicity and Histopathology Induced by the Oral Administration of Pseudanabaena galeata and Geitlerinema splendidum (Cyanobacteria Extracts to Mice

Directory of Open Access Journals (Sweden)

Marisa Rangel

2014-01-01

Full Text Available Cyanobacteria are common members of the freshwater microbiota in lakes and drinking water reservoirs, and are responsible for several cases of human intoxications in Brazil. Pseudanabaena galeata and Geitlerinema splendidum are examples of the toxic species that are very frequently found in reservoirs in Sao Paulo, which is the most densely populated area in Brazil. In the search for toxic strains collected from water reservoirs and maintained in the Cyanobacterial Culture Collection (CCIBt of the Institute of Botany of Brazil, the acetic acid extracts (AE of P. galeata CCIBt 3082 and G. splendidum CCIBt 3223 were analyzed by planar chromatography, which indicated the absence of cyanotoxins. Animal tests were then carried out, and both extracts were found to induce toxic effects in mice when administered intraperitoneally. The present study aimed to investigate whether the oral ingestion of the above mentioned cyanobacteria extracts would also induce toxic effects in mice. Necropsy and histopathological studies were conducted using tissue samples from the animals, which were euthanized one week after the administration of the extracts. The AE of P. galeata did not cause death but did induce transient symptoms, including eyebrow ptosis, straub tail, and pain. The euthanized animals presented hemorrhage in the liver, whereas the histological analysis showed disorganization of the hepatic parenchyma, necrosis, hyperemia, and proximity of the centrilobular vein in the liver. In addition, alterations in the convoluted tubules of the kidneys were observed, and the lungs were unaffected. The AE of G. splendidum caused only one death, and induced transient symptoms, such as dyspnea, paralysis, and pain, in the other mice. The necropsy of the euthanized mice showed hemorrhage in the lungs and liver. The lungs presented hemorrhagic focuses, alveolar collapse, and granulomatous foci. The liver presented hemorrhagic and enlarged sinusoids, hyperemia

The effect of oral administration of Allium sativum extracts on lead nitrate induced toxicity in male mice.

Science.gov (United States)

Sharma, Veena; Sharma, Arti; Kansal, Leena

2010-03-01

Lead is a common environmental occupational toxic metal, known to have indirect oxidative effects. Considering the antioxidant properties of garlic, this study was undertaken to evaluate the therapeutic efficacy of garlic extracts in terms of normalization of altered hematological, biochemical and immunological parameters, and depletion of inorganic lead burden in blood, kidney and brain tissues. Chronic lead nitrate ingestion showed a significant decline in total erythrocyte count, total leukocyte count, hemoglobin concentration, lymphocyte and monocyte content, while neutrophil content increased in lead nitrate treated group. Pb(NO(3))(2) exposure elicited a significant escalation in thiobarbituric acid reactive substances level and depletion in reduced glutathione content and antioxidant enzymes namely, superoxide dismutase and catalase in kidney and brain. Activities of aspartate transaminase, alanine transaminase, acid phosphatase and alkaline phosphatase augmented significantly in kidney and brain of lead exposed mice. Lead nitrate treatment decreased protein content while cholesterol and lead burden increased significantly. A decrease in viability of macrophage, phagocytic index, immunoglobulin level and plaque count were the salient features observed in lead exposed animals. However, oral administration of garlic extracts to Pb(NO(3))(2) treated groups attenuated the deranged parameters to some extent. This indicates that garlic can be a protective regimen for lead toxicity. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Subchronic Oral Bromocriptine Methanesulfonate Enhances Open Field Novelty-Induced Behavior and Spatial Memory in Male Swiss Albino Mice

OpenAIRE

Onaolapo, Olakunle James; Onaolapo, Adejoke Yetunde

2012-01-01

This study set out to assess the neurobehavioral effects of subchronic, oral bromocriptine methanesulfonate using the open field and the Y-maze in healthy male mice. Sixty adult Swiss albino mice were assigned into three groups. Controls received normal saline, while test groups received bromocriptine methanesulfonate at 2.5 and 5 mg/kg/day, respectively, for a period of 21 days. Neurobehavioral tests were carried out on days 1 and 21 after administration. Open field assessment on day 1 after...

Effects of BCL oral administation and herbal acupuncture at BL18, BL19 on Liver function changes induced by Alcohol in the mice

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Sa-Hyun Park

2002-02-01

Full Text Available This dissertation was designed to evaluate the effect of BCL(refinded Bambusae Caulis in Liqua-men oral administration and herbal acupuncture on alcohol metabolism and liver function. For this study. mice were damaged by a large quantity of alcohol and received treatment of either BCL 1 mg/kg in oral or BCL 250㎍/kg in herbal acupuncture-BL18 . BL19 bilateral. and then such parameters as GOT. GPT. catalase and superoxide dismustase(CuZn-SOD, Mn-SOD were measured. The results of the experiments were summarized as follows. 1. Compared with control group, the proper degree of alcohol in serum was not significantly differ from oral administration group and herbal acupuncture group. 2. Compared with control group. the activity of GOT in serum was significantly reduced both oral administration and herbal acupuncture group. 3. Compared with control group. the activity of GPT in serum was significantly reduced both oral administration and herbal acupuncture group. 4. The activity of catalase in liver cell tissue, compared with control group. was not sigificantly affected either by oral administration and herbal acupuncture group. 5. The activity of CuZn-SOD in liver cell tissue was not significantly change in herbal acupuncture and oral administration group. The activity of Mn-SOD was significantly increased in oral administration group. while it was not the case in acupuncture group. In conclusion. we consider that BCL oral administration and herbal acupuncture is highly effetive in recovering alcohol metabolism and liver disfunction induced by alcohol.

Operant ethanol self-administration in ethanol dependent mice.

Science.gov (United States)

Lopez, Marcelo F; Becker, Howard C

2014-05-01

While rats have been predominantly used to study operant ethanol self-administration behavior in the context of dependence, several studies have employed operant conditioning procedures to examine changes in ethanol self-administration behavior as a function of chronic ethanol exposure and withdrawal experience in mice. This review highlights some of the advantages of using operant conditioning procedures for examining the motivational effects of ethanol in animals with a history of dependence. As reported in rats, studies using various operant conditioning procedures in mice have demonstrated significant escalation of ethanol self-administration behavior in mice rendered dependent via forced chronic ethanol exposure in comparison to nondependent mice. This paper also presents a summary of these findings, as well as suggestions for future studies. Copyright © 2014 Elsevier Inc. All rights reserved.

Efficacy of thiolated eudragit microspheres as an oral vaccine delivery system to induce mucosal immunity against enterotoxigenic Escherichia coli in mice.

Science.gov (United States)

Lee, Won-Jung; Cha, Seungbin; Shin, Minkyoung; Jung, Myunghwan; Islam, Mohammad Ariful; Cho, Chong-su; Yoo, Han Sang

2012-05-01

A vaccine delivery system based on thiolated eudragit microsphere (TEMS) was studied in vivo for its ability to elicit mucosal immunity against enterotoxigenic Escherichia coli (ETEC). Groups of mice were orally immunized with F4 or F18 fimbriae of ETEC and F4 or F18 loaded in TEMS. Mice that were orally administered with F4 or F18 loaded TEMS showed higher antigen-specific IgG antibody responses in serum and antigen-specific IgA in saliva and feces than mice that were immunized with antigens only. In addition, oral vaccination of F4 or F18 loaded TEMS resulted in higher numbers of IgG and IgA antigen-specific antibody secreting cells in the spleen, lamina propria, and Peyer's patches of immunized mice than other groups. Moreover, TEMS administration loaded with F4 or F18 induced mixed Th1 and Th2 type responses based on similarly increased levels of IgG1 and IgG2a. These results suggest that F4 or F18 loaded TEMS may be a promising candidate for an oral vaccine delivery system to elicit systemic and mucosal immunity against ETEC. Copyright © 2012 Elsevier B.V. All rights reserved.

Nickel Excretion in Urine after Oral Administration

DEFF Research Database (Denmark)

Menne, T.; Mikkelsen, H. I.; Solgaard, Per Bent

1978-01-01

In recent years the importance of internal exposure to nickel in patients with recurrent hand eczema and nickel allergy has become evident. The present study was performed in order to investigate the value of urinary nickel determinations as an index of oral nickel intake. After oral administration...

Cystic echinococcosis therapy: Albendazole-loaded lipid nanocapsules enhance the oral bioavailability and efficacy in experimentally infected mice.

Science.gov (United States)

Pensel, Patricia E; Ullio Gamboa, Gabriela; Fabbri, Julia; Ceballos, Laura; Sanchez Bruni, Sergio; Alvarez, Luis I; Allemandi, Daniel; Benoit, Jean Pierre; Palma, Santiago D; Elissondo, María C

2015-12-01

Therapeutic failures attributed to medical management of cystic echinococcosis (CE) with albendazole (ABZ) have been primarily linked to the poor drug absorption rate resulting in low drug level in plasma and hydatid cysts. Lipid nanocapsules (LNCs) represent nanocarriers designed to encapsulate lipophilic drugs, such as ABZ. The goals of the current work were: (i) to characterize the plasma and cyst drug exposure after the administration of ABZ as ABZ-LNCs or ABZ suspension (ABZ-SUSP) in mice infected with Echinococcus granulosus, and ii) to compare the clinical efficacies of both ABZ formulations. Enhanced ABZ sulphoxide (ABZ-SO) concentration profiles were obtained in plasma and cysts from ABZ-LNC treated animals. ABZSO exposure (AUC0-LOQ) was significantly higher in plasma and cyst after the ABZ-LNC treatments, both orally and subcutaneously, compared to that observed after oral administration of ABZ-SUSP. Additionally, ABZSO concentrations measured in cysts from ABZ-LNC treated mice were 1.7-fold higher than those detected in plasma. This enhanced drug availability correlated with an increased efficacy against secondary CE in mice observed for the ABZ-LNCs, while ABZ-SUSP did not reach differences with the untreated control group. This new pharmacotechnically-based strategy could be a potential alternative to improve the treatment of human CE. Copyright © 2015 Elsevier B.V. All rights reserved.

Oral administration of Bifidobacterium bifidum G9-1 alleviates rotavirus gastroenteritis through regulation of intestinal homeostasis by inducing mucosal protective factors.

Science.gov (United States)

Kawahara, Tomohiro; Makizaki, Yutaka; Oikawa, Yosuke; Tanaka, Yoshiki; Maeda, Ayako; Shimakawa, Masaki; Komoto, Satoshi; Moriguchi, Kyoko; Ohno, Hiroshi; Taniguchi, Koki

2017-01-01

Human rotavirus (RV) infection is a leading cause of dehydrating diarrhea in infants and young children worldwide. Since therapeutic approaches to RV gastroenteritis are limited to alleviation of dehydration with oral rehydration solutions, more direct approaches to palliate symptoms of RV gastroenteritis are required. Treatments with probiotics have been increasingly recognized as alternative safe and low cost treatments for moderate infectious diarrhea. In this study, Bifidobacterium bifidum G9-1 (BBG9-1), which has been used as an intestinal drug for several decades, was shown to have a remarkable protective effect against RV gastroenteritis in a suckling mice model. As well as prophylactic oral administration of BBG9-1 from 2 days before RV infection, therapeutic oral administration of BBG9-1 from 1 day after RV infection significantly alleviated RV-induced diarrhea. Therapeutic administration of BBG9-1 reduced various types of damage in the small intestine, such as epithelial vacuolization and villous shortening, and significantly diminished the infectious RV titer in mixtures of cecal contents and feces. It was also shown that therapeutic administration of BBG9-1 significantly increased the number of acidic mucin-positive goblet cells and the gene expression of mucosal protective factors including MUC2, MUC3, MUC4, TGFβ1 and TFF3 in the small intestine. This led to alleviation of low gut permeability shown as decreased gene expression levels of occludin, claudin-1 and villin-1 after RV infection. Furthermore, in the small intestine, therapeutic administration of BBG9-1 significantly palliated the decreased gene expression of SGLT-1, which plays an important role in water absorption. In the large intestine, administered BBG9-1 was shown to replicate to assimilate undigested nutrients, resulting in normalization of the abnormally high osmotic pressure. These results suggested that water malabsorption caused by RV infection was alleviated in mice administered

Oral administration of Bifidobacterium bifidum G9-1 alleviates rotavirus gastroenteritis through regulation of intestinal homeostasis by inducing mucosal protective factors.

Directory of Open Access Journals (Sweden)

Tomohiro Kawahara

Full Text Available Human rotavirus (RV infection is a leading cause of dehydrating diarrhea in infants and young children worldwide. Since therapeutic approaches to RV gastroenteritis are limited to alleviation of dehydration with oral rehydration solutions, more direct approaches to palliate symptoms of RV gastroenteritis are required. Treatments with probiotics have been increasingly recognized as alternative safe and low cost treatments for moderate infectious diarrhea. In this study, Bifidobacterium bifidum G9-1 (BBG9-1, which has been used as an intestinal drug for several decades, was shown to have a remarkable protective effect against RV gastroenteritis in a suckling mice model. As well as prophylactic oral administration of BBG9-1 from 2 days before RV infection, therapeutic oral administration of BBG9-1 from 1 day after RV infection significantly alleviated RV-induced diarrhea. Therapeutic administration of BBG9-1 reduced various types of damage in the small intestine, such as epithelial vacuolization and villous shortening, and significantly diminished the infectious RV titer in mixtures of cecal contents and feces. It was also shown that therapeutic administration of BBG9-1 significantly increased the number of acidic mucin-positive goblet cells and the gene expression of mucosal protective factors including MUC2, MUC3, MUC4, TGFβ1 and TFF3 in the small intestine. This led to alleviation of low gut permeability shown as decreased gene expression levels of occludin, claudin-1 and villin-1 after RV infection. Furthermore, in the small intestine, therapeutic administration of BBG9-1 significantly palliated the decreased gene expression of SGLT-1, which plays an important role in water absorption. In the large intestine, administered BBG9-1 was shown to replicate to assimilate undigested nutrients, resulting in normalization of the abnormally high osmotic pressure. These results suggested that water malabsorption caused by RV infection was alleviated in

The pharmacokinetics of L-tryptophan following its intravenous and oral administration.

OpenAIRE

Green, A R; Aronson, J K; Cowen, P J

1985-01-01

The pharmacokinetics of L-tryptophan (5 g and 7.5 g) have been studied after its intravenous administration to healthy subjects and the results compared with those obtained after oral administration (0.7 g-3.5 g). In order to do this, we have re-analysed previously published data relating to oral administration. The data obtained following the oral administration of L-tryptophan suggest that the total body clearance and apparent volume of distribution are saturable. The pharmacokinetics of tr...

Comparison of the Intraperitoneal, Retroorbital and per Oral Routes for F 18 FDG Administration as Effective Alternatives to Intravenous Administration in Mouse Tumor Models Using Small Animal PET/CT Studies

International Nuclear Information System (INIS)

Kim, Chulhan; Kim, In Hye; Kim, Seo il; Kim, Young Sang; Kang, Se Hun; Moon, Seung Hwan; Kim, Tae Sung; Kim, Seok ki

2011-01-01

We compared alternative routes for 18F fluorodeoxyglucose (FDG) administration, such as the retroorbital (RO), intraperitoneal (IP) and per oral (PO) routes, with the intravenous (IV) route in normal tissues and tumors of mice. CRL 1642 (ATCC, Lewis lung carcinoma) cells were inoculated in female BALB/c nu/nu mice 6 to 10 weeks old. When the tumor grew to about 9mm in diameter, positron emission tomography (PET) scans were performed after FDG administration via the RO, IP, PO or IV route. Additional serial PET scans were performed using the RO, IV or IP route alternatively from 5 to 29 days after the tumor cell injection. There was no significant difference in the FDG uptake in normal tissues at 60 min after FDG administration via RO, IP and IV routes. PO administration, however, showed delayed distribution and unwanted high gastrointestinal uptake. Tumoral uptake of FDG showed a similar temporal pattern and increased until 60 min after FDG administration in the RO, IP and IV injection groups. In the PO administration group, tumoral uptake was delayed and reduced. There was no statistical difference among the RO, IP and IV administration groups for additional serial PET scans. RO administration is an effective alternative route to IV administration for mouse FDG PET scans using normal mice and tumor models. In addition, IP administration can be a practical alternative in the late phase, although the initial uptake is lower than those in the IV and RO groups.

The effect of chronic administration of ketoconazol on spermatogenesis indices and testis tissue in mice

Directory of Open Access Journals (Sweden)

S.E Safavi

2009-02-01

Full Text Available Ketoconazole, a broad spectrum antifungal agent has been employed widely in the treatment of fungal diseases. In addition to being antifungal, studies have indicated that this drug has an inhibitory effect on steroid hormone production including glucocorticoids and sex hormones and also its administration causes reduction in the amount of blood testosterone level and histologic changes in testicular tissue of laboratory animals. The aim of this study is to determine the effect of long term ketoconazole administration on spermatogenesis indices in testicular tissue of mice. In this experimental study 50 male mice were used which were allocated to 5 groups each containing 10 animals. The mice received a 50 mg/kg dose of ketoconazole daily for a period of 15 days, 1, 2 and 3 months orally. One group was used as the control and the other 4 groups received Ketoconazole, testicular tissue samples were collected at the end of the aforementioned time period, and after preparation of tissue sections and staining with hematoxylin and coin the spermiogenesis indices including tubular differentiation index (TDI, spermatogenesis index (SI and repopulation index (RI were studied. The results indicated that SI and RI decreased significantly (p

Fenproporex and amphetamine pharmacokinetics in oral fluid after controlled oral administration of fenproporex.

Science.gov (United States)

Comiran, Eloisa; Souza, Daniele Zago; Boehl, Paula Otero; Cássia Mariotti, Kristiane de; Pechansky, Flavio; Duarte, Paulina do Carmo Arruda Vieira; De Boni, Raquel Brandini; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

2012-10-01

Fenproporex hydrochloride (FEN) is an anorectic drug used in the treatment of obesity, and its major metabolite is amphetamine (AMP), another central nervous system stimulant. The concentration versus time profile of FEN and its metabolite AMP has been described in classic biological matrices such as plasma and urine; however, there are no reports of such data in oral fluid. The aim of this study is to describe the pharmacokinetics of FEN and AMP in oral fluid after intake of FEN. Twenty-five milligrams of FEN (1 capsule of Desobesi-m) was orally administered to 6 male volunteers, and oral fluid samples were collected with a Quantisal device during 24.00 hours after drug ingestion. These samples were submitted to solid-phase microextraction before analysis by gas chromatography-mass spectrometry in the selected-ion-monitoring mode, using deuterium-labeled AMP as internal standard. After FEN administration, both analytes could be detected in oral fluid of all volunteers with an initial detection time varying from 0.50 to 1.00 hour. FEN peak concentrations occurred between 1.00 and 1.50 hours after administration and were between 70.7 and 227.5 μg/L. For AMP, peak concentration occurred between 1.50 and 4.00 hours, reaching 33.0-150.9 μg/L. The authors observed that oral administration of FEN resulted in significant amounts of FEN and AMP in oral fluid, showing that oral fluid could be a biological matrix suitable for pharmacokinetic studies for both analytes. Using a compartmental approach, FEN data were best fitted by 1-compartment model with first-order input and output, whereas AMP followed a 2-compartment model with first-order input and output.

Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

Science.gov (United States)

Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

2012-01-01

The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

Pharmacokinetics of oxiracetam and its degraded substance (HOPAA after oral and intravenous administration in rats

Directory of Open Access Journals (Sweden)

Xinhuan Wan

2014-12-01

Full Text Available The pharmacokinetics of oxiracetam and its degraded substance (4-hydroxy-2-oxo-1-pyrrolidine acetic acid, HOPAA after oral and intravenous administration in rats were studied using an established UPLC-MS/MS method. Three groups of rats after an overnight fasted received 10 g/kg (n = 6 oxiracetam suspensions orally, and 2 g/kg (n = 6 normal or degraded oxiracetam injections intravenously via a caudal tail vein, respectively. Before the pharmacokinetic experiment, a simple safety evaluation test was conducted on the degraded oxiracetam injections containing 16.16% HOPAA in mice. There was no mortality by a single intravenous dose of 2 g/kg of degraded oxiracetam injections within two weeks, demonstrating that HOPAA was non-toxic in mice. Following intravenous administration of the normal injections, the plasma concentration-time curves of oxiracetam and HOPAA both showed a rapid elimination phase. The values of t1/2 were 3.1 ± 1.5 h for oxiracetam and 0.8 ± 0.2 h for HOPAA, and the mean residence times (MRT were 1.2 ± 0.1 h and 0.8 ± 0.1 h, respectively. Oxiracetam and HOPAA after intravenous administration of the degraded oxiracetam injections presented elimination patterns similar to those observed in the normal injections. Oral pharmacokinetic results showed that the Tmax was less than 1.5 h for the two analytes, and both had a longer t1/2 and MRT than those of intravenous administration. Contents of HOPAA in three groups were calculated based on AUC0–t values of the two analytes. The quantitative change of HOPAA in vivo was also evaluated by comparing the plasma concentrations of HOPAA and oxiracetam at the same time for every group. Additionally, the values of absolute bioavailability of oxiracetam were about 8.0% and 7.4% calculated by the normal or degraded oxiracetam injections, which were far less than the value of 75% reported in literature, indicating the necessity of further study.

Symbiotic maple saps minimize disruption of the mice intestinal microbiota after oral antibiotic administration.

Science.gov (United States)

Hammami, Riadh; Ben Abdallah, Nour; Barbeau, Julie; Fliss, Ismail

2015-01-01

This study was undertaken to evaluate the in vivo impact of new symbiotic products based on liquid maple sap or its concentrate. Sap and concentrate, with or without inulin (2%), were inoculated with Bifidobacterium lactis Bb12 and Lactobacillus rhamnosus GG valio at initial counts of 2-4 × 10(8) cfu mL(-1). The experiments started with intra-gastric administration of antibiotic (kanamycin 40 mg in 0.1 cc) (to induce microbiota disturbance and/or diarrhea) to 3-to-5-week-old C57BL/6 female mice followed by a combination of prebiotic and probiotics included in the maple sap or its concentrate for a week. The combination inulin and probiotics in maple sap and concentrate appeared to minimize the antibiotic-induced breakdown of mice microbiota with a marked effect on bifidobacterium and bacteroides levels, thus permitting a more rapid re-establishment of the baseline microbiota levels. Results suggest that maple sap and its concentrate represent good candidates for the production of non-dairy functional foods.

Toxoplasma gondii oral infection induces intestinal inflammation and retinochoroiditis in mice genetically selected for immune oral tolerance resistance.

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Raul Ramos Furtado Dias

Full Text Available Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS or resistance (TR to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-γ and TNF-α. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis.

Toxoplasma gondii Oral Infection Induces Intestinal Inflammation and Retinochoroiditis in Mice Genetically Selected for Immune Oral Tolerance Resistance

Science.gov (United States)

Dias, Raul Ramos Furtado; de Carvalho, Eulógio Carlos Queiroz; Leite, Carla Cristina da Silva; Tedesco, Roberto Carlos; Calabrese, Katia da Silva; Silva, Antonio Carlos; DaMatta, Renato Augusto; de Fatima Sarro-Silva, Maria

2014-01-01

Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS) or resistance (TR) to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-γ and TNF-α. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis. PMID:25437299

Oral Administration of Pentoxifylline Reduces Endometriosis-Like Lesions in a Nude Mouse Model.

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Perelló, Maria; González-Foruria, Iñaki; Castillo, Paola; Martínez-Florensa, Mario; Lozano, Francisco; Balasch, Juan; Carmona, Francisco

2017-06-01

Recent reports consider endometriosis to be an immunological disorder, thus suggesting potential efficacy of immunomodulators for its treatment. The aim of this study was to assess the effects of oral administration of pentoxifylline on endometriosis-like lesions in a heterologous mice model. Human endometrial tissue obtained from women (n = 5) undergoing surgery for benign conditions was implanted in nude female mice (n = 30). The animals were distributed into 3 experimental groups receiving: saline 0.1 mL/d (control, group 1); pentoxifylline 100 mg/kg/d (group 2), and pentoxifylline 200 mg/kg/d (group 3). After 28 days, the number of implants and the total volume of surgically extracted tissue were recorded. Immunohistochemical analysis was performed to assess the area of endometriosis and vascularization of endometriosis-like lesions. Cytokine levels in peritoneal fluid samples were measured. Macroscopic quantification showed a trend to dose-dependent reduction in the number of the endometriosis-like lesions after 28 days. The volume was significantly reduced in group 3 versus group 2 and controls (399.10 ± 120.68 mm 3 vs 276.75 ± 94.30 mm 3 and 145.33 ± 38.20 mm 3 , respectively; P = .04). Similarly, the mean area of endometriosis was significantly lower in group 3 (0.12 ± 0.08 mm 2 ) versus group 2 (1.35 ± 0.43 mm 2 ) and control (2.84 ± 0.60 mm 2 ; P = .001). Vascularization and cytokine levels were also reduced posttreatment. Our results suggest that the oral administration of pentoxifylline may be an alternative to current therapies for endometriosis. Nonetheless, further studies are required.

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

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Maaike van Putten

2014-01-01

Full Text Available 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.

A 5-month toxicity study of the ethanol extract of the leaves of Heliotropium indicum in Sprague Dawley rats after oral administration.

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Owolabi, M A; Oribayo, O O; Ukpo, G E; Mbaka, G O; Akindehin, O E

2015-01-01

Heliotropium indicum Linn. (Boraginaceae) is used in Nigerian traditional medicine to treat tuberculosis with treatment lasting for 3 months; however, information on its toxicity is scarce. This study investigated the safety of the leaves of Heliotropium indicum after a 5 month oral administration. The leaves of H. indicum were dried; extracted in 70% ethanol and concentrated to dryness. Swiss mice were administered orally with single doses of the extract (0.5 to 12.0 g/kg b.wt /day); mortality was examined for up to 14 days. In another study, the plant material (0.5 to 2.0 g/kg b.wt /day) were administered daily by oral gavage to Sprague Dawley rats. Body weight was monitored weekly, hematological, biochemical and organ parameters were determined at the end of the 1st, 2nd and 5th months of extract administration. The oral administration of the ethanol extract of H. indicum caused dose-dependent mortality. The LD50 was 9.78 g/kg b.wt for the Swiss mice; no harmful effect was observed on the liver and kidney except the testes which exhibited considerable inflammatory changes at the highest dose of 2.0 g/kg b.wt./day after the 5th month treatment. No significant difference (P>0.05) was shown in the enzyme study, marginal increase occurred in some haematological parameters. The increase in body weight of the treated rats after its initial reduction was consistent and significantly different (P<0.05) from their initial body weight. Prolonged administration of the crude leaf extract of H. indicum is considered to be safe and nontoxic at the doses studied. However, there is a probability of a negative effect on the testes at a higher dose of the extract.

Evaluation of Sub-acute Oral Toxicity of Lithium Carbonate Microemulsion (Nano Size) on Liver and Kidney of Mice

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Kalantari, Heibatullah; Salimi, Anayatollah; Rezaie, Anahita; Jazayeri Shushtari, Fereshteh; Goudarzi, Mehdi

2015-01-01

Background: The development of drug delivery systems has improved the therapeutic and toxic properties of existing drugs in therapy. Microemulsion systems are novel vehicles for drug delivery, which have been developed in recent years. These systems are currently of interest to the pharmaceutical scientist because of their considerable potential to act as drug delivery vehicles by incorporating into a wide range of drug molecules. Although these systems improved solubility and bioavailability of drugs, they may have potential toxic effects on the body organs. Objectives: The purpose of this study was to examine a possible hepatotoxic and nephrotoxic effect of lithium carbonate microemulsion (LCME) in a mice model. Materials and Methods: Eighty male Swiss albino mice were randomly allocated to eight experimental groups, as follows: Group 1, as negative control group were treated orally with normal saline (0.9% NaCl); Group 2, received microemulsion base without drug as control group; Groups 3 to 5, received lithium carbonate (LC) solution in doses of 50, 100, and 200 mg/kg, respectively; Groups 6 to 8, received LCME orally in doses of 50, 100, and 200 mg/kg, respectively. All drugs were administered orally for ten consecutive days. Serum glutamate pyruvate aminotransferase (SGPT), serum glutamate oxaloacetate aminotransferase (SGOT), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and plasma creatinine (Cr), as markers of liver and kidney toxicity in treated mice, were measured. Furthermore, the changes of tissue were assessed by histopathologic examination. Results: The findings showed that serum activity of ALP, SGOT, and SGPT and the levels of BUN and Cr in microemulsion base group was greater than normal saline group. However, this difference was not significant. Administration of LC and LCME in all doses resulted in a significant increase in the levels of BUN and serum activity of SGOT and SGPT in comparison to normal saline group (P < 0

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

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Qi Ying Lean

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

The distribution of radioiodine administrated to pregnant mice and the effect of non radioactive iodide

International Nuclear Information System (INIS)

Okui, Toyo; Kobayashi, Satoshi

1987-01-01

Radioiodine, 131 I, which has a high fission yield in the nuclear reactor, is easily taken into the human body, accumilating in the thyroid gland, when released to the environment. 131 I was administrated orally to pregnant mice, and its transportation to the tissues, particularly the fetus, was examined closely. And further, the non-radioactive iodide, i.e., KI, was administrated to see its radiation protection effect. The transportation of 131 I to the fetus is the second highest, following the thyroid gland in the mother mouse. This transportation to the fetus becomes the higher, the larger the gestation period at which the 131 I administration is made. The administration of the non-radioactive iodide has large radiation protection effect in the thyroid gland of the mother mouse and of the fetus. But, depending on its concentration, the non-radioactive iodide may conversely increase overall exposure of the fetus. (Mori, K.)

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

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Siden, Rivka; Wolf, Matthew

2013-06-01

The administration of oral chemotherapeutic drugs can be problematic in patients with swallowing difficulties. Inability to swallow solid dosage forms can compromise compliance and may lead to poor clinical outcome. The current technique of tablet crushing to aid in administration is considered an unsafe practice. By developing a technique to disintegrate tablets in an oral syringe, the risk associated with tablet crushing can be avoided. The purpose of this study was to determine the feasibility of using disintegration in an oral syringe for the administration of oral chemotherapeutic tablets. Eight commonly used oral chemotherapeutic drugs were tested. Tablets were placed in an oral syringe and allowed to disintegrate in tap water. Various volumes and temperatures were tested to identify which combination allows for complete disintegration of the tablet in the shortest amount of time. The oral syringe disintegration method was considered feasible if disintegration occurred in ≤15 min and in ≤20 mL of water and the dispersion passed through an oral syringe tip. The following tablets were shown to disintegrate within 15 min and in disintegration test. Disintegrating oral chemotherapeutic tablets in a syringe provides a closed system to administer hazardous drugs and allows for the safe administration of oral chemotherapeutic drugs in a tablet form to patients with swallowing difficulties.

Oral Administration of Heat-Killed Lactobacillus gasseri OLL2809 Reduces Cedar Pollen Antigen-Induced Peritoneal Eosinophilia in Mice

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Toshihiro Sashihara

2008-01-01

Conclusions: We demonstrated that the oral administration of heat-killed L. gasseri OLL2809 suppresses eosinophilia via the modulation of Th1/Th2 balance. These observations suggested that heat-killed L. gasseri OLL2809 might potentially ameliorate the increased number of eosinophils in patients with Japanese cedar pollinosis.

Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.

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Matsushita, Masaki; Mishima, Kenichi; Esaki, Ryusaku; Ishiguro, Naoki; Ohno, Kinji; Kitoh, Hiroshi

2017-01-01

OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3 ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3 ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony bridges were scored on PD 4.5. In wild-type mice, tissue concentrations of meclozine in ED 17.5 fetuses and PD 6.5 pups were investigated. RESULTS The area of the foramen magnum was significantly smaller in 17-day-old Fgfr3 ach mice than in wild-type mice (p < 0.005). There were no bony bridges in the spheno-occipital and anterior intraoccipital synchondroses in wild-type mice, while some of the synchondroses prematurely closed in untreated Fgfr3 ach mice at PD 4.5. The average bony bridge score in the cranial base was 7.053 ± 1.393 in untreated Fgfr3 ach mice and 6.125 ± 2.029 in meclozine-treated Fgfr3 ach mice. The scores were not statistically significant between mice with and those without meclozine treatment (p = 0.12). The average tissue concentration of meclozine was significantly higher (508.88 ± 205.16 ng/g) in PD 6.5 mice than in ED 17.5 mice (56.91 ± 20.05 ng/g) (p < 0.005). CONCLUSIONS Maternal administration of meclozine postponed premature

Oral Metformin-Ascorbic Acid Co-Administration Ameliorates Alcohol ...

African Journals Online (AJOL)

Oral Metformin-Ascorbic Acid Co-Administration Ameliorates Alcohol-Induced Hepatotoxicity In Rats. ... Nigerian Quarterly Journal of Hospital Medicine ... the present in vivo animal study was to determine whether metformin-ascorbic acid co-administration also prevents alcoholic hepatotoxicity in chronic alcohol exposure.

Antibiotic administration alleviates the aggravating effect of orthodontic force on ligature-induced experimental periodontitis bone loss in mice.

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Shi, J; Liu, Z; Kawai, T; Zhou, Y; Han, X

2017-08-01

It is recognized that orthodontic force (OF) has an aggravating effect on the progression of destructive periodontitis if periodontitis have not been well controlled. However, the underlying mechanism is not completely clear. This study was to investigate the effect of antibiotic administration on OF-aggravated, ligature-induced experimental periodontitis in mice. C57BL/6 mice (male, 8 wk old) were divided into three groups (n = 8). Silk ligatures (SL) were tied around the maxillary right (group 1) or both (groups 2 and 3) first molars on day 0, removed on day 8 and systemic antibiotics was administered through drinking water (group 3) since day 8. OF was applied on the maxillary right first molars since day 13 (groups 2 and 3). All mice were killed on day 20. Total oral bacteria load was significantly higher in group 2 when compared to group 1 on day 20, whereas such count was greatly reduced in group 3 when antibiotics were administered. Periodontal bone loss was significantly increased on SL side vs. control side in group 1. Periodontal bone loss was significantly increased on OF + SL side vs. SL side in group 2 (p periodontal space and tooth movement were observed on OF + SL side in groups 2 and 3. Our results suggest that reduction of oral bacterial load by antibiotic administration alleviate orthodontic force-aggravated periodontitis bone loss. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Oral Administration of Recombinant Saccharomyces boulardii Expressing Ovalbumin-CPE Fusion Protein Induces Antibody Response in Mice.

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Bagherpour, Ghasem; Ghasemi, Hosnie; Zand, Bahare; Zarei, Najmeh; Roohvand, Farzin; Ardakani, Esmat M; Azizi, Mohammad; Khalaj, Vahid

2018-01-01

Saccharomyces boulardii , a subspecies of Saccharomyces cerevisiae , is a well-known eukaryotic probiotic with many benefits for human health. In the present study, a recombinant strain of S. boulardii was prepared to use as a potential oral vaccine delivery vehicle. In this sense, a ura3 auxotroph strain of S. boulardii CNCM I-745 (known as S. cerevisiae HANSEN CBS 5926, Yomogi ® ) was generated using CRISPR/Cas9 methodology. Then a gene construct encoding a highly immunogenic protein, ovalbumin (OVA), was prepared and transformed into the ura3 - S. boulardii . To facilitate the transport of the recombinant immunogen across the intestinal barrier, a claudin-targeting sequence from Clostridium perfringens enterotoxin (CPE) was added to the C-terminus of the expression cassette. The recombinant S. boulardii strain expressing the OVA-CPE fusion protein was then administered orally to a group of mice, and serum IgG and fecal IgA levels were evaluated by ELISA. Our results demonstrated that anti-OVA IgG in serum significantly increased in test group ( P boulardii or PBS), and the fecal IgA titer was significantly higher in test group ( P boulardii strain expressing the similar construct lacking C-terminal CPE was also administered orally. The result showed an increased level of serum IgG in group receiving yeasts expressing the CPE negative construct compared to control groups; however, the fecal IgA levels did not increase significantly. In conclusion, our findings indicated that the yeast S. boulardii , as a delivery vehicle with possible immunomodulatory effects, and c-CPE, as a targeting tag, synergistically assist to stimulate systemic and local immunity. This proposed recombinant S. boulardii system might be useful in the expression of other antigenic peptides, making it as a promising tool for oral delivery of vaccines or therapeutic proteins.

Effects of Oral Administration of Fucoidan Extracted from Cladosiphon okamuranus on Tumor Growth and Survival Time in a Tumor-Bearing Mouse Model

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Yoshiharu Okamoto

2012-10-01

Full Text Available We evaluated the anti-tumor activities of the oral administration of fucoidan extracted from Cladosiphon okamuranus using a tumor (colon 26-bearing mouse model. The materials used included low-molecular-weight fucoidan (LMWF: 6.5–40 kDa, intermediate-molecular-weight fucoidan (IMWF: 110–138 kDa and high-molecular-weight fucoidan (HMWF: 300–330 kDa. The IMWF group showed significantly suppressed tumor growth. The LMWF and HMWF groups showed significantly increased survival times compared with that observed in the control group (mice fed a fucoidan-free diet. The median survival times in the control, LMWF, IMWF and HMWF groups were 23, 46, 40 and 43 days, respectively. It was also found that oral administration of fucoidan increased the population of natural killer cells in the spleen. Furthermore, from the results of the experiment using Myd-88 knockout mice, it was found that these effects are related to gut immunity. These results suggest that fucoidan is a candidate anti-tumor functional food.

Repeated oral administration of capsaicin increases anxiety-like ...

Indian Academy of Sciences (India)

This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02% capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy ...

Immunohematopoietic modulation by oral β-1,3-glucan in mice infected with Listeria monocytogenes.

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Torello, Cristiane O; de Souza Queiroz, Julia; Oliveira, Sueli C; Queiroz, Mary L S

2010-12-01

In this study we demonstrated that the oral administration of β-1,3-glucan (Imunoglucan®) protects mice from a lethal dose of Listeria monocytogenes (LM) when administered prophylactically for 10 days at the doses of 150 and 300 mg/kg, with survival rates up to 40%. These doses also prevented the myelosuppression and the splenomegaly caused by a sublethal infection with LM, due to increased numbers of granulocyte-macrophage progenitors (CFU-GM) in the bone marrow. Investigation of the production of colony-stimulating factors revealed an increased colony-stimulating activity (CSA) in the serum of infected mice pre-treated with Imunoglucan®. The treatment also restored the reduced ability of stromal cells to display myeloid progenitors in long-term bone marrow cultures (LTBMC) and up-regulated IL-6 and IL-1α production by these cells in the infected mice, which was consistent with higher number of non-adherent cells. Additional studies to investigate the levels of interferon-gamma (INF-γ) in the supernatant of splenocyte cultures demonstrated a further increase in the level of this cytokine in infected-treated mice, compared to infected controls. In all cases, no differences were observed between the responses of the two optimal biologically effective doses. In contrast, no significant changes were produced by the treatment with the 50mg/kg dose. In addition, no changes were observed in normal mice treated with the three doses used. All together our results suggest that orally given Imunoglucan® indirectly modulates immune activity and probably disengages Listeria induced suppression of these responses by inducing a higher reserve of myeloid progenitors in the bone marrow in consequence of biologically active cytokine release (CSFs, IL-1α, IL-6, and INF-γ). Copyright © 2010 Elsevier B.V. All rights reserved.

Efficacy of oral immunotherapy with a rice-based edible vaccine containing hypoallergenic Japanese cedar pollen allergens for treatment of established allergic conjunctivitis in mice.

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Fukuda, Ken; Ishida, Waka; Harada, Yosuke; Wakasa, Yuhya; Takagi, Hidenori; Takaiwa, Fumio; Fukushima, Atsuki

2018-01-01

We have previously shown that prophylactic oral administration of transgenic rice seeds expressing hypoallergenic modified antigens suppressed the development of allergic conjunctivitis induced by Japanese cedar pollen. We have now investigated the efficacy of oral immunotherapy with such transgenic rice for established allergic conjunctivitis in mice. BALB/c mice were sensitized with two intraperitoneal injections of Japanese cedar pollen in alum, challenged with pollen in eyedrops, and then fed for 16 days with transgenic rice seeds expressing modified Japanese cedar pollen allergens Cry j 1 and Cry j 2 or with nontransgenic rice seeds as a control. They were then challenged twice with pollen in eyedrops, with clinical signs being evaluated at 15 min after the first challenge and the eyes, blood, spleen, and lymph nodes being isolated at 24 h after the second challenge. The number of eosinophils in the conjunctiva and the clinical score for conjunctivitis were both significantly lower in mice fed the transgenic rice than in those fed nontransgenic rice. Oral vaccination with transgenic rice seeds also resulted in a significant increase in the production of IFN-γ by splenocytes, whereas it had no effect on the number of CD4 + CD25 + Foxp3 + regulatory T cells in the spleen or submandibular or mesenteric lymph nodes. Oral administration of transgenic rice seeds expressing hypoallergenic allergens ameliorated allergic conjunctivitis in the established setting. Such a rice-based edible vaccine is potentially both safe and effective for oral immunotherapy in individuals with allergic conjunctivitis. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

Hepatoprotective effect of Fufang-Huanglu oral liquid on α ...

African Journals Online (AJOL)

Purpose: To investigate the effect of Fufang-Huanglu Oral Liquid (HOL) on hepatitis jaundice in mice. Methods: A total of 72 mice .... after 2 days of drug administration, the mice .... and reproduction in any medium, provided the original work is ...

Inhibition of Carrageenan-Induced Acute Inflammation in Mice by Oral Administration of Anthocyanin Mixture from Wild Mulberry and Cyanidin-3-Glucoside

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Neuza Mariko Aymoto Hassimotto

2013-01-01

Full Text Available Anthocyanins are flavonoids which demonstrated biological activities in in vivo and in vitro models. Here in the anti-inflammatory properties of an anthocyanin-enriched fraction (AF extracted from wild mulberry and the cyanidin-3-glucoside (C3G, the most abundant anthocyanin in diet, were studied in two acute inflammation experimental models, in the peritonitis and in the paw oedema assays, both of which were induced by carrageenan (cg in mice. In each trial, AF and C3G (4 mg/100 g/animal were orally administered in two distinct protocols: 30 min before and 1 h after cg stimulus. The administration of both AF and C3G suppresses the paw oedema in both administration times (P<0.05. In the peritonitis, AF and C3G reduced the polymorphonuclear leukocytes (PMN influx in the peritoneal exudates when administered 1 h after cg injection. AF was more efficient reducing the PMN when administered 30 min before cg. Both AF and C3G were found to suppress mRNA as well as protein levels of COX-2 upregulated by cg in both protocols, but the inhibitory effect on PGE2 production in the peritoneal exudates was observed when administered 30 min before cg (P<0.05. Our findings suggest that AF and C3G minimize acute inflammation and they present positive contributions as dietary supplements.

Arabidopsis thaliana plants expressing Rift Valley fever virus antigens: Mice exhibit systemic immune responses as the result of oral administration of the transgenic plants.

Science.gov (United States)

Kalbina, Irina; Lagerqvist, Nina; Moiane, Bélisario; Ahlm, Clas; Andersson, Sören; Strid, Åke; Falk, Kerstin I

2016-11-01

The zoonotic Rift Valley fever virus affects livestock and humans in Africa and on the Arabian Peninsula. The economic impact of this pathogen due to livestock losses, as well as its relevance to public health, underscores the importance of developing effective and easily distributed vaccines. Vaccines that can be delivered orally are of particular interest. Here, we report the expression in transformed plants (Arabidopsis thaliana) of Rift Valley fever virus antigens. The antigens used in this study were the N protein and a deletion mutant of the Gn glycoprotein. Transformed lines were analysed for specific mRNA and protein content by RT-PCR and Western blotting, respectively. Furthermore, the plant-expressed antigens were evaluated for their immunogenicity in mice fed the transgenic plants. After oral intake of fresh transgenic plant material, a proportion of the mice elicited specific IgG antibody responses, as compared to the control animals that were fed wild-type plants and of which none sero-converted. Thus, we show that transgenic plants can be readily used to express and produce Rift Valley Fever virus proteins, and that the plants are immunogenic when given orally to mice. These are promising findings and provide a basis for further studies on edible plant vaccines against the Rift Valley fever virus. Copyright © 2016 Elsevier Inc. All rights reserved.

Administrative Challenges to the Integration of Oral Health With Primary Care

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

2017-01-01

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

[Treatment of Chemotherapy Related Leukocytopenia by Oral Administration of Multiple Leucogenic Drugs Combined with G-CSF: an Experimental Study].

Science.gov (United States)

Zhang, Xi-ping; Zhang, Xiang; Yang, Hong-jian; Zou, De-hong; He, Xiang-ming; Yu, Xing-fei; Li, Yong-feng

2015-07-01

To evaluate efficacies of three commonly used oral drugs including Berbamine Hydrochloride Tablet (B), Qijiao Shengbai Capsule (Q), and Leucogen Tablet (L) (by single drug, two drugs or three drugs) combined with granulocyte colony-stimulating factor (G-CSF) for treat ment of chemotherapy related leukocytopenia in mice. Totally 156 Kunming male mice were divided into the normal control group (A, n=24), the model group (B, n=24), the G-CSF group (C, n =24), the G-CSF+Q group (D, n=12), G-CSF+ B (E, n=12), the G-CSF+L group (F, n=12), the G-CSF + Q + B group (G, n=12), the G-CSF + Q + L group (H, n=12), the G-CSF + L + B group (I, n=12), and the G-CSF + L + Q + B (J, n=12). Mouse models of chemotherapy related leukocytopenia were established by intraperitoneal injection of cyclophosphamide (CTX). A G-CSF group was set up as a positive control. Mice were treated by a single oral drug, a single oral drug combined with G-CSF, and two or three drugs combined with G-CSF respectively, and the death rate calculated. Hemocytes [such as white blood cells (WBC) and its classification, red blood cells (RBC), platelet (PLT), hemoglobin (Hb)] were calculated by hematology analyzer. Mice were anatomized and important organs weighed. Organ indices were calculated. There was no statistical difference in the mortality rate among all groups (P > 0.05). Compared with Group B, WBC was elevated in all other groups (P drug B and L (P chemotherapy related leukopenia or decreased three blood series was to administrate three commonly oral drugs combined with G-CSF. Authors speculated that G-CSF and Q might have a certain effect on CTX induced immune inhibition.

Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer

International Nuclear Information System (INIS)

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

2012-01-01

Highlights: ► A novel FAK inhibitor TAE226 suppressed FAK activity in HCT116 colon cancer cells. ► TAE226 suppressed proliferation and migration, with a modest effect on adhesion. ► Silencing of FAK by siRNA made no obvious difference on cancer cell attachment. ► TAE226 treatment suppressed the progression of peritoneal dissemination. ► 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 together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable

Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer

Energy Technology Data Exchange (ETDEWEB)

Hao, Hui-fang [Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558 (Japan); Takaoka, Munenori [Department of General Surgery, Kawasaki Medical School, 2-1-80 Nakasange, Kita-ku, Okayama 700-8505 (Japan); Bao, Xiao-hong [Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558 (Japan); Wang, Zhi-gang [College of Life Science, Inner Mongolia University, The Key Laboratory of Mammal Reproductive Biology and Biotechnology, Ministry of Education, Hohhot 010021 (China); Tomono, Yasuko [Division of Molecular and Cell Biology, Shigei Medical Research Institute, 2117 Yamada, Okayama 700-0202 (Japan); Sakurama, Kazufumi; Ohara, Toshiaki [Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558 (Japan); Fukazawa, Takuya; Yamatsuji, Tomoki [Department of General Surgery, Kawasaki Medical School, 2-1-80 Nakasange, Kita-ku, Okayama 700-8505 (Japan); Fujiwara, Toshiyoshi [Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558 (Japan); Naomoto, Yoshio, E-mail: ynaomoto@med.kawasaki-m.ac.jp [Department of General Surgery, Kawasaki Medical School, 2-1-80 Nakasange, Kita-ku, Okayama 700-8505 (Japan)

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

Oral administration of Lentinus edodes β-glucans ameliorates DSS-induced ulcerative colitis in mice via MAPK-Elk-1 and MAPK-PPARγ pathways.

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Shi, Limin; Lin, Qinlu; Yang, Tao; Nie, Ying; Li, Xinhua; Liu, Bo; Shen, Junjun; Liang, Ying; Tang, Yiping; Luo, Feijun

2016-11-09

To evaluate the anti-inflammatory effect of β-glucans from Lentinus edodes, and its molecular mechanism, the dextran sulfate sodium salt (DSS) induced colitis model of mice and the LPS-stimulated RAW264.7 cell inflammation model were used in this study. 40 ICR male mice were randomly divided into 4 groups: Control, DSS (DSS treated only), DSS + low-βGs (500 mg kg -1 d -1 ) and DSS + high-βGs (1000 mg kg -1 d -1 ). The body weight of the mice with Lentinus edodes β-glucan supplementation increased significantly compared to the DSS group and the disease activity index (DAI) was improved in both βG-treated groups. Compared with the DSS group, histopathological analysis showed that the infiltration of inflammatory cells of both βG-treated groups decreased significantly in colonic tissues. Furthermore, oral administration of β-glucans decreases the concentration of malondialdehyde (MDA) and myeloperoxidase (MPO) and inhibits the expression of iNOS and several inflammatory factors: TNF-α, IL-1β and IL-6 as well as nitric oxide (NO) of the colonic tissues. The mitogen-activated protein kinase (MAPK) pathway is closely related to the expression of pro-inflammatory factors. In the DSS-induced colitis model and the LPS-stimulated RAW264.7 cell model, βGs inhibited the expression of pro-inflammatory factors and blocked the phosphorylation of JNK/ERK1/2 and p38; βGs also suppress the phosphorylation of Elk-1 at Ser84 and the phosphorylation of PPARγ at Ser112. Altogether, these results suggest that Lentinus edodes βGs could inhibit the DSS-induced ulcerative colitis and decrease inflammatory factor expressions. The molecular mechanism may be involved in suppressing MAPK signaling and inactivation of Elk-1 and activation of PPARγ.

Bioavailability and pharmacokinetics of oral and injectable formulations of methadone after intravenous, oral, and intragastric administration in horses.

Science.gov (United States)

Linardi, Renata L; Stokes, Ashley M; Keowen, Michael L; Barker, Steven A; Hosgood, Giselle L; Short, Charles R

2012-02-01

To characterize the bioavailability and pharmacokinetics of oral and injectable formulations of methadone after IV, oral, and intragastric administration in horses. 6 healthy adult horses. Horses received single doses (each 0.15 mg/kg) of an oral formulation of methadone hydrochloride orally or intragastrically or an injectable formulation of the drug orally, intragastrically, or IV (5 experimental treatments/horse; 2-week washout period between each experimental treatment). A blood sample was collected from each horse before and at predetermined time points over a 360-minute period after each administration of the drug to determine serum drug concentration by use of gas chromatography-mass spectrometry analysis and to estimate pharmacokinetic parameters by use of a noncompartmental model. Horses were monitored for adverse effects. In treated horses, serum methadone concentrations were equivalent to or higher than the effective concentration range reported for humans, without induction of adverse effects. Oral pharmacokinetics in horses included a short half-life (approx 1 hour), high total body clearance corrected for bioavailability (5 to 8 mL/min/kg), and small apparent volume of distribution corrected for bioavailability (0.6 to 0.9 L/kg). The bioavailability of methadone administered orally was approximately 3 times that associated with intragastric administration. Absorption of methadone in the small intestine in horses appeared to be limited owing to the low bioavailability after intragastric administration. Better understanding of drug disposition, including absorption, could lead to a more appropriate choice of administration route that would enhance analgesia and minimize adverse effects in horses.

Immunization with r-Lactococcus lactis expressing outer membrane protein A of Shigella dysenteriae type-1: evaluation of oral and intranasal route of administration.

Science.gov (United States)

Yagnik, B; Sharma, D; Padh, H; Desai, P

2017-02-01

To evaluate the comparative immunogenic potential of food grade Lactococcus lactis expressing outer membrane protein A (OmpA) of Shigella dysenteriae type-1 (SD-1) when administered either orally or intranasally. OmpA of SD-1 was cloned and expressed first in Escherichia coli and then in L. lactis. Presence of recombinant gene was confirmed by restriction enzyme digestion and immunoblot analysis. Using immobilized metal affinity chromatography, OmpA was purified from recombinant E. coliBL21 (DE3) and subcutaneously administered in BALB/c mice. Detection of OmpA-specific IgG antibodies by enzyme-linked immunosorbent assay (ELISA) confirmed the immunogenicity of OmpA. In order to establish r-L. lactis as a mucosal delivery vehicle, it was administered orally and nasally in BALB/c mice. Serum IgG and faecal IgA were assessed through ELISA to compare the relative potential of immunization routes and immunogenic potential of r-L. lactis. Immunization via the oral route proved superior to intranasal exposure. Recombinant L. lactis expressing OmpA of SD-1 was found to be immunogenic. Oral administration of r-L. lactis elicited higher systemic and mucosal immune response when compared with the nasal route. Using food grade recombinant L. lactis has implications in the development of a prophylactic against multidrug-resistant Shigella, which can be used as a prospective vaccine candidate. Evaluating mucosal routes of immunization demonstrated that the oral route of administration elicited better immune response against OmpA of Shigella. © 2016 The Society for Applied Microbiology.

[Experimental oral candidiasis in healthy and immunocompromised BALB/c mice].

Science.gov (United States)

Karaman, Meral; Kiray, Müge; Bayrakal, Vahide; Bağrıyanık, H Alper; Yılmaz, Osman; Bahar, I Hakkı

2011-04-01

Oral candidiasis which is the most common type of Candida infections affecting humans, is most frequently caused by C.albicans. Immune response of the host, as well as a variety of virulence factors of the causative agent, play important roles in the development of Candida infections. The colonization rate of Candida in the oral cavity of healthy individuals, is between 25-30%, however, this rate is reported to be increased in immunosuppressive subjects. In our study, we established an oral candidiasis model with C.albicans in healthy and experimentally immunocompromised mice and aimed to compare Candida colonization rates and histopathological changes occurred in the tongue and esophagus tissues of the animal groups. A total of 21 BALB/c mice were grouped as control (Group 1; n= 7), healthy (Group 2; n= 7) and immunocompromised (Group 3; n= 7) groups. Immunosuppression in mice was performed by subcutaneous injection of prednisolone. For experimental oral candidiasis, cotton swab impregnated with C.albicans strains which did not have acid proteinase and phospholipase enzyme activity, no biofilm production, and sensitive to fluconazole and amphotericin B, were used. In the control group, physiological saline solution was used instead of C.albicans strain. In the forth day of experimental oral candidiasis model swab samples taken from the dorsal tongue surface of mice were evaluated by quantitative cultivation method. No yeast colonies were detected in Group 1 while more significant number of yeast colonies were observed in Group 3 compared to Group 2 (p= 0.002). Tongue and esophagus tissues of mice were stained with hematoxylin-eosin and periodic acid schiff staining and evaluated in terms of inflammatory response, abscess formation, vascular congestion, vasodilation and for the presence of yeast and hyphae. When the inflammation in esophagus was considered, statistically significant difference was determined between group 1 and group 3 (p= 0.023), however, no

Oral Administration of Probiotics Increases Paneth Cells and Intestinal Antimicrobial Activity

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Silvia I. Cazorla

2018-04-01

Full Text Available The huge amount of intestinal bacteria represents a continuing threat to the intestinal barrier. To meet this challenge, gut epithelial cells produce antimicrobial peptides (AMP that act at the forefront of innate immunity. We explore whether this antimicrobial activity and Paneth cells, the main intestinal cell responsible of AMP production, are influenced by probiotics administration, to avoid the imbalance of intestinal microbiota and preserve intestinal barrier. Administration of Lactobacillus casei CRL 431 (Lc 431 and L. paracasei CNCM I-1518 (Lp 1518 to 42 days old mice, increases the number of Paneth cells on small intestine, and the antimicrobial activity against the pathogens Staphylococcus aureus and Salmonella Typhimurium in the intestinal fluids. Specifically, strong damage of the bacterial cell with leakage of cytoplasmic content, and cellular fragmentation were observed in S. Typhimurium and S. aureus. Even more important, probiotics increase the antimicrobial activity of the intestinal fluids at the different ages, from weaning (21 days old to old age (180 days old. Intestinal antimicrobial activity stimulated by oral probiotics, do not influence significantly the composition of total anaerobic bacteria, lactobacilli and enterobacteria in the large intestine, at any age analyzed. This result, together with the antimicrobial activity observed against the same probiotic bacteria; endorse the regular consumption of probiotics without adverse effect on the intestinal homeostasis in healthy individuals. We demonstrate that oral probiotics increase intestinal antimicrobial activity and Paneth cells in order to strengthen epithelial barrier against pathogens. This effect would be another important mechanism by which probiotics protect the host mainly against infectious diseases.

Urinary profile of methylprednisolone and its metabolites after oral and topical administrations.

Science.gov (United States)

Matabosch, Xavier; Pozo, Oscar J; Monfort, Núria; Pérez-Mañá, Clara; Farré, Magi; Marcos, Josep; Segura, Jordi; Ventura, Rosa

2013-11-01

Methylprednisolone (MP) is prohibited in sports competitions when administered by systemic routes; however its use by topical administration is allowed. Therefore, analytical approaches to distinguish between these different administration pathways are required. A reporting level of 30ng/mL was established for this purpose. However, the suitability of that reporting level for MP is not known. In the present work, excretion profiles of MP and different metabolites after oral and topical administrations have been compared. A method for the quantification of MP and the qualitative detection of fifteen previously reported metabolites has been validated. The method involved an enzymatic hydrolysis, liquid-liquid extraction and analysis by liquid chromatography coupled to tandem mass spectrometry. The method was found to be linear, selective, precise and accurate. The high sensitivity (limit of detection 0.1ng/mL) and linear range (0.1-250ng/mL) achieved allowed for the quantification of MP at both the low concentrations present after topical administration and the high concentrations detected after oral intake. The method was applied to samples collected after oral (4 or 40mg) and topical administration (10mg of MP aceponate/day for 5 consecutive days) to healthy volunteers. After oral administration, MP and all metabolites were detected in urines collected up to at least 36h. Only MP and five metabolites were detected in samples obtained after topical treatment. As expected, concentrations of MP after topical administration were well below current reporting level (30ng/mL), however 3 out of 4 samples in range 8-24h after the low oral dose (4mg) were also below that concentration. Taking into account metabolites detected after both administration routes, metabolites 16β,17α,21-trihydroxy-6α-methylpregna-1,4-diene-3,11,20-trione (M8) and 17α,20α,21-trihydroxy-6α-methylpregna-1,4-diene-3,11-dione (M11) are best markers to differentiate between topical and oral

Oral Administration of Recombinant Saccharomyces boulardii Expressing Ovalbumin-CPE Fusion Protein Induces Antibody Response in Mice

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Ghasem Bagherpour

2018-04-01

Full Text Available Saccharomyces boulardii, a subspecies of Saccharomyces cerevisiae, is a well-known eukaryotic probiotic with many benefits for human health. In the present study, a recombinant strain of S. boulardii was prepared to use as a potential oral vaccine delivery vehicle. In this sense, a ura3 auxotroph strain of S. boulardii CNCM I-745 (known as S. cerevisiae HANSEN CBS 5926, Yomogi® was generated using CRISPR/Cas9 methodology. Then a gene construct encoding a highly immunogenic protein, ovalbumin (OVA, was prepared and transformed into the ura3- S. boulardii. To facilitate the transport of the recombinant immunogen across the intestinal barrier, a claudin-targeting sequence from Clostridium perfringens enterotoxin (CPE was added to the C-terminus of the expression cassette. The recombinant S. boulardii strain expressing the OVA-CPE fusion protein was then administered orally to a group of mice, and serum IgG and fecal IgA levels were evaluated by ELISA. Our results demonstrated that anti-OVA IgG in serum significantly increased in test group (P < 0.001 compared to control groups (receiving wild type S. boulardii or PBS, and the fecal IgA titer was significantly higher in test group (P < 0.05 than control groups. In parallel, a recombinant S. boulardii strain expressing the similar construct lacking C-terminal CPE was also administered orally. The result showed an increased level of serum IgG in group receiving yeasts expressing the CPE negative construct compared to control groups; however, the fecal IgA levels did not increase significantly. In conclusion, our findings indicated that the yeast S. boulardii, as a delivery vehicle with possible immunomodulatory effects, and c-CPE, as a targeting tag, synergistically assist to stimulate systemic and local immunity. This proposed recombinant S. boulardii system might be useful in the expression of other antigenic peptides, making it as a promising tool for oral delivery of vaccines or therapeutic

Oral administration of hot water extracts of Chlorella vulgaris increases physical stamina in mice.

Science.gov (United States)

An, Hyo-Jin; Choi, Hyun-Myung; Park, Hyeung-Suk; Han, Jae-Gab; Lee, Eun-Hee; Park, Young-Sig; Um, Jae-Young; Hong, Seung-Heon; Kim, Hyung-Min

2006-01-01

A unicellular algae, Chlorella vulgaris, was used as a biological response modifier. Although hot water extracts of C. vulgaris (CVE) are thought to augment immune responses, the effect of CVE on fatigue and physical stamina has not been studied. In the present study, we investigated the effect of CVE on forced swimming test and blood biochemical parameters related to fatigue, blood urea nitrogen (BUN), creatine kinase (CK), lactic dehydrogenase (LDH), glucose (Glc), and total protein (TP). CVE (0.05-0.15 g/kg/day) was orally administered to mice. After 7 days, the immobility time was decreased in the 0.1- and 0.15-g/kg CVE-treated groups (179 +/- 8.3 and 175 +/- 2.1 s) in comparison with the control group (223 +/- 5.4 s). In addition, the contents of BUN, CK, and LDH in the blood serum were decreased in the CVE-fed group. However, they had no effect on the elevation of Glc and TP level. The results predict a potential benefit of CVE for enhancing immune function and improving physical stamina. Copyright 2006 S. Karger AG, Basel.

Single Oral Dose Toxicity Test of Blue Honeysuckle Concentrate in Mice

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Park, Sang-In; Choi, Seung-Hoon; Song, Chang-Hyun; Park, Soo-Jin; Shin, Yong-Kook; Han, Chang-Hyun; Lee, Young Joon; Ku, Sae-Kwang

2015-01-01

The objective of this study was to obtain single oral dose toxicity information for concentrated and lyophilized powder of blue honeysuckle (Lonicera caerulea L., Caprifoliaceae; BHcL) in female and male ICR mice to aid in the process of developing natural origin medicinal ingredients or foods following proximate analysis and phytochemical profile measurement. The proximate analysis revealed that BHcL had an energy value of 3.80 kcal/g and contained 0.93 g/g of carbohydrate, 0.41 g/g of sugar, 0.02 g/g of protein, and 0.20 mg/g of sodium. BHcL did not contain lipids, including saturated lipids, trans fats, or cholesterols. Further, BHcL contained 4.54% of betaine, 210.63 mg/g of total phenols, 159.30 mg/g of total flavonoids, and 133.57 mg/g of total anthocyanins. Following administration of a single oral BHcL treatment, there were no treatment-related mortalities, changes in body weight (bw) or organ weight, clinical signs, necropsy or histopathological findings up to 2,000 mg/kg bw, the limited dosage for rodents of both sexes. We concluded that BHcL is a practically non-toxic material in toxicity potency. PMID:25874034

Oral nanotherapeutics: Redox nanoparticles attenuate ultraviolet B radiation-induced skin inflammatory disorders in Kud:Hr- hairless mice.

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Feliciano, Chitho P; Nagasaki, Yukio

2017-10-01

The active participation of an anti-inflammatory drug in the biological pathways of inflammation is crucial for the achievement of beneficial and therapeutic effects. This study demonstrated the development of redox nanoparticles that can circulate in the blood at significantly high levels, thus increasing their efficacy as an oral treatment against the deleterious effects of reactive oxygen species (ROS) in an in vivo inflammatory skin model. To confirm the blood bioavailability of the nanoparticles, mice were injected with the nanoparticles solution (RNP N ) via oral gavage. Using electron spin resonance and radioactive labeling techniques, the blood circulation of the redox polymer that forms the nanoparticles was confirmed 24 h after oral administration. This contrasted with its low molecular weight counterpart (NH 2 -TEMPO), which peaked 15 min post injection and was found to be cleared rapidly within minutes after the peak. We then tested its efficacy in the inflammatory skin model. Kud:Hr-hairless mice were irradiated with UVB (302 nm) to induce skin damage and inflammation. Throughout the entire period of UVB irradiation, RNP N was administered to mice by free drinking. NH 2 -TEMPO was used as the control. The results showed that oral supplementation of RNP N significantly improved the therapeutic effects of the core nitroxide radical compared with its low molecular weight counterpart. Furthermore, RNP N significantly reduced UVB-induced skin aging, epidermal thickening, edema, erythema, skin lesions, and various pathological skin inflammatory disorders in vivo. From the obtained data, we concluded that the use of long-circulating redox nanoparticles (RNP N ) provided an effective treatment against the damaging effects of excessive ROS in the body. Copyright © 2017 Elsevier Ltd. All rights reserved.

Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice.

Science.gov (United States)

Nakata, Daisuke; Masaki, Tsuneo; Tanaka, Akira; Yoshimatsu, Mie; Akinaga, Yumiko; Asada, Mari; Sasada, Reiko; Takeyama, Michiyasu; Miwa, Kazuhiro; Watanabe, Tatsuya; Kusaka, Masami

2014-01-15

TAK-385 (relugolix) is a novel, non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist, which builds on previous work with non-peptide GnRH antagonist TAK-013. TAK-385 possesses higher affinity and more potent antagonistic activity for human and monkey GnRH receptors compared with TAK-013. Both TAK-385 and TAK-013 have low affinity for the rat GnRH receptor, making them difficult to evaluate in rodent models. Here we report the human GnRH receptor knock-in mouse as a humanized model to investigate pharmacological properties of these compounds on gonadal function. Twice-daily oral administration of TAK-013 (10mg/kg) for 4 weeks decreased the weights of testes and ventral prostate in male knock-in mice but not in male wild-type mice, demonstrating the validity of this model to evaluate antagonists for the human GnRH receptor. The same dose of TAK-385 also reduced the prostate weight to castrate levels in male knock-in mice. In female knock-in mice, twice-daily oral administration of TAK-385 (100mg/kg) induced constant diestrous phases within the first week, decreased the uterus weight to ovariectomized levels and downregulated GnRH receptor mRNA in the pituitary after 4 weeks. Gonadal function of TAK-385-treated knock-in mice began to recover after 5 days and almost completely recovered within 14 days after drug withdrawal in both sexes. Our findings demonstrate that TAK-385 acts as an antagonist for human GnRH receptor in vivo and daily oral administration potently, continuously and reversibly suppresses the hypothalamic-pituitary-gonadal axis. TAK-385 may provide useful therapeutic interventions in hormone-dependent diseases including endometriosis, uterine fibroids and prostate cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice

International Nuclear Information System (INIS)

Porter, J.B.; Morgan, J.; Hoyes, K.P.; Burke, L.C.; Huehns, E.R.; Hider, R.C.

1990-01-01

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown by a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02)

Fructose- and glucose-conditioned preferences in FVB mice: strain differences in post-oral sugar appetition

Science.gov (United States)

Zukerman, Steven; Ackroff, Karen

2014-01-01

Recent studies indicate that, unlike glucose, fructose has little or no post-oral preference conditioning actions in C57BL/6J (B6) mice. The present study determined whether this is also the case for FVB mice, which overconsume fructose relative to B6 mice. In experiment 1, FVB mice strongly preferred a noncaloric 0.1% sucralose + 0.1% saccharin (S+S) solution to 8% fructose in a 2-day choice test but switched their preference to fructose after separate experience with the two sweeteners. Other FVB mice displayed a stronger preference for 8% glucose over S+S. In a second experiment, ad libitum-fed FVB mice trained 24 h/day acquired a significant preference for a flavor (CS+) paired with intragastric (IG) self-infusions of 16% fructose over a different flavor (CS−) paired with IG water infusions. IG fructose infusions also conditioned flavor preferences in food-restricted FVB mice trained 1 h/day. IG infusions of 16% glucose conditioned stronger preferences in FVB mice trained 24- or 1 h/day. Thus, fructose has post-oral flavor conditioning effects in FVB mice, but these effects are less pronounced than those produced by glucose. Further studies of the differential post-oral conditioning effects of fructose and glucose in B6 and FVB mice should enhance our understanding of the physiological processes involved in sugar reward. PMID:25320345

Two cases of corneal perforation after oral administration of nonsteroidal anti-inflammatory drugs: oral NSAID-induced corneal damage.

Science.gov (United States)

Masuda, Ikuya; Matsuo, Toshihiko; Okamoto, Kazuo; Matsushita, Kyoko; Ohtsuki, Hiroshi

2010-01-01

To report 2 cases of corneal perforation associated with the use of oral nonsteroidal anti-inflammatory drugs (NSAIDs). In a 62-year-old woman and a 79-year-old woman, corneal perforation occurred after 7 days and 5 months of oral NSAIDs administration, respectively. After NSAIDs were discontinued, the cornea epithelialized and the anterior chamber formed within 14 and 10 days, respectively. It is well known that topical NSAIDs cause corneal perforation. Observations in the present cases suggest that the oral administration of NSAIDs may also cause corneal damage, and hence, medical professionals should consider the risk of damage to the cornea when administering these drugs orally.

Induction of oral tolerance with micro-doses of ovomucoid depends on the length of the feeding period

DEFF Research Database (Denmark)

Kjær, Tanja; Frøkiær, Hanne

2002-01-01

Oral administration of antigen induces antigen-specific immunologic tolerance, which is known to be dose-dependent. We studied the influence of continuous oral administration of nanogram and microgram doses of antigen on oral tolerance induction. Mice were continuously exposed to varying doses (1...

Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation

Directory of Open Access Journals (Sweden)

Gabriela López-Armas

2016-01-01

Full Text Available Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1 control, (2 REMSD, (3 melatonin (10 mg/kg plus REMSD, (4 melatonin and intraperitoneal luzindole (once a day at 5 mg/kg plus REMSD, and (5 luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P<0.021. The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD.

Oral administration of type-II collagen peptide 250-270 suppresses specific cellular and humoral immune response in collagen-induced arthritis.

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Zhu, Ping; Li, Xiao-Yan; Wang, Hong-Kun; Jia, Jun-Feng; Zheng, Zhao-Hui; Ding, Jin; Fan, Chun-Mei

2007-01-01

Oral antigen is an attractive approach for the treatment of autoimmune and inflammatory diseases. Establishment of immune markers and methods in evaluating the effects of antigen-specific cellular and humoral immune responses will help the application of oral tolerance in the treatment of human diseases. The present article observed the effects of chicken collagen II (CII), the recombinant polymerized human collagen II 250-270 (rhCII 250-270) peptide and synthesized human CII 250-270 (syCII 250-270) peptide on the induction of antigen-specific autoimmune response in rheumatoid arthritis (RA) peripheral blood mononuclear cells (PBMC) and on the specific cellular and humoral immune response in collagen-induced arthritis (CIA) and mice fed with CII (250-270) prior to immunization with CII. In the study, proliferation, activation and intracellular cytokine production of antigen-specific T lymphocytes were simultaneously analyzed by bromodeoxyuridine (BrdU) incorporation and flow cytometry at the single-cell level. The antigen-specific antibody and antibody-forming cells were detected by ELISA and ELISPOT, respectively. CII (250-270) was found to have stimulated the response of specific lymphocytes in PBMC from RA patients, including the increase expression of surface activation antigen marker CD69 and CD25, and DNA synthesis. Mice, fed with CII (250-270) before CII immunization, had significantly lower arthritic scores than the mice immunized with CII alone, and the body weight of the former increased during the study period. Furthermore, the specific T cell activity, proliferation and secretion of interferon (IFN)-gamma in spleen cells were actively suppressed in CII (250-270)-fed mice, and the serum anti-CII, anti-CII (250-270) antibody activities and the frequency of specific antibody-forming spleen cells were significantly lower in CII (250-270)-fed mice than in mice immunized with CII alone. These observations suggest that oral administration of CII (250-270) can

Oral administration of curcumin suppresses production of matrix metalloproteinase (MMP)-1 and MMP-3 to ameliorate collagen-induced arthritis: inhibition of the PKCdelta/JNK/c-Jun pathway.

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Mun, Se Hwan; Kim, Hyuk Soon; Kim, Jie Wan; Ko, Na Young; Kim, Do Kyun; Lee, Beob Yi; Kim, Bokyung; Won, Hyung Sik; Shin, Hwa-Sup; Han, Jeung-Whan; Lee, Hoi Young; Kim, Young Mi; Choi, Wahn Soo

2009-09-01

We investigated whether oral administration of curcumin suppressed type II collagen-induced arthritis (CIA) in mice and its effect and mechanism on matrix metalloproteinase (MMP)-1 and MMP-3 production in CIA mice, RA fibroblast-like synoviocytes (FLS), and chondrocytes. CIA in mice was suppressed by oral administration of curcumin in a dose-dependent manner. Macroscopic observations were confirmed by histological examinations. Histological changes including infiltration of immune cells, synovial hyperplasia, cartilage destruction, and bone erosion in the hind paw sections were extensively suppressed by curcumin. The histological scores were consistent with clinical arthritis indexes. Production of MMP-1 and MMP-3 were inhibited by curcumin in CIA hind paw sections and tumor necrosis factor (TNF)-alpha-stimulated FLS and chondrocytes in a dose-dependent manner. As for the mechanism, curcumin inhibited activating phosphorylation of protein kinase Cdelta (PKCdelta) in CIA, FLS, and chondrocytes. Curcumin also suppressed the JNK and c-Jun activation in those cells. This study suggests that the suppression of MMP-1 and MMP-3 production by curcumin in CIA is mediated through the inhibition of PKCdelta and the JNK/c-Jun signaling pathway.

Effects of Salvia miltiorrhiza extract with supplemental liquefied calcium on osteoporosis in calcium-deficient ovariectomized mice.

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Park, Bongkyun; Song, Hae Seong; Kwon, Jeong Eun; Cho, Se Min; Jang, Seon-A; Kim, Mi Yeon; Kang, Se Chan

2017-12-20

Extracts from Salvia miltiorrhiza Bunge have been used in traditional Asian medicine to treat coronary heart disease, chronic renal failure, atherosclerosis, myocardial infraction, angina pectoris, myocardial ischemia, dysmenorrheal, neurasthenic insomnia, liver fibrosis and cirrhosis. The aim of the study was to investigate the anti-RANK signal effect of the combination of S.miltiorrhiza Bunge (SME) and liquefied calcium (LCa) supplement with ovariectomized (OVX-SML) mice, a osteoporosis animal model. Results were compared to 17β-estradiol (E 2 ) treatment. A total of 70 female ICR strain mice (7 weeks) were randomly divided into 10 groups with 7 mice in each group as follows: (1) sham-operated control mice (sham) received daily oral phosphate-buffered-saline (PBS) of equal volumes through oral administration. (2) OVX mice received a daily oral administration of PBS (OVX). (3) OVX mice treated daily with 50 mg/kg b.w./ day of SME (4) with 100 mg/kg b.w./day of SME or (5) with 200 mg/kg b.w./day of SME via oral administration. (6) OVX mice treated daily with 50 mg/kg b.w./day of SML (7) with 100 mg/kg b.w./day of SML or (8) with 200 mg/kg b.w./day of SML via oral administration. (9) OVX mice treated daily with 10 ml/kg b.w./day of LCa (10) OVX mice received i.p. injections of 17β-estradiol (E 2 ) (0.1 mg/kg b.w./day) three times per week for 12 weeks. micro-CT analysis revealed that oral administration of SML inhibited tibial bone loss, sustained trabecular bone state, and ameliorated bone biochemical markers. In addition, SML administration compared to SEM and LCa reduced serum levels of RANKL, osteocalcin and BALP through increased serum levels of OPG and E 2 in OVX mice. SML also had more beneficial effects on protection of estrogen-dependent bone loss through blocking expression of TRAF6 and NFTAc1 and produces cathepsin K and calcitonin receptor to develop osteoclast differentiation. These data suggest that S. miltiorrhiza Bunge combined with

Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice.

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Baumgardt, Shelley L; Paterson, Mark; Leucker, Thorsten M; Fang, Juan; Zhang, David X; Bosnjak, Zeljko J; Warltier, David C; Kersten, Judy R; Ge, Zhi-Dong

2016-01-01

Diabetic heart disease is associated with tetrahydrobiopterin oxidation and high arginase activity, leading to endothelial nitric oxide synthase dysfunction. Sepiapterin (SEP) is a tetrahydrobiopterin precursor, and L-citrulline (L-Cit) is converted to endothelial nitric oxide synthase substrate, L-arginine. Whether SEP and L-Cit are effective at reducing diabetic heart disease is not known. The present study examined the effects of SEP and L-Cit on diabetic cardiomyopathy and ischemia/reperfusion injury in obese type 2 diabetic mice. Db/db and C57BLKS/J mice at 6 to 8 weeks of age received vehicle, SEP, or L-Cit orally alone or in combination for 8 weeks. Cardiac function was evaluated with echocardiography. Db/db mice displayed hyperglycemia, obesity, and normal blood pressure and cardiac function compared with C57BLKS/J mice at 6 to 8 weeks of age. After vehicle treatment for 8 weeks, db/db mice had reduced ejection fraction, mitral E/A ratio, endothelium-dependent relaxation of coronary arteries, tetrahydrobiopterin concentrations, ratio of endothelial nitric oxide synthase dimers/monomers, and nitric oxide levels compared with vehicle-treated C57BLKS/J mice. These detrimental effects of diabetes mellitus were abrogated by co-administration of SEP and L-Cit. Myocardial infarct size was increased, and coronary flow rate and ± dP/dt were decreased during reperfusion in vehicle-treated db/db mice subjected to ischemia/reperfusion injury compared with control mice. Co-administration of SEP and L-Cit decreased infarct size and improved coronary flow rate and cardiac function in both C57BLKS/J and db/db mice. Co-administration of SEP and L-Cit limits diabetic cardiomyopathy and ischemia/reperfusion injury in db/db mice through a tetrahydrobiopterin/endothelial nitric oxide synthase/nitric oxide pathway. © 2016 American Heart Association, Inc.

effect of oral administration of aqueous extract of cassia occidentalis

African Journals Online (AJOL)

DR. AMINU

seeds extract's relation with acid – base balance of the body. Serum concentrations ... Oral administration of aqueous extract of C. occidentalis ... irrespective of duration of administration (weeks). .... Student 't' test was used to analyse the data.

A shorter and more specific oral sensitization-based experimental model of food allergy in mice.

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Bailón, Elvira; Cueto-Sola, Margarita; Utrilla, Pilar; Rodríguez-Ruiz, Judith; Garrido-Mesa, Natividad; Zarzuelo, Antonio; Xaus, Jordi; Gálvez, Julio; Comalada, Mònica

2012-07-31

Cow's milk protein allergy (CMPA) is one of the most prevalent human food-borne allergies, particularly in children. Experimental animal models have become critical tools with which to perform research on new therapeutic approaches and on the molecular mechanisms involved. However, oral food allergen sensitization in mice requires several weeks and is usually associated with unspecific immune responses. To overcome these inconveniences, we have developed a new food allergy model that takes only two weeks while retaining the main characters of allergic response to food antigens. The new model is characterized by oral sensitization of weaned Balb/c mice with 5 doses of purified cow's milk protein (CMP) plus cholera toxin (CT) for only two weeks and posterior challenge with an intraperitoneal administration of the allergen at the end of the sensitization period. In parallel, we studied a conventional protocol that lasts for seven weeks, and also the non-specific effects exerted by CT in both protocols. The shorter protocol achieves a similar clinical score as the original food allergy model without macroscopically affecting gut morphology or physiology. Moreover, the shorter protocol caused an increased IL-4 production and a more selective antigen-specific IgG1 response. Finally, the extended CT administration during the sensitization period of the conventional protocol is responsible for the exacerbated immune response observed in that model. Therefore, the new model presented here allows a reduction not only in experimental time but also in the number of animals required per experiment while maintaining the features of conventional allergy models. We propose that the new protocol reported will contribute to advancing allergy research. Copyright © 2012 Elsevier B.V. All rights reserved.

Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice

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Weber Mitch

2008-03-01

Full Text Available Abstract Background Women with polycystic ovary syndrome (PCOS are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD, which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a mice, possessing a mutation (Ay in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction. Methods Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4 or an equal volume of vehicle (DMSO; n = 4 for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression. Results Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM, and actin-related protein 6 homolog (ARP6. For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a non-mutant lean mice. Conclusion TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.

Orally administered indomethacin acutely reduces cellular prion protein in the small intestine and modestly increases survival of mice exposed to infectious prions.

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Martin, Gary R; Sharkey, Keith A; Jirik, Frank R

2015-05-01

The oral uptake of infectious prions represents a common way to acquire a prion disease; thus, host factors, such as gut inflammation and intestinal "leakiness", have the potential to influence infectivity. For example, the ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to induce intestinal inflammation and increase intestinal permeability. Previously, we reported that normal cellular prion protein (PrP(C)) expression was increased in experimental colitis, and since the level of PrP(C) expressed is a determinant of prion disease propagation, we hypothesized that NSAID administration prior to the oral inoculation of mice with infectious prions would increase intestinal PrP(C) expression and accelerate the onset of neurological disease. In the long-term experiments, one group of mice was gavaged with indomethacin, followed by a second gavage with brain homogenate containing mouse-adapted scrapie (ME7). Control mice received ME7 brain homogenate alone. Brain and splenic tissues were harvested at several time points for immunoblotting, including at the onset of clinical signs of disease. In a second series of experiments, mice were gavaged with indomethacin to assess the acute effects of this treatment on intestinal PrP(C) expression. Acutely, NSAID treatment reduced intestinal PrP(C) expression, and chronically, there was a modest delay in the onset of neurological disease. In contrast to our hypothesis, brief exposure to an NSAID decreased intestinal PrP(C) expression and led to a modest survival advantage following oral ingestion of infectious prions.

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

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Sawaguchi, Akiyo; Sasaki, Kazuaki; Miyanaga, Keisuke; Nakayama, Mitsuhiro; Nagasue, Masato; Shimoda, Minoru

2016-10-01

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

Single oral dose toxicity test of platycodin d, a saponin from platycodin radix in mice.

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Lee, Won-Ho; Gam, Cheol-Ou; Ku, Sae-Kwang; Choi, Seong-Hun

2011-12-01

The object of this study was to evaluate the single oral dose toxicity of platycodin D, a saponin from the root of Platycodon grandiflorum in male and female mice. Platycodin D was administered to female and male mice as an oral dose of 2000, 1000, 500, 250 and 125 mg/kg (body wt.). Animals were monitored for the mortality and changes in body weight, clinical signs and gross observation during 14 days after treatment, upon necropsy, organ weight and histopathology of 14 principle organs were examined. As the results, no platycodin D treatment related mortalities, clinical signs, changes on the body and organ weights, gross and histopathological observations against 14 principle organs were detected up to 2000 mg/kg in both female and male mice. Therefore, LD50 (50% lethal dose) and approximate LD of playtcodin D after single oral treatment in female and male mice were considered over 2000 mg/kg - the limited dosages recommended by KFDA Guidelines [2009-116, 2009], respectively.

Estimate of the absorbed dose in the mouse organs and tissues after tritium administration

International Nuclear Information System (INIS)

Saito, Masahiro

2000-01-01

Chronic and accidental release of tritium from future fusion facilities may cause some extent of hazardous effect to the public health. Various experiments using small animals such as mice have been performed to mimic the dose accumulation due to tritium intake by the human body. An difficulty in such animal experiments using small animals is that it is rather difficult to administer tritium orally and estimate the dose to small organs or tissues. In the course of our study, a simple method to administer THO and T-labeled amino acids orally to the mouse was dictated and dose accumulation in various organs and tissues was determined. The tritium retention in the bone marrow was also determined using the micro-centrifuge method. Throughout our experiment, colony-bred DDY mice were used. The 8-10 week old male mice were orally and intraperitoneally administered THO water or T-amino acids mixture solution. For the purpose of oral administration, a 10 μl aliquot of T-containing saline solution was placed on the tongue of the mice using an automatic micropipette. At various times after tritium administration, the animals were sacrificed and the amount of tritium in various tissues and organs including bone marrow was examined. Dose accumulation pattern after THO intake and T-amino acids was compared between intraperitoneal injection and oral administration. The accumulated dose after oral administration of THO exhibited a tendency to be 10-20% higher than after intraperitoneal injection. The bone marrow dose after oral intake of THO was found to be lower than the doses to urine, blood, liver and testis. In contrast, the blood dose gave a conservative estimate for the dose to the other tissues and organs. (author)

Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice

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Zhongfa, Liu; Chiu, Ming; Wang, Jiang; Chen, Wei; Yen, Winston; Fan-Havard, Patty; Yee, Lisa D.; Chan, Kenneth K.

2012-01-01

Purpose Curcumin has shown a variety of biological activity for various human diseases including cancer in preclinical setting. Its poor oral bioavailability poses significant pharmacological barriers to its clinical application. Here, we established a practical nano-emulsion curcumin (NEC) containing up to 20% curcumin (w/w) and conducted the pharmacokinetics of curcuminoids and curcumin metabolites in mice. Methods This high loading NEC was formulated based on the high solubility of curcumin in polyethylene glycols (PEGs) and the synergistic enhancement of curcumin absorption by PEGs and Cremophor EL. The pharmacokinetics of curcuminoids and curcumin metabolites was characterized in mice using a LC–MS/MS method, and the pharmacokinetic parameters were determined using WinNonlin computer software. Results A tenfold increase in the AUC0→24h and more than 40-fold increase in the Cmax in mice were observed after an oral dose of NEC compared with suspension curcumin in 1% methylcellulose. The plasma pharmacokinetics of its two natural congeners, demethoxycurcumin and bisdemethoxycurcumin, and three metabolites, tetrahydrocurcumin (THC), curcumin-O-glucuronide, and curcumin-O-sulfate, was characterized for the first time in mice after an oral dose of NEC. Conclusion This oral absorption enhanced NEC may provide a practical formulation to conduct the correlative study of the PK of curcuminoids and their pharmacodynamics, e.g., hypomethylation activity in vivo. PMID:21968952

Oral administration of insulin by means of liposomes in animal experiments

International Nuclear Information System (INIS)

Tragl, K.H.; Pohl, A.; Kinast, H.

1979-01-01

Liposomes are an effective vehicle for the oral administration of insulin. They are prepared from lipid emulsions by sonication and particles of homogeneous size are generated by elution through sepharose columns. Liposomes are taken up into the gastric mucosa by endocytosis and then transported to the liver via the portal circulation. Oral administration of 10 U insulin/kg body weight to rats is followed by a reduction in blood glucose to 67% of the initial value. When liposome-trapped insulin was injected intravenously a decrease in blood glucose to 40% of the initial value was obtained by the administration of 5 IU insulin/kg body weight. While the effect of orally-administered liposome-trapped insulin is obvious, the problems of standardization of the insulin content of the liposomes and the great variability of liposome uptake into the gastric mucosa by endocytosis remain unsolved. (author)

Indomethacin Treatment of Mice with Premalignant Oral Lesions Sustains Cytokine Production and Slows Progression to Cancer.

Science.gov (United States)

Johnson, Sara D; Young, M Rita I

2016-01-01

Current treatment options for head and neck squamous cell carcinoma (HNSCC) patients are often ineffective due to tumor-localized and systemic immunosuppression. Using the 4-NQO mouse model of oral carcinogenesis, this study showed that premalignant oral lesion cells produce higher levels of the immune modulator, PGE 2 , compared to HNSCC cells. Inhibiting prostaglandin production of premalignant lesion cells with the pan-cyclooxygenase inhibitor indomethacin stimulated their induction of spleen cell cytokine production. In contrast, inhibiting HNSCC prostaglandin production did not stimulate their induction of spleen cell cytokine production. Treatment of mice bearing premalignant oral lesions with indomethacin slowed progression of premalignant oral lesions to HNSCC. Flow cytometric analysis of T cells in the regional lymph nodes of lesion-bearing mice receiving indomethacin treatment showed an increase in lymph node cellularity and in the absolute number of CD8 + T cells expressing IFN-γ compared to levels in lesion-bearing mice receiving diluent control treatment. The cytokine-stimulatory effect of indomethacin treatment was not localized to regional lymph nodes but was also seen in the spleen of mice with premalignant oral lesions. Together, these data suggest that inhibiting prostaglandin production at the premalignant lesion stage boosts immune capability and improves clinical outcomes.

Oral administration of kefiran induces changes in the balance of immune cells in a murine model.

Science.gov (United States)

Medrano, Micaela; Racedo, Silvia M; Rolny, Ivanna S; Abraham, Analía G; Pérez, Pablo F

2011-05-25

The aim of the present study was to evaluate the effect of the oral administration of kefiran on the balance of immune cells in a murine model. Six week old BALB/c mice were treated with kefiran (300 mg/L) for 0, 2 and 7 days. Kefiran treatment increased the number of IgA+ cells in lamina propria after 2 and 7 days. Percentage of B220+/MHCII(high) cells in mesenteric lymph nodes (2 days) and Peyer's patches (7 days) was higher compared to untreated control mice. An increase of macrophages (F4/80+ cells) was observed in lamina propria and peritoneal cavity (2 and 7 days). In contrast, at day 7, macrophage population decreased in Peyer's patches. These results show the ability of kefiran to modify the balance of immune cells in intestinal mucosa. This property could be highly relevant for the comprehension of the probiotic effect attributed to kefir.

Polybrominated Diphenyl Ethers Orally Administration to Mice Were Tansferred to Offspring during Gestation and Lactation with Disruptions on the Immune System.

Science.gov (United States)

Hong, Soon Keun; Sohn, Kyung Hee; Kim, In Young; Lee, Jong Kwon; Ju, Jung Hun; Kim, Jin Ho; Lim, Chae Hyung; Han, Beom Seok; Jung, Hwa Chul; Lee, Jin Yong; Park, Kui Lea

2010-04-01

The present study was undertaken to examine the immunological effects of pentabrominated diphenyl ether (penta-BDE) and decabrominated diphenyl ether (deca-BDE) on the immune system of the dams and the developmental immune system of the offsprings. In this study, mated female C57BL/6J mice were orally administered penta-BDE, deca-BDE or corn oil for 5 weeks, from gestational day 6 to lactational day 21. The body weight of PND21 exposed to penta-BDE was significantly decreased relative to control mice, but that of post-natal day 63 (PND63) were recovered. Orally dosed dams with penta-BDE had significantly smaller absolute and relative spleen masses than control mice. Absolute and relative spleen and thymus masses of PND21 exposed to penta-BDE were significantly decreased over control. The exposure of dams and PND21 with penta-BDE reduced the number of splenocytes and thymocytes. As results of hematologic analysis, percentage WBC and percentage neutrophils increased in dams with deca-BDE. Splenic T cell proliferation in dams and PND21 exposed to penta-BDE was increased, and there were no significant difference in splenic B cell proliferation in all treatment groups. As results of flow cytometric analysis of splenocyte, percentage total T cell, Th cell and Tc cell in PND21 exposed to penta-BDE was slightly increased, and percentage macrophage in dams and PND21 exposed to deca-BDE was decreased. The ELISA results of antibody production show no significant difference in all treatment groups relative to controls. These results imply that PBDEs given to the dam were transferred to the offspring during gestation and lactation, and PBDEs transferred from the dam affect immune system of offspring.

Effects of sub acute oral administration of aqueous extract of ...

African Journals Online (AJOL)

The study evaluates the effects of sub acute oral administration (28 days) of aqueous extract of Stereospermum kunthianum stem bark on the body weight and haematological indices of rats. Treatments were administered by oral gavage once daily for a total of 28 days. The first group (control) received distilled water (5 ...

Technetium-99m-labeled deoxynivalenol from Fusarium mycotoxin alters organ toxicity in BALB/c mice by oral and intravenous route

International Nuclear Information System (INIS)

Chattopadhyay, P; Pandey, A; Goyary, D; Chaurasia, A; Singh, L; Veer, V.

2012-01-01

The toxicity of deoxynivalenol, both intravenously and orally, was investigated in male and female BALB/c mice. Technetium-99m ( 99m Tc)-labeled deoxynivalenol was administered to mice by tail vein injection and orally dosed. Distribution of labeled deoxynivalenol at 26 hours was monitored by gamma scintigraphy. In the evaluated organs, the accumulation of radioactive deoxynivalenol was correlated with the amount of radioactivity. In addition, the toxicity of deoxynivalenol was measured by biochemical assays followed by histopathological findings. Kidney and hepatic marker enzymes were significantly increased in intravenously administered deoxynivalenol as compared to orally treated mice. Intravenously treated mice showed severe damage in liver and kidney when compared to those orally exposed. Biodistribution of 99m Tc-labeled deoxynivalenol differed between oral and intravenous treatment. In intravenously exposed mice, deoxynivalenol was distributed primarily in the liver and kidney whereas in oral exposure, it was found in the stomach and intestines after 26 hours. Deoxynivalenol toxicity, associated with its biodistribution and organ toxicity, was greatest where it had accumulated. The results show that the toxicity of deoxynivalenol is associated with organ accumulation. (author)

A less stressful alternative to oral gavage for pharmacological and toxicological studies in mice

International Nuclear Information System (INIS)

Walker, Mary K.; Boberg, Jason R.; Walsh, Mary T.; Wolf, Valerie; Trujillo, Alisha; Duke, Melissa Skelton; Palme, Rupert; Felton, Linda A.

2012-01-01

Oral gavage dosing can induce stress and potentially confound experimental measurements, particularly when blood pressure and heart rate are endpoints of interest. Thus, we developed a pill formulation that mice would voluntarily consume and tested the hypothesis that pill dosing would be significantly less stressful than oral gavage. C57Bl/6 male mice were singly housed and on four consecutive days were exposed to an individual walking into the room (week 1, control), a pill being placed into the cage (week 2), and a dose of water via oral gavage (week 3). Blood pressure and heart rate were recorded by radiotelemetry continuously for 5 h after treatment, and feces collected 6–10 h after treatment for analysis of corticosterone metabolites. Both pill and gavage dosing significantly increased mean arterial pressure (MAP) during the first hour, compared to control. However, the increase in MAP was significantly greater after gavage and remained elevated up to 5 h, while MAP returned to normal within 2 h after a pill. Neither pill nor gavage dosing significantly increased heart rate during the first hour, compared to control; however, pill dosing significantly reduced heart rate while gavage significantly increased heart rate 2–5 h post dosing. MAP and heart rate did not differ 24 h after dosing. Lastly, only gavage dosing significantly increased fecal corticosterone metabolites, indicating a systemic stress response via activation of the hypothalamic–pituitary–adrenal axis. These data demonstrated that this pill dosing method of mice is significantly less stressful than oral gavage. -- Highlights: ► Developed a novel oral dosing method using a pill that mice will readily consume. ► Assessed stress by blood pressure, heart rate, and fecal corticosterone metabolites. ► Demonstrated that pill dosing is significantly less stressful than oral gavage.

A less stressful alternative to oral gavage for pharmacological and toxicological studies in mice

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Walker, Mary K., E-mail: mwalker@salud.unm.edu [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM (United States); Boberg, Jason R.; Walsh, Mary T.; Wolf, Valerie; Trujillo, Alisha; Duke, Melissa Skelton [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM (United States); Palme, Rupert [Department of Biomedical Sciences/Biochemistry, University of Veterinary Medicine, Vienna (Austria); Felton, Linda A. [Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM (United States)

2012-04-01

Oral gavage dosing can induce stress and potentially confound experimental measurements, particularly when blood pressure and heart rate are endpoints of interest. Thus, we developed a pill formulation that mice would voluntarily consume and tested the hypothesis that pill dosing would be significantly less stressful than oral gavage. C57Bl/6 male mice were singly housed and on four consecutive days were exposed to an individual walking into the room (week 1, control), a pill being placed into the cage (week 2), and a dose of water via oral gavage (week 3). Blood pressure and heart rate were recorded by radiotelemetry continuously for 5 h after treatment, and feces collected 6–10 h after treatment for analysis of corticosterone metabolites. Both pill and gavage dosing significantly increased mean arterial pressure (MAP) during the first hour, compared to control. However, the increase in MAP was significantly greater after gavage and remained elevated up to 5 h, while MAP returned to normal within 2 h after a pill. Neither pill nor gavage dosing significantly increased heart rate during the first hour, compared to control; however, pill dosing significantly reduced heart rate while gavage significantly increased heart rate 2–5 h post dosing. MAP and heart rate did not differ 24 h after dosing. Lastly, only gavage dosing significantly increased fecal corticosterone metabolites, indicating a systemic stress response via activation of the hypothalamic–pituitary–adrenal axis. These data demonstrated that this pill dosing method of mice is significantly less stressful than oral gavage. -- Highlights: ► Developed a novel oral dosing method using a pill that mice will readily consume. ► Assessed stress by blood pressure, heart rate, and fecal corticosterone metabolites. ► Demonstrated that pill dosing is significantly less stressful than oral gavage.

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

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

2015-12-03

Titanium dioxide nanoparticles (TiO2 NPs) have been widely used in various consumer products, especially food and personal care products. Compared to the well-characterized adverse cardiovascular effect of inhaled ambient ultrafine particles, research on the health response to orally administrated TiO2 NPs is still limited. In our study, we performed an in vivo study in Sprague-Dawley rats to understand the cardiovascular effect of TiO2 NPs after oral intake. After daily gastrointestinal administration of TiO2 NPs at 0, 2, 10, 50 mg/kg for 30 and 90 days, heart rate (HR), blood pressure, blood biochemical parameters and histopathology of cardiac tissues was assessed to quantify cardiovascular damage. Mild and temporary reduction of HR and systolic blood pressure as well as an increase of diastolic blood pressure was observed after daily oral administration of TiO2 NPs for 30 days. Injury of cardiac function was observed after daily oral administration of TiO2 NPs for 90 days as reflected in decreased activities of lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBDH) and creatine kinase (CK). Increased white blood cells count (WBC) and granulocytes (GRN) in blood as well as increased concentrations of tumor necrosis factor α (TNF α) and interleukin 6 (IL-6) in the serum indicated inflammatory response initiated by TiO2 NPs exposure. It was hypothesize that cardiac damage and inflammatory response are the possible mechanisms of the adverse cardiovascular effects induced by orally administrated TiO2 NPs. Data from our study suggested that even at low dose of TiO2 NPs can induce adverse cardiovascular effects after 30 days or 90 days of oral exposure, thus warranting concern for the dietary intake of TiO2 NPs for consumers. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Oral L-Arginine Stimulates GLP-1 Secretion to Improve Glucose Tolerance in Male Mice

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Clemmensen, Christoffer; Smajilovic, Sanela; Smith, Eric P

2013-01-01

Pharmacological and surgical interventions that increase glucagon-like peptide 1 (GLP-1) action are effective to improve glucose homeostasis in type 2 diabetes mellitus. In light of this, nutritional strategies to enhance postprandial GLP-1 secretion, particularly in the context of diet......-induced obesity, may provide an alternative therapeutic approach. Importantly, recent evidence suggests the amino acid l-arginine, a well-known insulin secretagogue, can also stimulate release of GLP-1 from isolated rat intestine. Here we tested the hypothesis that oral l-arginine acts as a GLP-1 secretagogue...... in vivo, to augment postprandial insulin secretion and improve glucose tolerance. To test this, we administered l-arginine or vehicle by oral gavage, immediately prior to an oral glucose tolerance test in lean and diet-induced obese mice. In both lean and obese mice oral l-arginine increased plasma GLP-1...

Reduction of influenza virus titer and protection against influenza virus infection in infant mice fed Lactobacillus casei Shirota.

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Yasui, Hisako; Kiyoshima, Junko; Hori, Tetsuji

2004-07-01

We investigated whether oral administration of Lactobacillus casei strain Shirota to neonatal and infant mice ameliorates influenza virus (IFV) infection in the upper respiratory tract and protects against influenza infection. In a model of upper respiratory IFV infection, the titer of virus in the nasal washings of infant mice administered L. casei Shirota (L. casei Shirota group) was significantly (P survival rate of the L. casei Shirota group was significantly (P L. casei Shirota group were significantly greater than those of mice in the control group. These findings suggest that oral administration of L. casei Shirota activates the immature immune system of neonatal and infant mice and protects against IFV infection. Therefore, oral administration of L. casei Shirota may accelerate the innate immune response of the respiratory tract and protect against various respiratory infections in neonates, infants, and children, a high risk group for viral and bacterial infections.

Fourteen days oral administration of therapeutic dosage of some ...

African Journals Online (AJOL)

Fourteen days oral administration of therapeutic dosage of some antibiotics reduced serum testosterone in male rats. FO Awobajo, Y Raji, II Olatunji-Bello, FT Kunle-Alabi, AO Adesanya, TO Awobajo ...

Preparation, characterization and bioavailability by oral administration of O/W curcumin nanoemulsions stabilized with lysophosphatidylcholine.

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Chávez-Zamudio, Rubi; Ochoa-Flores, Angélica A; Soto-Rodríguez, Ida; Garcia-Varela, Rebeca; García, Hugo Sergio

2017-09-20

Curcumin is the main and most abundant bioactive component in Curcuma longa L. with documented properties in the prevention and treatment of chronic degenerative and infectious diseases. However, curcumin has low solubility in aqueous media, hence low bioavailability when administered orally. The use of nanoemulsions as carriers can provide a partial solution to bioavailability restrictions. In our study, O/W nanoemulsions of curcumin were prepared using lysophosphatidylcholine, a phospholipid with proven emulsification capacity; nevertheless, such qualities have not been previously reported in the preparation of nanoemulsions. Lysophosphatidylcholine was obtained by enzymatic removal of one fatty acid residue from phosphatidylcholine. The objective of our work was to formulate stable curcumin nanoemulsions and evaluate their bioavailability in BALB/c mice plasma after oral administration. Formulated nanoemulsions had a droplet size mean of 154.32 ± 3.10 nm, a polydispersity index of 0.34 ± 0.07 and zeta potential of -10.43 ± 1.10 mV; stability was monitored for 12 weeks. Lastly, in vivo pharmacokinetic parameters, using BALB/c mice, were obtained; namely, C max of 610 ± 65.0 μg mL -1 and T max of 2 h. Pharmacokinetic data revealed a higher bioavailability of emulsified as opposed to free curcumin. Research regarding other potential emulsifiers that may provide better health benefits and carry nano-encapsulated bioactive compounds more effectively, is necessary. This study provides important data on the preparation and design of nanoencapsulated Curcumin using lysophosphatidylcholine as an emulsifier.

Effect of Maternal Administration of Edible Bird’s Nest on the Learning and Memory Abilities of Suckling Offspring in Mice

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Yong Xie

2018-01-01

Full Text Available Although human brains continue developing throughout the underage developmental stages, the infancy period is considered the most important one for the whole life. It has been reported that sialic acid from edible bird’s nest (EBN can facilitate the development of brain and intelligence. In this study, by oral administration of EBN to female mice during the pregnancy or lactation period, the effects of EBN on the levels of sialic acid in mouse milk were determined using high-performance liquid chromatography (HPLC. Furthermore, the spatial learning performances of their offspring were assessed using the Morris water maze test. Additionally, cerebral malondialdehyde (MDA, superoxide dismutase (SOD, choline acetyltransferase (ChAT, and acetylcholinesterase (AChE in cubs nursed by the female mice given the EBN homogenate were examined, while BDNF immunohistochemical staining and neuron count in hippocampi were investigated as well. These results showed that administration with EBN in maternal mice during pregnancy or lactation period can improve the learning and memory functions in their offspring, possibly by increasing the activities of SOD and ChAT and, at the meantime, decreasing the levels of MDA and activities of AChE. Moreover, BDNF levels for CA1, CA2, and CA3 regions in hippocampi and the numbers of dyed neurons in CA1, CA2, CA3, and DG regions among the offspring were significantly enhanced due to the intake of EBN by the maternal mice. We concluded that maternal administration of EBN during the pregnancy and lactation periods can improve the spatial learning performances in the offspring.

Lipid Emulsion Administered Intravenously or Orally Attenuates Triglyceride Accumulation and Expression of Inflammatory Markers in the Liver of Nonobese Mice Fed Parenteral Nutrition Formula123

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Ito, Kyoko; Hao, Lei; Wray, Amanda E.; Ross, A. Catharine

2013-01-01

The accumulation of hepatic TG and development of hepatic steatosis (HS) is a serious complication of the use of parenteral nutrition (PN) formulas containing a high percentage of dextrose. But whether fat emulsions or other nutrients can ameliorate the induction of HS by high-carbohydrate diets is still uncertain. We hypothesized that administration of a lipid emulsion (LE; Intralipid) and/or the vitamin A metabolite retinal (RAL) will reduce hepatic TG accumulation and attenuate indicators of inflammation. C57BL/6 male mice were fed PN formula as their only source of hydration and nutrition for 4–5 wk. In Expt. 1, mice were fed PN only or PN plus treatment with RAL (1 μg/g orally), LE (200 μL i.v.), or both LE and RAL. In Expt. 2, LE was orally administered at 4 and 13.5% of energy to PN-fed mice. All PN mice developed HS compared with mice fed normal chow (NC) and HS was reduced by LE. The liver TG mass was lower in the PN+LE and PN+RAL+LE groups compared with the PN and PN+RAL groups (P < 0.01) and in the 4% and 13.5% PN+LE groups compared with PN alone. Hepatic total retinol was higher in the RAL-fed mice (P < 0.0001), but RAL did not alter TG mass. mRNA transcripts for fatty acid synthase (Fasn) and sterol regulatory element-binding protein-1c (Srebpf1) were higher in the PN compared with the NC mice, but FAS protein and Srebpf1 mRNA were lower in the PN+LE groups compared with PN alone. The inflammation marker serum amyloid P component was also reduced. In summary, LE given either i.v. or orally may be sufficient to reduce the steatotic potential of orally fed high-dextrose formulas and may suppress the early development of HS during PN therapy. PMID:23325918

Modulation of gut microbiota and increase in fecal water content in mice induced by administration of Lactobacillus kefiranofaciens DN1.

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Jeong, Dana; Kim, Dong-Hyeon; Kang, Il-Byeong; Kim, Hyunsook; Song, Kwang-Young; Kim, Hong-Seok; Seo, Kun-Ho

2017-02-22

Lactobacillus kefiranofaciens is the key probiotic bacterium in kefir. In this study, we investigated the effects of oral consumption of L. kefiranofaciens on the fecal quality and intestinal microbiota of mice. Four-week-old Balb/c mice were divided into two groups (n = 8 each) and administered 0.2 mL of saline (control group) or saline containing 2 × 10 8 cfu L. kefiranofaciens DN1 (LKF_DN1 group) for two weeks. At the end of the experiment, their fecal samples were collected and the fecal quality and microbiota were assessed. The LKF_DN1 group exhibited higher total fecal weight and fecal weight per stool sample than the control group (p kefiranofaciens DN1 administration could alleviate constipation and improve gut microbiota.

Technetium-99m-labeled deoxynivalenol from Fusarium mycotoxin alters organ toxicity in BALB/c mice by oral and intravenous route

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Chattopadhyay, P; Pandey, A; Goyary, D; Chaurasia, A; Singh, L; Veer, V. [Division of Pharmaceutical Technology, Defence Research Laboratory, Assam (India); Department of Life Sciences, Defense Research Development and Organization, New Delhi (India)

2012-07-01

The toxicity of deoxynivalenol, both intravenously and orally, was investigated in male and female BALB/c mice. Technetium-99m ({sup 99m} Tc)-labeled deoxynivalenol was administered to mice by tail vein injection and orally dosed. Distribution of labeled deoxynivalenol at 26 hours was monitored by gamma scintigraphy. In the evaluated organs, the accumulation of radioactive deoxynivalenol was correlated with the amount of radioactivity. In addition, the toxicity of deoxynivalenol was measured by biochemical assays followed by histopathological findings. Kidney and hepatic marker enzymes were significantly increased in intravenously administered deoxynivalenol as compared to orally treated mice. Intravenously treated mice showed severe damage in liver and kidney when compared to those orally exposed. Biodistribution of {sup 99m}Tc-labeled deoxynivalenol differed between oral and intravenous treatment. In intravenously exposed mice, deoxynivalenol was distributed primarily in the liver and kidney whereas in oral exposure, it was found in the stomach and intestines after 26 hours. Deoxynivalenol toxicity, associated with its biodistribution and organ toxicity, was greatest where it had accumulated. The results show that the toxicity of deoxynivalenol is associated with organ accumulation. (author)

Technetium-99m-labeled deoxynivalenol from Fusarium mycotoxin alters organ toxicity in BALB/c mice by oral and intravenous route

Directory of Open Access Journals (Sweden)

P Chattopadhyay

2012-01-01

Full Text Available The toxicity of deoxynivalenol, both intravenously and orally, was investigated in male and female BALB/c mice. Technetium-99m (99m Tc-labeled deoxynivalenol was administered to mice by tail vein injection and orally dosed. Distribution of labeled deoxynivalenol at 26 hours was monitored by gamma-scintigraphy. In the evaluated organs, the accumulation of radioactive deoxynivalenol was correlated with the amount of radioactivity. In addition, the toxicity of deoxynivalenol was measured by biochemical assays followed by histopathological findings. Kidney and hepatic marker enzymes were significantly increased in intravenously administered deoxynivalenol as compared to orally treated mice. Intravenously treated mice showed severe damage in liver and kidney when compared to those orally exposed. Biodistribution of 99mTc-labeled deoxynivalenol differed between oral and intravenous treatment. In intravenously exposed mice, deoxynivalenol was distributed primarily in the liver and kidney whereas in oral exposure, it was found in the stomach and intestines after 26 hours. Deoxynivalenol toxicity, associated with its biodistribution and organ toxicity, was greatest where it had accumulated. The results show that the toxicity of deoxynivalenol is associated with organ accumulation.

Expression of cholera toxin B-proinsulin fusion protein in lettuce and tobacco chloroplasts--oral administration protects against development of insulitis in non-obese diabetic mice.

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Ruhlman, Tracey; Ahangari, Raheleh; Devine, Andrew; Samsam, Mohtahsem; Daniell, Henry

2007-07-01

Lettuce and tobacco chloroplast transgenic lines expressing the cholera toxin B subunit-human proinsulin (CTB-Pins) fusion protein were generated. CTB-Pins accumulated up to ~16% of total soluble protein (TSP) in tobacco and up to ~2.5% of TSP in lettuce. Eight milligrams of powdered tobacco leaf material expressing CTB-Pins or, as negative controls, CTB-green fluorescent protein (CTB-GFP) or interferon-GFP (IFN-GFP), or untransformed leaf, were administered orally, each week for 7 weeks, to 5-week-old female non-obese diabetic (NOD) mice. The pancreas of CTB-Pins-treated mice showed decreased infiltration of cells characteristic of lymphocytes (insulitis); insulin-producing beta-cells in the pancreatic islets of CTB-Pins-treated mice were significantly preserved, with lower blood or urine glucose levels, by contrast with the few beta-cells remaining in the pancreatic islets of the negative controls. Increased expression of immunosuppressive cytokines, such as interleukin-4 and interleukin-10 (IL-4 and IL-10), was observed in the pancreas of CTB-Pins-treated NOD mice. Serum levels of immunoglobulin G1 (IgG1), but not IgG2a, were elevated in CTB-Pins-treated mice. Taken together, T-helper 2 (Th2) lymphocyte-mediated oral tolerance is a likely mechanism for the prevention of pancreatic insulitis and the preservation of insulin-producing beta-cells. This is the first report of expression of a therapeutic protein in transgenic chloroplasts of an edible crop. Transplastomic lettuce plants expressing CTB-Pins grew normally and transgenes were maternally inherited in T(1) progeny. This opens up the possibility for the low-cost production and delivery of human therapeutic proteins, and a strategy for the treatment of various other autoimmune diseases.

Combined administration of oseltamivir and hochu-ekki-to (TJ-41) dramatically decreases the viral load in lungs of senescence-accelerated mice during influenza virus infection.

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Ohgitani, Eriko; Kita, Masakazu; Mazda, Osam; Imanishi, Jiro

2014-02-01

To enhance the effect of anti-influenza-virus agent treatment, the effect of combined administration of oseltamivir phosphate and hochu-ekki-to (Japanese traditional herbal medicine, HET) on early viral clearance was examined. Senescence-accelerated mice were given HET in drinking water for 2 weeks, followed by intranasal infection with influenza A virus strain PR8. After 4 hours of infection, oseltamivir was administered orally for 5 days. The viral loads in the lungs of the group receiving combined treatment were dramatically lower when compared with the viral loads in the lungs of the group receiving oseltamivir alone. HET significantly increased the induction of IL-1β and TNF-α in the lungs of PR8-infected mice and stimulated alveolar macrophage phagocytosis. From these results, we conclude that these functions may be responsible the increased effect on viral load reduction. Here, we show that the combined administration of oseltamivir and HET is very useful for influenza treatment in senescence-accelerated mice.

Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers

DEFF Research Database (Denmark)

Villesen, Hanne H.; Kristensen, Kim; Hansen, Steen Honoré

2007-01-01

After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-g......-glucuronide (M3G) and M6G. The aims of this study were to confirm and elucidate the biphasic absorption profile as well as clarify the conversion of M6G to morphine after a single oral administration of M6G in healthy volunteers....

[Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose].

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Liao, Li; Hua, Hua; Zhao, Jun-Ning; Luo, Heng; Yang, An-Dong

2014-03-01

To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC.

Administration of midazolam in infancy does not affect learning and memory of adult mice.

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Xu, Hua; Liu, Zhi-Qiang; Liu, Yi; Zhang, Wei-Shi; Xu, Bo; Xiong, Yuan-Chang; Deng, Xiao-Ming

2009-12-01

1. Midazolam is a common fast-acting GABA(A) receptor agonist. Recent data suggest that exposure to midazolam in early life may cause long-term effects on brain function through stable epigenetic reprogramming. The aim of the present study was to determine whether the administration of midazolam to infant mice would affect their learning and memory in adulthood. 2. An open-field test was conducted before and then 3, 24, 48 and 72 h after administration of midazolam (50 mg/kg, i.p.) to infant mice. Saline control mice received an equal volume of saline i.p. 3 h before the open-field test. Total movements, total movement time, total movement distance and velocity were analysed. Novel object recognition (NOR), Morris water-maze and passive avoidance tests were performed when the treated mice grew to adulthood (105 days of age). 3. The results of open-field test showed that midazolam significantly reduced locomotor activity (total movements, total movement time, total movement distance and velocity) in infant mice 3 and 24 h after drug administration and that these effects had disappeared by 72 h after drug administration. The results of the water-maze, NOR and passive avoidance tests in adulthood (at 105 days of age) indicated that administration of midazolam in infancy had no long-term effects on the learning and memory behaviours of adult mice compared with the saline control. 4. Acute midazolam administration to infant mice affected spontaneous locomotor activity for approximately 2 days, but did not seem to have any significant impact on cognitive functioning that lasted into adulthood.

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

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Li-Jen Lin

2016-01-01

Full Text Available 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.

Oral vaccine of Lactococcus lactis harbouring pandemic H1N1 2009 haemagglutinin1 and nisP anchor fusion protein elevates anti-HA1 sIgA levels in mice.

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Joan, Stella Siaw Xiu; Pui-Fong, Jee; Song, Adelene Ai-Lian; Chang, Li-Yen; Yusoff, Khatijah; AbuBakar, Sazaly; Rahim, Raha Abdul

2016-05-01

An oral lactococcal-based vaccine which haboured the haemagglutinin1 (HA1) antigen fused to nisP anchor protein for the purpose of surface displaying the HA1 antigen was developed against H1N1 virus. Recombinant L. lactis strains expressed HA1-nisP fusion proteins when induced with nisin, as confirmed through western blotting. However, immunofluorescense did not detect any surface-displayed proteins, suggesting that the protein was either unsuccessfully translocated or improperly displayed. Despite this, oral administration of recombinant L. lactis strains to BALB/c mice revealed that significant levels of anti-HA1 sIgA antibodies were detected in mice fecal suspension samples of mice group NZ9000 (pNZ:HN) when compared to the negative control NZ9000 (pNZ8048) group. Specific anti-HA1 sIgA antibodies were locally produced and live recombinant lactococcal vaccine was able to elicit humoral response of BALB/c mice despite unsuccessful surface display of the HA1 epitope.

Oral and intraperitoneal administration of quercetin decreased lymphocyte DNA damage and plasma lipid peroxidation induced by TSA in vivo.

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Chan, Shu-Ting; Lin, Yi-Chin; Chuang, Cheng-Hung; Shiau, Rong-Jen; Liao, Jiunn-Wang; Yeh, Shu-Lan

2014-01-01

Our previous study showed that quercetin enhances the anticancer effect of trichostatin A (TSA) in xenograft mice given quercetin intraperitoneally (10 mg/kg, 3 times/week). Herein, we investigate whether quercetin administered orally exerts such an effect and prevents the cytotoxic side effects of TSA. We found that quercetin given orally (20 and 100 mg/kg, 3 times/week) failed to enhance the antitumor effect of TSA although it increased the total quercetin concentration more than quercetin administered intraperitoneally in the plasma. The compound quercetin-3-glucuronide (Q3G) increased the most. However, quercetin administered intraperitoneally increased the total quercetin level in tumor tissues more than oral quercetin. Oral and intraperitoneal administration of quercetin similarly decreased lymphocyte DNA damage and plasma lipid peroxidation level induced by TSA. Furthermore, we found that the enhancing effect of Q3G on the antitumor effect of TSA and the incorporation of Q3G was less than that of quercetin in A549 cells. However, we found that A549 cells possessed the ability to convert Q3G to quercetin. In conclusion, different from quercetin administered intraperitoneally, quercetin administered orally failed to enhance the antitumor effect of TSA because of its metabolic conversion. However, it prevented TSA-induced DNA damage and lipid peroxidation.

Effects of oral administration of yam tuber storage protein, dioscorin, to BALB/c mice for 21-days on immune responses.

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Liu, Yen-Wenn; Liu, Ju-Chi; Huang, Chun-Yao; Wang, Chung-Kwe; Shang, Huey-Fang; Hou, Wen-Chi

2009-10-14

Dioscorin, the tuber storage protein of yam, was reported to have immunomodulatory activity in RAW264.7 murine macrophage cell lines ( Food and Chemical Toxicology , 2007 , 45 , 2312 -2318 ). However, the immunomodulatory function of dioscorin after being ingested was not elucidated in vivo. Hence, BALB/c mice were given oral dioscorin (2.5 and 20 mg/kg/day) once a day for 21-days. Lymphocyte subpopulation changes in the peripheral blood and splenocytes, stimulation in phagocytosis of the polymorphonuclear cell (PMN) and monocytes, the natural killer (NK) cell cytotoxicity, the splenocyte proliferation, and cytokine secretions in the presence of PHA were determined. The number changes of Peyer's patches and secreted IgA (sIgA) in the feces were determined. Oral dioscorin for 21-days increased the subpopulation in natural killer cells (CD49(+)) and/or B cells (CD19(+)), elevated the phagocytosis of PMN (p dioscorin and significant difference to those of the control (p dioscorin exhibited systemic and mucosal immunomodulatory activities after being ingested in vivo.

Conscious sedation by oral administration of midazolam in paediatric dental treatment.

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Erlandsson, A L; Bäckman, B; Stenström, A; Stecksén-Blicks, C

2001-01-01

Midazolam is a short-acting benzodiazepine with rapid onset, short duration of action and minimal side effects. The aim of this study was to evaluate the oral administration of midazolam as pre-operative sedation in the dental treatment of uncooperative pediatric patients. Included in the study were 160 children with a mean age of 6.7 +/- 2.6 years (1-14 years), 83 boys and 77 girls. All the patients had been referred for specialist treatment due to behavioral management problems. Treatment was performed in 250 sessions. All the children received an oral dose of 0.2 mg/kg body weight of midazolam. Acceptance of treatment was evaluated according to Rud & Kisling. Local anesthesia followed by restorative treatment and/or extractions constituted more than 90% of the performed treatments. Of the 250 sessions, 63% were performed with total acceptance and 30% with doubtful acceptance. In 7%, no treatment could be performed. No serious complications were registered during or after treatment. All the children were able to leave the clinic one hour after treatment. In conclusion, we consider oral administration of midazolam a safe form of premedication. The route of administration, the short waiting-time and half-life, in combination with a level of sedation that allows treatment to be performed, are the principal advantages of conscious sedation with orally administered midazolam.

Anti-tumour immune effect of oral administration of Lactobacillus

Indian Academy of Sciences (India)

Our results indicated that oral administration with L. plantarum inhibited CT26 cell ... (but not IL-4 or IL-17) production, and promotion of Th1-type CD4+ T differentiation. ... College of Animal Science and Technology, Jilin Agricultural University, ...

Expression of cholera toxin B–proinsulin fusion protein in lettuce and tobacco chloroplasts – oral administration protects against development of insulitis in non-obese diabetic mice

Science.gov (United States)

Ruhlman, Tracey; Ahangari, Raheleh; Devine, Andrew; Samsam, Mohtahsem; Daniell, Henry

2008-01-01

Summary Lettuce and tobacco chloroplast transgenic lines expressing the cholera toxin B subunit–human proinsulin (CTB-Pins) fusion protein were generated. CTB-Pins accumulated up to ~16% of total soluble protein (TSP) in tobacco and up to ~2.5% of TSP in lettuce. Eight milligrams of powdered tobacco leaf material expressing CTB-Pins or, as negative controls, CTB–green fluorescent protein (CTB-GFP) or interferon–GFP (IFN-GFP), or untransformed leaf, were administered orally, each week for 7 weeks, to 5-week-old female non-obese diabetic (NOD) mice. The pancreas of CTB-Pins-treated mice showed decreased infiltration of cells characteristic of lymphocytes (insulitis); insulin-producing β-cells in the pancreatic islets of CTB-Pins-treated mice were significantly preserved, with lower blood or urine glucose levels, by contrast with the few β-cells remaining in the pancreatic islets of the negative controls. Increased expression of immunosuppressive cytokines, such as interleukin-4 and interleukin-10 (IL-4 and IL-10), was observed in the pancreas of CTB-Pins-treated NOD mice. Serum levels of immunoglobulin G1 (IgG1), but not IgG2a, were elevated in CTB-Pins-treated mice. Taken together, T-helper 2 (Th2) lymphocyte-mediated oral tolerance is a likely mechanism for the prevention of pancreatic insulitis and the preservation of insulin-producing β-cells. This is the first report of expression of a therapeutic protein in transgenic chloroplasts of an edible crop. Transplastomic lettuce plants expressing CTB-Pins grew normally and transgenes were maternally inherited in T1 progeny. This opens up the possibility for the low-cost production and delivery of human therapeutic proteins, and a strategy for the treatment of various other autoimmune diseases. PMID:17490448

Active invasion of oral and aortic tissues by Porphyromonas gingivalis in mice causally links periodontitis and atherosclerosis.

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Irina M Velsko

Full Text Available Atherosclerotic vascular disease is a leading cause of myocardial infarction and cerebrovascular accident, and independent associations with periodontal disease (PD are reported. PD is caused by polymicrobial infections and aggressive immune responses. Genomic DNA of Porphyromonas gingivalis, the best-studied bacterial pathogen associated with severe PD, is detected within atherosclerotic plaque. We examined causal relationships between chronic P. gingivalis oral infection, PD, and atherosclerosis in hyperlipidemic ApoEnull mice. ApoEnull mice (n = 24 were orally infected with P. gingivalis for 12 and 24 weeks. PD was assessed by standard clinical measurements while the aorta was examined for atherosclerotic lesions and inflammatory markers by array. Systemic inflammatory markers serum amyloid A, nitric oxide, and oxidized low-density lipoprotein were analyzed. P. gingivalis infection elicited specific antibodies and alveolar bone loss. Fluorescent in situ hybridization detected viable P. gingivalis within oral epithelium and aorta, and genomic DNA was detected within systemic organs. Aortic plaque area was significantly increased in P. gingivalis-infected mice at 24 weeks (P<0.01. Aortic RNA and protein arrays indicated a strong Th2 response. Chronic oral infection with P. gingivalis results in a specific immune response, significant increases in oral bone resorption, aortic inflammation, viable bacteria in oral epithelium and aorta, and plaque development.

Protection of mice from oral Candidiasis by heat-killed enterococcus faecalis, possibly through its direct binding to Candida albicans.

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Ishijima, Sanae A; Hayama, Kazumi; Ninomiya, Kentaro; Iwasa, Masahiro; Yamazaki, Masatoshi; Abe, Shigeru

2014-01-01

To develop a new therapy against oral candidiasis, a commensal microorganism, Enterococcus faecalis was tested for its ability to modulate Candida growth in vitro and its therapeutic activities against a murine model in vivo. Addition of heat-killed E. faecalis strain EF2001 (EF2001) isolated from healthy human feces to the culture of C. albicans strain TIMM1768 inhibited adherence of the latter to a microtiter plate in a dose dependent manner and Candida cells surrounded by EF2001 were increased. To examine the protective activities of EF2001 in vivo, heat-killed EF2001 was applied orally before and after inoculation of Candida to the tongue of mice previously immunosuppressed. Two days after inoculation this inoculation, both the symptom score and CFU from swabbed-tongue were significantly reduced in the EF2001-treated animals. Histological analysis indicated that EF2001 may potentiate the accumulation of polymorphnuclear cells near a Candida-infected region. These results suggest that oral administration of EF2001 has protective activity against oral candidiasis and that the in vivo activity may be reflected by direct interaction between EF2001 and Candida cells in vitro and the potentiation of an immunostimulatory effect of EF2001.

Acute agmatine administration, similar to ketamine, reverses depressive-like behavior induced by chronic unpredictable stress in mice.

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Neis, Vivian B; Bettio, Luis E B; Moretti, Morgana; Rosa, Priscila B; Ribeiro, Camille M; Freitas, Andiara E; Gonçalves, Filipe M; Leal, Rodrigo B; Rodrigues, Ana Lúcia S

Agmatine is an endogenous neuromodulator that has been shown to have antidepressant-like properties. We have previously demonstrated that it can induce a rapid increase in BDNF levels after acute administration, suggesting that agmatine may be a fast-acting antidepressant. To investigate this hypothesis, the present study evaluated the effects of a single administration of agmatine in mice subjected to chronic unpredictable stress (CUS), a model of depression responsive only to chronic treatment with conventional antidepressants. The ability of agmatine to reverse CUS-induced behavioral and biochemical alterations was evaluated and compared with those elicited by the fast-acting antidepressant (ketamine) and the conventional antidepressant (fluoxetine). After exposed to CUS for 14days, mice received a single oral dose of agmatine (0.1mg/kg), ketamine (1mg/kg) or fluoxetine (10mg/kg), and were submitted to behavioral evaluation after 24h. The exposure to CUS caused an increased immobility time in the tail suspension test (TST) but did not change anhedonic-related parameters in the splash test. Our findings provided evidence that, similarly to ketamine, agmatine is able to reverse CUS-induced depressive-like behavior in the TST. Western blot analyses of prefrontal cortex (PFC) demonstrated that mice exposed to CUS and/or treated with agmatine, fluoxetine or ketamine did not present alterations in the immunocontent of synaptic proteins [i.e. GluA1, postsynaptic density protein 95 (PSD-95) and synapsin]. Altogether, our findings indicate that a single administration of agmatine is able to reverse behavioral alterations induced by CUS in the TST, suggesting that this compound may have fast-acting antidepressant-like properties. However, there was no alteration in the levels of synaptic proteins in the PFC, a result that need to be further investigated in other time points. Copyright © 2016 Elsevier Inc. All rights reserved.

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy

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Yanamandra, Kiran; Patel, Tirth K.; Jiang, Hong; Schindler, Suzanne; Ulrich, Jason D.; Boxer, Adam L.; Miller, Bruce L.; Kerwin, Diana R.; Gallardo, Gilbert; Stewart, Floy; Finn, Mary Beth; Cairns, Nigel J.; Verghese, Philip B.; Fogelman, Ilana; West, Tim; Braunstein, Joel; Robinson, Grace; Keyser, Jennifer; Roh, Joseph; Knapik, Stephanie S.; Hu, Yan; Holtzman, David M.

2017-01-01

Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain. PMID:28424326

Pharmacological Protection From Radiation ± Cisplatin-Induced Oral Mucositis

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Cotrim, Ana P.; Yoshikawa, Masanobu; Sunshine, Abraham N.; Zheng Changyu; Sowers, Anastasia L.; Thetford, Angela D.; Cook, John A.; Mitchell, James B.; Baum, Bruce J.

2012-01-01

Purpose: To evaluate if two pharmacological agents, Tempol and D-methionine (D-met), are able to prevent oral mucositis in mice after exposure to ionizing radiation ± cisplatin. Methods and Materials: Female C3H mice, ∼8 weeks old, were irradiated with five fractionated doses ± cisplatin to induce oral mucositis (lingual ulcers). Just before irradiation and chemotherapy, mice were treated, either alone or in combination, with different doses of Tempol (by intraperitoneal [ip] injection or topically, as an oral gel) and D-met (by gavage). Thereafter, mice were sacrificed and tongues were harvested and stained with a solution of Toluidine Blue. Ulcer size and tongue epithelial thickness were measured. Results: Significant lingual ulcers resulted from 5 × 8 Gy radiation fractions, which were enhanced with cisplatin treatment. D-met provided stereospecific partial protection from lingual ulceration after radiation. Tempol, via both routes of administration, provided nearly complete protection from lingual ulceration. D-met plus a suboptimal ip dose of Tempol also provided complete protection. Conclusions: Two fairly simple pharmacological treatments were able to markedly reduce chemoradiation-induced oral mucositis in mice. This proof of concept study suggests that Tempol, alone or in combination with D-met, may be a useful and convenient way to prevent the severe oral mucositis that results from head-and-neck cancer therapy.

Oral feeding with polyunsaturated fatty acids fosters hematopoiesis and thrombopoiesis in healthy and bone marrow-transplanted mice.

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Limbkar, Kedar; Dhenge, Ankita; Jadhav, Dipesh D; Thulasiram, Hirekodathakallu V; Kale, Vaijayanti; Limaye, Lalita

2017-09-01

Hematopoietic stem cells play the vital role of maintaining appropriate levels of cells in blood. Therefore, regulation of their fate is essential for their effective therapeutic use. Here we report the role of polyunsaturated fatty acids (PUFAs) in regulating hematopoiesis which has not been explored well so far. Mice were fed daily for 10 days with n-6/n-3 PUFAs, viz. linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid and docosahexanoic acid (DHA) in four separate test groups with phosphate-buffered saline fed mice as control set. The bone marrow cells of PUFA-fed mice showed a significantly higher hematopoiesis as assessed using side population, Lin-Sca-1 + ckit+, colony-forming unit (CFU), long-term culture, CFU-spleen assay and engraftment potential as compared to the control set. Thrombopoiesis was also stimulated in PUFA-fed mice. A combination of DHA and AA was found to be more effective than when either was fed individually. Higher incorporation of PUFAs as well as products of their metabolism was observed in the bone marrow cells of PUFA-fed mice. A stimulation of the Wnt, CXCR4 and Notch1 pathways was observed in PUFA-fed mice. The clinical relevance of this study was evident when bone marrow-transplanted recipient mice, which were fed with PUFAs, showed higher engraftment of donor cells, suggesting that the bone marrow microenvironment may also be stimulated by feeding with PUFAs. These data indicate that oral administration of PUFAs in mice stimulates hematopoiesis and thrombopoiesis and could serve as a valuable supplemental therapy in situations of hematopoietic failure. Copyright © 2017 Elsevier Inc. All rights reserved.

Cholera toxin subunit B peptide fusion proteins reveal impaired oral tolerance induction in diabetes-prone but not in diabetes-resistant mice.

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Presa, Maximiliano; Ortiz, Angela Zarama; Garabatos, Nahir; Izquierdo, Cristina; Rivas, Elisa I; Teyton, Luc; Mora, Conchi; Serreze, David; Stratmann, Thomas

2013-11-01

The cholera toxin B subunit (CTB) has been used as adjuvant to improve oral vaccine delivery in type 1 diabetes. The effect of CTB/peptide formulations on Ag-specific CD4(+) T cells has remained largely unexplored. Here, using tetramer analysis, we investigated how oral delivery of CTB fused to two CD4(+) T-cell epitopes, the BDC-2.5 T-cell 2.5 mi mimotope and glutamic acid decarboxylase (GAD) 286-300, affected diabetogenic CD4(+) T cells in nonobese diabetic (NOD) mice. When administered i.p., CTB-2.5 mi activated 2.5 mi(+) T cells and following intragastric delivery generated Ag-specific Foxp3(+) Treg and Th2 cells. While 2.5 mi(+) and GAD-specific T cells were tolerized in diabetes-resistant NODxB6.Foxp3(EGFP) F1 and nonobese resistant (NOR) mice, this did not occur in NOD mice. This indicated that NOD mice had a recessive genetic resistance to induce oral tolerance to both CTB-fused epitopes. In contrast to NODxB6.Foxp3(EGFP) F1 mice, oral treatment in NOD mice lead to strong 2.5 mi(+) T-cell activation and the sequestration of these cells to the effector-memory pool. Oral treatment of NOD mice with CTB-2.5 mi failed to prevent diabetes. These findings underline the importance of investigating the effect of oral vaccine formulations on diabetogenic T cells as in selected cases they may have counterproductive consequences in human patients. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Optical imaging of absorption and distribution of RITC-SiO2 nanoparticles after oral administration

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Lee CM

2014-12-01

Full Text Available Chang-Moon Lee,1 Tai Kyoung Lee,2–5 Dae-Ik Kim,1,6 Yu-Ri Kim,7 Meyoung-Kon Kim,7 Hwan-Jeong Jeong,2–5 Myung-Hee Sohn,2–5 Seok Tae Lim2–5 1Department of Biomedical Engineering, Chonnam National University, Yeosu, Jeollanam-Do, Republic of Korea; 2Department of Nuclear Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeollabuk-Do, Republic of Korea; 3Cyclotron Research Center, Chonbuk National University Medical School and Hospital, Jeonju, Jeollabuk-Do, Republic of Korea; 4Biomedical Research Institute, Chonbuk National University Medical School and Hospital, Jeonju, Jeollabuk-Do, Republic of Korea; 5Molecular Imaging and Therapeutic Medicine Research Center, Chonbuk National University Medical School and Hospital, Jeonju, Jeollabuk-Do, Republic of Korea; 6School of Electrical, Electronic Communication, and Computer Engineering, Chonnam National University, Yeosu, Jeollanam-Do, Republic of Korea; 7Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seounbuk-Gu, Seoul, Republic of Korea Purpose: In this study, we investigated the absorption and distribution of rhodamine B isothiocyanate (RITC-incorporated silica oxide nanoparticles(SiNPs (RITC-SiNPs after oral exposure, by conducting optical imaging, with a focus on tracking the movement of RITC-SiNPs of different particle size and surface charge. Methods: RITC-SiNPs (20 or 100 nm; positively or negatively charged were used to avoid the dissociation of a fluorescent dye from nanoparticles via spontaneous or enzyme-catalyzed reactions in vivo. The changes in the nanoparticle sizes and shapes were investigated in an HCl solution for 6 hours. RITC-SiNPs were orally administered to healthy nude mice at a dose of 100 mg/kg. Optical imaging studies were performed at 2, 4, and 6 hours after oral administration. The mice were sacrificed at 2, 4, 6, and 10 hours post-administration, and ex vivo imaging studies were performed

Oral administration of methysticin improves cognitive deficits in a mouse model of Alzheimer's disease

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Athanassios Fragoulis

2017-08-01

Full Text Available Introduction: There is increasing evidence for the involvement of chronic inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD. Nuclear factor erythroid 2-related factor 2 (Nrf2 is an anti-inflammatory transcription factor that regulates the oxidative stress defense. Our previous experiments demonstrated that kavalactones protect neuronal cells against Amyloid β (Aβ-induced oxidative stress in vitro by Nrf2 pathway activation. Here, we tested an in vivo kavalactone treatment in a mouse model of AD. Methods: The kavalactone methysticin was administered once a week for a period of 6 months to 6 month old transgenic APP/Psen1 mice by oral gavage. Nrf2 pathway activation was measured by methysticin treatment of ARE-luciferase mice, by qPCR of Nrf2-target genes and immunohistochemical detection of Nrf2. Aβ burden was analyzed by CongoRed staining, immunofluorescent detection and ELISA. Neuroinflammation was assessed by immunohistochemical stainings for microglia and astrocytes. Pro-inflammatory cytokines in the hippocampus was determined by Luminex multi-plex assays. The hippocampal oxidative damage was detected by oxyblot technique and immunohistochemical staining against DT3 and 4-HNE. The cognitive ability of mice was evaluated using Morris water maze. Results: Methysticin treatment activated the Nrf2 pathway in the hippocampus and cortex of mice. The Aβ deposition in brains of methysticin-treated APP/Psen1 mice was not altered compared to untreated mice. However, methysticin treatment significantly reduced microgliosis, astrogliosis and secretion of the pro-inflammatory cytokines TNF-α and IL-17A. In addition, the oxidative damage of hippocampi from APP/Psen1 mice was reduced by methysticin treatment. Most importantly, methysticin treatment significantly attenuated the long-term memory decline of APP/Psen1 mice. Conclusion: In summary, these findings show that methysticin administration activates the Nrf2 pathway

Oral Modeling of an Adenovirus-Based Quadrivalent Influenza Vaccine in Ferrets and Mice.

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Scallan, Ciaran D; Lindbloom, Jonathan D; Tucker, Sean N

2016-06-01

Oral vaccines delivered as tablets offer a number of advantages over traditional parenteral-based vaccines including the ease of delivery, lack of needles, no need for trained medical personnel, and the ability to formulate into temperature-stable tablets. We have been evaluating an oral vaccine platform based on recombinant adenoviral vectors for the purpose of creating a prophylactic vaccine to prevent influenza, and have demonstrated vaccine efficacy in animal models and substantial immunogenicity in humans. These studies have evaluated monovalent vaccines to date. To protect against the major circulating A and B influenza strains, a multivalent influenza vaccine will be required. In this study, the immunogenicity of orally delivered monovalent, bivalent, trivalent, and quadrivalent vaccines was tested in ferrets and mice. The various vaccine combinations were tested by blending monovalent recombinant adenovirus vaccines, each expressing hemagglutinin from a single strain. Human tablet delivery was modeled in animals by oral gavage in mice and by endoscopic delivery in ferrets. We demonstrated minimal interference between the various vaccine vectors when used in combination and that the oral quadrivalent vaccine compared favorably to an approved trivalent inactivated vaccine. The quadrivalent vaccine presented here produced immune responses that we predict should be capable of providing protection against multiple influenza strains, and the platform should have applications to other multivalent vaccines. Vaxart, Inc.

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

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Aggar, Christina; Dawson, Sonja

2014-06-01

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

Effect of chronic pain on fentanyl self-administration in mice.

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Carrie L Wade

Full Text Available The development of opioid addiction in subjects with established chronic pain is an area that is poorly understood. It is critically important to clearly understand the neurobiology associated with propensity toward conversion to addiction under conditions of chronic pain. To pose the question whether the presence of chronic pain influences motivation to self-administer opioids for reward, we applied a combination of rodent models of chronic mechanical hyperalgesia and opioid self-administration. We studied fentanyl self-administration in mice under three conditions that induce chronic mechanical hyperalgesia: inflammation, peripheral nerve injury, and repeated chemotherapeutic injections. Responding for fentanyl was compared among these conditions and their respective standard controls (naïve condition, vehicle injection or sham surgery. Acquisition of fentanyl self-administration behavior was reduced or absent in all three conditions of chronic hyperalgesia relative to control mice with normal sensory thresholds. To control for potential impairment in ability to learn the lever-pressing behavior or perform the associated motor tasks, all three groups were evaluated for acquisition of food-maintained responding. In contrast to the opioid, chronic hyperalgesia did not interfere with the reinforcing effect of food. These studies indicate that the establishment of chronic hyperalgesia is associated with reduced or ablated motivation to seek opioid reward in mice.

Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice.

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Verma, Dheeraj; Moghimi, Babak; LoDuca, Paul A; Singh, Harminder D; Hoffman, Brad E; Herzog, Roland W; Daniell, Henry

2010-04-13

To address complications of pathogenic antibody or life-threatening anaphylactic reactions in protein replacement therapy for patients with hemophilia or other inherited protein deficiencies, we have developed a prophylactic protocol using a murine hemophilia B model. Oral delivery of coagulation factor IX fused with cholera toxin beta-subunit (with or without a furin cleavage site; CTB-FFIX or CTB-FIX), expressed in chloroplasts (up to 3.8% soluble protein or 0.4 mg/g leaf tissue), bioencapsulated in plant cells, effectively blocked formation of inhibitory antibodies (undetectable or up to 100-fold less than controls). Moreover, this treatment eliminated fatal anaphylactic reactions that occurred after four to six exposures to intravenous F.IX. Whereas only 20-25% of control animals survived after six to eight F.IX doses, 90-93% of F.IX-fed mice survived 12 injections without signs of allergy or anaphylaxis. Immunostaining confirmed delivery of F.IX to Peyer's patches in the ileum. Within 2-5 h, feeding of CTB-FFIX additionally resulted in systemic delivery of F.IX antigen. This high-responder strain of hemophilia B mice represents a new animal model to study anaphylactic reactions. The protocol was effective over a range of oral antigen doses (equivalent to 5-80 microg recombinant F.IX/kg), and controlled inhibitor formation and anaphylaxis long-term, up to 7 months (approximately 40% life span of this mouse strain). Oral antigen administration caused a deviant immune response that suppressed formation of IgE and inhibitory antibodies. This cost-effective and efficient approach of antigen delivery to the gut should be applicable to several genetic diseases that are prone to pathogenic antibody responses during treatment.

Pharmacokinetics and skin concentrations of lincomycin after intravenous and oral administration to cats

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Gabriela A. Albarellos

2013-10-01

Full Text Available The aim of the present study was to describe the plasma pharmacokinetic profile and skin concentrations of lincomycin after intravenous administration of a 15% solution and oral administration of 300 mg tablets at a dosing rate of 15 mg/kg to cats. Susceptibility of staphylococci (n = 31 and streptococci (n = 23 strains isolated from clinical cases was also determined. Lincomycin plasma and skin concentrations were determined by microbiological assay using Kocuria rhizophila ATCC 9341 as test microorganism. Susceptibility was established by the antimicrobial disc diffusion test. Individual lincomycin plasma concentration–time curves were analysed by a non-compartmental approach. After intravenous administration, volume of distribution, body clearance and elimination half-life were 0.97 L/kg ± 0.15 L/kg, 0.17 L/kg ± 0.06 L/h.kg and 4.20 h ± 1.12 h, respectively. After oral administration, peak plasma concentration, time of maximum plasma concentration and bioavailability were 22.52 µg/mL ± 10.97 µg/mL, 0.80 h ± 0.11 h and 81.78% ± 24.05%, respectively. Two hours after lincomycin administration, skin concentrations were 17.26 µg/mL ± 1.32 µg/mL (intravenous and 16.58 µg/mL ± 0.90 µg/mL (oral. The corresponding skin: plasma ratios were 2.08 ± 0.47 (intravenous and 1.84 ± 0.97 (oral. The majority of staphylococci and streptococci tested in this study were susceptible to lincosamides (87.09% and 69.56%, respectively. In conclusion, lincomycin administered orally at the assayed dose showed a good pharmacokinetic profile, with a long elimination half-life and effective skin concentration. Therefore, it could be a good first option for treating skin infections in cats.

Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice

International Nuclear Information System (INIS)

Ikebe, E; Kawaguchi, A; Tezuka, K; Taguchi, S; Hirose, S; Matsumoto, T; Mitsui, T; Senba, K; Nishizono, A; Hori, M; Hasegawa, H; Yamada, Y; Ueno, T; Tanaka, Y; Sawa, H; Hall, W; Minami, Y; Jeang, K T; Ogata, M; Morishita, K; Hasegawa, H; Fujisawa, J; Iha, H

2013-01-01

In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90's ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression

Administration of vitamin K does not counteract the ectopic mineralization of connective tissues in Abcc6−/− mice, a model for pseudoxanthoma elasticum

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Jiang, Qiujie; Li, Qiaoli; Grand-Pierre, Alix E; Schurgers, Leon J; Uitto, Jouni

2011-01-01

Pseudoxanthoma elasticum (PXE) is a heritable multisystem disorder manifesting with ectopic calcification of peripheral connective tissues, caused by mutations in the ABCC6 gene. Alterations in vitamin K metabolism have been suggested to contribute to the pathomechanisms of the mineralization process. In this study we administered vitamin K or its glutathione conjugate (K3-GSH) into Abcc6−/− mice that recapitulate features of PXE. Oral administration of vitamin K2, in dosages that vastly exce...

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

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

2012-08-01

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

Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects.

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Abbas, Richat; Hug, Bruce A; Leister, Cathie; Burns, Jaime; Sonnichsen, Daryl

2011-04-01

The primary objective was to evaluate the pharmacokinetics of a single dose of neratinib, a potent, low-molecular-weight, orally administered, irreversible pan-ErbB (ErbB-1, -2, -4) receptor tyrosine kinase inhibitor, during co-administration with ketoconazole, a potent CYP3A4 inhibitor. This was an open-label, randomized, two-period, crossover study. Fasting healthy adults received a single oral dose of neratinib 240 mg alone and with multiple oral doses of ketoconazole 400 mg. Blood samples were collected up to 72 h after each neratinib dose. Plasma concentration data were analyzed using a noncompartmental method. The least square geometric mean ratios [90% confidence interval (CI)] of C(max) (neratinib+ketoconazole): C(max) (neratinib alone), and AUC(neratinib+ketoconazole): AUC(neratinib alone) were assessed. Twenty-four subjects were enrolled. Compared with neratinib administered alone, co-administration of ketoconazole increased neratinib C(max) by 3.2-fold (90% CI: 2.4, 4.3) and AUC by 4.8-fold (3.6, 6.5). Median t(max) was 6.0 h with both regimens. Ketoconazole decreased mean apparent oral clearance of neratinib from 346 lh(-1) to 87.1 lh(-1) and increased mean elimination half-life from 11.7 h to 18.0 h. The incidence of adverse events was comparable between the two regimens (50% neratinib alone, 65% co-administration with ketoconazole). Co-administration of neratinib with ketoconazole, a potent CYP3A inhibitor, increased neratinib C(max) by 3.2-fold and AUC by 4.8-fold compared with administration of neratinib alone. These results indicate that neratinib is a substrate of CYP3A and is susceptible to interaction with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Use of anesthesia dramatically alters the oral glucose tolerance and insulin secretion in C57Bl/6 mice

DEFF Research Database (Denmark)

Windeløv, Johanne A; Pedersen, Jens; Holst, Jens J

2016-01-01

Evaluation of the impact of anesthesia on oral glucose tolerance in mice. Anesthesia is often used when performing OGTT in mice to avoid the stress of gavage and blood sampling, although anesthesia may influence gastrointestinal motility, blood glucose, and plasma insulin dynamics. C57Bl/6 mice...... in the time frame -15 to +150 min. Plasma insulin concentration was measured at time 0 and 20 min. All four anesthetic regimens resulted in impaired glucose tolerance compared to saline/no anesthesia. (1) hypnorm/midazolam increased insulin concentrations and caused an altered glucose tolerance; (2) ketamine...... regimens altered the oral glucose tolerance, and we conclude that anesthesia should not be used when performing metabolic studies in mice....

Preventive Intra Oral Treatment of Sea Cucumber Ameliorate OVA-Induced Allergic Airway Inflammation.

Science.gov (United States)

Lee, Da-In; Park, Mi-Kyung; Kang, Shin Ae; Choi, Jun-Ho; Kang, Seok-Jung; Lee, Jeong-Yeol; Yu, Hak Sun

2016-01-01

Sea cucumber extracts have potent biological effects, including anti-viral, anti-cancer, antibacterial, anti-oxidant, and anti-inflammation effects. To understand their anti-asthma effects, we induced allergic airway inflammation in mice after 7 oral administrations of the extract. The hyper-responsiveness value in mice with ovalbumin (OVA)-alum-induced asthma after oral injection of sea cucumber extracts was significantly lower than that in the OVA-alum-induced asthma group. In addition, the number of eosinophils in the lungs of asthma-induced mice pre-treated with sea cucumber extract was significantly decreased compared to that of PBS pre-treated mice. Additionally, CD4[Formula: see text]CD25[Formula: see text]Foxp3[Formula: see text]T (regulatory T; Treg) cells significantly increased in mesenteric lymph nodes after 7 administrations of the extract. These results suggest that sea cucumber extract can ameliorate allergic airway inflammation via Treg cell activation and recruitment to the lung.

Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir Following Intravenous and Oral Administrations in Rats: A Study Involving In vivo Corneal Uptake of Acyclovir Following Oral Dosing

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Ravi S.Talluri

2009-10-01

Full Text Available Objective: To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV in rats. Methods: Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV, L-valine- D-valine-acyclovir (LDACV and D-valine-L-valine acyclovir (DLACV prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results: Following i.v. administration, the area under the curve (AUC in µM*min of generated ACV was in the order of LACV › LDACV › DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 µM*min, respectively. DLACV exhibited poor oral absorption. Cmax (µM and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions: LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV. Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration.

Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir Following Intravenous and Oral Administrations in Rats: A Study Involving In vivo Corneal Uptake of Acyclovir Following Oral Dosing

Science.gov (United States)

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

2009-01-01

Objective To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV) in rats. Methods Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV), L-valine-D-valine-acyclovir (LDACV) and D-valine-L-valine acyclovir (DLACV) prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results Following i.v. administration, the area under the curve (AUC) in μM*min of generated ACV was in the order of LACV > LDACV > DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 μM*min, respectively. DLACV exhibited poor oral absorption. Cmax (μM) and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV. Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration. PMID:23861607

Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir following Intravenous and Oral Administrations in Rats: A study Involving in vivo corneal Uptake of Acyclovir following Oral Dosing

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Ravi S. Talluri

2009-01-01

Full Text Available Objective To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV in rats. Methods Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV, L-valine-D-valine-acyclovir (LDACV and D-valine-L-valine acyclovir (DLACV prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results Following i.v. administration, the area under the curve (AUC in μM*min of generated ACV was in the order of LACV > LDACV > DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 μM*min, respectively. DLACV exhibited poor oral absorption. C max (μM and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration.

Development of oral cancer vaccine using recombinant Bifidobacterium displaying Wilms' tumor 1 protein.

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Kitagawa, Koichi; Oda, Tsugumi; Saito, Hiroki; Araki, Ayame; Gonoi, Reina; Shigemura, Katsumi; Hashii, Yoshiko; Katayama, Takane; Fujisawa, Masato; Shirakawa, Toshiro

2017-06-01

Several types of vaccine-delivering tumor-associated antigens (TAAs) have been developed in basic and clinical research. Wilms' tumor 1 (WT1), identified as a gene responsible for pediatric renal neoplasm, is one of the most promising TAA for cancer immunotherapy. Peptide and dendritic cell-based WT1 cancer vaccines showed some therapeutic efficacy in clinical and pre-clinical studies but as yet no oral WT1 vaccine can be administrated in a simple and easy way. In the present study, we constructed a novel oral cancer vaccine using a recombinant Bifidobacterium longum displaying WT1 protein. B. longum 420 was orally administered into mice inoculated with WT1-expressing tumor cells for 4 weeks to examine anti-tumor effects. To analyze the WT1-specific cellular immune responses to oral B. longum 420, mice splenocytes were isolated and cytokine production and cytotoxic activities were determined. Oral administrations of B. longum 420 significantly inhibited WT1-expressing tumor growth and prolonged survival in mice. Immunohistochemical study and immunological assays revealed that B. longum 420 substantially induced tumor infiltration of CD4 + T and CD8 + T cells, systemic WT1-specific cytokine production, and cytotoxic activity mediated by WT1-epitope specific cytotoxic T lymphocytes, with no apparent adverse effects. Our novel oral cancer vaccine safely induced WT1-specific cellular immunity via activation of the gut mucosal immune system and achieved therapeutic efficacy with several practical advantages over existing non-oral vaccines.

Oral administration of Allium sativum extract protects against infectious bursal disease in chickens

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Sufen ZHAO,Yuanyuan JIA,Weiwei ZHANG,Lili WANG,Yunfei MA,Kedao TENG

2015-12-01

Full Text Available Garlic (Allium sativum, Liliaceae has been safely used for more than 5000 years, and research on garlic extract is rapidly increasing because of its multiple biological functions. The in vivo effects of oral administration of garlic mixture (GM, water-soluble extract on infectious bursal disease virus (IBDV-infected specific pathogen free male white leghorn chicken were examined through histopathological, immunohistochemical, and Western blot analyses, and enzyme-linked immunosorbent assay. The results confirmed the protective effects of oral administration of 5 mg·kg-1 BW GM (Group GM1 on bursal lesions after IBDV infection. In particular, protein expression of IBDV in the bursa decreased in Group GM1, indicating that GM administration decreased IBDV replication in the bursa. Furthermore, immunoglobulin M- and A-bearing B lymphocytes significantly increased 7 days post infection in bursae in Group GM1 (P<0.01, suggesting that the oral administration of 5 mg·kg-1 GM offers moderate protection against B cell destruction after IBDV infection. During infection, the concentration of bursal interferon gamma (IFN-g increased and peaked in Group GM1 earlier than in Group T (IBDV-exposed, demonstrating that GM administration prompted the production of IFN-g to protect against IBDV infection.

Oral tolerance induction with altered forms of ovalbumin

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Stransky B.

1998-01-01

Full Text Available As a T cell-dependent phenomenon, oral tolerance is not expected to depend necessarily on native configuration of antigens. We investigated the induction of oral tolerance with modified ovalbumin (Ova. Oral administration of heat-denatured (HD-Ova and cyanogen bromide-degraded ovalbumin was less effective than native Ova in inducing oral tolerance in B6D2F1 mice. HD-Ova was effective in suppressing delayed-type hypersensitivity (DTH reactions but did not suppress specific antibody formation. Injection of Ova directly into the stomach, but not into the ileum or cecum, suppressed subsequent immunization to DTH reactions. Gavage with protease inhibitors (aprotinin or ovomucoid before gavage with Ova was ineffective in blocking tolerance induction. Treatment with hydroxyurea to destroy cycling cells 24 h before gavage with Ova blocked oral tolerance induction and also the possibility to passively transfer tolerance to naive recipients with the serum of mice gavaged with Ova 1 h before. The implications of these findings about oral tolerance induction are discussed

Studies on the absorption of iron after oral administration in piglets

International Nuclear Information System (INIS)

Thoren-Tolling, K.

1975-01-01

72 newborn piglets from 9 litters were used to determinate the retention and distribution in the body of labelled iron given either orally as ferrous fumarate (100 mg Fe 2+ ) or iron dextran (200 mg Fe 3+ ), or by injection as iron dextran (100 mg Fe 3+ ). About 25-30 % of the radioiron from a single oral dose of labelled ferrous fumarate (100 mg Fe 2+ ), and about 55-60 % from a single oral dose of labelled iron dextran (200 mg Fe 3+ ) were absorbed by the body. As iron is excreted throughout the experiment, only about 20% and 40-50% respectively of the radio-iron from these iron compounds were recovered 3 weeks after treatment. The total amounts of labelled iron retained in the body after oral administration of the same doses of these iron compounds, alone or in combination, were compared. A slight retardation of the absorption of ferrous iron was observed when iron dextran was administered simultaneeously. The absorption of iron dextran was not influenced by the simultaneous administration of ferrous fumarate. The importance of the liver as the main iron storage site was shown, and the rapid utilization of iron from storage sites, about 2-3 weeks after treatment was demonstrated. The concentration of labelled iron in urine and some lymphglands was measured. Only minute quantities of radio-iron were excreted in the urine throughout the entire experiment. The lymph nodes seem to act as iron stones after administration of iron dextran. The importance of the lymphatic tissue in absorption and storage of labelled iron is discussed. (author)

Dietary medium-chain triglycerides promote oral allergic sensitization and orally induced anaphylaxis to peanut protein in mice

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Li, Jianing; Wang, Yu; Tang, Lihua; de Villiers, Willem JS; Cohen, Donald; Woodward, Jerold; Finkelman, Fred D; Eckhardt, Erik RM

2012-01-01

BACKGROUND The prevalence of peanut allergies is rising. Peanuts and many other allergen sources contain significant amounts of triglycerides, which affect absorption of antigens but have unknown effects on sensitization and anaphylaxis. We recently reported that dietary medium-chain triglycerides (MCT), which bypass mesenteric lymph and directly enter portal blood, reduce intestinal antigen absorption into blood compared to long-chain triglycerides (LCT), which stimulate mesenteric lymph flow and are absorbed in chylomicrons via mesenteric lymph. OBJECTIVE Test how dietary MCT affect food allergy. METHODS C3H/HeJ mice were fed peanut butter protein in MCT, LCT (peanut oil), or LCT plus an inhibitor of chylomicron formation (Pluronic L81; “PL81”). Peanut-specific antibodies in plasma, responses of the mice to antigen challenges, and intestinal epithelial cytokine expression were subsequently measured. RESULTS MCT suppressed antigen absorption into blood, but stimulated absorption into Peyer's patches. A single gavage of peanut protein with MCT as well as prolonged feeding in MCT-based diets caused spontaneous allergic sensitization. MCT-sensitized mice experienced IgG-dependent anaphylaxis upon systemic challenge and IgE-dependent anaphylaxis upon oral challenge. MCT feeding stimulated jejunal-epithelial TSLP, IL-25 and IL-33 expression compared to LCT, and promoted Th2 cytokine responses in splenocytes. Moreover, oral challenges of sensitized mice with antigen in MCT significantly aggravated anaphylaxis compared to challenges with LCT. Importantly, effects of MCT could be mimicked by adding PL81 to LCT, and in vitro assays indicated that chylomicrons prevent basophil activation. CONCLUSION Dietary MCT promote allergic sensitization and anaphylaxis by affecting antigen absorption and availability and by stimulating Th2 responses. PMID:23182172

Sex differences in shotgun proteome analyses for chronic oral intake of cadmium in mice.

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Yoshiharu Yamanobe

Full Text Available Environmental diseases related to cadmium exposure primarily develop owing to industrial wastewater pollution and/or contaminated food. In regions with high cadmium exposure in Japan, cadmium accumulation occurs primarily in the kidneys of individuals who are exposed to the metal. In contrast, in the itai-itai disease outbreak that occurred in the Jinzu River basin in Toyama Prefecture in Japan, cadmium primarily accumulated in the liver. On the other hand, high concentration of cadmium caused renal tubular disorder and osteomalacia (multiple bone fracture, probably resulting from the renal tubular dysfunction and additional pathology. In this study, we aimed to establish a mouse model of chronic cadmium intake. We administered cadmium-containing drinking water (32 mg/l to female and male mice ad libitum for 11 weeks. Metal analysis using inductively coupled plasma mass spectrometry revealed that cadmium accumulated in the kidneys (927 x 10 + 185 ng/g in females and 661 x 10 + 101 ng/g in males, liver (397 x 10 + 199 ng/g in females and 238 x 10 + 652 ng/g in males, and thyroid gland (293 + 93.7 ng/g in females and 129 + 72.7 ng/g in males of mice. Female mice showed higher cadmium accumulation in the kidney, liver, and thyroid gland than males did (p = 0.00345, p = 0.00213, and p = 0.0331, respectively. Shotgun proteome analyses after chronic oral administration of cadmium revealed that protein levels of glutathione S-transferase Mu2, Mu4, and Mu7 decreased in the liver, and those of A1 and A2 decreased in the kidneys in both female and male mice.

Reducing radiation exposure during oral I-131 therapy administration

International Nuclear Information System (INIS)

Trujillo, J.; Krinsky, S.; Wilson, B.; Teague, E.

1982-01-01

A new, closed-system method to reduce air-, direct-, and incidental-contamination during therapeutic administration of oral I-131 was experimentally evaluated on twelve patients. We studied a standard control population using the routine practice of drinking the solution through a straw and compared results with our new technique. Various measurements were performed throughout all phases of dose administration to assess the relative difference of the two approaches. Using the closed system method before and during iodine administration revealed between 100 and 1000 times less activity per millimeter of air sample; whereas, the direct radiation exposure values were higher for the control population. Both the experimental and control methods had similar levels of incidental contamination

Withdrawal from Chronic Nicotine Administration Impairs Contextual Fear Conditioning in C57BL/6 Mice

OpenAIRE

Davis, Jennifer A.; James, John R.; Siegel, Steven J.; Gould, Thomas J.

2005-01-01

The effects of acute nicotine administration (0.09 mg/kg nicotine), chronic nicotine administration (6.3 mg/kg/d nicotine for 14 d), and withdrawal from chronic nicotine administration on fear conditioning in C57BL/6 mice were examined. Mice were trained using two coterminating conditioned stimulus (30 s; 85 dB white noise)– unconditioned stimulus (2 s; 0.57 mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. Acute nicotine administration enhanced contextu...

Oral dosing by voluntary  administration of jellybeans. Refinement and reduction of variability

DEFF Research Database (Denmark)

Pakula, Malgorzata Maria; Dagnæs-Hansen, Frederik

2016-01-01

Administration of substances by oral gavage is a common procedure in biomedical research involving laboratory animals, however although highly efficient, the procedure includes fixation of the animals and is technically challenging. Oral gavage is a precise way to dose animals, however it may ind...

Pharmacokinetics of [3H]levamisole in pigs after oral and intramuscular administration

International Nuclear Information System (INIS)

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

1983-01-01

A single oral (10 mg/kg of body weight) or IM (7.5 mg/kg) dose of [ 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

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

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

2013-03-01

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

Administration of kefir-fermented milk protects mice against Giardia intestinalis infection.

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Franco, Mariana Correa; Golowczyc, Marina A; De Antoni, Graciela L; Pérez, Pablo F; Humen, Martín; Serradell, María de los Angeles

2013-12-01

Giardiasis, caused by the protozoan Giardia intestinalis, is one of the most common intestinal diseases worldwide and constitutes an important problem for the public health systems of various countries. Kefir is a probiotic drink obtained by fermenting milk with 'kefir grains', which consist mainly of bacteria and yeasts that coexist in a complex symbiotic association. In this work, we studied the ability of kefir to protect mice from G. intestinalis infection, and characterized the host immune response to this probiotic in the context of the intestinal infection. Six- to 8-week-old C75BL/6 mice were separated into four groups: controls, kefir mice (receiving 1 : 100 dilution of kefir in drinking water for 14 days), Giardia mice (infected orally with 4×10(7) trophozoites of G. intestinalis at day 7) and Giardia-kefir mice (kefir-treated G. intestinalis-infected mice), and killed at 2 or 7 days post-infection. Kefir administration was able to significantly reduce the intensity of Giardia infection at 7 days post-infection. An increase in the percentage of CD4(+) T cells at 2 days post-infection was observed in the Peyer's patches (PP) of mice belonging to the Giardia group compared with the control and kefir groups, while the percentage of CD4(+) T cells in PP in the Giardia-kefir group was similar to that of controls. At 2 days post-infection, a reduction in the percentage of B220-positive major histocompatibility complex class II medium cells in PP was observed in infected mice compared with the other groups. At 7 days post-infection, Giardia-infected mice showed a reduction in RcFcε-positive cells compared with the control group, suggesting a downregulation of the inflammatory response. However, the percentages of RcFcε-positive cells did not differ from controls in the kefir and Giardia-kefir groups. An increase in IgA-positive cells was observed in the lamina propria of the kefir group compared with controls at 2 days post-infection. Interestingly, the

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

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Pin Marie

2005-04-01

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

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

Science.gov (United States)

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

2013-06-01

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

Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections

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Larissa B. Thackray

2018-03-01

Full Text Available Summary: Although the outcome of flavivirus infection can vary from asymptomatic to lethal, environmental factors modulating disease severity are poorly defined. Here, we observed increased susceptibility of mice to severe West Nile (WNV, Dengue, and Zika virus infections after treatment with oral antibiotics (Abx that depleted the gut microbiota. Abx treatment impaired the development of optimal T cell responses, with decreased levels of WNV-specific CD8+ T cells associated with increased infection and immunopathology. Abx treatments that resulted in enhanced WNV susceptibility generated changes in the overall structure of the gut bacterial community and in the abundance of specific bacterial taxa. As little as 3 days of treatment with ampicillin was sufficient to alter host immunity and WNV outcome. Our results identify oral Abx therapy as a potential environmental determinant of systemic viral disease, and they raise the possibility that perturbation of the gut microbiota may have deleterious consequences for subsequent flavivirus infections. : Thackray et al. observed increased susceptibility to West Nile, Zika, and Dengue virus infections following oral antibiotic treatment in mice. Antibiotics altered the bacterial abundance and community structure and the development of optimal T cell immunity. These data suggest that antibiotics may have deleterious consequences for subsequent flavivirus infections. Keywords: West Nile virus, Dengue virus, Zika virus, flavivirus, oral antibiotics, gut microbiota, risk factors, pathogenesis determinants, immunity

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

Science.gov (United States)

2010-04-01

... § 416.1448 Deciding a case without an oral hearing before an administrative law judge. (a) Decision... the decision is based. (b) Parties do not wish to appear. (1) The administrative law judge may decide... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Deciding a case without an oral hearing...

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

Science.gov (United States)

2010-04-01

....948 Deciding a case without an oral hearing before an administrative law judge. (a) Decision wholly... is based. (b) Parties do not wish to appear. (1) The administrative law judge may decide a case on... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Deciding a case without an oral hearing...

Evaluation of Cardiopulmonary Toxicity Following Oral Administration of Multi-walled Carbon Nanotubes in Wistar Rats

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Ehsan Zayerzadeh

2016-07-01

Full Text Available Objective(s: Carbon nanotubes have unique mechanical, electrical, and thermal properties, with potential different applications in nanomedicine, electronics, and other industries. These new applications of carbon nanotubes in different industries lead to the increased exposure risk of nanomaterials to human. Up to now, all aspects of carbon nanotubes toxicity are not completely clear following human and animal exposures with these novel compounds. The aim of this study was to assess cardiopulmonary toxicity of multi-walled carbon nanotubes following oral administration in rats with respect to the histopathological and biochemical evaluation. Methods: In the present investigation, we studied cardiorespiratory toxicity of multi-wall carbon nanotubes (MWCNT with regard to histopathological changes and some biomarkers including TnT, CK-MB and LDH in experimental rats following oral administration. One dose per 24 h of MWCNT suspension was administered orally (gavage technique to animals at the doses of 500, 1000 and 2000 mg/kg/day BW for 5 days. Results: The results of these study showed oral administration of MWCNT induces histopathological complications such as severe alveolar edema and hemorrhage in lungs and myocytolysis in heart of all experimental groups of animals. In all of the groups, troponin T level showed no changes when compared to baseline. Lactate dehydrogenase and CK-MB activity showed significant increment in all of animal groups following oral administration of carbon nanotubes. Conclusions: It can be concluded that oral exposure of MWCNT may be toxic for cardiovascular and respiratory systems, because MWCNT induced biochemical alterations and histopathological abnormalities in these vital systems.

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

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

2016-01-01

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

Ethanol self-administration in serotonin transporter knockout mice: unconstrained demand and elasticity.

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Lamb, R J; Daws, L C

2013-10-01

Low serotonin function is associated with alcoholism, leading to speculation that increasing serotonin function could decrease ethanol consumption. Mice with one or two deletions of the serotonin transporter (SERT) gene have increased extracellular serotonin. To examine the relationship between SERT genotype and motivation for alcohol, we compared ethanol self-administration in mice with zero (knockout, KO), one (HET) or two copies (WT) of the SERT gene. All three genotypes learned to self-administer ethanol. The SSRI, fluvoxamine, decreased responding for ethanol in the HET and WT, but not the KO mice. When tested under a progressive ratio schedule, KO mice had lower breakpoints than HET or WT. As work requirements were increased across sessions, behavioral economic analysis of ethanol self-administration indicated that the decreased breakpoint in KO as compared to HET or WT mice was a result of lower levels of unconstrained demand, rather than differences in elasticity, i.e. the proportional decreases in ethanol earned with increasing work requirements were similar across genotypes. The difference in unconstrained demand was unlikely to result from motor or general motivational factors, as both WT and KO mice responded at high levels for a 50% condensed milk solution. As elasticity is hypothesized to measure essential value, these results indicate that KO value ethanol similarly to WT or HET mice despite having lower break points for ethanol. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Flos Puerariae Extract Ameliorates Cognitive Impairment in Streptozotocin-Induced Diabetic Mice

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Zhong-he Liu

2015-01-01

Full Text Available Objective. The effects of Flos Puerariae extract (FPE on cognitive impairment associated with diabetes were assessed in C57BL/6J mice. Methods. Experimental diabetic mice model was induced by one injection of 50 mg/kg streptozotocin (STZ for 5 days consecutively. FPE was orally administrated at the dosages of 50, 100, or 200 mg/kg/day, respectively. The learning and memory ability was assessed by Morris water maze test. Body weight, blood glucose, free fatty acid (FFA and total cholesterol (TCH in serum, malondialdehyde (MDA, superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GSH-Px, and acetylcholinesterase (AChE activities in cerebral cortex and hippocampus were also measured. Results. Oral administration of FPE significantly improved cognitive deficits in STZ-induced diabetic mice. FPE treatment also maintained body weight and ameliorated hyperglycemia and dyslipidemia in diabetic mice. Additionally, decreased MDA level, enhanced CAT, and GSH-Px activities in cerebral cortex or hippocampus, as well as alleviated AChE activity in cerebral cortex, were found in diabetic mice supplemented with FPE. Conclusion. This study suggests that FPE ameliorates memory deficits in experimental diabetic mice, at least partly through the normalization of metabolic abnormalities, ameliorated oxidative stress, and AChE activity in brain.

Autobacteriographic studies of clarithromycin and erythromycin in mice

International Nuclear Information System (INIS)

Kohno, Y.; Ohta, K.; Suwa, T.; Suga, T.

1990-01-01

The antimicrobial activity of clarithromycin was compared with that of erythromycin in experimentally infected mice by whole-body autobacteriography. In mice with systemic staphylococcal infections, the number of vital microbes in the body was relatively low in the early period after oral administration of erythromycin, but increased thereafter to the levels found in nonmedicated control mice. On the other hand, with clarithromycin treatment, a significantly smaller number of microbes was evident throughout the body. The microbes were scarcely seen in the parenchyma of any organs during the examination period. This potent antimicrobial activity of clarithromycin compared with that of erythromycin was further demonstrated in mice with respiratory infections. On the other hand, to examine the distribution properties of both antibiotics in the whole body, an autoradiographic study was carried out with [N-methyl-14C]clarithromycin and [N-methyl-14C]erythromycin. Both labeled antibiotics were distributed widely throughout the body after oral administration in both uninfected control mice and mice with systemic infections. However, the radioactivity was more marked and persistent for [14C]clarithromycin than it was for [14C]erythromycin, particularly in the lungs. The observations described above indicate the superior in vivo antimicrobial activity of clarithromycin compared with that of erythromycin and suggest that the superiority of clarithromycin is largely attributed to its favorable distribution properties. The advantages of whole-body autobacteriography, coupled with whole-body autoradiography, are discussed

Oral administration of Rauwolfia vomitoria extract has no untoward ...

African Journals Online (AJOL)

The effect of ethanolic extract of leaf and root of Rauwolfia vomitoria on kidney and liver functions in rats was investigated. Rats were given daily oral administration of ethanolic extracts of either root or leaf of R. vomitoria at two different concentrations (1.0 and 2.0 g/kg body weight) for a period of 14 days. Some biochemical ...

Orally administrated cinnamon extract reduces β-amyloid oligomerization and corrects cognitive impairment in Alzheimer's disease animal models.

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Anat Frydman-Marom

Full Text Available An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of β-amyloid polypeptide (Aβ play a key role in Alzheimer's disease (AD pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aβ plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aβ oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt, which markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aβ oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aβ species formation in AD through the utilization of a compound that is currently in use in human diet.

[The humoral immune response in mice induced by recombinant Lactococcus lactis expressing HIV-1 gag].

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Zhao, Xiaofei; Zhang, Cairong; Liu, Xiaojuan; Ma, Zhenghai

2014-11-01

To analyze the humoral immune response induced by recombinant Lactococcus lactis expressing HIV-1 gag in mice immunized orally, intranasally, subcutaneously or in the combined way of above three. Fifty BALB/c mice were randomly divided into 5 groups, 10 mice per group. The mice were immunized consecutively three times at two week intervals with 10(9) CFU of recombinant Lactococcus lactis expressing gag through oral, intranasal, subcutaneous administration or the mix of them. The mice that were immunized orally with Lactococcus lactis containing PMG36e served as a control group. The sera of mice were collected before primary immunization and 2 weeks after each immunization to detect the gag specific IgG by ELISA. Compared with the control group, the higher titer of serum gag specific IgG was detected in the four groups immunized with recombinant Lactococcus lactis expressing gag, and it was the highest in the mixed immunization group (PLactococcus lactis expressing gag can induce humoral immune response in mice by oral, intranasal, subcutaneous injection or the mix of them, and the mixed immunization can enhance the immune effects of Lactococcus lactis vector vaccine.

Protective effect of bovine milk against HCl and ethanol-induced gastric ulcer in mice.

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Yoo, Jeong-Hyun; Lee, Jeong-Sang; Lee, You-Suk; Ku, SaeKwang; Lee, Hae-Jeung

2018-05-01

The purpose of this study was to investigate the gastroprotective effects of bovine milk on an acidified ethanol (HCl-ethanol) mixture that induced gastric ulcers in a mouse model. Mice received different doses of commercial fresh bovine milk (5, 10, and 20 mL/kg of body weight) by oral gavage once a day for 14 d. One hour after the last oral administration of bovine milk, the HCl-ethanol mixture was orally intubated to provoke severe gastric damage. Our results showed that pretreatment with bovine milk significantly suppressed the formation of gastric mucosa lesions. Pretreatment lowered gastric myeloperoxidase and increased gastric mucus contents and antioxidant enzymes catalase and superoxide dismutase. Administration of bovine milk increased nitrate/nitrite levels and decreased the malondialdehyde levels and the expression of proinflammatory genes, including transcription factor nuclear factor-κB, cyclooxygenase-2, and inducible nitric oxide synthase in the stomach of mice. These results suggest that bovine milk can prevent the development of gastric ulcer caused by acid and alcohol in mice. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Anti-Diabetic Effects of CTB-APSL Fusion Protein in Type 2 Diabetic Mice

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Yunlong Liu

2014-03-01

Full Text Available To determine whether cholera toxin B subunit and active peptide from shark liver (CTB-APSL fusion protein plays a role in treatment of type 2 diabetic mice, the CTB-APSL gene was cloned and expressed in silkworm (Bombyx mori baculovirus expression vector system (BEVS, then the fusion protein was orally administrated at a dose of 100 mg/kg for five weeks in diabetic mice. The results demonstrated that the oral administration of CTB-APSL fusion protein can effectively reduce the levels of both fasting blood glucose (FBG and glycosylated hemoglobin (GHb, promote insulin secretion and improve insulin resistance, significantly improve lipid metabolism, reduce triglycerides (TG, total cholesterol (TC and low density lipoprotein (LDL levels and increase high density lipoprotein (HDL levels, as well as effectively improve the inflammatory response of type 2 diabetic mice through the reduction of the levels of inflammatory cytokines tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6. Histopathology shows that the fusion protein can significantly repair damaged pancreatic tissue in type 2 diabetic mice, significantly improve hepatic steatosis and hepatic cell cloudy swelling, reduce the content of lipid droplets in type 2 diabetic mice, effectively inhibit renal interstitial inflammatory cells invasion and improve renal tubular epithelial cell nucleus pyknosis, thus providing an experimental basis for the development of a new type of oral therapy for type 2 diabetes.

Suppression of Alzheimer's disease-related phenotypes by geranylgeranylacetone in mice.

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Tatsuya Hoshino

Full Text Available Amyloid-β peptide (Aβ plays an important role in the pathogenesis of Alzheimer's disease (AD. Aβ is generated by the secretase-mediated proteolysis of β-amyloid precursor protein (APP, and cleared by enzyme-mediated degradation and phagocytosis. Transforming growth factor (TGF-β1 stimulates this phagocytosis. We recently reported that the APP23 mouse model for AD showed fewer AD-related phenotypes when these animals were crossed with transgenic mice expressing heat shock protein (HSP 70. We here examined the effect of geranylgeranylacetone, an inducer of HSP70 expression, on the AD-related phenotypes. Repeated oral administration of geranylgeranylacetone to APP23 mice for 9 months not only improved cognitive function but also decreased levels of Aβ, Aβ plaque deposition and synaptic loss. The treatment also up-regulated the expression of an Aβ-degrading enzyme and TGF-β1 but did not affect the maturation of APP and secretase activities. These outcomes were similar to those observed in APP23 mice genetically modified to overexpress HSP70. Although the repeated oral administration of geranylgeranylacetone did not increase the level of HSP70 in the brain, a single oral administration of geranylgeranylacetone significantly increased the level of HSP70 when Aβ was concomitantly injected directly into the hippocampus. Since geranylgeranylacetone has already been approved for use as an anti-ulcer drug and its safety in humans has been confirmed, we propose that this drug be considered as a candidate drug for the prevention of AD.

Detection of oral early cancerous lesion by using polarization-sensitive optical coherence tomography: mice model

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Lee, Hong-Yi; Chen, Ping-Hsien; Lee, Tzu-Han; Chang, Kuo-Wei; Kuo, Wen-Chuan

2018-02-01

Oral cancer is the 11th most common cancer worldwide, especially in a male adult. The median age of death in oral cancer was 55 years, 10-20 years earlier than other cancers. Presently, oral cancer is often found in late stage, because the lesion is often flat in early stage and is difficult to diagnose under traditional white light imaging. The only definitive method for determining cancer is an invasive biopsy and then using histology examination. How to detect precancerous lesions or early malignant lesions is an important issue for improving prognosis of oral cancer. Optical coherence tomography (OCT) is a new optical tool for diagnosing early malignant lesions in the skin or gastrointestinal tract recently. Here we report a new method for detecting precancerous or early malignant oral lesions by using swept source polarization-sensitive optical coherence tomography (PS-OCT) with center-wavelength 1310 nm, bandwidth 110 nm and 100 kHz swept rate. We used all single-mode fiber design to detect the change of birefringence information in the epithelium structure. This system has an advantage that enables measurement of backscattered intensity and birefringence simultaneously with only one A-scan per transverse location. In preliminary result, we computed the slope of the every A-scan signal in tissue part using a linear-curve fitting in backscattered intensity and birefringence on the enface. In this research, we used an oral cancer mice model for observing the change of structure and birefringence properties in different stages of oral cancer mice. We presented the parametric enface imaging that can detect the early oral malignant lesions.

Chronic Uridine Administration Induces Fatty Liver and Pre-Diabetic Conditions in Mice.

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Yasuyo Urasaki

Full Text Available Uridine is a pyrimidine nucleoside that exerts restorative functions in tissues under stress. Short-term co-administration of uridine with multiple unrelated drugs prevents drug-induced liver lipid accumulation. Uridine has the ability to modulate liver metabolism; however, the precise mechanism has not been delineated. In this study, long-term effects of uridine on liver metabolism were examined in both HepG2 cell cultures and C57BL/6J mice. We report that uridine administration was associated with O-GlcNAc modification of FOXO1, increased gluconeogenesis, reduced insulin signaling activity, and reduced expression of a liver-specific fatty acid binding protein FABP1. Long-term uridine feeding induced systemic glucose intolerance and severe liver lipid accumulation in mice. Our findings suggest that the therapeutic potentials of uridine should be designed for short-term acute administration.

Neuroendocrine stress reactivity of male C57BL/6N mice following chronic oral corticosterone exposure during adulthood or adolescence.

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Shahanoor, Ziasmin; Sultana, Razia; Baker, Madelyn R; Romeo, Russell D

2017-12-01

Adolescence is associated with the maturation of the hypothalamic-pituitary-adrenal (HPA) axis, the major neuroendocrine axis mediating the hormonal stress response. Adolescence is also a period in development marked by a variety of stress-related vulnerabilities, including psychological and physiological dysfunctions. Many of these vulnerabilities are accompanied by a disrupted HPA axis. In adult mice, a model of disrupted HPA function has been developed using oral chronic corticosterone administration via the drinking water, which results in various physiological and neurobehavioral abnormalities, including changes in stress reactivity and anxiety-like behaviors. In an effort to further complement and extend this model, we tested the impact of HPA disruption in adolescent mice. We also examined whether this disruption led to different outcomes depending on whether the treatment happened during adolescence or adulthood. In the current set of experiments, we exposed adult (70days of age) or adolescent (30days of age) male C57BL/6N mice to 4 weeks of either 0 or 25μg/ml oral corticosterone via their drinking water. We measured body weight during treatment and plasma corticosterone levels and activation of the paraventricular nucleus (PVN), as indexed by FOS immunohistochemistry, before and after a 30min session of restraint stress. Our data indicate that adolescent animals exposed to chronic corticosterone showed weight loss during treatment, an effect not observed in adults. Further, we found stress failed to elevate plasma corticosterone levels in treated mice, regardless of whether exposure occurred in adulthood or adolescence. Despite this reduced hormonal responsiveness, we found significant neural activation in the PVN of both adult- and adolescent-treated mice, indicating a dissociation between stress-induced peripheral and central stress responses following chronic corticosterone exposure. Moreover, stress-induced neural activation in the PVN was unaffected

Immune response in mice to ingested soya protein: antibody production, oral tolerance and maternal transfer

DEFF Research Database (Denmark)

Christensen, Hanne Risager; Pedersen, Susanne Brix; Frøkiær, Hanne

2004-01-01

antibody response in the offspring, bat in this case in the absence of oral tolerance. This indicates that, under certain conditions, factors involved in spontaneous antibody production can be transmitted from mother to offspring. Understanding the immune response to soya protein ingested under healthy...... by ELISA, and to the presence of oral tolerance detected as a suppressed antibody and cell-proliferation response upon immunisation with soya protein. F0 mice generated soya-specific antibodies, while oral tolerance to the same soya proteins was also clearly induced. When F0 dams were transferred to soya...

Comparison of oral versus rectal administration of acetaminophen with codeine in postoperative pediatric adenotonsillectomy patients.

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Owczarzak, Vicki; Haddad, Joseph

2006-08-01

To examine whether acetaminophen with codeine administered per rectum is an effective alternative for pain control compared with oral administration after an adenotonsillectomy. A prospective, randomized control study. Seventy-five children aged 1 to 5 were recruited for this study. Each child was assigned randomly to receive either rectal or oral postoperative pain medication. A journal with eight questions was kept for 10 days after the operation, and an overall survey of five questions was filled out at the first postoperative visit. Postoperative pain was adequately controlled in those patients receiving suppositories when compared with those patients receiving oral pain medication. Adverse effects and total number of doses given per day were similar. Parents found the suppositories easy to administer, and more parents would switch or consider switching from oral pain medication to suppositories if given the choice. The suppositories achieved equivalent pain control as oral medication with few side effects and good tolerance. Furthermore, many parents preferred the suppositories to oral medication in maintaining postoperative pain control because of ease of administration. If given the choice for future surgeries, many parents would switch or consider switching from oral pain medication to suppositories.

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

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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.

Methodological Study to Develop Standard Operational Protocol on Oral Drug Administration for Children.

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Bijarania, Sunil Kumar; Saini, Sushma Kumari; Verma, Sanjay; Kaur, Sukhwinder

2017-05-01

To develop standard operational protocol (SOP) on oral drug administration and checklist to assess the implementation of the developed SOP. In this prospective methodological study, SOPs were developed in five phases. In the first phase, the preliminary draft of SOPs and checklists were prepared based on literature review, assessment of current practices and focus group discussion (FGD) with bedside working nurses. In the second phase, content validity was checked with the help of Delphi technique (12 experts). Total four drafts were prepared in stages and necessary modifications were made as per suggestions after each Delphi round. Fourth Delphi round was performed after conducting a pilot study. In the fourth phase, all bedside nurses were trained as per SOPs and asked to practice accordingly and observation of thirty oral drug administrations in children was done to check reliability of checklists for implementation of SOPs. In Phase-V, 7 FGDs were conducted with bedside nurses to assess the effectiveness of SOPs. The Content Validity Index (CVI) of SOP and checklists was 99.77%. Overall standardized Cronbach's alpha was calculated as 0.94. All the nurses felt that the SOP is useful. Valid and feasible SOP for drug administration to children through oral route along with valid and reliable checklist were developed. It is recommended to use this document for drug administration to children.

Therapeutic administration of enrofloxacin in mice does not select for fluoroquinolone resistance in Campylobacter jejuni.

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Inglis, G Douglas; Zaytsoff, S J M; Selinger, L Brent; Taboada, Eduardo N; Uwiera, R R E

2018-05-11

Enrofloxacin is registered for therapeutic use in beef cattle to treat bovine respiratory disease in Canada. A murine model was used to experimentally examine the impact of therapeutic administration of enrofloxacin on fluoroquinolone resistance development in Campylobacter jejuni. Administration of enrofloxacin to mice via subcutaneous injection or per os routes resulted in equivalent levels of bioactive enrofloxacin within the intestine, but bioactivity was short-lived (Enrofloxacin administration did not affect densities of total bacteria, Firmicutes, or Bacteroidetes in digesta, and had modest impacts on densities of Enterobacteriaceae. All mice inoculated with C. jejuni NCTC 11168 became persistently colonized by the bacterium. Enrofloxacin reduced C. jejuni cell densities within the cecal and colonic digesta for all treatments, and densities shed in feces as a function of antibiotic duration. None of the C. jejuni isolates recovered from mice after administration of enrofloxacin (n=260) developed resistance to ciprofloxacin regardless of method or duration of administration. Furthermore, only modest shifts in the minimum inhibitory concentration of the isolates by treatment were noted. The study findings indicate that the risk posed by short-term subcutaneous administration of enrofloxacin for the development of fluoroquinolone resistance in mammals is low.

Metabolism and disposition of 2-ethylhexyl-p-methoxycinnamate following oral gavage and dermal exposure in Harlan Sprague Dawley rats and B6C3F1/N mice and in hepatocytes in vitro.

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Fennell, Timothy R; Mathews, James M; Snyder, Rodney W; Hong, Yan; Watson, Scott L; Black, Sherry R; McIntyre, Barry S; Waidyanatha, Suramya

2017-11-23

1. 2-Ethylhexyl-p-methoxycinnamate (EHMC) is commonly used as an ingredient in sunscreens, resulting in potential oral and dermal exposure in humans. 2. Clearance and metabolism of EHMC in hepatocytes and disposition and metabolism of EHMC in rodents following oral (8-800 mg/kg) intravenous (IV) (8 mg/kg) or dermal (0.8-80 mg/kg representing 0.1-10% formulation concentration) exposure to [ 14 C]EHMC were investigated in rats and mice. 3. EHMC was rapidly cleared from rat and mouse hepatocytes (half-life ≤3.16 min) and less rapidly (half-life ≤48 min) from human hepatocytes. 4. [ 14 C]EHMC was extensively absorbed and excreted primarily in urine by 72 h after oral administration to rats (65-80%) and mice (63-72%). Oral doses to rats were excreted to a lesser extent (3-8%) in feces and as CO 2 (1-4%). Radioactive residues in tissues were <1% of the dose. There were no sex or species differences in disposition in rats. 5. Following dermal application, 34-42% of an 8-mg/kg dose was absorbed in rats, and 54-62% in mice in 72-h. 6. Among numerous urinary metabolites associated with hydrolysis of the ester, two potential reproductive and developmental toxicants, 2-ethylhexanol and 2-ethylhexanoic acid were produced by metabolism of EHMC.

A Novel, Ecologically Relevant, Highly Preferred, and Non-invasive Means of Oral Substance Administration for Rodents

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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 ...

Uric acid ameliorates indomethacin-induced enteropathy in mice through its antioxidant activity.

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Yasutake, Yuichi; Tomita, Kengo; Higashiyama, Masaaki; Furuhashi, Hirotaka; Shirakabe, Kazuhiko; Takajo, Takeshi; Maruta, Koji; Sato, Hirokazu; Narimatsu, Kazuyuki; Yoshikawa, Kenichi; Okada, Yoshikiyo; Kurihara, Chie; Watanabe, Chikako; Komoto, Shunsuke; Nagao, Shigeaki; Matsuo, Hirotaka; Miura, Soichiro; Hokari, Ryota

2017-11-01

Uric acid is excreted from blood into the intestinal lumen, yet the roles of uric acid in intestinal diseases remain to be elucidated. The study aimed to determine whether uric acid could reduce end points associated with nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. A mouse model of NSAID-induced enteropathy was generated by administering indomethacin intraperitoneally to 8-week-old male C57BL/6 mice, and then vehicle or uric acid was administered orally. A group of mice treated with indomethacin was also concurrently administered inosinic acid, a uric acid precursor, and potassium oxonate, an inhibitor of uric acid metabolism, intraperitoneally. For in vitro analysis, Caco-2 cells treated with indomethacin were incubated in the presence or absence of uric acid. Oral administration of uric acid ameliorated NSAID-induced enteropathy in mice even though serum uric acid levels did not increase. Intraperitoneal administration of inosinic acid and potassium oxonate significantly elevated serum uric acid levels and ameliorated NSAID-induced enteropathy in mice. Both oral uric acid treatment and intraperitoneal treatment with inosinic acid and potassium oxonate significantly decreased lipid peroxidation in the ileum of mice with NSAID-induced enteropathy. Treatment with uric acid protected Caco-2 cells from indomethacin-induced oxidative stress, lipid peroxidation, and cytotoxicity. Uric acid within the intestinal lumen and in serum had a protective effect against NSAID-induced enteropathy in mice, through its antioxidant activity. Uric acid could be a promising therapeutic target for NSAID-induced enteropathy. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

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

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Tomohiro Osaki

2015-08-01

Full Text Available 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.

Treatment of experimental colitis in mice with LMP-420, an inhibitor of TNF transcription

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Cianciolo George

2008-03-01

Full Text Available Abstract Background LMP-420 is a boronic acid-containing purine nucleoside analogue that transcriptionally inhibits TNF production but is non-cytotoxic to TNF-producing cells. Methods This study investigated the efficacy of LMP-420 as an anti-inflammatory agent in acute and chronic colitis induced by oral administration of dextran sulfate sodium (DSS to mice and in chronic colitis following piroxicam administration to IL-10-deficient mice. The severity of colon inflammation was assessed histologically. TNF levels were measured by enzyme immunoassay. Results Administration of DSS for 7 days resulted in severe acute colitis that was associated with a marked increase in stool and colon tissue TNF levels. Initiation of therapy with intraperitoneal (i.p. LMP-420 on day 4 of DSS exposure decreased colonic TNF to near normal levels on day 7. However, neither i.p. nor oral treatment with LMP-420 affected the development or severity of acute DSS colitis. Initiation of LMP-420 therapy after 3 cycles of DSS administration to establish chronic colitis also had no effect on the severity of chronic colitis. Analysis of colonic TNF combined with longitudinal analysis of TNF and TNF receptor (TNF-RII levels in stool during the development of chronic DSS colitis demonstrated that the initially elevated colonic TNF levels returned to normal despite intense on-going inflammation in mice with chronic colitis. RAG-2-/- mice deficient in T and B cells also developed severe ongoing colitis in response to 3 cycles of DSS, but showed marked differences vs. wild type mice in stool TNF and TNF-RII in response to DSS exposure. Systemic and oral LMP-420 treatment for 16 days decreased colonic TNF levels in IL-10-deficient mice with chronic colitis, with a trend to decreased histologic inflammation for oral LMP-420. Conclusion These studies demonstrate that short-term treatment with a transcriptional inhibitor of TNF production can decrease systemic and local colonic levels

Daily oral intake of theanine prevents the decline of 5-bromo-2′-deoxyuridine incorporation in hippocampal dentate gyrus with concomitant alleviation of behavioral abnormalities in adult mice with severe traumatic stress

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Takeshi Takarada

2015-03-01

Full Text Available Posttraumatic stress disorder is a long-lasting psychiatric disease with the consequence of hippocampal atrophy in humans exposed to severe fatal stress. We demonstrated a positive correlation between the transient decline of 5-bromo-2′-deoxyuridine (BrdU incorporation in the hippocampal dentate gyrus (DG and long-lasting behavioral abnormalities in mice with traumatic stress. Here, we investigated pharmacological properties of theanine on the declined BrdU incorporation and abnormal behaviors in mice with traumatic stress. Prior daily oral administration of theanine at 50–500 mg/kg for 5 days significantly prevented the decline of BrdU incorporation, while theanine significantly prevented the decline in the DG even when administered for 5 days after stress. Consecutive daily administration of theanine significantly inhibited the prolonged immobility in mice with stress in forced swimming test seen 14 days later. Although traumatic stress significantly increased spontaneous locomotor activity over 30 min even when determined 14 days later, the increased total locomotion was significantly ameliorated following the administration of theanine at 50 mg/kg for 14 days after stress. These results suggest that theanine alleviates behavioral abnormalities together with prevention of the transient decline of BrdU incorporation in the hippocampal DG in adult mice with severe traumatic stress.

PHARMACOKINETICS OF DICLOFENAC SODIUM AND PAPAVERINE HYDROCHLORIDE AFTER ORAL ADMINISTRATION OF TABLETS TO RABBITS.

Science.gov (United States)

Kasperek, Regina; Zimmer, Łukasz; Jawień, Wojciech; Poleszak, Ewa

2015-01-01

Non-compartmental pharmacokinetic analysis of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) after oral administration of composed tablets to rabbits was developed. HPLC method for determination of DIC and PAP in rabbit plasma was developed and validated. Chromatographic separation of DIC, PAP and the IS was achieved on a Zorbax SB C18 5-µm column (150 mm x 4.6 mm) using methanol-water (55:45, v/v) as mobile phase at a flow rate of 0.8 mL/min. Pharmacokinetic analysis showed that oral administration of a tablet composed of DIC and PAP do not change the pharmacokinetic parameters such as MRT, MAT, Cl and bioavailability of the active substances compared with single administration of DIC and PAP after single dose.

Effects of Oral Prednisone Administration on Serum Cystatin C in Dogs.

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Muñoz, J; Soblechero, P; Duque, F J; Macías-García, B; Ruiz, P; Zaragoza, C; Barrera, R

2017-11-01

Oral administration of glucocorticoid alters serum cystatin C (sCysC) concentration in humans. To determine if oral administration of prednisone alters sCysC in dogs without pre-existing renal disease. Forty six dogs were included: 10 dogs diagnosed with steroid responsive meningitis arteritis (SRMA; group A), 20 dogs diagnosed of pituitary-dependent hyperadrenocorticism (PDH; group B), and 16 healthy control dogs (group C). Retrospective observational study. SRMA diagnosed dogs were administered prednisone 4 mg/kg/24 h PO 7 days, reducing the dose to 2 mg/kg/24 h 7 days before medication withdrawal. In group A, sampling was performed at days 0, 7, 14 and a final control at day 21. Blood and urine samples were collected in the 3 groups, and in group A, sampling was performed at all time points (days 1, 7, 14, and 21). In group A, sCysC was significantly higher at day 7 compared to the control group (0.4 ± 0.04 mg/L vs. 0.18 ± 0.03 mg/L mean ± SEM respectively P 0.05). Dogs with PDH included in group B did not have significant differences in sCysC (0.22 ± 0.03 mg/L) compared to control (P > 0.05). Oral administration of prednisone unlike altered endogenous glucocorticoid production, increases sCysC in dogs in a dose-dependent fashion. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Effect of the Velvet Antler of Formosan Sambar Deer (Cervus unicolor swinhoei on the Prevention of an Allergic Airway Response in Mice

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Ching-Yun Kuo

2012-01-01

Full Text Available Two mouse models were used to assay the antiallergic effects of the velvet antler (VA of Formosan sambar deer (Cervus unicolor swinhoei in this study. The results using the ovalbumin- (OVA- sensitized mouse model showed that the levels of total IgE and OVA-specific IgE were reduced after VA powder was administrated for 4 weeks. In addition, the ex vivo results indicated that the secretion of T helper cell 1 (Th1, regulatory T (Treg, and Th17 cytokines by splenocytes was significantly increased (P<0.05 when VA powder was administered to the mice. Furthermore, OVA-allergic asthma mice that have been orally administrated with VA powder showed a strong inhibition of Th2 cytokine and proinflammatory cytokine production in bronchoalveolar fluid compared to control mice. An increase in the regulatory T-cell population of splenocytes in the allergic asthma mice after oral administration of VA was also observed. All the features of the asthmatic phenotype, including airway inflammation and the development of airway hyperresponsiveness, were reduced by treatment with VA. These findings support the hypothesis that oral feeding of VA may be an effective way of alleviating asthmatic symptoms in humans.

Efficacy of oral active ether lipid analogs of cidofovir in a lethal mousepox model

International Nuclear Information System (INIS)

Buller, R. Mark; Owens, Gelita; Schriewer, Jill; Melman, Lora; Beadle, James R.; Hostetler, Karl Y.

2004-01-01

Cidofovir (CDV) is a highly effective inhibitor of orthopoxvirus replication and may be used intravenously to treat smallpox or complications arising from the smallpox vaccine under an investigational new drug application (IND). However, CDV is absorbed poorly following oral administration and is inactive orally. To improve the bioavailability of CDV, others synthesized alkoxyalkanol esters of CDV and observed >100-fold more activity than unmodified CDV against cowpox, vaccinia, and variola virus (VARV) replication. These ether lipid analogs of CDV have high oral bioavailability in mice. In this study, we compared the oral activity of CDV with the hexadecyloxypropyl (HDP)-, octadecyloxyethyl-, oleyloxypropyl-, and oleyloxyethyl-esters of CDV in a lethal, aerosol ectromelia virus (ECTV) challenge model in A/NCR mice. Octadecyloxyethyl-CDV appeared to be the most potent CDV analog as a dose regimen of 5 mg/kg started 4 h following challenge completely blocked virus replication in spleen and liver, and protected 100% of A/NCR mice, although oral, unmodified CDV was inactive. These results suggest that this family of compounds deserves further evaluation as poxvirus antiviral

Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation.

Science.gov (United States)

Xiong, Xi; Ren, Yuqian; Cui, Yun; Li, Rui; Wang, Chunxia; Zhang, Yucai

2017-12-01

Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury. Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Effects of Oral Administration of Nicotine on Organ Weight, Serum ...

African Journals Online (AJOL)

This study investigated the effects of oral administration of nicotine on body and reproductive organ weight, serum testosterone level and testicular histology in adult male rats. Forty male rats divided into five groups and treated for a period of 30 days with 0.5mg/kg (low dose) and 1.0mg/kg (high dose) body weight of ...

Oral treatment with γ-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice.

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Jide Tian

Full Text Available Adipocyte and β-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM, which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of γ-aminobutyric acid (GABA receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4(+Foxp3(+ Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic.

Comparison of hepatotoxicity and metabolism of butyltin compounds in the liver of mice, rats and guinea pigs

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Ueno, Shunji; Kashimoto, Takashige; Susa, Nobuyuki; Ishii, Masamitsu; Chiba, Toshikazu [Laboratory of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Mutoh, Ken-ichiro [Laboratory of Veterinary Anatomy, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Hoshi, Fumio [Laboratory of Veterinary Anatomy, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628, Towada-shi, Aomori (Japan); Suzuki, Takashi [Laboratory of Environmental Health and Toxicology, Kyoto Prefectural University, Hangi-cho, Shimogamo, Sakyo-ku, 606-5822, Kyoto (Japan); Sugiyama, Masayasu [Sugiyama Pharmacy, 1335-1 Shimotama, Tamagawa-cho, 759-3112, Yamaguchi (Japan)

2003-03-01

The hepatotoxicity of tributyltin chloride (TBTC) and dibutyltin dichloride (DBTC) was compared among mice, rats and guinea pigs in vivo. Further, the metabolism of these butyltin compounds in the liver was also investigated in these species. The oral administration of TBTC and DBTC to mice induced obvious liver injury, as demonstrated by both serodiagnosis and histopathological diagnosis. The concentrations of TBTC and DBTC that induced hepatotoxicity in mice at 24 h after oral administration were 180 and 60 {mu}mol/kg, respectively. In the case of rats, the liver injury induced by TBTC and DBTC was detected at 24 h by the serodiagnosis, but not by histopathological diagnosis. On the other hand, in guinea pigs, TBTC and DBTC administration did not produce any clear liver injury at 24 h, as evaluated by these two diagnostic methods. Thus, the following ranking was obtained with regard to increasing order of sensitivity to liver injury caused by TBTC and DBTC: mice, rats and guinea pigs. The total butyltin contents in the liver of mice were equivalent at 3 h and 24 h after the administration of TBTC or DBTC; however, the contents in the liver of rats and guinea pigs were relatively lower at 3 h and higher at 24 h than those of mice, although there were no differences between rats and guinea pigs in the total liver butyltin content. Concerning the liver metabolism of these butyltin compounds, the main form of butyltin compounds in these animals treated with TBTC was DBTC within 3 h after oral administration, while the main metabolites at 24 h were different in each species, indicating that the liver metabolism of TBTC might vary by animal type. When the animals were treated with DBTC orally, DBTC was hardly metabolized in the livers of these animals even at 24 h, and the liver levels of DBTC were two times greater in mice and guinea pigs than in rats at 3 h and were lower in mice at 24 h than in rats and guinea pigs. The analysis of cellular distributions of DBTC in

Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice

International Nuclear Information System (INIS)

Kawamoto, Yuko; Matsuyama, Wakoto; Wada, Masahiro; Hishikawa, Junko; Chan, Melissa Pui Ling; Nakayama, Aki; Morisawa, Shinsuke

2007-01-01

Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses

Combined effects of radon inhalation and antioxidant vitamin administration on acute alcohol-induced hepatopathy in mice

International Nuclear Information System (INIS)

Etani, Reo; Kataoka, Takahiro; Nishiyama, Yuichi; Takata, Yuji; Yamaoka, Kiyonori

2015-01-01

It has been reported that radon inhalation activates antioxidative functions in liver and has an antioxidative effect against hepatopathy similar to that of the antioxidative effects of ascorbic acid (VC) or α-tocopherol (VE). In this study, we examined the combined effects of radon inhalation and antioxidant vitamin administration on acute alcohol-induced hepatopathy in mice. ICR mice were subjected to intraperitoneal (i.p.) administration of alcohol after pretreating with air only (sham) or radon at a concentration of approximately 2000 Bq/m 3 for 24 hours and i.p. administration of VC (300 mg/kg body weight) or VE (300 mg/kg body weight). In mice injected with alcohol, the combined radon and antioxidant vitamins treatment significantly decreased the activities of glutamic oxaloacetic transaminase in serum compared to not only the alcohol-administered group (sham group), but also the radon inhalation with alcohol administration group or the vitamin and alcohol administration group. In addition, radon inhalation significantly increased the antioxidant level, in such as the catalase activity and the total glutathione content in liver compared to the sham group. These results suggested that the combined radon and antioxidant vitamin treatment could effectively inhibit alcohol-induced hepatopathy in mice without any antagonizing action. (author)

Oral administration of sitagliptin activates CREB and is neuroprotective in murine model of brain trauma

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Brian Dellavalle

2016-12-01

Full Text Available Introduction: Traumatic brain injury is a major cause of mortality and morbidity. We have previously shown that the injectable glucagon-like peptide-1 (GLP-1 analogue, liraglutide, significantly improved the outcome in mice after severe traumatic brain injury (TBI. In this study we are interested in the effects of oral treatment of a different class of GLP-1 based therapy, dipeptidyl peptidase IV (DPP-IV inhibition on mice after TBI. DPP-IV inhibitors reduce the degradation of endogenous GLP-1 and extend circulation of this protective peptide in the bloodstream. This class has yet to be investigated as a potential therapy for TBI. Methods: Mice were administrated once-daily 50 mg/kg of sitagliptin in a Nutella® ball or Nutella® alone throughout the study, beginning two days before severe trauma was induced with a stereotactic cryo-lesion. At two days post trauma, lesion size was determined. Brains were isolated for immunoblotting for assessment of selected biomarkers for pathology and protection.Results: Sitagliptin treatment reduced lesion size at day 2 post-injury by ~28% (p0.05. Conversely, apoptotic tone (alpha-spectrin fragmentation, Bcl-2 levels and the neuroinflammatory markers IL-6, and Iba-1 were not affected by treatment.Conclusions: This study shows, for the first time, that DPP-IV inhibition ameliorates both anatomical and biochemical consequences of TBI and activates CREB in the brain. Moreover, this work supports previous studies suggesting that the effect of GLP-1 analogues in models of brain damage relates to GLP-1 receptor stimulation in a dose-dependent manner.Keywords: GLP-1, Traumatic Brain Injury, TBI, sitagliptin, liraglutide, CREB, Oxidative Stress, GIP, DPP-IV, DPP-4

Flurbiprofen concentration in soft tissues is higher after topical application than after oral administration

Science.gov (United States)

Kai, Shuken; Kondo, Eiji; Kawaguchi, Yasuyuki; Kitamura, Nobuto; Yasuda, Kazunori

2013-01-01

Aim To compare tissue concentrations of flurbiprofen resulting from topical application and oral administration according to the regulatory approved dosing guidelines. Method Sixteen patients were included in this study. Each patient was randomly assigned to the topical application or oral administration group. In each group, a pair of tapes or a tablet, containing a total of 40 mg flurbiprofen, was administered twice at 16 and 2 h before the surgery. Results The flurbiprofen concentration in the fat, tendon, muscle and periosteum tissues was significantly higher (P flurbiprofen to the human body, particularly to soft tissues near the body surface. PMID:22822928

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

Science.gov (United States)

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

2017-10-01

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

Long-term effect of oral immunization against influenza with a gamma-inactivated vaccine in mice

International Nuclear Information System (INIS)

Noack, K.; Tischner, H.; Pohl, W.D.; Braeuniger, S.; Nordheim, W.

1986-01-01

NMRI mice were immunized orally twice within 10 days with an influenza vaccine inactivated by gamma radiation. The immunization with a relatively low dosis led to the occurence of low specific antibody titer in the lung lavage fluid up to 6th month. Despite of the low titer, immunized mice were protected against aerogenic infection for about 6 months. Protection was demonstrated in comparison to non-immunized mice by a limited increase of cells in bronchoalveolar lavage, low virus titer in the lung and survival of most animals after a lethal aerosol challenge with the live virus. (author)

Therapeutic effects of the joint administration of magnesium aspartate and adenosine monophosphate in gamma-irradiated mice

International Nuclear Information System (INIS)

Pospisil, M.; Netikova, J.; Pipalova, I.; Kozubik, A.

1990-01-01

The joint administration of magnesium aspartate and adenosine monophosphate, injected on days 1 to 4 post radiation, has been found to exert stimulatory effects on the recovery of hemopoietic functions in sublethally gamma-irradiated mice. These therapeutical effects were enhanced in animals protected by peroral administration of cystamine. The treatment scheme used did not modify survival of lethally irradiated mice. The therapeutic effects of magnesium aspartate and adenosine monophosphate in sublethally irradiated mice are explained by the stimulatory action of these drugs on the cell adenylate cyclase system, which influences the erythropoietic functions. (author)

Orally administered conjugated linoleic acid ameliorates allergic dermatitis induced by repeated applications of oxazolone in mice.

Science.gov (United States)

Nakanishi, Tomonori; Tokunaga, Yuzo; Yamasaki, Masao; Erickson, Laurie; Kawahara, Satoshi

2016-12-01

Conjugated linoleic acid (CLA) is one of the constituents of animal products with possible health benefits such as anti-carcinogenic and anti-obesity effects. In this study, we investigated the immunomodulatory effects of CLA using a mouse model of allergic dermatitis. Mice were orally administered either a CLA mixture containing equal amounts of 9c, 11 t-CLA and 10 t, 12c-CLA, or high linoleic acid safflower oil, and allergic dermatitis was induced on the ear by repeated topical applications of oxazolone. Oral administration of the CLA mixture but not the high linoleic safflower oil attenuated the symptoms of allergic dermatitis in both ear weights and clinical scores. This effect was associated with decreased levels of ear interleukin-4 (IL-4) and plasma immunoglobulin E. The immunomodulatory effects of the CLA isomers were compared by an in vitro cytokine production assay. The results showed that 9c, 11 t-CLA, the most predominant isomer in animal products, significantly inhibited IL-4 and interferon-γ production from mouse splenocytes with similar potency to 10 t, 12c-CLA. These findings suggest that CLA, a constituent of animal products, has a potentially beneficial effect for amelioration of allergic dermatitis. © 2016 Japanese Society of Animal Science.

Voluntary Ingestion of Antiparasitic Drugs Emulsified in Honey Represents an Alternative to Gavage in Mice

OpenAIRE

Küster, Tatiana; Zumkehr, Beatrice; Hermann, Corina; Theurillat, Regula; Thormann, Wolfgang; Gottstein, Bruno; Hemphill, Andrew

2012-01-01

The oral route is the most frequently used method of drug intake in humans. Oral administration of drugs to laboratory animals such as mice typically is achieved through gavage, in which a feeding needle is introduced into the esophagus and the drug is delivered directly into the stomach. This method requires technical skill, is stressful for animals, and introduces risk of injury, pain and morbidity. Here we investigated another method of drug administration. The benzimidazole derivative alb...

Nursing Administrators' Views on Oral Health in Long-Term Care Facilities: An exploratory study.

Science.gov (United States)

Urata, Janelle Y; Couch, Elizabeth T; Walsh, Margaret M; Rowe, Dorothy J

2018-04-01

Purpose: To explore the knowledge, attitudes, and practices of supervising nurse administrators (SNAs) regarding the oral care provided to long-term care facility (LTCF) residents and the role of dental professionals in those facilities. Methods: The investigators of this study partnered with the National Association of Nursing Administrators to send this cross-sectional study consisting of a 35-item electronic survey to its members whose email addresses were in their database. Online software tabulated responses and calculated frequencies (percentages) of responses for each survey item. Results: Of the 2,359 potential participants, 171 (n=171) completed the survey for a 7% response rate. Only 25% of the respondents were familiar with the expertise of dental hygienists (DHs), however once informed, the majority were interested in having DHs perform oral health staff trainings, oral screenings, and dental referrals and initiate fluoride varnish programs. Most respondents correctly answered the oral health-related knowledge items, understood that oral health is important to general health, but reported that the LTCF residents' oral health was only "good" or "fair." Fewer than half, (48%) of the SNAs were "very satisfied" with the quality of oral care provided to the residents. While more than half reported that they had no dentist on staff or on-site dental equipment, 77% reported that they would consider on-site mobile oral care services. Oral health training for staff was provided primarily by registered nurses, however only 32% reported including identification of dental caries as part of the in-service training. Conclusion: This exploratory study lays the foundation for more extensive research investigating various strategies to improve the oral health of LTCF residents, including increased collaboration between DHs and SNAs. Copyright © 2018 The American Dental Hygienists’ Association.

Distribution of enrofloxacin in intestinal tissue and contents of healthy pigs after oral and intramuscular administrations

DEFF Research Database (Denmark)

Wiuff, C.; Lykkesfeldt, J.; Aarestrup, Frank Møller

2002-01-01

The concentration of enrofloxacin in plasma, intestinal tissue, lymph nodes and intestinal contents was investigated in healthy pigs after oral (p.o.) and intramuscular (i.m.) administration of a single dose of 2.5 mg/kg bw. Tissue and content samples were collected from jejunum, ileum, caecum...... administration, and maximum concentrations in tissue and plasma were determined later than after i.m. administration. No difference between route of administration was observed in the intestinal content. Enrofloxacin concentrations in faeces during a 5-day dosing regimen with i.m. and p.o. administration were....... On the basis of these results it was concluded that in order to ensure an immediate high concentration of enrofloxacin, and thereby avoid an initial selection for resistant mutants, the intramuscular route seems to be preferable to the oral route....

Pharmacokinetics of posaconazole in koalas (Phascolarctos cinereus) after intravenous and oral administration.

Science.gov (United States)

Gharibi, S; Kimble, B; Vogelnest, L; Barnes, J; Stadler, C K; Govendir, M

2017-12-01

The pharmacokinetic profile of posaconazole in clinically normal koalas (n = 8) was investigated. Single doses of posaconazole were administered intravenously (i.v.; 3 mg/kg; n = 2) or orally (p.o.; 6 mg/kg; n = 6) with serial plasma samples collected over 24 and 36 hr, respectively. Plasma concentrations of posaconazole were quantified by validated high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis of data was performed. Following i.v. administration, estimates of the median (range) of plasma clearance (CL) and steady-state volume of distribution (V ss ) were 0.15 (0.13-0.18) L hr -1  kg -1 and 1.23 (0.93-1.53) L/kg, respectively. The median (range) elimination half-life (t 1/2 ) after i.v. and p.o. administration was 7.90 (7.62-8.18) and 12.79 (11.22-16.24) hr, respectively. Oral bioavailability varied from 0.43 to 0.99 (median: 0.66). Following oral administration, maximum plasma concentration (C max ; median: 0.72, range: 0.55-0.93 μg/ml) was achieved in 8 (range 6-12) hr. The in vitro plasma protein binding of posaconazole incubated at 37°C was 99.25 ± 0.29%. Consideration of posaconazole pharmacokinetic/pharmacodynamic (PK/PD) targets for some yeasts such as disseminated candidiasis suggests that posaconazole could be an efficacious treatment for cryptococcosis in koalas. © 2017 John Wiley & Sons Ltd.

Labeling of red blood cells with Tc-99m after oral administration of SnCl2. Concise communication

International Nuclear Information System (INIS)

Patel, M.C.; Parab, P.B.; Samuel, A.M.; Ganatra, R.D.

1979-01-01

In vivo labeling of red blood cells with Tc-99m was possible after prior oral administration of SnCl 2 , both in rats and human volunteers. Absorption of oral SnCl 2 was low but sufficient for more than 95% labeling efficiency. Prior i.v. administration of stannous chloride is known to induce in vivo labeling of red blood cells with pertechnetate. We have observed that such labeling is possible even after oral administration of stannous chloide. Nearly 95% of the circulating radioactivity and 93.7% of the administered radioactivity was in RBCs 30 min after i.v. injection of /sup 99m/TcO 4 - in rats that were fed 5 mg of stannous chloride (3.13 mg Sn 2+ ion) 2 hr before injection. Red blood cells from four human volunteers could bind pertechnetate, both in vitro and in vivo, after oral administration of 100 mg of SnCl 2 . We have obtained a blood-pool image of the human heart by labeling the RBCs in vivo by this method. We have also studied various parameters affecting the in vivo binding of RBCs with Tc-99m - such as the amount of orally administered SnCl 2 , the time of injection of radionuclide after oral SnCl 2 , and the optimum time for the imaging

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

Science.gov (United States)

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, ptoxic effect as a possible pathomechanism of PPE.

A Real-Time Near-Infrared Fluorescence Imaging Method for the Detection of Oral Cancers in Mice Using an Indocyanine Green-Labeled Podoplanin Antibody.

Science.gov (United States)

Ito, Akihiro; Ohta, Mitsuhiko; Kato, Yukinari; Inada, Shunko; Kato, Toshio; Nakata, Susumu; Yatabe, Yasushi; Goto, Mitsuo; Kaneda, Norio; Kurita, Kenichi; Nakanishi, Hayao; Yoshida, Kenji

2018-01-01

Podoplanin is distinctively overexpressed in oral squamous cell carcinoma than oral benign neoplasms and plays a crucial role in the pathogenesis and metastasis of oral squamous cell carcinoma but its diagnostic application is quite limited. Here, we report a new near-infrared fluorescence imaging method using an indocyanine green (ICG)-labeled anti-podoplanin antibody and a desktop/a handheld ICG detection device for the visualization of oral squamous cell carcinoma-xenografted tumors in nude mice. Both near-infrared imaging methods using a desktop (in vivo imaging system: IVIS) and a handheld device (photodynamic eye: PDE) successfully detected oral squamous cell carcinoma tumors in nude mice in a podoplanin expression-dependent manner with comparable sensitivity. Of these 2 devices, only near-infrared imaging methods using a handheld device visualized oral squamous cell carcinoma xenografts in mice in real time. Furthermore, near-infrared imaging methods using the handheld device (PDE) could detect smaller podoplanin-positive oral squamous cell carcinoma tumors than a non-near-infrared, autofluorescence-based imaging method. Based on these results, a near-infrared imaging method using an ICG-labeled anti-podoplanin antibody and a handheld detection device (PDE) allows the sensitive, semiquantitative, and real-time imaging of oral squamous cell carcinoma tumors and therefore represents a useful tool for the detection and subsequent monitoring of malignant oral neoplasms in both preclinical and some clinical settings.

Poliomyelitis in transgenic mice expressing CD155 under the control of the Tage4 promoter after oral and parenteral poliovirus inoculation.

Science.gov (United States)

Khan, Shaukat; Toyoda, Hidemi; Linehan, Melissa; Iwasaki, Akiko; Nomoto, Akio; Bernhardt, Günter; Cello, Jeronimo; Wimmer, Eckard

2014-08-01

An important step in poliovirus (PV) infection by the oral route in humans is replication of the virus in lymphatic tissues of the gastrointestinal (GI) tract, thought to be mainly in the Peyer's patches of the small intestine. No immunocompetent transgenic (tg) mice that express human PV receptor (CD155) under the control of different promoters can be infected orally. The mouse orthologue of human CD155 is Tage4, a protein expressed at the surface of enterocytes and in the Peyer's patches. We describe here the generation of a tg mouse model in which the Tage4 promoter was used to drive expression of the human PV receptor-coding region (Tage4-CD155tg mice). In this model, CD155 expression was observed by immunostaining in different regions in the Peyer's patches but not in their germinal centres. Although a similar pattern of staining was observed between 3- and 6-week-old Tage4-CD155tg mice, poliomyelitis was only seen in the younger mice after PV infection by the oral route. When compared with TgPVR21 mice that expressed CD155 driven by its human promoter, 3-week-old Tage4-CD155tg mice were more susceptible to gut infection and paralysis following feeding with PV. Also, Tage4-CD155tg mice exhibited higher susceptibility to poliomyelitis after parenteral inoculation of PV. Remarkably, the LD50 after intracerebral inoculation of PV was similar in both CD155 tg mouse strains. The CD155 tg mouse model reported here, although moderately susceptible to oral infection, may be suitable to study mechanisms of PV replication in the gastrointestinal tract and to dissect important aspects of PV neuroinvasiveness. © 2014 The Authors.

Effects of yam tuber protein, dioscorin, on attenuating oxidative status and learning dysfunction in d-galactose-induced BALB/c mice.

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Han, Chuan-Hsiao; Lin, Yuh-Feng; Lin, Yin-Shiou; Lee, Tai-Lin; Huang, Wei-Jan; Lin, Shyr-Yi; Hou, Wen-Chi

2014-03-01

The yam tuber is a traditional Chinese medicine used in long-term treatment as a juvenescent substance. The purified yam tuber's major water-soluble protein, dioscorin, and its protease hydrolysates have been reported to have several biological activities. In this study, d-galactose (Gal) was subcutaneously injected into the dorsal necks of BALB/c mice daily for 10weeks (Gal group) to induce oxidative stress. By the fifth week, 20 or 80mg dioscorin/kg was orally administered daily combined with a daily Gal injection until the end of the study. The plasma malondialdehyde (MDA) level and advanced glycation end-products obtained after dioscorin oral administrations were lower compared to the Gal group. In addition, the latency and swimming distance in the mice that received dioscorin administration were significantly improved compared to the Gal group in the Morris water maze. Dioscorin administration resulted in higher GSH levels and oxygen radical antioxidant capacity (ORAC) activity and lower MDA and inducible nitric oxide synthase (iNOS) levels in the brain compared to mice in the Gal group. These elevated antioxidant activities following oral administration of yam dioscorin in vivo may reflect traditional juvenescent uses with the potential for anti-aging treatments. Copyright © 2014 Elsevier Ltd. All rights reserved.

Developmental toxicity of orally administered sildenafil citrate (Viagra) in SWR/J mice.

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Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy; Al-Meteri, Mokhlid Hamed

2011-04-01

Normal adult inbred SWR/J mice were used to investigate the teratogenic and other possible toxic effects of various dose levels of sildenafil citrate (Viagra) on fetuses. Multiple dose levels of 6.5, 13.0, 19.5, 26.0, 32.5 or 40.0 mg of sildenafil citrate/kg body weight (which correspond to the multiples of 1, 2, 3, 4, 5 or 6 of human 50 mg Viagra, respectively) were orally administered into pregnant mice on days 7-9, 10-12 or 13-15 of gestation. On day 17 of pregnancy, all fetuses were removed and examined for toxic phenomena (embryo-fetal toxicity) and for external, internal and skeletal malformations. A total of 285 pregnant mice were used in the present study. None of the dams treated with sildenafil citrate at any of the oral dose levels used in the present study died during the experimental period and all dams treated with the drug failed to reveal overt signs of maternal toxicity. Moreover, the results of the present study clearly demonstrate that none of the multiple oral dose levels of the drug at any time interval used has induced any external, internal or skeletal malformations in the fetuses obtained from treated females. However, the dose level of 40 mg/kg body weight of sildenafil citrate has a growth suppressing effect on alive fetuses when it was administered at all the time intervals used in the present study. Furthermore, the dose levels 26.0, 32.5 and 40 mg/kg of the drug have embryo-fetal toxicity when the drug is applied on days 13-15 of gestation. The possible mechanisms involved in the embryo-fetal toxicity and fetal growth suppressing effects of sildenafil citrate were discussed. The results of this study have important implications for the widespread use of this drug.

Exposure to bifenthrin causes immunotoxicity and oxidative stress in male mice.

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Jin, Yuanxiang; Pan, Xiuhong; Fu, Zhengwei

2014-09-01

Bifenthrin (BF) is one of the most commonly used pesticides among the synthetic pyrethroids. The effects of BF exposure on the induction of immunotoxicity and oxidative stress were studied both in adolescent and adult male ICR mice. Both the weights of the spleen and thymus decreased significantly in the adolescent mice when they were treated with 20 mg/kg BF for 3 weeks. We found that the 3-week oral administration of BF during puberty increased the transcriptional levels of the genes TNF and IL2 in the spleen and IL2 as well as IL4 in the thymus. The effect of BF exposure on the induction of oxidative stress was also studied in serum and liver samples. The total antioxidant capacity and activity of superoxide dismutase were altered significantly in the serum of the 20 mg/kg BF-treated adolescent mice, and the activity of glutathione peroxidase (GPX) decreased significantly in the serum of adolescent and adult mice after 3 weeks of oral administration of 20 mg/kg BF. Compared to serum, hepatic GSH content increased significantly in both the adolescent and adult mice exposed to 20 mg/kg BF; hepatic CAT and GPX activities were altered significantly, even in adolescent mice, after treatment with 10 mg/kg BF. Taken together, the results of this study suggest that exposure to BF, especially during puberty, has the potential to induce immunotoxicity accompanied by oxidative stress in male mice. These findings will help in elucidating the mechanism of toxicity induced by BF in mice. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.

Defective IL-17- and IL-22-dependent mucosal host response to Candida albicans determines susceptibility to oral candidiasis in mice expressing the HIV-1 transgene.

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Goupil, Mathieu; Cousineau-Côté, Vincent; Aumont, Francine; Sénéchal, Serge; Gaboury, Louis; Hanna, Zaher; Jolicoeur, Paul; de Repentigny, Louis

2014-10-26

The tissue-signaling cytokines IL-17 and IL-22 are critical to host defense against oral Candida albicans infection, by their induction of oral antimicrobial peptide expression and recruitment of neutrophils. Mucosal Th17 cells which produce these cytokines are preferentially depleted in HIV-infected patients. Here, we tested the hypothesis that defective IL-17- and IL-22-dependent host responses to C. albicans determine the phenotype of susceptibility to oropharyngeal candidiasis (OPC) in transgenic (Tg) mice expressing HIV-1. Naïve CD4+ T-cells and the differentiated Th1, Th2, Th17, Th1Th17 and Treg lineages were all profoundly depleted in cervical lymph nodes (CLNs) of these Tg mice. However, naive CD4+ cells from Tg mice maintained the capacity to differentiate into these lineages in response to polarizing cytokines in vitro. Expression of Il17, Il22, S100a8 and Ccl20 was enhanced in oral mucosal tissue of non-Tg, but not of Tg mice, after oral infection with C. albicans. Treatment of infected Tg mice with the combination of IL-17 and IL-22, but not IL-17 or Il-22 alone, significantly reduced oral burdens of C. albicans and abundance of Candida hyphae in the epithelium of tongues of infected Tg mice, and restored the ability of the Tg mice to up-regulate expression of S100a8 and Ccl20 in response to C. albicans infection. These findings demonstrate that defective IL-17- and IL-22-dependent induction of innate mucosal immunity to C. albicans is central to the phenotype of susceptibility to OPC in these HIV transgenic mice.

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

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

2012-08-01

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

Intravenous or oral administration of vinorelbine in adjuvant chemotherapy with cisplatin and vinorelbine for resected NSCLC

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Sorensen, Steffen Filskov; Carus, Andreas; Meldgaard, Peter

2015-01-01

OBJECTIVES: Cisplatin and vinorelbine given intravenously is a well-established adjuvant chemotherapy regimen after surgery for early-stage NSCLC. Vinorelbine can also be administered orally. However, the efficacy of orally administrated vinorelbine in adjuvant treatment of NSCLC is unknown. We...... University Hospital (Denmark) from 2005 to 2012 for adjuvant chemotherapy after surgery for NSCLC. RESULTS AND CONCLUSION: Of the 265 patients included in this study, 126 patients received i.v. and 139 received p.o. vinorelbine/cisplatin. The two groups were comparable with respect to important baseline....... In conclusion we observed that intravenous or oral administration of vinorelbine in combination with cisplatin after surgery for NSCLC appear equally effective in terms of overall and disease-free survival....

alpha-Glucosidase-albumin conjugates: effect of chronic administration in mice

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Allen, T.M.; Murray, L.; Bhardwaj, D.; Poznansky, M.J.

1985-01-01

Enzyme albumin conjugates have been proposed as a means of increasing the efficacy of enzyme use in vivo and decreasing immune response to the enzyme. Particulate drug carriers, however, have a pronounced tendency to localize in the mononuclear phagocyte (reticuloendothelial) system. The authors have examined in mice the effect on phagocytic index, tissue distribution and organ size of continued administration of conjugates of alpha-glucosidase with either homologous or heterologous albumin. Mice received 10 X 2-mg injections of bovine serum albumin (BSA) or mouse serum albumin (MSA), either free, polymerized or conjugated with alpha-glucosidase. Experiments involving BSA had to be terminated before the end of the experiment because of anaphylaxis, but these reactions were less severe to the polymerized albumin than to free albumin. Free BSA, BSA polymer and BSA-enzyme conjugates all caused a decrease in phagocytic index after six injections. Mice receiving MSA showed no evidence of anaphylaxis, but mice receiving six or more injections of free MSA, MSA polymer or MSA-enzyme conjugate had significantly decreased phagocytic indices as compared to controls. Phagocytic indices had returned to normal by 7 days after the final injection. Tissue distribution of 125 I-labeled albumin preparations was determined in either naive or chronically injected mice

Chronic benzylamine administration in the drinking water improves glucose tolerance, reduces body weight gain and circulating cholesterol in high-fat diet-fed mice.

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Iffiú-Soltész, Zsuzsa; Wanecq, Estelle; Lomba, Almudena; Portillo, Maria P; Pellati, Federica; Szöko, Eva; Bour, Sandy; Woodley, John; Milagro, Fermin I; Alfredo Martinez, J; Valet, Philippe; Carpéné, Christian

2010-04-01

Benzylamine is found in Moringa oleifera, a plant used to treat diabetes in traditional medicine. In mammals, benzylamine is metabolized by semicarbazide-sensitive amine oxidase (SSAO) to benzaldehyde and hydrogen peroxide. This latter product has insulin-mimicking action, and is involved in the effects of benzylamine on human adipocytes: stimulation of glucose transport and inhibition of lipolysis. This study examined whether chronic, oral administration of benzylamine could improve glucose tolerance and the circulating lipid profile without increasing oxidative stress in overweight and pre-diabetic mice. The benzylamine diffusion across the intestine was verified using everted gut sacs. Then, glucose handling and metabolic markers were measured in mice rendered insulin-resistant when fed a high-fat diet (HFD) and receiving or not benzylamine in their drinking water (3600micromol/(kgday)) for 17 weeks. HFD-benzylamine mice showed lower body weight gain, fasting blood glucose, total plasma cholesterol and hyperglycaemic response to glucose load when compared to HFD control. In adipocytes, insulin-induced activation of glucose transport and inhibition of lipolysis remained unchanged. In aorta, benzylamine treatment partially restored the nitrite levels that were reduced by HFD. In liver, lipid peroxidation markers were reduced. Resistin and uric acid, surrogate plasma markers of metabolic syndrome, were decreased. In spite of the putative deleterious nature of the hydrogen peroxide generated during amine oxidation, and in agreement with its in vitro insulin-like actions found on adipocytes, the SSAO-substrate benzylamine could be considered as a potential oral agent to treat metabolic syndrome. Copyright 2010 Elsevier Ltd. All rights reserved.

Epicutaneous immunotherapy (EPIT blocks the allergic esophago-gastro-enteropathy induced by sustained oral exposure to peanuts in sensitized mice.

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Lucie Mondoulet

Full Text Available Food allergy may affect the gastrointestinal tract and eosinophilia is often associated with allergic gastrointestinal disorders. Allergy to peanuts is a life-threatening condition and effective and safe treatments still need to be developed. The present study aimed to evaluate the effects of sustained oral exposure to peanuts on the esophageal and jejunal mucosa in sensitized mice. We also evaluated the effects of desensitization with epicutaneous immunotherapy (EPIT on these processes.Mice were sensitized by gavages with whole peanut protein extract (PPE given with cholera toxin. Sensitized mice were subsequently exposed to peanuts via a specific regimen and were then analysed for eosinophilia in the esophagus and gut. We also assessed mRNA expression in the esophagus, antibody levels, and peripheral T-cell response. The effects of EPIT were tested when intercalated with sensitization and sustained oral peanut exposure.Sustained oral exposure to peanuts in sensitized mice led to severe esophageal eosinophilia and intestinal villus sub-atrophia, i.e. significantly increased influx of eosinophils into the esophageal mucosa (136 eosinophils/mm(2 and reduced villus/crypt ratios (1.6±0.15. In the sera, specific IgE levels significantly increased as did secretion of Th2 cytokines by peanut-reactivated splenocytes. EPIT of sensitized mice significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines as well as esophageal eosinophilia (50 eosinophils/mm(2, p<0.05, mRNA expression of Th2 cytokines in tissue--eotaxin (p<0.05, IL-5 (p<0.05, and IL-13 (p<0.05--GATA-3 (p<0.05, and intestinal villus sub-atrophia (2.3±0.15. EPIT also increased specific IgG2a (p<0.05 and mRNA expression of Foxp3 (p<0.05 in the esophageal mucosa.Gastro-intestinal lesions induced by sustained oral exposure in sensitized mice are efficaciously treated by allergen specific EPIT.

A mechanistic study to increase understanding of titanium dioxide nanoparticles-increased plasma glucose in mice.

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Hu, Hailong; Li, Li; Guo, Qian; Jin, Sanli; Zhou, Ying; Oh, Yuri; Feng, Yujie; Wu, Qiong; Gu, Ning

2016-09-01

Titanium dioxide nanoparticle (TiO2 NP) is an authorized food additive. Previous studies determined oral administration of TiO2 NPs increases plasma glucose in mice via inducing insulin resistance. An increase in reactive oxygen species (ROS) has been considered the possible mechanism of increasing plasma glucose. However, persistently high plasma glucose is also a mechanism of increasing ROS. This study aims to explore whether TiO2 NPs increase plasma glucose via ROS. We found after oral administration of TiO2 NPs, an increase in ROS preceded an increase in plasma glucose. Subsequently, mice were treated with two antioxidants (resveratrol and vitamin E) at the same time as oral administration of TiO2 NPs. Results showed resveratrol and vitamin E reduced TiO2 NPs-increased ROS. An increase in plasma glucose was also inhibited. Further research showed resveratrol and vitamin E inhibited the secretion of TNF-α and IL-6, and the phosphorylation of JNK and p38 MAPK, resulting in improved insulin resistance. These results suggest TiO2 NPs increased ROS levels, and then ROS activated inflammatory cytokines and phosphokinases, and thus induced insulin resistance, resulting in an increase in plasma glucose. Resveratrol and vitamin E can reduce TiO2 NPs-increased ROS and thereby inhibit an increase in plasma glucose in mice. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dietary lactoferrin alleviates age-related lacrimal gland dysfunction in mice.

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Motoko Kawashima

Full Text Available BACKGROUND: Decrease in lacrimal gland secretory function is related to age-induced dry eye disease. Lactoferrin, the main glycoprotein component of tears, has multiple functions, including anti-inflammatory effects and the promotion of cell growth. We investigated how oral administration of lactoferrin affects age-related lacrimal dysfunction. METHODS AND FINDINGS: Twelve-month-old male C57BL/6Cr Slc mice were randomly divided into a control fed group and an oral lactoferrin treatment group. Tear function was measured at a 6-month time-point. After euthanasia, the lacrimal glands were subjected to histological examination with 8-hydroxy-2'-deoxyguanosine (8-OHdG antibodies, and serum concentrations of 8-OHdG and hexanoyl-lysine adduct (HEL were evaluated. Additionally, monocyte chemotactic protein-1(MCP-1 and tumor necrosis factor-α (TNF-α gene expression levels were determined by real-time PCR. The volume of tear secretion was significantly larger in the treated group than in the control. Lactoferrin administration reduced inflammatory cell infiltration and the MCP-1 and TNF-α expression levels. Serum concentrations of 8-OHdG and HEL in the lactoferrin group were lower than those in the control group and were associated with attenuated 8-OHdG immunostaining of the lacrimal glands. CONCLUSION: Oral lactoferrin administration preserves lacrimal gland function in aged mice by attenuating oxidative damage and suppressing subsequent gland inflammation.

Pharmacokinetics of dexmedetomidine combined with methadone following oral-transmucosal and intramuscular administration in dogs

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Federica Di Cesare

2017-05-01

Full Text Available Oral-transmucosal (OTM drug delivery refers to noninvasive and painless administration of medical preparations through any oral cavity membrane to achieve systemic effects (Sattar et al., 2014. Regarding sedative drugs, OTM administration is very attractive in veterinary medicine, especially for patients difficult to inject and restrain (Messenger et al., 2016. This study aims to compare the pharmacokinetics of dexmedetomidine after OTM and intramuscular (IM administration combined with methadone. After obtaining Ethical Committee approval and owner’s written consent, eight dogs, were administered with dexmedetomidine (10 mg/kg and methadone (0.4 mg/kg by OTM and other 4 dogs by IM route. Blood samples were collected at prefixed times up to four hours. Dexmedetomidine was quantified by a validated HPLC-MS method. On dexmedetomidine concentrations, a pharmacokinetic analysis was carried out with a noncompartmental approach (Phoenix WinNonlin® 7.0, Pharsight, Cary, NC. Mean ± SD terminal half-lives of dexmedetomidine were 187.42 ± 109.66 and 94.78 ± 34.08 min after OTM and IM administration, respectively. Maximum serum (Cmax concentrations were 0.83 ± 0.32 and 9.09 ± 2.46 ng/mL for OTM and IM administration, respectively. Time to maximum concentration (Tmax were 44.38 ± 32.16 and 21.25±11.39 min by OTM and IM administration, respectively. Area under the curve from 0 to the last measured concentration (AUClast were 103.75 ± 30.23 and 614.87 ± 77.15 min*ng/mL for OTM and IM administration, respectively. Cmax, Tmax and AUClast values by OTM route demonstrate a lower and delayed absorption of the drug compared to IM. To complete the study, the pharmacokinetic analysis of methadone is foreseen, so as a clinical trial to compare the clinical effects of the combination of dexmedetomidine and methadone by OTM and IM administration and to establish an effective dosage of oral-transumucosal route in dogs for this association.

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

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

2016-01-01

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. 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. 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. These findings provide a better understanding of the bioavailability of CUR and CUR-NP following oral administration. To improve the bioavailability of CUR, future

Effect of heat-inactivated kefir-isolated Lactobacillus kefiranofaciens M1 on preventing an allergic airway response in mice.

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Hong, Wei-Sheng; Chen, Yen-Po; Dai, Ting-Yeu; Huang, I-Nung; Chen, Ming-Ju

2011-08-24

In this study, we assessed the anti-asthmatic effects of heat-inactivated Lactobacillus kefiranofaciens M1 (HI-M1) and its fermented milk using different feeding procedures and at various dosage levels. The possible mechanisms whereby HI-M1 has anti-allergic asthmatic effects were also evaluated. Ovalbumin (OVA)-allergic asthma mice that have been orally administrated the HI-M1 samples showed strong inhibition of production of T helper cell (Th) 2 cytokines, pro-inflammatory cytokines, and Th17 cytokines in splenocytes and bronchoalveolar fluid compared to control mice. An increase in regulatory T cell population in splenocytes in the allergic asthma mice after oral administration of H1-M1 was also observed. In addition, all of the features of the asthmatic phenotype, including specific IgE production, airway inflammation, and development of airway hyperresponsiveness, were depressed in a dose-dependent manner by treatment. These findings support the possibility that oral feeding of H1-M1 may be an effective way of alleviating asthmatic symptoms in humans.

Protective effect of oral administration of transgenic tobacco seeds against verocytotoxic Escherichia coli strain in piglets.

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Rossi, Luciana; Dell'Orto, Vittorio; Vagni, Simona; Sala, Vittorio; Reggi, Serena; Baldi, Antonella

2014-03-01

The use of transgenic plants as delivery system for antigenic proteins is attractive for its simplicity and increases likelihood for local immune response at sites of infection. The aim of this study was to evaluate the protective effect of oral administration of tobacco seeds, expressing the FedA, the major protein of the F18 adhesive fimbriae, and B subunit of verocytotoxin, against verocytotoxin-producing E. coli (VTEC) strain in piglets. Forty-three early weaned piglets, were randomly divided into 4 experimental groups: 3 test groups and a control. Treatment groups orally received a bolus, with different dose of tobacco seeds on 0, 1, 2, 14 days post primary administration. After challenge, with 1*10(10) CFU of O138 Escherichia coli strain, piglets showed clinical scores significantly higher in the control group compared to orally immunized groups (P administration of recombinant tobacco seeds expressing antigenic proteins against VTEC strains can induce a protective effect against challenger strain in piglets.

Protective Effect of Casperome®, an Orally Bioavailable Frankincense Extract, on Lipopolysaccharide- Induced Systemic Inflammation in Mice

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Konstantin Loeser

2018-04-01

Full Text Available Introduction: Despite recent advances in critical care, sepsis remains a crucial cause of morbidity and mortality in intensive care units. Therefore, the identification of new therapeutic strategies is of great importance. Since ancient times, frankincense is used in traditional medicine for the treatment of chronic inflammatory disorders such as rheumatoid arthritis. Thus, the present study intends to evaluate if Casperome® (Casp, an orally bioavailable soy lecithin-based formulation of standardized frankincense extract, is able to ameliorate systemic effects and organ damages induced by severe systemic inflammation using a murine model of sepsis, i.e., intraperitoneal administration of lipopolysaccharides (LPS.Methods: Male 60-day-old mice were assigned to six treatment groups: (1 control, (2 LPS, (3 soy lecithin (blank lecithin without frankincense extract, (4 Casp, (5 soy lecithin plus LPS, or (6 Casp plus LPS. Soy lecithin and Casp were given 3 h prior to LPS treatment; 24 h after LPS administration, animals were sacrificed and health status and serum cytokine levels were evaluated. Additionally, parameters representing liver damage or liver function and indicating oxidative stress in different organs were determined. Furthermore, markers for apoptosis and immune cell redistribution were assessed by immunohistochemistry in liver and spleen.Results: LPS treatment caused a decrease in body temperature, blood glucose levels, liver glycogen content, and biotransformation capacity along with an increase in serum cytokine levels and oxidative stress in various organs. Additionally, apoptotic processes were increased in spleen besides a pronounced immune cell infiltration in both liver and spleen. Pretreatment with Casp significantly improved health status, blood glucose values, and body temperature of the animals, while serum levels of pro-inflammatory cytokines and oxidative stress in all organs tested were significantly diminished. Finally

Targeted delivery of antigen to intestinal dendritic cells induces oral tolerance and prevents autoimmune diabetes in NOD mice.

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Chen, Yulin; Wu, Jie; Wang, Jiajia; Zhang, Wenjing; Xu, Bohui; Xu, Xiaojun; Zong, Li

2018-03-15

The intestinal immune system is an ideal target to induce immune tolerance physiologically. However, the efficiency of oral protein antigen delivery is limited by degradation of the antigen in the gastrointestinal tract and poor uptake by antigen-presenting cells. Gut dendritic cells (DCs) are professional antigen-presenting cells that are prone to inducing antigen-specific immune tolerance. In this study, we delivered the antigen heat shock protein 65-6×P277 (H6P) directly to the gut DCs of NOD mice through oral vaccination with H6P-loaded targeting nanoparticles (NPs), and investigated the ability of this antigen to induce immune tolerance to prevent autoimmune diabetes in NOD mice. A targeting NP delivery system was developed to encapsulate H6P, and the ability of this system to protect and facilitate H6P delivery to gut DCs was assessed. NOD mice were immunised with H6P-loaded targeting NPs orally once a week for 7 weeks and the onset of diabetes was assessed by monitoring blood glucose levels. H6P-loaded targeting NPs protected the encapsulated H6P from degradation in the gastrointestinal tract environment and significantly increased the uptake of H6P by DCs in the gut Peyer's patches (4.1 times higher uptake compared with the control H6P solution group). Oral vaccination with H6P-loaded targeting NPs induced antigen-specific T cell tolerance and prevented diabetes in 100% of NOD mice. Immune deviation (T helper [Th]1 to Th2) and CD4 + CD25 + FOXP3 + regulatory T cells were found to participate in the induction of immune tolerance. In this study, we successfully induced antigen-specific T cell tolerance and prevented the onset of diabetes in NOD mice. To our knowledge, this is the first attempt at delivering antigen to gut DCs using targeting NPs to induce T cell tolerance.

Oral delivery of Acid Alpha Glucosidase epitopes expressed in plant chloroplasts suppresses antibody formation in treatment of Pompe mice.

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Su, Jin; Sherman, Alexandra; Doerfler, Phillip A; Byrne, Barry J; Herzog, Roland W; Daniell, Henry

2015-10-01

Deficiency of acid alpha glucosidase (GAA) causes Pompe disease in which the patients systemically accumulate lysosomal glycogen in muscles and nervous systems, often resulting in infant mortality. Although enzyme replacement therapy (ERT) is effective in treating patients with Pompe disease, formation of antibodies against rhGAA complicates treatment. In this report, we investigated induction of tolerance by oral administration of GAA expressed in chloroplasts. Because full-length GAA could not be expressed, N-terminal 410-amino acids of GAA (as determined by T-cell epitope mapping) were fused with the transmucosal carrier CTB. Tobacco transplastomic lines expressing CTB-GAA were generated through site-specific integration of transgenes into the chloroplast genome. Homoplasmic lines were confirmed by Southern blot analysis. Despite low-level expression of CTB-GAA in chloroplasts, yellow or albino phenotype of transplastomic lines was observed due to binding of GAA to a chloroplast protein that has homology to mannose-6 phosphate receptor. Oral administration of the plant-made CTB-GAA fusion protein even at 330-fold lower dose (1.5 μg) significantly suppressed immunoglobulin formation against GAA in Pompe mice injected with 500 μg rhGAA per dose, with several-fold lower titre of GAA-specific IgG1 and IgG2a. Lyophilization increased CTB-GAA concentration by 30-fold (up to 190 μg per g of freeze-dried leaf material), facilitating long-term storage at room temperature and higher dosage in future investigations. This study provides the first evidence that oral delivery of plant cells is effective in reducing antibody responses in ERT for lysosomal storage disorders facilitating further advances in clinical investigations using plant cell culture system or in vitro propagation. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Postlactational changes in cadmium retention in mice orally exposed to cadmium during pregnancy and lactation

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Bhattacharyya, M.H.; Sellers, D.A.; Peterson, D.P.

1986-01-01

Mice were continuously exposed to 109Cd in drinking water (0.03 microCi/ml; 0.11 ppb total cadmium) during pregnancy and lactation. After cessation of exposure, 109 Cd retention and distribution were examined during a 4-week postlactational period. At the start of the postlactational period (0 time), the fraction of oral 109 Cd retained by the dams was 2.4 times greater than that retained by similarly exposed nonpregnant mice. 109 Cd concentrations at 0 time were greater in the dams than in the nonpregnant mice in kidney (5-fold), liver (2.6-fold), mammary tissue (greater than 28-fold), and duodenum (13-fold). No changes in 109 Cd content of the whole body (minus gastrointestinal tract) occurred during the 4 weeks after cessation of exposure in either the dams or the nonpregnant mice; i.e., pregnancy-dependent increases in 109 Cd contents of individual organs were maintained during the 4 weeks of observation. An indication of translocation of 109 Cd from liver to kidney was observed in the dams but not in the nonpregnant mice. 109 Cd concentrations in the mammary tissue of the dams increased 2-fold during the postlactational period concomitant with a 3-fold decrease in mammary tissue mass. 109 Cd in the duodenum of the pregnant/lactating mice decreased, with a half-life of 14 days. Results indicate that multiparous women exposed to environmental levels of cadmium may takeup and retain in their kidneys, livers, and mammary tissue a greater fraction of their dietary cadmium than women with few or no children. Such results may bear on the etiology of Itai-Itai disease, a disease of the skeleton potentially related to oral cadmium exposure, with an incidence predominantly among postmenopausal women with a history of multiple childbirths

Oral and transdermal DL-methylphenidate-ethanol interactions in C57BL/6J mice: potentiation of locomotor activity with oral delivery.

Science.gov (United States)

Bell, Guinevere H; Griffin, William C; Patrick, Kennerly S

2011-12-01

Many abusers of dl-methylphenidate co-abuse ethanol. The present animal study examined behavioral effects of oral or transdermal DL-methylphenidate in combination with a high, depressive dose of ethanol to model co-abuse. Locomotor activity of C57BL/6J mice was recorded for 3 h following dosing with either oral DL-methylphenidate (7.5 mg/kg) or transdermal DL-methylphenidate (Daytrana®;1/4 of a 12.5 cm(2) patch; mean dose 7.5 mg/kg), with or without oral ethanol (3 g/kg). Brains were enantiospecifically analyzed for the isomers of methylphenidate and the transesterification metabolite ethylphenidate. An otherwise depressive dose of ethanol significantly potentiated oral DL-methylphenidate induced increases in total distance traveled for the first 100 min (pbrain D-methylphenidate concentrations were significantly elevated by ethanol in both the oral (65% increase) and transdermal (88% increase) groups. The corresponding L-ethylphenidate concentrations were 10 ng/g and 130 ng/g. Stimulant induced motor activity in rodents may correlate with abuse liability. Potentiation of DL-methylphenidate motor effects by concomitant ethanol carries implications regarding increased abuse potential of DL-methylphenidate when combined with ethanol. Copyright © 2011 Elsevier Inc. All rights reserved.

Humoral immune response of C57Bl/6j and BALB/c mice immunized with irradiated tachyzoites of Toxoplasma gondii RH strain and oral challenge with ME-49 strain

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Jimenez Galisteo Junior, Andres [Instituto de Pesquisas Energeticas e Nucleares IPEN/CNEN-SP, Sao Paulo, SP (Brazil). Centro de Biotecnologia; Instituto de Medicina Tropical de Sao Paulo, Sao Paulo, SP (Brazil). Lab. de Protozoologia; E-mail: galisteo@usp.br; Zorgi, Nahiara Esteves; Andrade Junior, Heitor Franco de [Instituto de Medicina Tropical de Sao Paulo, Sao Paulo, SP (Brazil). Lab. de Protozoologia; Alves, Janaina Baptista; Nascimento, Nanci do [Instituto de Pesquisas Energeticas e Nucleares IPEN/CNEN-SP, Sao Paulo, SP (Brazil). Centro de Biotecnologia; Hiramoto, Roberto Mitsuyoshi [instituto Adolfo Lutz, Sao Paulo, SP (Brazil)

2007-07-01

Toxoplasmosis, a prevalent widespread infection in man and animals, is mainly transmitted by oral route, through ingestion of oocysts from water and food contaminated with cat feces or infected animal tissue cysts in undercooked meat. Vaccine development implies in effective intestinal immunity, the first site of parasite entry. Radiation (255 Gy/{sup 60}Co) sterilized T. gondii RH strain tachyzoites (RST) induced significant protection when parentally administered, similar to chronically infected and acute disease protected animal. We study the humoral immune response in C57Bl/6j and BALB/c mice immunized with 10{sup 7} RST, by oral (with aluminium hydroxide 3%) or parenteral 3 biweekly administrations. T. gondii antigens specific ELISA for IgG, IgA, IgG1, IgG2a and IgG2b detection was performed in weekly blood samples during immunization. Also we evaluate of the intestinal epithelial of immunized mice the integrity of the radiated parasites by electronic microscopy. After 2 weeks, immunized and control animals were challenged with 10 cysts of ME-49 strain p.o. Protection was determined at the 30th day by brain cyst counting. As it was possible to observe in the intestinal mucosal, the aluminium hydroxide seems to maintain unchanged the parasite morphology and its mechanisms of invasion, probably due to keeping it safe from extreme pH condition of stomach. All immunized groups presented significant protection when challenged with ME-49; however, BALB/c mice showed better protection levels, with only one positive animal on brain microscopic analysis. IgG production in the serum of the animals was higher in groups immunized by i.p route, however, IgA and IgG1 levels were higher in BALB/c mice immunized by oral route. This higher protection found in BALB/c group could probably also be related to the Th2 response, demonstrated by higher IgG1 levels. All these data provide insights in oral immunization schedules for toxoplasmosis prevention, suggesting that oral

Humoral immune response of C57Bl/6j and BALB/c mice immunized with irradiated tachyzoites of Toxoplasma gondii RH strain and oral challenge with ME-49 strain

International Nuclear Information System (INIS)

Jimenez Galisteo Junior, Andres

2007-01-01

Toxoplasmosis, a prevalent widespread infection in man and animals, is mainly transmitted by oral route, through ingestion of oocysts from water and food contaminated with cat feces or infected animal tissue cysts in undercooked meat. Vaccine development implies in effective intestinal immunity, the first site of parasite entry. Radiation (255 Gy/ 60 Co) sterilized T. gondii RH strain tachyzoites (RST) induced significant protection when parentally administered, similar to chronically infected and acute disease protected animal. We study the humoral immune response in C57Bl/6j and BALB/c mice immunized with 10 7 RST, by oral (with aluminium hydroxide 3%) or parenteral 3 biweekly administrations. T. gondii antigens specific ELISA for IgG, IgA, IgG1, IgG2a and IgG2b detection was performed in weekly blood samples during immunization. Also we evaluate of the intestinal epithelial of immunized mice the integrity of the radiated parasites by electronic microscopy. After 2 weeks, immunized and control animals were challenged with 10 cysts of ME-49 strain p.o. Protection was determined at the 30th day by brain cyst counting. As it was possible to observe in the intestinal mucosal, the aluminium hydroxide seems to maintain unchanged the parasite morphology and its mechanisms of invasion, probably due to keeping it safe from extreme pH condition of stomach. All immunized groups presented significant protection when challenged with ME-49; however, BALB/c mice showed better protection levels, with only one positive animal on brain microscopic analysis. IgG production in the serum of the animals was higher in groups immunized by i.p route, however, IgA and IgG1 levels were higher in BALB/c mice immunized by oral route. This higher protection found in BALB/c group could probably also be related to the Th2 response, demonstrated by higher IgG1 levels. All these data provide insights in oral immunization schedules for toxoplasmosis prevention, suggesting that oral vaccines could

Lactobacillus casei ssp.casei induced Th1 cytokine profile and natural killer cells activity in invasive ductal carcinoma bearing mice.

Science.gov (United States)

Soltan Dallal, Mohammad Mehdi; Yazdi, Mohammad Hossein; Holakuyee, Marzieh; Hassan, Zuhair Mohammad; Abolhassani, Mohsen; Mahdavi, Mehdi

2012-06-01

Lactic acid bacteria which are used as probiotics have ability to modulate immune responses and modify immune mechanisms. It has also been indicated that some strains of this family can affect the immune responses against solid tumors. In the present work, we proposed to study the effects of oral administration of L.cacesi ssp casei on the NK cells cytotoxicity and also production of cytokines in spleen cells culture of BALB/c mice bearing invasive ductal carcinoma. 30 female In-bred BALB/c mice, were used and divided in two groups of test and control each containing 15 mice. Every day from 2 weeks before tumor transplantation 0.5 ml of PBS containing 2.7×108 CFU/ml of L.casei spp casei was orally administered to the test mice and it was followed 3 weeks after transplantation as well with 3 days interval between each week. Control mice received an equal volume of PBS in a same manner. Results showed that oral administration of L. casei significantly increased the production of IL-12 and IFN-γ (Psurvival was significantly prolonged in comparison to the controls. Our findings suggest that daily intake of L.casei can improve immune responses in mice bearing invasive ductal carcinoma, but further studies are needed to investigate the other involving mechanisms in this case.

Motivational Disturbances and Effects of L-dopa Administration in Neurofibromatosis-1 Model Mice

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Wozniak, David F.; Diggs-Andrews, Kelly A.; Conyers, Sara; Yuede, Carla M.; Dearborn, Joshua T.; Brown, Jacquelyn A.; Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F.; Gutmann, David H.

2013-01-01

Children with neurofibromatosis type 1 (NF1) frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice). In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below) suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening) under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg) administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at ameliorating NF1

Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice.

Directory of Open Access Journals (Sweden)

David F Wozniak

Full Text Available Children with neurofibromatosis type 1 (NF1 frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice. In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at

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

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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 (Amazon

Protection and systemic translocation of siRNA following oral administration of chitosan/siRNA nanoparticles

DEFF Research Database (Denmark)

Gonzalez, Borja Ballarin; Dagnæs-Hansen, Frederik; Fenton, Robert A.

2013-01-01

, gastrointestinal (GI) deposition, and translocation into peripheral tissue of nonmodified siRNA after oral gavage of chitosan/siRNA nanoparticles in mice. In contrast to naked siRNA, retained structural integrity and deposition in the stomach, proximal and distal small intestine, and colon was observed at 1 and 5...... hours for siRNA within nanoparticles. Furthermore, histological detection of fluorescent siRNA at the apical regions of the intestinal epithelium suggests mucoadhesion provided by chitosan. Detection of intact siRNA in the liver, spleen, and kidney was observed 1 hour after oral gavage, with an organ...

Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin.

Science.gov (United States)

Morçöl, T; Nagappan, P; Nerenbaum, L; Mitchell, A; Bell, S J D

2004-06-11

An oral delivery system for insulin was developed and functional activity was tested in a non-obese diabetic (NOD) mice model. Calcium phosphate particles containing insulin was synthesized in the presence of PEG-3350 and modified by aggregating the particles with caseins to obtain the calcium phosphate-PEG-insulin-casein (CAPIC) oral insulin delivery system. Single doses of CAPIC formulation were tested in NOD mice under fasting or fed conditions to evaluate the glycemic activity. The blood glucose levels were monitored every 1-2h for 12h following the treatments using an ACCU CHECK blood glucose monitoring system. Orally administered and subcutaneously injected free insulin solution served as controls in the study. Based on the results obtained we propose that: (1). the biological activity of insulin is preserved in CAPIC formulation; (2). insulin in CAPIC formulations, but not the free insulin, displays a prolonged hypoglycemic effect after oral administration to diabetic mice; (3). CAPIC formulation protects insulin from degradation while passing through the acidic environment of the GI track until it is released in the less acidic environment of the intestines where it can be absorbed in its biologically active form; (4). CAPIC formulation represents a new and unique oral delivery system for insulin and other macromolecules.

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis).

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Sanchez-Migallon Guzman, David; Flammer, Keven; Papich, Mark G; Grooters, Amy M; Shaw, Shannon; Applegate, Jeff; Tully, Thomas N

2010-04-01

To determine the pharmacokinetics and safety of voriconazole administered orally in single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). 15 clinically normal adult Hispaniolan Amazon parrots. Single doses of voriconazole (12 or 24 mg/kg) were administered orally to 15 and 12 birds, respectively; plasma voriconazole concentrations were determined at intervals via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) or water was administered orally to 6 and 4 birds, respectively, every 8 hours for 11 days (beginning day 0); trough plasma voriconazole concentrations were evaluated on 3 days. Birds were monitored daily, and clinicopathologic variables were evaluated before and after the trial. Voriconazole elimination half-life was short (0.70 to 1.25 hours). In the single-dose experiments, higher drug doses yielded proportional increases in the maximum plasma voriconazole concentration (C(max)) and area under the curve (AUC). In the multiple-dose trial, C(max), AUC, and plasma concentrations at 2 and 4 hours were decreased on day 10, compared with day 0 values; however, there was relatively little change in terminal half-life. With the exception of 1 voriconazole-treated parrot that developed polyuria, adverse effects were not evident. In Hispaniolan Amazon parrots, oral administration of voriconazole was associated with proportional kinetics following administration of single doses and a decrease in plasma concentration following administration of multiple doses. Oral administration of 18 mg of voriconazole/kg every 8 hours would require adjustment to maintain therapeutic concentrations during long-term treatment. Safety and efficacy of voriconazole treatment in this species require further investigation.

Post-sensitization administration of non-digestible oligosaccharides and Bifidobacterium breve M-16V reduces allergic symptoms in mice.

Science.gov (United States)

van Esch, Betty C A M; Abbring, Suzanne; Diks, Mara A P; Dingjan, Gemma M; Harthoorn, Lucien F; Vos, A Paul; Garssen, Johan

2016-06-01

To support dietary management of severe cow's milk allergic infants, a synbiotic mixture of non-digestible oligosaccharides and Bifidobacterium breve M-16V ( B. breve ) was designed from source materials that are completely cow's milk-free. It was investigated whether this specific synbiotic concept can reduce an established food allergic response in a research model for hen's egg allergy. Mice were orally sensitized once a week for 5 weeks to ovalbumin (OVA) using cholera toxin (CT) as an adjuvant. Non-sensitized mice received CT in PBS only. Sensitized mice were fed a control diet or a diet enriched with short-chain- (scFOS) and long-chain fructo-oligosaccharides (lcFOS), B. breve or scFOSlcFOS +  B. breve for 3 weeks starting after the last sensitization. Non-sensitized mice received the control diet. Anaphylactic shock symptoms, acute allergic skin responses and serum specific IgE, mMCP-1 and galectin-9 were measured upon OVA challenge. Activated Th2-, Th1-cells and regulatory T-cells were quantified in spleen and mesenteric lymph nodes (MLN) and cytokine profiles were analyzed. Short chain fatty acids (SCFA) were measured in ceacal samples. The acute allergic skin response was reduced in mice fed the scFOSlcFOS +  B. breve diet compared to mice fed any of the other diets. A reduction in mast cell degranulation (mMCP-1) and anaphylactic shock symptoms was also observed in these mice. Unstimulated splenocyte cultures produced increased levels of IL10 and IFNg in mice fed the scFOSlcFOS +  B. breve diet. Correspondingly, increased percentages of activated Th1 cells were observed in the spleen. Allergen-specific re-stimulation of splenocytes showed a decrease in IL5 production. In summary; post-sensitization administration of scFOSlcFOS +  B. breve was effective in reducing allergic symptoms after allergen challenge. These effects coincided with changes in regulatory and effector T-cell subsets and increases in the SCFA propionic acid. These

Corticosteroid administration in oral and orthognathic surgery: a systematic review of the literature and meta-analysis

DEFF Research Database (Denmark)

Dan, Anne E B; Thygesen, Torben H; Pinholt, Else M

2010-01-01

was made. The primary predictor variable was CS administration and the outcome variables were edema, pain, and infection. A meta-analysis was performed. The risk of other side effects was evaluated through a simple review. RESULTS: In oral surgery, most clinical trials showed a significant decrease...... toward a neuroregeneration effect, but no statistical analysis could be performed. Regarding the risk of other side effects, in oral surgery, a minimal risk of chronic adrenal suppression was seen; in orthognathic surgery, an elevated risk of avascular osteonecrosis, steroid-induced psychosis......, and adrenal suppression was seen. There were no reports of decreased healing. CONCLUSION: These findings suggest that the administration of CS in oral surgery decreases edema and pain significantly, with no higher risk of infection and with a minimum risk of other side effects....

Effect of Guava Extract Administration on Megakaryocytes Amount in Mice Femur

Directory of Open Access Journals (Sweden)

Nur Atik

2017-06-01

Full Text Available Dengue fever is a disease spread by mosquito’s bite. Dengue fever is marked by the presence of thrombocytopenia. Traditional crops such as guava are commonly used to treat dengue fever. This research aims to know the effect of guava extract administration towards megakaryocytes amount in mice femur. The study was conducted at the Laboratory of Pharmacology and Therapy, Histology Laboratory of Faculty of Medicine at Universitas Padjadjaran, Eijkman, Bandung from September until November 2016 using laboratory experimental study design. 20 Swiss webster mice strains were divided randomly into 4 groups. Group I and II were administered quinine 2.8 mg/20 grBW/day for 14 days to decrease amount of trombocytes. Group II and III were administered guava extract 0.785 mg/20 grBW/day for 5 days. Group IV was administered aquadest for 19 days. In the 27th day, the mice left femurs were collected and made into paraffin section preparations with hematoxylin-eosin staining and then observed under microscope. Group IV had the most megakaryocytes followed by Group II, III, and I. Based on Kruskal-Wallis test, a significant difference was shown (p<0.05. Mann-Whitney test showed that there were significant differences between Group I and Group II, III, and IV. Meanwhile there was no significant difference between normal mice and extract-given mice. Guava extract is proven statistically significant to increase the megakaryocytes amount in thrombocytopenic mice without increasing number of megakaryocytes in normal mice.

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

Science.gov (United States)

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

2010-04-01

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.

Oral and nasal administration of chicken type II collagen suppresses adjuvant arthritis in rats with intestinal lesions induced by meloxicam.

Science.gov (United States)

Zheng, Yong-Qiu; Wei, Wei; Shen, Yu-Xian; Dai, Min; Liu, Li-Hua

2004-11-01

To investigate the curative effects of oral and nasal administration of chicken type II collagen (CII) on adjuvant arthritis (AA) in rats with meloxicam-induced intestinal lesions. AA model in Sprague-Dawley (SD) rats with or without intestinal lesions induced by meloxicam was established and those rats were divided randomly into six groups which included AA model, AA model+meloxicam, AA model+oral CII, AA model+nasal CII, AA model+ meloxicam+oral C II and AA model+meloxicam+nasal CII (n = 12). Rats was treated with meloxicam intragastrically for 7 d from d 14 after immunization with complete Freund's adjuvant (CFA), and then treated with chicken CII intragastrically or nasally for 7 d. Histological changes of right hind knees were examined. Hind paw secondary swelling and intestinal lesions were evaluated. Synoviocyte proliferation was measured by 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) method. Activities of myeloperoxidase (MPO) and diamine oxidase (DAO) from supernatants of intestinal homogenates were assayed by spectrophotometric analysis. Intragastrical administration of meloxicam (1.5 mg/kg) induced multiple intestinal lesions in AA rats. There was a significant decrease of intestinal DAO activities in AA+meloxicam group (P<0.01) and AA model group (P<0.01) compared with normal group. DAO activities of intestinal homogenates in AA+meloxicam group were significantly less than those in AA rats (P<0.01). There was a significant increase of intestinal MPO activities in AA+meloxicam group compared with normal control (P<0.01). Oral or nasal administration of CII (20 microg/kg) could suppress the secondary hind paw swelling(P<0.05 for oral CII; P<0.01 for nasal CII), synoviocyte proliferation (P<0.01) and histopathological degradation in AA rats, but they had no significant effects on DAO and MPO changes. However, oral administration of CII (20 microg/kg) showed the limited efficacy on arthritis in AA+meloxicam model and the

Ursodeoxycholic Acid Ameliorates Intrahepatic Cholestasis Independent of Biliary Bicarbonate Secretion in Vil2kd/kd Mice.

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Hatano, Ryo; Kawaguchi, Kotoku; Togashi, Fumitaka; Sugata, Masato; Masuda, Shizuka; Asano, Shinji

2017-01-01

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid that possesses many pharmacological effects, including increasing bile flow, changing the hydrophobicity of the bile acid pool, and modulation of the immune response. UDCA has been approved for treating cholestatic liver disease, such as primary biliary cholangitis. However, several unanticipated severe side effects of UDCA are observed in cholestatic patients, and its pharmacological benefits remain controversial. We reported that ezrin-knockdown (Vil2 kd/kd ) mice exhibited severe hepatic injury because of a functional disorder in bile duct fluidity and alkalinity regulation, resembling human intrahepatic cholestatic disease. Here we used Vil2 kd/kd mice as a cholestatic model to investigate the pharmacological effects of UDCA. We investigated the effects of oral and parenteral administration of UDCA on Vil2 kd/kd mice. In Vil2 kd/kd mice, fed a 0.5% (w/w) UDCA diet for 3 weeks, hepatic injury was exacerbated, although oral administration of a lower dose of UDCA slightly improved hepatic function in Vil2 kd/kd mice. On the other hand, intraperitoneal administration of UDCA (50 mg/kg/d) ameliorated hepatic function and markedly reduced periductal fibrosis and cholangiocyte proliferation in Vil2 kd/kd mice although biliary pH and HCO 3 - concentration were not improved. The expression levels of inflammatory and profibrotic genes were also significantly decreased in these mice. Furthermore, UDCA prevented cholangiocytes from hydrophobic bile acid-induced cytotoxicity independent of extracellular pH in in vitro experiments. These results suggest that an appropriate dosage of UDCA can ameliorate the intrahepatic cholestasis in Vil2 kd/kd mice without changing the biliary bicarbonate secretion.

New radiation mitigators to reduce bone marrow death of mice by post-irradiation administration

International Nuclear Information System (INIS)

Anzai, Kazunori

2009-01-01

We have found recently that heat-treated mineral yeast preparations and water-soluble analogs of vitamin E are potent radiation mitigator to reduce bone marrow death of mice by post-irradiation administration. When administered immediately after whole-body X-irradiation (7.5 Gy), both Zn-yeast and γ-tocopherol dimethylglycine ester (TDMG) significantly increased the viability of mice from 0% (control) to more than 90% (treated). Zn-yeast did not inhibit the tumor-regulation by γ-rays but even sensitize the radiation effect in mice xenografts of HeLa cells. (author)

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

Science.gov (United States)

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

2011-08-01

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

Safety of 8-weeks oral administration of Arctium lappa L.

Science.gov (United States)

Bok, So-Hyeon; Cho, Seung Sik; Bae, Chun-Sik; Park, Dae-Hun; Park, Kyung-Mok

2017-09-01

Recently, worldwide dietary reference intakes have been considered an important guideline for public health. Some governments and the World Health Organization (WHO) provide guidelines concerning dietary intake. Although an ingredient may have a history of use as a culinary material, changes in the environment over time suggest that the acceptable maximum intake each of food/culinary material should be regularly evaluated. Arctium lappa L. has been used as a culinary material for many centuries in Korea and Japan and some recent studies have reported related therapeutic effects. However, there are no reports on the safety of repeated oral administration. In this study, we evaluated the safety of a 8-weeks repeated oral intake of A. lappa . We concluded that treatment with lappa , which was within the safety range, resulted in body weight decrease and blood glucose suppression.

Pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses.

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Tsujimura, Koji; Yamada, Masayuki; Nagata, Shun-ichi; Yamanaka, Takashi; Nemoto, Manabu; Kondo, Takashi; Kurosawa, Masahiko; Matsumura, Tomio

2010-03-01

We investigated the pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses. Following an oral dose of famciclovir at 20 mg/kg, maximum plasma concentrations of penciclovir occurred between 0.75 and 1.5 hr (mean 0.94 + or - 0.38 hr) after dosing and were in the range 2.22 to 3.56 microg/ml (mean 2.87 + or - 0.61 microg/ml). The concentrations of penciclovir declined in a biphasic manner after the peak concentration was attained. The mean half-life of the rapid elimination phase was 1.73 + or - 0.34 hr whereas that of the slow elimination phase was 34.34 + or - 13.93 hr. These pharmacokinetic profiles observed were similar to those of another antiherpesvirus drug, acyclovir, previously reported in horses following oral dosing of its prodrug valacyclovir.

Human T-cell responses to oral streptococci in human PBMC-NOD/SCID mice.

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Salam, M A; Nakao, R; Yonezawa, H; Watanabe, H; Senpuku, H

2006-06-01

We investigated cellular and humoral immune responses to oral biofilm bacteria, including Streptococcus mutans, Streptococcus anginosus, Streptococcus sobrinus, and Streptococcus sanguinis, in NOD/SCID mice immunized with human peripheral blood mononuclear cells (hu-PBMC-NOD/SCID mice) to explore the pathogenicity of each of those organisms in dental and oral inflammatory diseases. hu-PBMC-NOD/SCID mice were immunized by intraperitoneal injections with the whole cells of the streptococci once a week for 3 weeks. FACS analyses were used to determine the percentages of various hu-T cell types, as well as intracellular cytokine production of interleukin-4 and interferon-gamma. Serum IgG and IgM antibody levels in response to the streptococci were also determined by enzyme-linked immunosorbent assay. S. anginosus induced a significant amount of the proinflammatory cytokine interferon-gamma in CD4(+) and CD8(+) T cells in comparison with the other streptococci. However, there was no significant differences between the streptococci in interleukin-4 production by CD4(+) and CD8(+) T cells after inoculation. Further, S. mutans significantly induced human anti-S. mutans IgG, IgG(1), IgG(2), and IgM antibodies in comparison with the other organisms. In conclusion, S. anginosus up-regulated Th1 and Tc1 cells, and S. mutans led to increasing levels of their antibodies, which was associated with the induction of Th2 cells. These results may contribute to a better understanding of human lymphocyte interactions to biofilm bacteria, along with their impact on dental and mucosal inflammatory diseases, as well as endocarditis.

Effect of the administration time of HS6101 on hematopoietic recovery in ICR mice injured by cyclophosphamide

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Shuang XING

2015-06-01

Full Text Available Objective　To explore the effect of the administration time of HS6101 on hematopoietic recovery in ICR mice injured by cyclophosphamide (CTX. Methods　One hundred and three male ICR mice were divided into 4 groups: CTX control, HS6101 prevention, HS6101 treatment, and HS6101 prevention+treatment groups. CTX was intraperitoneally injected into the ICR mice at a dose of 100mg/(kg.d for three consecutive days to establish a chemotherapeutics-injured model. HS6101 at a dose of 27μg/mouse in 0.2ml was subcutaneously injected into the mice 1h before the first administration of CTX in HS6101-prevention group, 1h after the last administration of CTX in HS6101 treatment group, and both at 1h before the first administration and 1h after the last administration of CTX in HS6101 prevention + treatment group. Physiological saline was subcutaneously injected into the mice in CTX control group (0.2ml/mouse. 10μl peripheral blood was collected from the caudal vein for WBC, neutrophil lymphocyte, RBC and platelet counts on day -1, 3, 5, 7, 9, 11, 13, 15, 17 with the MEK-7222K cell analyzer, and the cell count was compared between HS6101 treatment mice and CTX control mice. Another 30 male ICR mice were used for bone marrow colony forming unit (CFU assay and bone marrow histopathological examination, and they were assigned into normal control, CTX control, HS6101 prevention, HS6101treatment and HS6101 prevention + treatment groups (each n=6. On the day 4 and day 9 after CTX injection, mice were sacrificed and bone marrow cells were collected from the left femur for mononuclear cell (MNC isolation. 1×104 MNCs were planted in 1.0ml mouse CFU culture medium M3434 and cultured in incubator with the temperature of 37℃, and 5% CO2 for 7 days. After that, granulocyte macrophage-colony-forming unit (GM-CFU, megakaryocyte colony forming unit (MK-CFU, mixture-colony-forming unit (Mix-CFU, burst-forming unit-erythroid (BFU-E and colony-forming unit-erythroid (CFU

Improvement of diabetes, obesity and hypertension in type 2 diabetic KKAy mice by bis(allixinato)oxovanadium(IV) complex

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Adachi, Yusuke; Yoshikawa, Yutaka; Yoshida, Jiro; Kodera, Yukihiro; Katoh, Akira; Takada, Jitsuya; Sakurai, Hiromu

2006-01-01

Previously, we found that bis(allixinato)oxovanadium(IV) (VO(alx) 2 ) exhibits a potent hypoglycemic activity in type 1-like diabetic mice. Since the enhancement of insulin sensitivity is involved in one of the mechanisms by which vanadium exerts its anti-diabetic effects, VO(alx) 2 was further tested in type 2 diabetes with low insulin sensitivity. The effect of oral administration of VO(alx) 2 was examined in obesity-linked type 2 diabetic KKA y mice. Treatment of VO(alx) 2 for 4 weeks normalized hyperglycemia, glucose intolerance, hyperinsulinemia, hypercholesterolemia and hypertension in KKA y mice; however, it had no effect on hypoadiponectinemia. VO(alx) 2 also improved hyperleptinemia, following attenuation of obesity in KKA y mice. This is the first example in which a vanadium compound improved leptin resistance in type 2 diabetes by oral administration. On the basis of these results, VO(alx) 2 is proposed to enhance not only insulin sensitivity but also leptin sensitivity, which in turn improves diabetes, obesity and hypertension in an obesity-linked type 2 diabetic animal

Pharmacokinetics of sulfamethoxazole and trimethoprim in Pacific white shrimp, Litopenaeus vannamei, after oral administration of single-dose and multiple-dose.

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Ma, Rongrong; Wang, Yuan; Zou, Xiong; Hu, Kun; Sun, Beibei; Fang, Wenhong; Fu, Guihong; Yang, Xianle

2017-06-01

The tissue distribution and depletion of sulfamethoxazole (SMZ) and trimethoprim (TMP) were studied in Pacific white shrimp, Litopenaeus vannamei, after single-dose and multiple-dose oral administration of SMZ-TMP (5:1) via medicated feed. In single-dose oral administration, shrimps were fed once at a dose of 100 mg/kg (drug weight/body weight). In multiple-dose oral administration, shrimps were fed three times a day for three consecutive days at a dose of 100mg/kg. The results showed the kinetic characteristic of SMZ was different from TMP in Pacific white shrimp. In the single-dose administration, the SMZ was widely distributed in the tissues, while TMP was highly concentrated in the hepatopancreas. The t 1/2z values of SMZ were larger and persist longer than TMP in Pacific white shrimp. In the multiple-dose administration, SMZ accumulated well in the tissues, and reached steady state level after successive administrations, while TMP did not. TMP concentration even appeared the downward trend with the increase of drug times. Compared with the single dose, the t 1/2z values of SMZ in hepatopancreas (8.22-11.33h) and muscle (6.53-10.92h) of Pacific white shrimps rose, but the haemolymph dropped (13.76-11.03) in the multiple-dose oral administration. Meanwhile, the corresponding values of TMP also rose in hepatopancreas (4.53-9.65h) and muscle (2.12-2.71h), and declined in haemolymph (7.38-5.25h) following single-dose and multiple-dose oral administration in Pacific white shrimps. In addition, it is worth mentioning that the ratios of SMZ and TMP were unusually larger than the general aim ratio. Copyright © 2017 Elsevier B.V. All rights reserved.

Zinc metabolism in genetically obese (ob/ob) mice

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Kennedy, M.L.; Failla, M.L.

1987-01-01

Recent reports indicate that the concentrations and total amounts of several essential trace metals in various tissues of genetically obese rodents differ markedly from those in lean controls. In the present studies the absorption, retention and tissue distribution of zinc and constitutive levels of zinc-metallothionein (Zn-MT) in selected tissues were compared in obese (ob/ob) and lean (+/?) C57BL/6J mice. When 5-, 10- and 22-wk-old mice were administered 1.2 mumol 65 Zn by stomach tube the apparent absorption of 65 Zn by obese mice was 1.5, 2.2 and 3.9 times higher, respectively, than that in age-matched lean mice. Retention of orally administered 65 Zn after 96 h was also substantially higher in obese mice than in lean mice. To assess the possible influences of hyperphagia and intestinal hypertrophy on the enhanced apparent absorption of 65 Zn by obese mice food intake by an additional group of obese mice was restricted to that of age-matched lean controls. When actual absorption of zinc was determined according to the method of Heth and Hoekstra, groups of ad libitum--fed obese, pair-fed obese and lean mice absorbed 38, 32 and 18% of administered 65 Zn, respectively. In contrast, the rate of 65 Zn excretion 2-6 d after oral or subcutaneous administration of the metal was similar for obese and lean mice. Unrestricted and pair-fed obese mice had significantly lower percentages of carcass 65 Zn present in skin, muscle plus bone, spleen and testes and higher percentages present in liver, small intestine and adipose tissue than lean mice

Amine functionalized cubic mesoporous silica nanoparticles as an oral delivery system for curcumin bioavailability enhancement

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Budi Hartono, Sandy; Hadisoewignyo, Lannie; Yang, Yanan; Meka, Anand Kumar; Antaresti; Yu, Chengzhong

2016-12-01

In the present work, a simple method was used to develop composite curcumin-amine functionalized mesoporous silica nanoparticles (MSN). The nanoparticles were used to improve the bioavailability of curcumin in mice through oral administration. We investigated the effect of particle size on the release profile, solubility and oral bioavailability of curcumin in mice, including amine functionalized mesoporous silica micron-sized-particles (MSM) and MSN (100-200 nm). Curcumin loaded within amine functionalized MSN (MSN-A-Cur) had a better release profile and a higher solubility compared to amine MSM (MSM-A-Cur). The bioavailability of MSN-A-Cur and MSM-A-Cur was considerably higher than that of ‘free curcumin’. These results indicate promising features of amine functionalized MSN as a carrier to deliver low solubility drugs with improved bioavailability via the oral route.

Effects of oral Lactobacillus administration on antioxidant activities and CD4+CD25+forkhead box P3 (FoxP3)+ T cells in NZB/W F1 mice.

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Tzang, Bor-Show; Liu, Chung-Hsien; Hsu, Kuo-Ching; Chen, Yi-Hsing; Huang, Chih-Yang; Hsu, Tsai-Ching

2017-09-01

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by a dysregulation of the immune system, which causes inflammation responses, excessive oxidative stress and a reduction in the number of cluster of differentiation (CD)4+CD25+forkhead box P3 (FoxP3)+ T cells. Supplementation with certain Lactobacillus strains has been suggested to be beneficial in the comprehensive treatment of SLE. However, little is known about the effect and mechanism of certain Lactobacillus strains on SLE. To investigate the effects of Lactobacillus on SLE, NZB/W F1 mice were orally gavaged with Lactobacillus paracasei GMNL-32 (GMNL-32), Lactobacillus reuteri GMNL-89 (GMNL-89) and L. reuteri GMNL-263 (GMNL-263). Supplementation with GMNL-32, GMNL-89 and GMNL-263 significantly increased antioxidant activity, reduced IL-6 and TNF-α levels and significantly decreased the toll-like receptors/myeloid differentiation primary response gene 88 signalling in NZB/W F1 mice. Notably, supplementation with GMNL-263, but not GMNL-32 and GMNL-89, in NZB/W F1 mice significantly increased the differentiation of CD4+CD25+FoxP3+ T cells. These findings reveal beneficial effects of GMNL-32, GMNL-89 and GMNL-263 on NZB/W F1 mice and suggest that these specific Lactobacillus strains can be used as part of a comprehensive treatment of SLE patients.

Excretion and metabolism of 1-nitropyrene in rats after oral or intraperitoneal administration

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Dutcher, J.S.; Sun, J.D.; Bechtold, W.E.; Unkefer, C.J.

1985-01-01

The metabolism and excretion of 1-nitropyrene (NP), a prevalent NPAH, by Fischer-344 rats after intraperitoneal (ip) or oral administration was studied. Radiolabeled NP was administered to rats (10 mg NP/kg body wt), and urine and feces were collected for 7 days. After ip administration of [ 14 C]NP, 60% of the radioactivity was found in the urine and 20% in the feces. Likewise, 55 and 35% of the orally administered 14 C was found in urine and feces, respectively. Both urine and feces were analyzed by high-pressure liquid chromatography for metabolites. The majority of the radioactivity in both urine and feces was associated with very polar metabolites, none accounting for more than 10% of the dose. Small amounts (less than 1% of the dose) of aminopyrene (AP), acetylaminopyrene, and NP were detected. A urinary metabolite (3-8% of the dose) was found that converted to acetylaminopyrene phenol (two isomers) when urine was heated overnight at 37 0 C at pH 4.5. More of this metabolite (2.2 times) as well as AP (1.8 times), was excreted after oral than after ip administration of NP. The NP metabolites found in this study demonstrate that reduction of the nitro group is a significant route of NP metabolism in rats. Since nitroreduction appears to be necessary in the activation of NPAHs to bacterial mutagens, this indicates that similar metabolic pathways are present in rats (catalyzed by mammalian and/or gut bacterial enzymes) and that activation of NPAHs to carcinogens or toxins by nitroreduction is possible. 29 references, 8 figures

Effect of Tribulus terrestris on Haloperidol-induced Catalepsy in Mice

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Nishchal, B. S.; Rai, S.; Prabhu, M. N.; Ullal, Sheetal D.; Rajeswari, S.; Gopalakrishna, H. N.

2014-01-01

Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspended in 1% gum acacia solution. Catalepsy was induced in mice with haloperidol (1.0 mg/kg, intraperitoneally). The first group received the vehicle (10 ml/kg, orally), the second group received trihexyphenidyl (10 mg/kg, orally) and the remaining two groups received Tribulus terrestris (100, 200 mg/kg, orally). The animals were assessed after single and repeated dose administration for ten days, 30 min prior to haloperidol, using standard bar test. The result of the present study demonstrates Tribulus terrestris has a protective effect against haloperidol-induced catalepsy, which is comparable to the standard drug used for the same purpose. Our study indicates Tribulus terrestris can be used to prevent haloperidol-induced extrapyramidal side effects. PMID:25593394

Effect of Tribulus terrestris on Haloperidol-induced Catalepsy in Mice.

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Nishchal, B S; Rai, S; Prabhu, M N; Ullal, Sheetal D; Rajeswari, S; Gopalakrishna, H N

2014-01-01

Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspended in 1% gum acacia solution. Catalepsy was induced in mice with haloperidol (1.0 mg/kg, intraperitoneally). The first group received the vehicle (10 ml/kg, orally), the second group received trihexyphenidyl (10 mg/kg, orally) and the remaining two groups received Tribulus terrestris (100, 200 mg/kg, orally). The animals were assessed after single and repeated dose administration for ten days, 30 min prior to haloperidol, using standard bar test. The result of the present study demonstrates Tribulus terrestris has a protective effect against haloperidol-induced catalepsy, which is comparable to the standard drug used for the same purpose. Our study indicates Tribulus terrestris can be used to prevent haloperidol-induced extrapyramidal side effects.

Oral administration of a medium containing both D-aspartate-producing live bacteria and D-aspartate reduces rectal temperature in chicks.

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Do, P H; Tran, P V; Bahry, M A; Yang, H; Han, G; Tsuchiya, A; Asami, Y; Furuse, M; Chowdhury, V S

2017-10-01

1. The aim of this study was to investigate the effects on the rectal temperature of young chicks of the oral administration of a medium that contained both live bacteria that produce D-aspartate (D-Asp) and D-Asp. 2. In Experiment 1, chicks were subjected to chronic oral administration of either the medium (containing live bacteria and 2.46 μmol D-Asp) or water from 7 to 14 d of age. Plasma-free amino acids as well as mitochondrial biogenic gene expression in the breast muscle were analysed. In Experiment 2, 7-d-old chicks were subjected to acute oral administration of the above medium or of an equimolar amount of D-Asp to examine their effect on changes in rectal temperature. In Experiment 3, after 1 week of chronic oral administration of the medium, 14-d-old chicks were exposed to either high ambient temperature (HT; 40 ± 1°C, 3 h) or control thermoneutral temperature (CT; 30 ± 1°C, 3 h) to monitor the changes in rectal temperature. 3. Chronic, but not acute, oral administration of the medium significantly reduced rectal temperature in chicks, and a chronic effect also appeared under HT conditions. 4. Chronic oral administration of the medium significantly reduced the mRNA abundance of the avian uncoupling protein (avUCP) in the breast muscle, but led to a significant increase in avian adenine nucleotide translocator (avANT) mRNA in the same muscle. 5. (a) These results indicate that the medium can reduce body temperature through the decline in avUCP mRNA expression in the breast muscle that may be involved in reduced mitochondrial proton leaks and heat production. (b) The increase in avANT further suggests a possible enhancement of adenosine triphosphate (ATP) synthesis.

Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice.

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Pardo, Marta; Cheng, Yuyan; Velmeshev, Dmitry; Magistri, Marco; Eldar-Finkelman, Hagit; Martinez, Ana; Faghihi, Mohammad A; Jope, Richard S; Beurel, Eleonore

2017-03-23

Molecular mechanisms underlying learning and memory remain imprecisely understood, and restorative interventions are lacking. We report that intranasal administration of siRNAs can be used to identify targets important in cognitive processes and to improve genetically impaired learning and memory. In mice modeling the intellectual deficiency of Fragile X syndrome, intranasally administered siRNA targeting glycogen synthase kinase-3β (GSK3β), histone deacetylase-1 (HDAC1), HDAC2, or HDAC3 diminished cognitive impairments. In WT mice, intranasally administered brain-derived neurotrophic factor (BDNF) siRNA or HDAC4 siRNA impaired learning and memory, which was partially due to reduced insulin-like growth factor-2 (IGF2) levels because the BDNF siRNA- or HDAC4 siRNA-induced cognitive impairments were ameliorated by intranasal IGF2 administration. In Fmr1 -/- mice, hippocampal IGF2 was deficient, and learning and memory impairments were ameliorated by IGF2 intranasal administration. Therefore intranasal siRNA administration is an effective means to identify mechanisms regulating cognition and to modulate therapeutic targets.

Acute behavioral effects of co-administration of mephedrone and MDMA in mice.

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Budzynska, Barbara; Michalak, Agnieszka; Frankowska, Małgorzata; Kaszubska, Katarzyna; Biała, Grażyna

2017-04-01

Abuse of more than one psychoactive drug is becoming a global problem. Our experiments were designed to examine the effects of a concomitant administration of 3,4-methylenedioxy-methamphetamine (MDMA) and mephedrone on depression- and anxiety-like behaviors and cognitive processes in Swiss mice. In order to investigate the drug interactions the forced swimming test (FST) - an animal model of depression, the passive avoidance (PA) test - a memory and learning paradigm, as well as the elevated plus maze (EPM) test - test for anxiety level were used. The results revealed that a concomitant administration of non-effective doses of mephedrone (1mg/kg) and MDMA (1mg/kg) exerted marked antidepressive effects in the FST. Also a co-administration of mephedrone (2.5mg/kg) and MDMA (1mg/kg) displayed a pro-cognitive action in the PA paradigm. Furthermore, even though mephedrone and MDMA can, in general, exert some anxiogenic effects in mice, the concomitant administration of nonactive doses of both drugs (0.05 and 0.1mg/kg, respectively) in the EPM test, did not show any synergistic effect in our study. The effects of mephedrone and MDMA combination on mammalian organisms were attempted to be evaluated in our study and the results are described in the present report. These results may help explain the reasons for and consequences of a concomitant administration of psychoactive substances with regards to the central nervous system, while being possibly useful in the treatment of polydrug intoxication. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Effect of Hibiscus sabdariffa on obesity in MSG mice.

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Alarcon-Aguilar, Francisco J; Zamilpa, Alejandro; Perez-Garcia, Ma Dolores; Almanza-Perez, Julio C; Romero-Nuñez, Eunice; Campos-Sepulveda, Efrain A; Vazquez-Carrillo, Laura I; Roman-Ramos, Ruben

2007-10-08

The aim of the present investigation was determine whether a standardized Hibiscus sabdariffa calyces aqueous extract has an effect on body weight in an obese animal model induced by the administration of monosodium glutamate. Hibiscus sabdariffa aqueous extract, containing 33.64 mg of total anthocyanins per each 120 mg of extract, was orally administered (120 mg/kg/day) for 60 days to healthy and obese mice, and body weight gain, food and liquid intake, aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, and triglycerides levels were measured. Hibiscus sabdariffa administration significantly reduced body weight gain in obese mice and increased liquid intake in healthy and obese mice. ALT levels were significantly increased on the 15th and 45th days in obese mice, but AST levels did not show significant changes. Mortality was not observed in the Hibiscus sabdariffa treated groups. Triglycerides and cholesterol levels showed non-significant reductions in animals treated with Hibiscus sabdariffa. Our data confirm the anti-obesity effect of Hibiscus sabdariffa reported by the Mexican population.

Mouse single oral dose toxicity test of bupleuri radix aqueous extracts.

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Kim, Kyung-Hu; Gam, Cheol-Ou; Choi, Seong-Hun; Ku, Sae-Kwang

2012-03-01

The aim of this study was to evaluate the single oral dose toxicity of Bupleuri Radix (BR) aqueous extracts, it has been traditionally used as anti-inflammatory agent, in male and female mice. BR extracts (yield = 16.52%) was administered to female and male ICR mice as an oral dose of 2,000, 1,000 and 500 mg/kg (body weight) according to the recommendation of Korea Food and Drug Administration (KFDA) Guidelines. Animals were monitored for the mortality and changes in body weight, clinical signs and gross observation during 14 days after dosing, upon necropsy; organ weight and histopathology of 14 principal organs were examined. As the results, no BR extracts treatment related mortalities, clinical signs, changes on the body and organ weights, gross and histopathological observations against 14 principal organs were detected up to 2,000 mg/kg in both female and male mice, except for soft feces and related body weight decrease detected in male mice treated with 2,000 mg/kg. Therefore, LD50 (50% lethal dose) and approximate LD of BR aqueous extracts after single oral treatment in female and male mice were considered over 2000 mg/kg, respectively. Although it was also observed that the possibilities of digestive disorders, like soft feces when administered over 2,000 mg/kg of BR extracts in the present study, these possibilities of digestive disorders can be disregard in clinical use because they are transient in the highest dosages male only.

Protective effect of N-Acetylcysteine against ethanol-induced gastric ulcer: a pharmacological assessment in mice

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Ausama Ayoob Jaccob

2015-06-01

Aim: Since there is an increasing need for gastric ulcer therapies with optimum benefit-risk profile. This study was conducted to investigate gastro-protective effects of N-Acetylcysteine (NAC against ethanol-induced gastric ulcer models in mice. Materials and Methods: Forty-two mice were allocated into six groups consisting of 7 mice each. Groups 1 (normal control and 2 (ulcer control received distilled water at a dose of 10 ml/kg, groups 3, 4 and 5 were given NAC at doses 100, 300 and 500 mg/kg, respectively, and the 6th group received ranitidine (50 mg/kg. All drugs administered orally once daily for 7 days, on the 8th day absolute ethanol (7 ml/kg was administrated orally to all mice to induce the acute ulcer except normal control group. Then 3 h after, all animals were sacrificed then consequently the stomachs were excised for examination. Results: NAC administration at the tested doses showed a dose-related potent gastro-protective effect with significant increase in curative ratio, PH of gastric juice and mucus content viscosity seen with the highest dose of NAC and it is comparable with that observed in ranitidine group. Conclusion: The present findings demonstrate that, oral NAC shows significant gastro-protective effects comparable to ranitidine confirmed by antisecretory, cytoprotective, histological and biochemical data but the molecular mechanisms behind such protection are complex. [J Intercult Ethnopharmacol 2015; 4(2.000: 90-95

Efficacy of protocols for induction of chronic hyperthyroidism in male and female mice.

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Engels, Kathrin; Rakov, Helena; Zwanziger, Denise; Hönes, Georg Sebastian; Rehders, Maren; Brix, Klaudia; Köhrle, Josef; Möller, Lars Christian; Führer, Dagmar

2016-10-01

Protocols for induction of hyperthyroidism in mice are highly variable and mostly involve short-term thyroid hormone (TH) treatment. In addition, little is known about a possible influence of sex on experimental TH manipulation. Here we analyzed the efficacy of intraperitoneal vs. oral levothyroxine (T4) administration to induce chronic hyperthyroidism in male and female mice and asked which T4 dosing intervals are required to achieve stable organ thyrotoxicosis. T4 was administered intraperitoneally or orally over a period of 6/7 weeks. Assessment included monitoring of body weight, TH serum concentrations, and serial quantitative TH target gene expression analysis in liver and heart. Our results show that both intraperitoneal and oral T4 treatment are reliable methods for induction of chronic hyperthyroidism in mice. Thereby T4 injection intervals should not exceed 48 h and oral levothyroxine should be administered continuously during experiments and up to sacrifice to ensure a hyperthyroid organ state. Furthermore, we found a sex-dependent variation in levothyroxine-induced TH serum state, with significantly higher T4 concentrations in female mice, while expression of investigated classical TH responsive genes in liver and heart did not vary with animal's sex. In summary, our study shows that common approaches for rendering rodents thyrotoxic can also be used for induction of chronic hyperthyroidism in male and female mice. Thereby T4 dosing intervals are critical as are read-out parameters to verify a chronic thyrotoxic organ state.

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

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

2013-10-01

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

Gastroprotective activity of ferruginol in mice and rats: effects on gastric secretion, endogenous prostaglandins and non-protein sulfhydryls.

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Areche, Carlos; Theoduloz, Cristina; Yáñez, Tania; Souza-Brito, Alba R M; Barbastefano, Víctor; de Paula, Débora; Ferreira, Anderson L; Schmeda-Hirschmann, Guillermo; Rodríguez, Jaime A

2008-02-01

The gastroprotective mechanism of the natural diterpene ferruginol was assessed in mice and rats. The involvement of gastric prostaglandins (PGE(2)), reduced glutathione, nitric oxide or capsaicin receptors was evaluated in mice either treated or untreated with indometacin, N-ethylmaleimide (NEM), N-nitro-L-arginine methyl ester (L-NAME) or ruthenium red, respectively, and then orally treated with ferruginol or vehicle. Gastric lesions were induced by oral administration of ethanol. The effects of ferruginol on the parameters of gastric secretion were assessed in pylorus-ligated rats. Gastric PGE(2) content was determined in rats treated with ferruginol and/or indometacin. The reduction of gastric glutathione (GSH) content was determined in rats treated with ethanol after oral administration of ferruginol, lansoprazole or vehicle. Finally, the acute oral toxicity was assessed in mice. Indometacin reversed the gastroprotective effect of ferruginol (25 mg kg(-1)) but not NEM, ruthenium red or L-NAME. The diterpene (25 mg kg(-1)) increased the gastric juice volume and its pH value, and reduced the titrable acidity but was devoid of effect on the gastric mucus content. Ferruginol (25, 50 mg kg(-1)) increased gastric PGE(2) content in a dose-dependent manner and prevented the reduction in GSH observed due to ethanol-induced gastric lesions in rats. Single oral doses up to 3 g kg(-1) ferruginol did not elicit mortality or acute toxic effects in mice. Our results showed that ferruginol acted as a gastroprotective agent stimulating the gastric PGE(2) synthesis, reducing the gastric acid output and improving the antioxidant capacity of the gastric mucosa by maintaining the GSH levels.

Effect of gamma irradiation on acute oral toxicity of ethanolic extract of red ginger (zingiber officinale)

International Nuclear Information System (INIS)

Ermin Katrin; Winarti Andayani; Susanto; Hendig Winarno

2014-01-01

Red ginger is widely used in traditional medicine to treat various types of diseases. Evaluation of the toxic properties of red ginger is very important to know the negative harmful impact to human health. Therefore, before it is consumed by humans, it is needed to conduct acute oral toxicity of red ginger extract in mice. Thin rhizome of red ginger in poly ethylene plastic packaging was irradiated by gamma rays at a dose of 10 kGy with a dose rate of 10 kGy/h. The ethanol extract of unirradiated as well as irradiated red ginger was then tested for the acute oral toxicity using OECD Guideline test method. The results showed that throughout the 14 days of treatment there was a change in behavior pattern, clinical symptoms and body weight of control mice and treatment groups. Histopathological examination of kidneys, heart, liver, lungs and spleen of the dose less than 1250 mg/kg body weight showed normal condition and no significant side effects observation. While central venous damage and a reduced number of hepatocyte cells in male mice occurred in the test dose higher than 2000 mg/kg body weight, whereas in female mice it occurred in the test group dose higher than 1250 mg/kg bw. Based on renal histology of male and female mice at doses higher than 1250 mg/kg body weight, there were damage to Bowman's capsule, glomerulus, proximal vessel and distal vessels. LD50 of unirradiated and irradiated with 10 kGy of ethanol extract of red ginger were 1887 mg/kg body weight and 2639 mg/kg body weight, respectively, and it can be categorized as moderately toxic. Oral administration of ethanol extract of red ginger with dose of 1250 mg/kg body weight gave an effect in mice organs. From these results it can be concluded that oral administration of both unirradiated and irradiated with a dose 10 kGy of ethanol extract consider safe at a dose less than 1250 mg/kg body weigh. (author)

Red Wine administration to Apolipoprotein E-deficient Mice reduces their Macrophage-derived Extracellular Matrix Atherogenic Properties

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MARIELLE KAPLAN

2004-01-01

Full Text Available Proteoglycans (PGs from the arterial extracellular matrix (ECM contribute to the trapping of LDL and oxidized LDL (Ox-LDL in the arterial wall, a phenomenon called "lipoprotein retention". Moreover, we have shown that subsequent to their binding to the matrix, LDL and Ox-LDL are taken up by macrophages. Oxidative stress significantly increases macrophage secretion of ECM-PGs, lipoprotein binding to the ECM and the uptake of ECM-retained lipoproteins by macrophages. The aim of the present study was to determine whether red wine administration to atherosclerotic mice would affect their peritoneal macrophage-derived extracellular matrix properties, such as the glycosaminoglycan content and the ability to bind LDL. In addition, we questioned the ability of LDL bound to the mice peritoneal macrophages-derived ECM to be taken up by macrophages. Red wine administration to atherosclerotic mice did not affect the mice peritoneal macrophages-derived ECM glycosaminoglycan content but it significantly reduced the mice peritoneal macrophages-derived ECM ability to bind LDL and the subsequent uptake of ECM-retained LDL by the macrophages. The present study thus clearly demonstrated the inhibitory effect of red wine consumption by E0 mice on their peritoneal macrophage-derived extracellular matrix atherogenic properties.

Effect of orally administered dipterinyl calcium pentahydrate on oral glucose tolerance in diet-induced obese mice

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Fuchs D

2012-02-01

Full Text Available Svetlana E Nikoulina1, Dietmar Fuchs2, Phillip Moheno11SanRx Pharmaceuticals, Inc, La Jolla, CA, USA; 2Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, AustriaAbstract: Calcium pterins have been shown to be significant immunotherapeutic agents in models of breast cancer, hepatitis B, and tuberculosis (Bacillus Calmette-Guérin mycobacteria. These compunds modulate the immuno-enzyme indoleamine 2,3-dioxygenase (IDO and the blood levels of several identified inflammatory cytokines. Recent research into the pathology of diabetes implicates inflammatory factors in the progression of the disease, leading the authors to study its possible control by one of the calcium pterins, dipterinyl calcium pentahydrate (DCP.The investigators tested DCP as a novel therapeutic for type 2 diabetes. Female C57BL/6 J mice with diet-induced obesity were fed a high-fat diet and were administered DCP in 0.4% carboxymethylcellulose for 21 days. Blood glucose was followed during the dosing period, and an oral glucose tolerance test (OGTT was carried out on day 21. Measurements of plasma indoleamine 2,3-dioxygenase metabolites (tryptophan and kynurenine and certain cytokines and chemokines were also taken. DCP 7 mg/kg/day reduced OGTT area under the curve (OGTT/AUC by 50% (P < 0.05. A significant multivariate regression (P = 0.013; R2 = 0.571 of OGTT/AUC was derived from DCP dosage and plasma Trp. Elevated plasma Trp concentration, likely from heterogeneity in diet and/or indoleamine 2,3-dioxygenase activity, was found to correlate with higher OGTT/AUC diabetic measures, possibly via inhibition of histamine degradation. In conclusion, an optimum dose of DCP 7 mg/kg/day significantly improved the OGTT diabetic state in these female diet-induced obese mice.Keywords: diabetes, immunotherapy, oral glucose tolerance test, tryptophan, kynurenine

Oral gadopentetate dimeglumine administration as a negative gastrointestinal contrast agent to improve image quality of MR cholangiopancreatography

International Nuclear Information System (INIS)

Chen Yi; Xu Yikai; Zhao Yuhui; Wang Guisheng

2008-01-01

Objective: To choose optimal concentration and volume of Gd-DTPA solution as a oral gastrointestinal negative contrast agent for MRCP. To evaluate the role of Gd-DTPA solution in improving image quality of MRCP. Methods: In vitro experiment: Gd-DTPA solution was made with different concentrations. T 1 WI, T 2 WI, two-dimensional single slice fast spin echo sequence and three-dimensional half-fourier acquisition single-shot fast spin echo sequence were performed to measure the signal intensity of these contrast agents respectively, so Gd-DTPA solution with the optimal concentration can be decided as oral negative gastrointestinal contrast agent on MRCP. Clinical study: The Gd-DTPA solution with optimal concentration and volume was regarded as an oral negative gastrointestinal contrast agent of MRCP. Twenty- four' patients were performed with MRCP before and after (5-10 minutes and 10-15 minutes) administration of oral negative gastrointestinal contrast agent and image quality was analyzed. Statistical analysis was performed using analysis of variance with SPSS 10.0. Results: When the concentration of Gd-DTPA solution was ≤0.01 mol/L, the contrast agent was hyperintense on T 1 WI. On T 2 WI, when the concentration was ≥0.015 mol/L, it was as hypointense as basic ground; On 2D FSE MRCP images, controls were hyperintense and the contrast agent with concentration ranging from 0.0025 mol/L to 0.03 mol/L was hypointense. On 3D HEAST MRCP image, controls were hyperintense and when the concentration of Gd-DTPA was ≥0.01 mol, the contrast agent was hypointense. The Gd-DTPA solution with the concentration of 0.01 mol/L and the volume of 100 ml was chosen as MRCP oral negative gastrointestinal contrast agent. On MRCP images after oral administration of the contrast agent, in 10-15 minutes, the average grade scores within 24 patients of the intrahepatic bile duct, the common hepatic bile duct, the gall bladder, the common bile duct and pancreatic duct (the average grade

Oral administration of fisetin promotes the induction of hippocampal long-term potentiation in vivo

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Wen-bin He

2018-01-01

Full Text Available To explore memory enhancing effect of the flavonoid fisetin, we investigated the effect of oral administration of flavonoids on the induction of long-term potentiation (LTP at hippocampal CA1 synapses of anesthetized rats. Among four flavonoids (fisetin, quercetin, luteolin and myricetin tested, only fisetin significantly facilitated the induction of hippocampal LTP. The effect of oral fisetin was abolished by intracerebroventricular injection of U0126, an agent that was previously found to inhibit its effect in hippocampal slices in vitro. These results suggest that orally administered fisetin crosses the blood–brain barrier and promotes synaptic functions in the hippocampus.

Desalted deep-sea water improves cognitive function in mice by increasing the production of insulin-like growth factor-I in the hippocampus.

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Harada, Naoaki; Zhao, Juan; Kurihara, Hiroki; Nakagata, Naomi; Okajima, Kenji

2011-08-01

The stimulation of sensory neurons in the gastrointestinal (GI) tract improves cognitive function by increasing the hippocampal production of insulin-like growth factor-I (IGF-I) in mice. In the current study, we examined whether oral administration of desalted deep-sea water (DSW) increases the hippocampal production of IGF-I by stimulating sensory neurons in the GI tract, thereby improving cognitive function in mice. Desalted DSW increased calcitonin gene-related peptide (CGRP) release from dorsal root ganglion (DRG) neurons isolated from wild-type (WT) mice by activating transient receptor potential vanilloid 1. The plasma levels of IGF-I and tissue levels of CGRP, IGF-I, and IGF-I mRNA in the hippocampus were increased by oral administration of desalted DSW in WT mice. In these animals, nociceptive information originating from the GI tract was transmitted to the hippocampus via the spinothalamic pathway. Improvement of spatial learning was observed in WT mice after administration of desalted DSW. Distilled DSW showed results similar to those of desalted DSW in vitro and in vivo. None of the effects of desalted DSW in WT mice were observed after the administration of desalted DSW in CGRP-knockout (CGRP-/-) mice. No volatile compounds were detected in distilled DSW on GC-MS analysis. These observations suggest that desalted DSW may increase the hippocampal IGF-I production via sensory neuron stimulation in the Gl tract, thereby improving cognitive function in mice. Such effects of desalted DSW might not be dependent on the minerals but are dependent on the function of the water molecule itself. Copyright © 2011 Mosby, Inc. All rights reserved.

Comparative pharmacokinetics of oxytetracycline in blunt-snout bream (Megalobrama amblycephala) with single and multiple-dose oral administration.

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Li, Ru-Qin; Ren, Yu-Wei; Li, Jing; Huang, Can; Shao, Jun-Hui; Chen, Xiao-Xuan; Wu, Zhi-Xin

2015-06-01

Research into the pharmacokinetics and residue elimination of oxytetracycline (OTC) is important both to determine the optimal dosage regimens and to establish a safe withdrawal time in fish. A depletion study is presented here for OTC in Megalobrama amblycephala with a single-dose (100 mg/kg) and multiple-dose (100 mg/kg for five consecutive days) oral administration. The study was conducted at 25 °C. As a result, a one-compartment model was developed. For the single dose, the absorption half-life was 5.79, 9.40, 6.96, and 8.06 h in the plasma, liver, kidney, and muscle, respectively. However, the absorption half-life was 3.62, 7.33, 4.59, and 6.02 h with multiple-dose oral administration. The elimination half-time in the plasma, liver, kidney, and muscle was 58.63, 126.43, 65.1, and 58.85 h when M. amblycephala was treated with a single dose. However, the elimination half-time changed to 91.75, 214.87, 126.22, and 135.84 h with multiple-dose oral administration.

Combined oral administration of bovine collagen peptides with calcium citrate inhibits bone loss in ovariectomized rats.

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

2015-01-01

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. 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. 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. 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.

Combined oral administration of bovine collagen peptides with calcium citrate inhibits bone loss in ovariectomized rats.

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JunLi Liu

Full Text Available 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.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.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.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.

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

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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.

Oral administration of fisetin promotes the induction of hippocampal long-term potentiation in vivo

OpenAIRE

Wen-bin He; Kazuho Abe; Tatsuhiro Akaishi

2018-01-01

To explore memory enhancing effect of the flavonoid fisetin, we investigated the effect of oral administration of flavonoids on the induction of long-term potentiation (LTP) at hippocampal CA1 synapses of anesthetized rats. Among four flavonoids (fisetin, quercetin, luteolin and myricetin) tested, only fisetin significantly facilitated the induction of hippocampal LTP. The effect of oral fisetin was abolished by intracerebroventricular injection of U0126, an agent that was previously found to...

Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes.

Science.gov (United States)

Suemizu, Hiroshi; Sota, Shigeto; Kuronuma, Miyuki; Shimizu, Makiko; Yamazaki, Hiroshi

2014-11-01

Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides. Copyright © 2014 Elsevier Inc. All rights reserved.

Oral Administration of Semicarbazide Limits Weight Gain together with Inhibition of Fat Deposition and of Primary Amine Oxidase Activity in Adipose Tissue

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Josep Mercader

2011-01-01

Full Text Available An enzyme hitherto named semicarbazide-sensitive amine oxidase (SSAO, involved in the oxidation of primary amines, is abundantly expressed in adipocytes. Although SSAO physiological functions remain unclear, several molecules inhibiting its activity have been described to limit fat accumulation in preadipocyte cultures or to reduce body weight gain in obese rodents. Here, we studied whether oral administration of semicarbazide, a prototypical SSAO inhibitor, limits fat deposition in mice. Prolonged treatment with semicarbazide at 0.125% in drinking water limited food and water consumption, hampered weight gain, and deeply impaired fat deposition. The adiposomatic index was reduced by 31%, while body mass was reduced by 15%. Such treatment completely inhibited SSAO, but did not alter MAO activity in white adipose tissue. Consequently, the insulin-like action of the SSAO substrate benzylamine on glucose transport was abolished in adipocytes from semicarbazide-drinking mice, while their insulin sensitivity was not altered. Although semicarbazide is currently considered as a food contaminant with deleterious effects, the SSAO inhibition it induces appears as a novel concept to modulate adipose tissue development, which is promising for antiobesity drug discovery.

Oral immunization of mice with engineered Lactobacillus gasseri NM713 strain expressing Streptococcus pyogenes M6 antigen.

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Mansour, Nahla M; Abdelaziz, Sahar A

2016-08-01

The aim of this in vivo study was to evaluate the effects of a recombinant probiotic strain, Lactobacillus gasseri NM713, which expresses the conserved region of streptococcal M6 protein (CRR6), as an oral vaccine against Streptococcus pyogenes. A dose of 10(9) cells of the recombinant strain in 150 μL PBS buffer was administered orally to a group of mice. One control group received an equivalent dose of Lb. gasseri NM613 (containing the empty plasmid without insert) or and another control group received PBS buffer. Each group contained 30 mice. The immunization protocol was followed on three consecutive days, after which two booster doses were administered at two week intervals. Fecal and serum samples were collected from the mice on Days 18, 32, 46, 58 after the first immunization and Day 0 prior to immunization. Anti-CRR6 IgA and IgG concentrations were measured by ELISA in fecal and sera samples, respectively, to assess immune responses. Vaccination with the recombinant Lb. gasseri NM713 strain induced significant protection after nasal challenge with S. pyogenes, only a small percentage of this group developing streptococcal infection (10%) or dying of it (3.3%) compared with the NM613 and PBS control groups, high percentages of which developed streptococcal infection (43.3% and 46.7%, respectively) and died of it (46.7% and 53%, respectively). These results indicate that recombinant Lb. gasseri NM713 has potential as an oral delivery vaccine against streptococcus group A. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

Models hosts for the study of oral candidiasis.

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Junqueira, Juliana Campos

2012-01-01

Oral candidiasis is an opportunistic infection caused by yeast of the Candida genus, primarily Candida albicans. It is generally associated with predisposing factors such as the use of immunosuppressive agents, antibiotics, prostheses, and xerostomia. The development of research in animal models is extremely important for understanding the nature of the fungal pathogenicity, host interactions, and treatment of oral mucosal Candida infections. Many oral candidiasis models in rats and mice have been developed with antibiotic administration, induction of xerostomia, treatment with immunosuppressive agents, or the use of germ-free animals, and all these models has both benefits and limitations. Over the past decade, invertebrate model hosts, including Galleria mellonella, Caenorhabditis elegans, and Drosophila melanogaster, have been used for the study of Candida pathogenesis. These invertebrate systems offer a number of advantages over mammalian vertebrate models, predominantly because they allow the study of strain collections without the ethical considerations associated with studies in mammals. Thus, the invertebrate models may be useful to understanding of pathogenicity of Candida isolates from the oral cavity, interactions of oral microorganisms, and study of new antifungal compounds for oral candidiasis.

Lactobacillus paracasei feeding improves the control of secondary experimental meningococcal infection in flu-infected mice.

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Belkacem, Nouria; Bourdet-Sicard, Raphaëlle; Taha, Muhamed-Kkeir

2018-04-10

The use of probiotics to improve anti-microbial defence, such as for influenza infections, is increasingly recommended. However, no data are available on the effect of probiotics on flu-associated secondary bacterial infections. There is strong evidence of a spatiotemporal association between influenza virus infection and invasive Neisseria meningitidis. We thus investigated the effect of feeding mice Lactobacillus paracasei CNCM I-1518 in a mouse model of sequential influenza-meningococcal infection. We intranasally infected BALB/c mice with a strain of influenza A virus (IAV) H3N2 that was first adapted to mice. Seven days later, a secondary bacterial infection was induced by intranasal administration of bioluminescent N. meningitidis. During the experiment, mice orally received either L. paracasei CNCM I-1518 or PBS as a control. The effect of L. paracasei administration on secondary bacterial infection by N. meningitidis was evaluated. Oral consumption of L. paracasei CNCM I-1518 reduced the weight loss of infected mice and lowered the bioluminescent signal of infecting meningococci. This improvement was associated with higher recruitment of inflammatory myeloid cells, such as interstitial monocytes and dendritic cells, to the lungs. Our data highlight the role of the gut-lung axis. L. paracasei CNCM I-1518 may boost the defence against IAV infection and secondary bacterial infection, which should be further studied and validated in clinical trials.

5-FU Metabolism in Cancer and Orally-Administrable 5-FU Drugs

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Iwao Sasaki

2010-09-01

Full Text Available 5-Fluorouracil (5-FU is a key anticancer drug that for its broad antitumor activity, as well as for its synergism with other anticancer drugs, has been used to treat various types of malignancies. In chemotherapeutic regimens, 5-FU has been combined with oxaliplatin, irinotecan and other drugs as a continuous intravenous infusion. Recent clinical chemotherapy studies have shown that several of the regimens with oral 5-FU drugs are not inferior compared to those involving continuous 5-FU infusion chemotherapy, and it is probable that in some regimens continuous 5-FU infusion can be replaced by oral 5-FU drugs. Historically, both the pharmaceutical industry and academia in Japan have been involved in the development of oral 5-FU drugs, and this review will focus on the current knowledge of 5-FU anabolism and catabolism, and the available information about the various orally-administrable 5-FU drugs, including UFT, S-1 and capecitabine. Clinical studies comparing the efficacy and adverse events of S-1 and capecitabine have been reported, and the accumulated results should be utilized to optimize the treatment of cancer patients. On the other hand, it is essential to elucidate the pharmacokinetic mechanism of each of the newly-developed drugs, to correctly select the drugs for each patient in the clinical setting, and to further develop optimized drug derivatives.

DNA damage detected by the alkaline comet assay in the liver of mice after oral administration of tetrachloroethylene

DEFF Research Database (Denmark)

Cederberg, H.; Henriksson, J.; Binderup, Mona-Lise

2010-01-01

in hepatocytes, indicating that tetrachloroethylene induced DNA damage in the liver. No effect on DNA damage was observed in the kidney. The results are in agreement with carcinogenicity data in mice, in which tetrachloroethylene induced tumours in the liver but not in the kidney, and support that a genotoxic...... mode of action might be involved in liver carcinogenicity in mice. An alternative interpretation of the results conveyed by the Study director at the test facility, involving that tetrachloroethylene did not induce DNA damage in the liver and kidney of mice, is also presented and discussed....

Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice

DEFF Research Database (Denmark)

Funda, David; Fundova, Petra; Hansen, Axel Kornerup

2014-01-01

gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis...

In vivo analysis of supersaturation/precipitation/absorption behavior after oral administration of pioglitazone hydrochloride salt; determinant site of oral absorption.

Science.gov (United States)

Tanaka, Yusuke; Sugihara, Masahisa; Kawakami, Ayaka; Imai, So; Itou, Takafumi; Murase, Hirokazu; Saiki, Kazunori; Kasaoka, Satoshi; Yoshikawa, Hiroshi

2017-08-30

The purpose of this study was to evaluate in vivo supersaturation/precipitation/absorption behavior in the gastrointestinal (GI) tract based on the luminal concentration-time profiles after oral administration of pioglitazone (PG, a highly permeable lipophilic base) and its hydrochloride salt (PG-HCl) to rats. In the in vitro precipitation experiment in the classic closed system, while the supersaturation was stable in the simulated gastric condition, PG drastically precipitated in the simulated intestinal condition, particularly at a higher initial degree of supersaturation. Nonetheless, a drastic and moderate improvement in absorption was observed in vivo at a low and high dose of PG-HCl, respectively. Analysis based on the luminal concentration of PG after oral administration of PG-HCl at a low dose revealed that most of the dissolved PG emptied from the stomach was rapidly absorbed before its precipitation in the duodenum. At a high dose of PG-HCl, PG partly precipitated in the duodenum but was absorbed to some extent. Therefore, the extent of the absorption was mainly dependent on the duodenal precipitation behavior. Furthermore, a higher-than expected absorption after oral administration of PG-HCl from in vitro precipitation study may be due to the absorption process in the small intestine, which suppresses the precipitation by removal of the drug. This study successfully clarify the impact of the absorption process on the supersaturation/precipitation/absorption behavior and key absorption site for a salt formulation of a highly permeable lipophilic base based on the direct observation of in vivo luminal concentration. Our findings may be beneficial in developing an ideal physiologically based pharmacokinetic model and in vitro predictive dissolution tools and/or translating the in silico and in vitro data to the in vivo outcome. Copyright © 2017 Elsevier B.V. All rights reserved.

ATP-ase positive cells in human oral mucosa transplanted to nude mice

DEFF Research Database (Denmark)

Dabelsteen, E; Kirkeby, S

1981-01-01

A model to study the differentiation of human oral epithelium in vivo utilizing transplantation of human tissue to nude mice has been described. Previous studies have described the epithelial cells in this model. In this study we demonstrate that 8 d after transplantation, Langerhans cells, ident......, identified as ATP-ase positive dendritic cells, have almost disappeared from the transplanted epithelium whereas at day 21 after transplantation such cells were abundant. It is suggested that the ATP-ase positive cells which reappear in the transplanted epithelium are of mouse origin....

Effect of some drugs on radioprotective effectiveness, toxicity and distribution of 35S-Aminopropyl-aminoethyl-thiophosphate orally administered to mice

International Nuclear Information System (INIS)

Grechka, I.I.; Belavina, L.P.; Kalistpatov, G.V.; Zherebchenko, P.G.

1979-01-01

Studied was the influence of adreno- adn cholinolytics and cholinomimetic substances on radioprotective effectiveness and toxicity of aminopropyl-aminoehtyl-thiophosphate (APAETP) and distribution thereof among organs after oral and intraperitoneal administration. Atropine and INPEA decrease the toxicity and radioprotectiVe efficiency of APAETP when administered orally and do not influence these properties after intraperitoneal in ection. Deposition of the labelled radioprotector within the organs after oral administration is also indicative that atropine and INPEA can delay the transfer of APAETP from the stomach to the intenstine

Lack of dose dependent kinetics of methyl salicylate-2-O-β-D-lactoside in rhesus monkeys after oral administration.

Science.gov (United States)

He, Yangyang; Yan, Yu; Zhang, Tiantai; Ma, Yinzhong; Zhang, Wen; Wu, Ping; Song, Junke; Wang, Shuang; Du, Guanhua

2015-04-22

Methyl salicylate-2-O-β-d-lactoside (MSL) is one of the main active components isolated from Gaultheria yunnanensis, which is a traditional Chinese medicine used to treat arthritis and various aches and pains. Pharmacological researches showed that MSL had various effective activities in both in vivo and in vitro experiments. However, the pharmacokinetics features and oral bioavailability of MSL in primates were not studied up to now. To study the pharmacokinetics of different doses of MSL in rhesus monkeys and investigate the absolute bioavailability of MSL after oral administration. Male and female rhesus monkeys were either orally administrated with MSL 200, 400 and 800 mg/kg or received an intravenous dose of 20mg/kg randomly. The levels of MSL and salicylic acid (SA) in plasma were simultaneous measured by a simple, sensitive and reproducible high performance liquid chromatography method. Mean peak plasma concentration values for groups treated with 200, 400 and 800 mg/kg doses ranged from 48.79 to 171.83 μg/mL after single-dose oral administration of MSL, and mean area under the concentration-time curve values ranged from 195.16 to 1107.76 μg/mL h. Poor linearity of the kinetics of SA after oral administration of MSL was observed in the regression analysis of the Cmax-dose plot (r(2)=0.812), CL-dose plot (r(2)=0.225) and AUC(0-t)-dose plot (r(2)=0.938). Absolute bioavailability of MSL was assessed to be 118.89 ± 57.50, 213.54 ± 58.98 and 168.72 ± 76.58%, respectively. Bioavailability of MSL after oral administration in rhesus monkeys was measured for the first time. Pharmacokinetics parameters did not appear to be dose proportional among the three oral doses of treatments, and MSL showed an apparent absolute bioavailability in excess of 100% in rhesus monkeys based on the present study. In addition, a rapid, sensitive and reliable HPLC method was established and demonstrated for the research of traditional Chinese medicine in this study. Copyright �

Low-dose oral tolerance due to antigen in the diet suppresses differentially the cholera toxin-adjuvantized IgE, IgA and IgG response

DEFF Research Database (Denmark)

Christensen, Hanne Risager; Kjær, Tanja; Frøkiær, Hanne

2003-01-01

Background: Cholera toxin (CT) is used as a mucosal adjuvant amongst other applications for studying food allergy because oral administration of antigen with CT induces an antigen-specific type 2 response, including IgE and IgA production. Priorly established oral tolerance due to antigen...... soy-trypsin inhibitor (KSTI) (F0 mice) and mice fed a soy-free diet (F2 mice) were orally immunized with KSTI and CT. KSTI-specific serum IgG1, IgG2a, IgA and IgE and fecal IgA were monitored. KSTI-stimulated cell proliferation and interleukin (IL)-6 production were determined. Results: The anti...... immunizations. However, cell proliferation and IL-6 production were clearly suppressed even after five immunizations. Conclusions: Priorly established low-dose oral tolerance considerably suppressed the CT-adjuvantized KSTI-specific IgE, IgA and cellular immune response but only weakly and transiently the Ig...

Reduction of Influenza Virus Titer and Protection against Influenza Virus Infection in Infant Mice Fed Lactobacillus casei Shirota

OpenAIRE

Yasui, Hisako; Kiyoshima, Junko; Hori, Tetsuji

2004-01-01

We investigated whether oral administration of Lactobacillus casei strain Shirota to neonatal and infant mice ameliorates influenza virus (IFV) infection in the upper respiratory tract and protects against influenza infection. In a model of upper respiratory IFV infection, the titer of virus in the nasal washings of infant mice administered L. casei Shirota (L. casei Shirota group) was significantly (P < 0.05) lower than that in infant mice administered saline (control group) (102.48 ± 100.31...

Prophylactic administration of an extract from Plantaginis Semen and its major component aucubin inhibits mechanical allodynia caused by paclitaxel in mice

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Tsugunobu Andoh

2016-07-01

Full Text Available The chemotherapeutic agent paclitaxel (PTX causes peripheral neuropathy as a major dose-limiting side effect, and this peripheral neuropathy is difficult to control. Our previous report showed that prophylactic repetitive administration of goshajinkigan (牛車腎氣丸 niú chē shèn qì wán, but not hachimijiogan (八味地黃丸 bā wèi dì huáng wán, which lacks two of the constituents of goshajinkigan, inhibited PTX-induced mechanical allodynia in mice. Thus, the herbal medicines Plantaginis Semen (車前子 chē qián zǐ or Achyranthis Radix (牛膝 niú xī may contribute to the inhibitory action of goshajinkigan on the exacerbation of PTX-induced mechanical allodynia [Andoh et al, J. Tradit. Complement. Med. 2014; 4: 293–297]. Therefore, in this study, we examined whether an extract of Plantaginis Semen (EPS or Achyranthis Radix (EAR would relieve PTX-induced mechanical allodynia in mice. A single intraperitoneal injection of PTX caused mechanical allodynia, which peaked on day 14 after injection. Repetitive oral administration of EPS, but not EAR, starting from the day after PTX injection significantly inhibited the exacerbation of PTX-induced mechanical allodynia. Repetitive intraperitoneal injection of aucubin, one of the main components of EPS, starting from the day after PTX injection also significantly reduced PTX-induced mechanical allodynia. However, repetitive intraperitoneal injection of geniposide acid (a precursor of aucubin or catalpol (a metabolite of aucubin did not prevent the exacerbation of mechanical allodynia. These results suggest that prophylactic administration of EPS is effective for preventing the exacerbation of PTX-induced allodynia. Aucubin may contribute to the inhibitory action of EPS on the exacerbation of PTX-induced allodynia.

Pharmacokinetics of /sup 3/H-pipethiaden after single oral and intravenous administration in rats

Energy Technology Data Exchange (ETDEWEB)

Lapka, R.; Franc, Z.; Smolik, S.

1985-01-01

Tritium labelled anti-migraine drug 4-(1-methyl-4-piperidyliden)-4,9-duhydrothieno(2,3-c)-2-benzothiepine (pipethiaden) was prepared. After oral and intravenous administration to rats not only the courses of total radioactivity in plasma and various organs were determined, but by means of TLC-radiometry also the levels of pipethiaden itself. After the oral dose 1.35 mg/kg the plasma levels of pipethiaden did not exceed 3.5 ng/ml. Some pharmacokinetic parameters (e.g. t/sub 1/2/el-4h) were calculated by compartmental analysis of plasma levels.

Delayed O-methylation of l-DOPA in MB-COMT-deficient mice after oral administration of l-DOPA and carbidopa.

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Tammimäki, Anne; Aonurm-Helm, Anu; Männistö, Pekka T

2018-04-01

1. Catechol-O-methyltransferase (COMT) is involved in the O-methylation of l-DOPA, dopamine, and other catechols. The enzyme is expressed in two isoforms: soluble (S-COMT), which resides in the cytoplasm, and membrane-bound (MB-COMT), which is anchored to intracellular membranes. 2. To obtain specific information on the functions of COMT isoforms, we studied how a complete MB-COMT deficiency affects the total COMT activity in the body, peripheral l-DOPA levels, and metabolism after l-DOPA (10 mg kg -1 ) plus carbidopa (30 mg kg -1 ) administration by gastric tube in wild-type (WT) and MB-COMT-deficient mice. l-DOPA and 3-O-methyl-l-DOPA (3-OMD) levels were assayed in plasma, duodenum, and liver. 3. We showed that the selective lack of MB-COMT did not alter the total COMT activity, COMT enzyme kinetics, l-DOPA levels, or the total O-methylation of l-DOPA but delayed production of 3-OMD in plasma and peripheral tissues.

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

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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.

Effects of subchronic oral toxic metal exposure on the intestinal microbiota of mice

Institute of Scientific and Technical Information of China (English)

Qixiao Zhai; Tianqi Li; Leilei Yu; Yue Xiao; Saisai Feng; Jiangping Wu; Jianxin Zhao; Hao Zhang; Wei Chen

2017-01-01

Oral exposure to toxic metals such as cadmium （Cd),lead (Pb),copper (Cu) and aluminum （Al) can induce various adverse health effects in humans and animals.However,the effects of these metals on the gut microbiota have received limited attention.The present study demonstrated that long-term toxic metal exposure altered the intestinal microbiota of mice in a metal-specific and time-dependent manner.Subchronic oral Cu exposure for eight weeks caused a profound decline in gut microbial diversity in mice,whereas no significant changes were observed in groups treated with other metals.Cd exposure significantly increased the relative abundances of organisms from the genera Alistipes and Odoribacter and caused marked decreases in Mollicutes and unclassified Ruminococcaceae.Pb exposure significantly decreased the abundances of eight genera:unclassified and uncultured Ruminococcaceae,unclassified Lachnospiraceae,Ruminiclostridium_9,Rikenellaceae_RC9_gut_group,Oscillibacter,Anaerotruncus and Lachnoclostridium.Cu exposure affected abundances of the genera Alistipes,Bacteroides,Ruminococcaceae_UCG-014,Allobaculum,Mollicutes_RFg_norank,Rikenellaceae_RC9_gut_group,Ruminococcaceae_unclassified and Turicibacter.Al exposure increased the abundance of Odoribacter and decreased that of Anaerotruncus.Exposure to any metal for eight weeks significantly decreased the abundance of Akkermansia.These results provide a new understanding regarding the role of toxic metals in the pathogenesis of intestinal and systemic disorders in the host within the gut microbiota framework.

Infecção via oral por Trypanosoma evansi em animais de laboratório Oral infection by Trypanosoma evansi in rats and mice

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Aleksandro Schafer da Silva

2007-06-01

Full Text Available Testou-se a infecção de Trypanosoma evansi pela via oral em ratos e camundongos, através de sangue contaminado de ambas as espécies. Dez ratos e dez camundongos foram alocados em quatro grupos iguais A e B (ratos, C e D (camundongos. Os grupos A e C receberam sangue contaminado de um rato e o grupo B e D de um camundongo, através de uma sonda. O volume de sangue administrado foi de 0,2ml, o qual apresentava uma concentração de 10(7 tripanossomas ml-1. Os animais foram mantidos em temperatura e umidade constantes (25°C e 80% UR, sendo realizados esfregaços sanguíneos diários para identificar o período pré-patente e a evolução do parasita na circulação. Nos grupos A e B, o período pré-patente variou de 19 a 25 dias, e o período entre a detecção dos parasitas e a morte dos animais foi em média de 12,7 dias. Os camundongos do grupo C e D não apresentaram infecção pelo parasita, sendo estes avaliados por 60 dias. Os ratos foram susceptíveis a infecção por T. evansi pela via oral; entretanto, os camundongos não se contaminaram com o protozoário por via digestiva.In this research, Trypanosoma evansi infection was tested in rats and mice by oral ingestion of contaminated blood. Groups of ten rats and ten mice were disposed in four experimental groups: A and B (rats, C and D (mice. The groups A and C were contaminated by rat-contaminated blood; B and C groups by mouse-contaminated blood. The blood was given using a probe filled with 0.2ml of contaminated blood with 10(7 trypanosomes ml-1. These animals were maintained at constant temperature and humidity (25°C and 80% UR. Dairy blood smear were done to identify the prepatent period and evolution of parasite in the circulation. In the A and B groups, the pre latency period varied from 19 to 25 days and the period of parasite detection and animals death was an average of 12.7 days. The C and D groups did not present infection by the parasite even when evaluated for 60 days

Thiomers for oral delivery of hydrophilic macromolecular drugs.

Science.gov (United States)

Bernkop-Schnürch, Andreas; Hoffer, Martin H; Kafedjiiski, Krum

2004-11-01

In recent years thiolated polymers (thiomers) have appeared as a promising new tool in oral drug delivery. Thiomers are obtained by the immobilisation of thio-bearing ligands to mucoadhesive polymeric excipients. By the formation of disulfide bonds with mucus glycoproteins, the mucoadhesive properties of thiomers are up to 130-fold improved compared with the corresponding unmodified polymers. Owing to the formation of inter- and intramolecular disulfide bonds within the thiomer itself, matrix tablets and particulate delivery systems show strong cohesive properties, resulting in comparatively higher stability, prolonged disintegration times and a more controlled drug release. The permeation of hydrophilic macromolecular drugs through the gastrointestinal (GI) mucosa can be improved by the use of thiomers. Furthermore, some thiomers exhibit improved inhibitory properties towards GI peptidases. The efficacy of thiomers in oral drug delivery has been demonstrated by various in vivo studies. A pharmacological efficacy of 1%, for example, was achieved in rats by oral administration of calcitonin tablets comprising a thiomer. Furthermore, tablets comprising a thiomer and pegylated insulin resulted in a pharmacological efficacy of 7% after oral application to diabetic mice. Low-molecular-weight heparin embedded in thiolated polycarbophil led to an absolute bioavailability of > or = 20% after oral administration to rats. In these studies, formulations comprising the corresponding unmodified polymer had only a marginal or no effect. These results indicate drug carrier systems based on thiomers appear to be a promising tool for oral delivery of hydrophilic macromolecular drugs.

Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration

DEFF Research Database (Denmark)

Bruun, Susanne W.; Josefsen, Knud; Tanassi, Julia T

2016-01-01

secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally...

Human plasma metabolic profiles of benzydamine, a flavin-containing monooxygenase probe substrate, simulated with pharmacokinetic data from control and humanized-liver mice.

Science.gov (United States)

Yamazaki-Nishioka, Miho; Shimizu, Makiko; Suemizu, Hiroshi; Nishiwaki, Megumi; Mitsui, Marina; Yamazaki, Hiroshi

2018-02-01

1. Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir. 2. Following oral administration of benzydamine (10 mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine. In contrast, in control and ganciclovir-treated TK-NOG mice, concentrations of demethyl benzydamine were slightly higher than those of benzydamine N-oxide. 3. Simulations of human plasma concentrations of benzydamine and its N-oxide were achieved using simplified physiologically based pharmacokinetic models based on data from control TK-NOG mice and from reported benzydamine concentrations after low-dose administration in humans. Estimated clearance rates based on data from humanized-liver and ganciclovir-treated TK-NOG mice were two orders magnitude high. 4. The pharmacokinetic profiles of benzydamine were different for control and humanized-liver TK-NOG mice. Humanized-liver mice are generally accepted human models; however, drug oxidation in mouse kidney might need to be considered when probe substrates undergo FMO-dependent drug oxidation in mouse liver and kidney.

Effects of acute and chronic administration of neurosteroid dehydroepiandrosterone sulfate on neuronal excitability in mice

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Svob Strac D

2016-03-01

Full Text Available Dubravka Svob Strac,1 Josipa Vlainic,1 Janko Samardzic,2 Julija Erhardt,3 Zeljka Krsnik41Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia; 2Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade, Belgrade, Serbia; 3Department of Animal Physiology, Faculty of Science, University of Zagreb, 4Croatian Institute for Brain Research, Department of Neuroscience, School of Medicine, University of Zagreb, Zagreb, CroatiaBackground: Neurosteroid dehydroepiandrosterone sulfate (DHEAS has been associated with important brain functions, including neuronal survival, memory, and behavior, showing therapeutic potential in various neuropsychiatric and cognitive disorders. However, the antagonistic effects of DHEAS on γ-amino-butyric acidA receptors and its facilitatory action on glutamatergic neurotransmission might lead to enhanced brain excitability and seizures and thus limit DHEAS therapeutic applications. The aim of this study was to investigate possible age and sex differences in the neuronal excitability of the mice following acute and chronic DHEAS administration.Methods: DHEAS was administered intraperitoneally in male and female adult and old mice either acutely or repeatedly once daily for 4 weeks in a 10 mg/kg dose. To investigate the potential proconvulsant properties of DHEAS, we studied the effects of acute and chronic DHEAS treatment on picrotoxin-, pentylentetrazole-, and N-methyl-d-aspartate-induced seizures in mice. The effects of acute and chronic DHEAS administration on the locomotor activity, motor coordination, and body weight of the mice were also studied. We also investigated the effects of DHEAS treatment on [3H]flunitrazepam binding to the mouse brain membranes.Results: DHEAS did not modify the locomotor activity, motor coordination, body weight, and brain [3H]flunitrazepam binding of male and female mice. The results

The Effects of Fat-soluble Vitamin Administration on Plasma Vitamin Status of Nursing Pigs Differ When Provided by Oral Administration or Injection

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Y. D. Jang

2014-05-01

Full Text Available Four experiments were conducted to investigate the effect of fat-soluble vitamin administration to sows or newborn pigs on plasma vitamin status. In Exp. 1 and 2, a total of 24 and 43 newborn pigs were allotted to control and vitamin treatments (vitamin D3 with variable addition of vitamins A and E orally or by i.m. injection. In Exp. 3, pigs from Exp. 2 were allotted to 2 treatments (±vitamins D3 and E in drinking water for 14 d postweaning. In Exp. 4, twenty-four gestating sows were used for 2 treatments (±injection of a vitamin D3/A/E product 2 wk prepartum. In Exp. 1 and 2, when vitamin D3 was administrated orally or by i.m. injection on d 1 of age, pigs had increased plasma 25-hydroxycholecalciferol (25-OH D3 concentration 10 d after administration compared with control pigs (p<0.05. The injectable administration with vitamin D3 and E was able to achieve higher plasma 25-OH D3 (p<0.05 and α-tocopherol (p<0.05 concentrations than oral administration. At weaning, the pigs in the injection group had higher plasma 25-OH D3 concentration than those in the other groups in both studies (p<0.05. In Exp. 3, water supplementation of vitamin D3 and E postweaning increased plasma 25-OH D3 and α-tocopherol concentrations at d 14 postweaning (p<0.01. In Exp. 4, when sows were injected with the vitamin D3 product prepartum, serum 25-OH D3 concentrations of sows at farrowing (p<0.01, and in their progeny at birth (p<0.01 and weaning (p<0.05 were increased. These results demonstrated that fat-soluble vitamin administration to newborn pigs increased plasma 25-OH D3 concentration regardless of administration routes and α-tocopherol concentration by the injectable route, and that water supplementation of vitamin D3 and E to nursery pigs increased plasma 25-OH D3 and α-tocopherol concentrations. Additionally, injecting sows with vitamin D3 prepartum increased 25-OH D3 in sows and their offspring. If continued research demonstrates that the serum levels of

CAST/EiJ and C57BL/6J Mice Differ in Their Oral and Postoral Attraction to Glucose and Fructose.

Science.gov (United States)

Sclafani, Anthony; Vural, Austin S; Ackroff, Karen

2017-03-01

A recent study indicated that CAST/EiJ and C57BL/6J mice differ in their taste preferences for maltodextrin but display similar sucrose preferences. The present study revealed strain differences in preferences for the constituent sugars of sucrose. Whereas B6 mice preferred 8% glucose to 8% fructose in 2-day tests, the CAST mice preferred fructose to glucose. These preferences emerged with repeated testing which suggested post-oral influences. In a second experiment, 2-day choice tests were conducted with the sugars versus a sucralose + saccharin (SS) mixture which is highly preferred in brief access tests. B6 mice strongly preferred glucose but not fructose to the non-nutritive SS whereas CAST mice preferred SS to both glucose and fructose even when food restricted. This implied that CAST mice are insensitive to the postoral appetite stimulating actions of the 2 sugars. A third experiment revealed, however, that intragastric glucose and fructose infusions conditioned significant but mild flavor preferences in CAST mice, whereas in B6 mice glucose conditioned a robust preference but fructose was ineffective. Thus, unlike other mouse strains and rats, glucose is not more reinforcing than fructose in CAST mice. Their oral preference for fructose over glucose may be related to a subsensitive maltodextrin receptor or glucose-specific receptor which is stimulated by glucose but not fructose. The failure of CAST mice to prefer glucose to a non-nutritive sweetener distinguishes this strain from other mouse strains and rats. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Oral intake of beet extract provides protection against skin barrier impairment in hairless mice.

Science.gov (United States)

Kawano, Ken-Ichi; Umemura, Kazuo

2013-05-01

The epidermis acts as a functional barrier against the external environment. Disturbances in the function of this barrier cause water loss and increase the chances of penetration by various irritable stimuli, leading to skin diseases such as dry skin, atopic dermatitis, and psoriasis. Ceramides are a critical natural element of the protective epidermal barrier. The aim of this study was to evaluate whether the oral intake of beet (Beta vulgaris) extract, a natural product rich in glucosylceramide (GlcCer), may prevent disturbance in skin barrier function. When HR-1 hairless mice were fed a special diet (HR-AD), transepidermal water loss (TEWL) from the dorsal skin increased, with a compensatory increase in water intake after 5 weeks. Mice fed with HR-AD had dry skin with erythema and showed increased scratching behaviour. Histological examinations revealed a remarkable increase in the thickness of the skin at 8 weeks. Supplemental addition of beet extract, which contained GlcCer at a final concentration of 0.1%, significantly prevented an increase TEWL, water intake, cumulative scratching time, and epidermal thickness at 8 weeks. These results indicate that oral intake of beet extract shows potential for preventing skin diseases associated with impaired skin barrier function. Copyright © 2012 John Wiley & Sons, Ltd.

Subcutaneous or oral immunization of mice with Lactococcus lactis expressing F4 fimbrial adhesin FaeG.

Science.gov (United States)

Liu, Shujie; Li, Yongming; Xu, Ziwei; Wang, Yicheng

2013-01-01

Enterotoxigenic Escherichia coli (ETEC) is one of the most common causes of diarrhea in neonatal and postweaning piglets. Fimbrial adhesion of ETEC has been considered an important colonization factor with antigenicity. To safely and effectively deliver the F4 (K88) fimbrial adhesin FaeG to the immune system, we have previously constructed the secretory expression vector pNZ8112-faeG, and FaeG was produced in cytoplasmic form in Lactococcus lactis. In this work, BALB/c mice were immunized with recombinant L. lactis to further determine the immunogenicity of recombinant FaeG (rFaeG) via the subcutaneous or oral route. Subcutaneous immunization in mice with recombinant L. lactis induced a significant increase in the F4-specific serum IgG titer and the number of antibody-secreting cells (ASCs) in the spleen. Oral immunization of mice with recombinant L. lactis induced mucosal and systemic F4-specific immune responses and increased the number of ASCs in the spleen, mesenteric lymph nodes and Peyer's patches. High-dose (2.8 × 10(11) CFU) recombinant strains and adjuvant cholera toxin B subunit enhanced specific mucosal immune responses. The results suggest the feasibility of delivering rFaeG expressed in L. lactis to the immune system in order to induce an F4-specific immune response.

Enhanced self-administration of alcohol in muscarinic acetylcholine M₄ receptor knockout mice

DEFF Research Database (Denmark)

de la Cour, Cecilie; Sørensen, Gunnar; Wörtwein, Gitta

2015-01-01

% and 10% alcohol in 60min sessions, 6 days/week, after having undergone a standard sucrose fading training procedure on a fixed ratio schedule. The mice were further subjected to an extinction period followed by a 1 day reinstatement trial. M4-/- mice consumed more alcohol at 5% and 8% compared to their M......4+/+ littermates. The highest alcohol concentration used (10%) did not immediately result in divergent drinking patterns, but after 4 weeks of 10% alcohol self-administration, baseline levels as well as a pattern of M4-/- mice consuming more alcohol than their M4+/+ controls were re...

Dextran sodium sulfate (DSS induces necrotizing enterocolitis-like lesions in neonatal mice.

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Marco Ginzel

Full Text Available Necrotizing enterocolitis (NEC is an inflammatory bowel disease of preterm human newborns with yet unresolved etiology. An established neonatal murine model for NEC employs oral administration of lipopolysaccharides (LPS combined with hypoxia/hypothermia. In adult mice, feeding dextran sodium sulfate (DSS represents a well-established model for experimental inflammatory bowel disease. Here we investigated the effect of DSS administration on the neonatal murine intestine in comparison with the established NEC model.3-day-old C57BL/6J mice were either fed formula containing DSS or LPS. LPS treated animals were additionally stressed by hypoxia/hypothermia twice daily. After 72 h, mice were euthanized, their intestinal tissue harvested and analyzed by histology, qRT-PCR and flow cytometry. For comparison, adult C57BL/6J mice were fed with DSS for 8 days and examined likewise. Untreated, age matched animals served as controls.Adult mice treated with DSS exhibited colonic inflammation with significantly increased Cxcl2 mRNA expression. In contrast, tissue inflammation in neonatal mice treated with DSS or LPS plus hypoxia/hypothermia was present in colon and small intestine as well. Comparative analysis of neonatal mice revealed a significantly increased lesion size and intestinal Cxcl2 mRNA expression after DSS exposure. Whereas LPS administration mainly induced local neutrophil recruitment, DSS treated animals displayed increased monocytes/macrophages infiltration.Our study demonstrates the potential of DSS to induce NEC-like lesions accompanied by a significant humoral and cellular immune response in the small and large intestine of neonatal mice. The new model therefore represents a good alternative to LPS plus hypoxia/hypothermia administration requiring no additional physical stress.

Oral candidosis by Candida albicans in normal and xerostomic mice Candidose oral por Candida albicans em camundongos normais e xerostômicos

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Marilda Aparecida Gonçalves Totti

2004-09-01

Full Text Available The aim of this study was to analyze the effect of sialoadenectomy on the development of oral candidosis after one or four inoculations of Candida albicans. Initially, a suspension containing 10(8 cells/ml of C. albicans ATCC 36801 was prepared. Seventy-eight sialoadenectomized mice and a similar amount of mice with normal salivary flow received a single inoculation of C. albicans suspension. Another group with a similar number of mice received 4 inoculations. The control group consisted of 6 sialoadenectomized mice and 6 mice with normal salivary flow that were not inoculated with C. albicans. Candidosis development was studied histologically in the tongue of the animals 1, 2, 3, 5, and 8 days after inoculation and at 15-day intervals up to 165 days. According to the results obtained, it could be concluded that sialoadenectomy and a higher frequency of yeast inoculation influenced the presence and extension of candidosis lesions.O objetivo deste estudo foi analisar o efeito da sialoadenectomia sobre o desenvolvimento da candidose oral após uma ou quatro inoculações de Candida albicans. Inicialmente, uma suspensão contendo 10(8 células/ml de C. albicans ATCC 36801 foi preparada. Setenta e oito camundongos sialoadenectomizados e mesma quantidade de camundongos com fluxo salivar normal receberam uma única inoculação de suspensão de C. albicans. Outro grupo, com o mesmo número de camundongos, recebeu 4 inoculações. O grupo controle consistiu de 6 camundongos sialoadenectomizados e 6 com fluxo salivar normal que não foram inoculados com C. albicans. O desenvolvimento de candidose foi estudado histologicamente na língua dos animais em períodos de 1, 2, 3, 5 e 8 dias após a inoculação e em intervalos de 15 dias até 165 dias. De acordo com os resultados obtidos, conclui-se que a sialoadenectomia e uma maior freqüência de inoculação influenciaram na presença e extensão das lesões de candidose.

The Protective Effects of Oral Low-dose Quercetin on Diabetic Nephropathy in Hypercholesterolemic Mice

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Isabele Beserra Santos Gomes

2015-09-01

Full Text Available Aims: Diabetic nephropathy (DN is one of the major causes of end-stage renal disease, and the incidence of DN is increasing worldwide. Considering our previous report indicating that chronic treatment with oral low-dose quercetin (10 mg/Kg demonstrated renoprotective, anti-oxidative and anti-apoptotic effects in the C57BL/6J model of diabetic nephropathy, we investigated whether this flavonoid could also have beneficial effects in concurrent DN and spontaneous atherosclerosis using the apolipoprotein E-deficient mouse (apoE-/-. Methods: DN was induced by streptozotocin (100 mg/kg/day, for 3 days in adult apoE-/-mice. Six weeks later, the mice were divided into the following groups: diabetic apoE-/- mice treated with quercetin (DQ, 10 mg/kg/day, 4 weeks, diabetic ApoE-/- mice treated with vehicle (DV and non-treated non-diabetic (ND mice.Results: Quercetin treatment caused a reduction in polyuria (~30%, glycemia (~25%, abolished the hypertriglyceridemia and had significant effects on renal function, including decreased proteinuria (~15% and creatininemia (~30%, which were accompanied by beneficial effects on the renal structural changes, including normalization of the index of glomerulosclerosis and kidney weight.Conclusions: Our data revealed that quercetin treatment significantly reduced DN in hypercholesterolemic mice by inducing biochemical and morphological modifications. Thus, this translational study highlights the importance of quercetin as a potential nutraceutical for the management of DN, including in diabetes associated with dyslipidemia.

The route of administration (oral vs intravenous) does not influence dose or outcome in Graves' disease and unifocal autonomy

International Nuclear Information System (INIS)

Schneider, Peter; Biko, Johannes; Haenscheid, Heribert; Hilliger, Stephan; Koutsampelas, Christos; Kranzfelder, Michael; Ladner, Stephan; Reiners, Christoph

2005-01-01

In a prospective randomised study, we investigated the influence of the route of administration of radioiodide on dosimetry and therapy outcome. Fifty-four patients suffering from Graves' disease (GD) and 60 patients with unifocal autonomy (UA) participated in the study and were randomly treated with either orally or intravenously administered radioiodide. Pretherapeutic dosimetry was based on single uptake measurements with a calibrated uptake probe system. The radioiodine kinetics during hospitalisation was assessed by daily bedside uptake measurements. Therapeutic dose was determined by half-life and thyroid uptake at the time of discharge using the same uptake probe as for the radioiodine test. No improvement in accuracy of dosimetry was achieved when radioiodide was administered intravenously. Mean therapeutic doses were identical following intravenous or oral administration. Variation in the achieved dose was slightly higher in the patients receiving oral administration, this being attributable to larger deviations in discrete activities of the capsules administered as compared with the values determined by dosimetry. No differences according to treatment modality were found with regard to therapeutic outcome. Eighty-seven patients attended 6-month follow-up after therapy. In the UA group, successful treatment, defined as a normal or elevated TSH level, was observed in 94% of patients after oral administration and in 80% after intravenous administration; corresponding figures in the GD group were 68% and 65%. The causes of individual differences between targeted and therapeutically achieved doses remain undetermined. Variations in the bioavailability of radioiodide or other parameters affecting thyroid status may be involved, and further investigations are needed to clarify this. (orig.)

Non-invasive diagnosis of isolated chylopericardium using precordial pericardial imaging after oral administration of 131I-triolein

International Nuclear Information System (INIS)

Fujiseki, Yoshiki; Katsura, Tadahiko; Goto, Masakatsu; Kawanishi, Katsuyuki

1982-01-01

Chylopericardium is a rare disease and affects both sexes equally from neonate to adult. Usually, there are abnormal connections between the pericardial cavity and thoracic lymphatic systems. These connections are detected by (1) recovery of orally administered Sudan III from pericardial fluid, (2) evidence of radioactivity in the pericardial fluid by paracentesis after oral administration of 131 I-labeled triolein, and (3) lymphangiography. However, these method are technically difficult and invasive, thus sometimes dangerous for children. We employed precordial pericardial imaging after oral administration of 131 I-labeled triolein on a 9-year-old Japanese girl wth isolated chylopericardium before and after surgery. Abnormal connections and the back-ward flow to the pulmonary lymphatics were demonstrated by this method. This is an easy, non-invasive, reliable and safe method for detecting the abnormal connections of pericardial and lymphatic systems in children with chylopericardium. (author)

Effects of Hot Water Extracts from Polygonum multiflorum on Ovariectomy Induced Osteopenia in Mice

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Yun-Ho Hwang

2016-01-01

Full Text Available Polygonum multiflorum (PM, a traditional Chinese medicine, is used to treat various diseases including nonalcoholic fatty liver disease and hyperlipidemia. However, the influence of PM on osteoporosis in animals is unclear. The present study investigated the antiosteoporotic effect of PM on bone mass in ovariectomized (OVX mice and its possible mechanism of action. Twenty-five female C3H/HeN mice were divided into five groups of five mice as follows. Sham-operated control mice received daily oral gavage of an equal volume of water, and OVX mice received daily oral gavage of water or an injection of β-estradiol or PM for 6 weeks. Administration of PM significantly suppressed body weight and organs weight and increased weight and length of bone compared with the OVX group. Treatment with PM reversed osteopenia in OVX mice, thereby improving the bone morphometric parameters. Moreover, histological analysis using hematoxylin and eosin staining showed that PM inhibited OVX-induced bone loss. Serum estradiol and bone alkaline phosphatase levels were significantly decreased in the OVX group, with the levels increasing with PM treatment. In addition, tartrate-resistant acid phosphatase activity was inhibited by PM in OVX mice. These results suggest that PM is effective in preventing bone loss in OVX mice.

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice.

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Jackson, Kristy L; Dampney, Bruno W; Moretti, John-Luis; Stevenson, Emily R; Davern, Pamela J; Carrive, Pascal; Head, Geoffrey A

2016-05-01

BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system. Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (-16.1 ± 1.6 and -11.0 ± 1.1 mm Hg, respectively;PBPH/2J mice (PBPH/2J mice have 29% more orexin neurons than BPN/3J mice which are preferentially located in the lateral hypothalamus. The results suggest that enhanced orexinergic signaling contributes to sympathetic overactivity and hypertension during the dark period in BPH/2J mice. © 2016 American Heart Association, Inc.

Anxiolytic effects of orcinol glucoside and orcinol monohydrate in mice.

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Wang, Xiaohong; Li, Guiyun; Li, Peng; Huang, Linyuan; Huang, Jianmei; Zhai, Haifeng

2015-06-01

Anxiety is a common psychological disorder, often occurring in combination with depression, but therapeutic drugs with high efficacy and safety are lacking. Orcinol glucoside (OG) was recently found to have an antidepressive action. To study the therapeutic potential of OG and orcinol monohydrate (OM) as anxiolytic agents. Anxiolytic effects in mice were measured using the elevated plus-maze, hole-board, and open-field tests. Eight groups of mice were included in each test. Thirty minutes before each test, mice in each group received one oral administration of OG (5, 10, or 20 mg/kg), OM (2.5, 5, or 10 mg/kg), the positive control diazepam (1 or 5 mg/kg), or control vehicle. Each mouse underwent only one test. Uptake of orcinol (5 mg/kg) in the brain was qualitatively detected using the HPLC-MS method. OG (5, 10, and 20 mg/kg) and OM (2.5 and 5 mg/kg) increased the time spent in open arms and the number of entries into open arms in the elevated plus-maze test. OG (5 and 10 mg/kg) and OM (2.5 and 5 mg/kg) increased the number of head-dips in the hole-board test. At all tested doses, OG and OM did not significantly affect the locomotion of mice in the open-field test. Orcinol could be detected in the mouse brain homogenates 30 min after oral OM administration, having confirmed that OM is centrally active. The results demonstrated that OG and OM are anxiolytic agents without sedative effects, indicating their therapeutic potential for anxiety.

Administrative Challenges to the Integration of Oral Health With Primary Care: A SWOT Analysis of Health Care Executives at Federally Qualified Health Centers.

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Norwood, Connor W; Maxey, Hannah L; Randolph, Courtney; Gano, Laura; Kochhar, Komal

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

Microbiota-Derived Metabolic Factors Reduce Campylobacteriosis in Mice.

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Sun, Xiaolun; Winglee, Kathryn; Gharaibeh, Raad Z; Gauthier, Josee; He, Zhen; Tripathi, Prabhanshu; Avram, Dorina; Bruner, Steven; Fodor, Anthony; Jobin, Christian

2018-05-01

Campylobacter jejuni, a prevalent foodborne bacterial pathogen, exploits the host innate response to induce colitis. Little is known about the roles of microbiota in C jejuni-induced intestinal inflammation. We investigated interactions between microbiota and intestinal cells during C jejuni infection of mice. Germ-free C57BL/6 Il10 -/- mice were colonized with conventional microbiota and infected with a single dose of C jejuni (10 9 colony-forming units/mouse) via gavage. Conventional microbiota were cultured under aerobic, microaerobic, or anaerobic conditions and orally transplanted into germ-free Il10 -/- mice. Colon tissues were collected from mice and analyzed by histology, real-time polymerase chain reaction, and immunoblotting. Fecal microbiota and bile acids were analyzed with 16S sequencing and high-performance liquid chromatography with mass spectrometry, respectively. Introduction of conventional microbiota reduced C jejuni-induced colitis in previously germ-free Il10 -/- mice, independent of fecal load of C jejuni, accompanied by reduced activation of mammalian target of rapamycin. Microbiota transplantation and 16S ribosomal DNA sequencing experiments showed that Clostridium XI, Bifidobacterium, and Lactobacillus were enriched in fecal samples from mice colonized with microbiota cultured in anaerobic conditions (which reduce colitis) compared with mice fed microbiota cultured under aerobic conditions (susceptible to colitis). Oral administration to mice of microbiota-derived secondary bile acid sodium deoxycholate, but not ursodeoxycholic acid or lithocholic acid, reduced C jejuni-induced colitis. Depletion of secondary bile acid-producing bacteria with antibiotics that kill anaerobic bacteria (clindamycin) promoted C jejuni-induced colitis in specific pathogen-free Il10 -/- mice compared with the nonspecific antibiotic nalidixic acid; colitis induction by antibiotics was associated with reduced level of luminal deoxycholate. We identified a

TRANSDERMAL ADMINISTRATION OF THE DOPAMINE AGONIST N-0437 AND 7 ESTER PRODRUGS - COMPARISON WITH ORAL-ADMINISTRATION IN THE 6-OHDA TURNING MODEL

NARCIS (Netherlands)

DENDAAS, [No Value; TEPPER, PG; ROLLEMA, H; HORN, AS

1990-01-01

The potent and selective D2-agonist N-0437 [2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin] undergoes considerable first-pass metabolism after oral administration due to glucuronidation of the phenolic group. In an attempt to improve its bioavailability, seven ester prodrugs of N-0437 were

Oral administration of fisetin promotes the induction of hippocampal long-term potentiation in vivo.

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He, Wen-Bin; Abe, Kazuho; Akaishi, Tatsuhiro

2018-01-01

To explore memory enhancing effect of the flavonoid fisetin, we investigated the effect of oral administration of flavonoids on the induction of long-term potentiation (LTP) at hippocampal CA1 synapses of anesthetized rats. Among four flavonoids (fisetin, quercetin, luteolin and myricetin) tested, only fisetin significantly facilitated the induction of hippocampal LTP. The effect of oral fisetin was abolished by intracerebroventricular injection of U0126, an agent that was previously found to inhibit its effect in hippocampal slices in vitro. These results suggest that orally administered fisetin crosses the blood-brain barrier and promotes synaptic functions in the hippocampus. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

APOA-1Milano muteins, orally delivered via genetically modified rice, show anti-atherogenic and anti-inflammatory properties in vitro and in Apoe-/- atherosclerotic mice.

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Romano, Gabriele; Reggi, Serena; Kutryb-Zajac, Barbara; Facoetti, Amanda; Chisci, Elisa; Pettinato, Mariateresa; Giuffrè, Maria Rita; Vecchio, Federica; Leoni, Silvia; De Giorgi, Marco; Avezza, Federica; Cadamuro, Massimiliano; Crippa, Luca; Leone, Biagio Eugenio; Lavitrano, Marialuisa; Rivolta, Ilaria; Barisani, Donatella; Smolenski, Ryszard Tomasz; Giovannoni, Roberto

2018-06-11

Atherosclerosis is a slowly progressing, chronic multifactorial disease characterized by the accumulation of lipids, inflammatory cells, and fibrous tissue that drives to the formation of asymmetric focal thickenings in the tunica intima of large and mid-sized arteries. Despite the high therapeutic potential of ApoA-1 proteins, the purification and delivery into the disordered organisms of these drugs is still limited by low efficiency in these processes. We report here a novel production and delivery system of anti-atherogenic APOA-1Milano muteins (APOA-1M) by means of genetically modified rice plants. APOA-1M, delivered as protein extracts from transgenic rice seeds, significantly reduced macrophage activation and foam cell formation in vitro in oxLDL-loaded THP-1 model. The APOA-1M delivery method and therapeutic efficacy was tested in healthy mice and in Apoe -/- mice fed with high cholesterol diet (Western Diet, WD). APOA-1M rice milk significantly reduced atherosclerotic plaque size and lipids composition in aortic sinus and aortic arch of WD-fed Apoe -/- mice as compared to wild type rice milk-treated, WD-fed Apoe -/- mice. APOA-1M rice milk also significantly reduced macrophage number in liver of WD-fed Apoe -/- mice as compared to WT rice milk treated mice. The delivery of therapeutic APOA-1M full length proteins via oral administration of rice seeds protein extracts (the 'rice milk') to the disordered organism, without any need of purification, might overcome the main APOA1-based therapies' limitations and improve the use of this molecules as therapeutic agents for cardiovascular patients. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

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

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Harigae T

2016-06-01

Full Text Available Takahiro Harigae,1 Kiyotaka Nakagawa,1 Taiki Miyazawa,2 Nao Inoue,3 Fumiko Kimura,1 Ikuo Ikeda,3 Teruo Miyazawa4,5 1Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; 2Vascular Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA; 3Laboratory of Food and Biomolecular Science, Graduate School of Agricultural Science, 4Food and Biotechnology Innovation Project, New Industry Creation Hatchery Center, 5Food and Health Science Research Unit, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan 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

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

Science.gov (United States)

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. © 2015 John Wiley & Sons Ltd.

Toxicity of Parasporin-4 and Health Effects of Pro-parasporin-4 Diet in Mice

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Shiro Okumura

2014-07-01

Full Text Available Parasporin-4 (PS4 is an aerolysin-type β-pore-forming toxin produced by Bacillus thuringiensis strain A1470. It exhibits specific cytotoxicity against human cancer cell lines; therefore, it is expected to be useful for the diagnosis and treatment of particular types of cancer cells. We examined the acute toxicity of PS4 on ICR mice. The LD50 value was 160 μg/kg by a subcutaneous route. Potassium, ammonium, magnesium ion, creatinine, and urea nitrogen decreased in urine by the injection of PS4. Simultaneously, creatinine and urea nitrogen in mice serum increased. These results imply that PS4 impairs kidney function in mice. PS4 is obtained from Pro-parasporin-4 (ProPS4 by processing, and ProPS4 is produced by recombinant Escherichia coli as the inclusion body. The inclusion body of ProPS4 can be solubilized in a weak acid solution and activated by pepsin, implying that it would be solubilized and activated in the stomach of mammals after oral administration. Thus, the influence of the oral administration of it by C57BL/6J mice was examined. Although ProPS4 was activated to PS4 in the mouse digestive tract, any serious health hazard was not observed and there was no significant difference in body weight change.

Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice

Energy Technology Data Exchange (ETDEWEB)

Li, Yuan-Yuan; Yu, Li-Fang; Zhang, Li-Na; Qiu, Bei-Ying; Su, Ming-Bo; Wu, Fang; Chen, Da-Kai; Pang, Tao; Gu, Min; Zhang, Wei; Ma, Wei-Ping; Jiang, Hao-Wen; Li, Jing-Ya, E-mail: jyli@mail.shcnc.ac.cn; Nan, Fa-Jun, E-mail: fjnan@mail.shcnc.ac.cn; Li, Jia, E-mail: jli@mail.shcnc.ac.cn

2013-12-01

AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK α subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. - Highlights: • C24 activates AMPK through antagonizing autoinhibition within α subunit. • C24 activates AMPK in hepatocytes and decreases glucose output via AMPK. • C24 exerts beneficial effects on diabetic db/db mice. • C24 represents a novel therapeutic for treatment of metabolic syndrome.

Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice

International Nuclear Information System (INIS)

Li, Yuan-Yuan; Yu, Li-Fang; Zhang, Li-Na; Qiu, Bei-Ying; Su, Ming-Bo; Wu, Fang; Chen, Da-Kai; Pang, Tao; Gu, Min; Zhang, Wei; Ma, Wei-Ping; Jiang, Hao-Wen; Li, Jing-Ya; Nan, Fa-Jun; Li, Jia

2013-01-01

AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK α subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. - Highlights: • C24 activates AMPK through antagonizing autoinhibition within α subunit. • C24 activates AMPK in hepatocytes and decreases glucose output via AMPK. • C24 exerts beneficial effects on diabetic db/db mice. • C24 represents a novel therapeutic for treatment of metabolic syndrome

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

Directory of Open Access Journals (Sweden)

Giuseppe Benagiano

2009-04-01

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

[Zaocys type II collagen regulates mesenteric lymph node Treg/Th17 cell balance in mice with collagen-induced arthritis].

Science.gov (United States)

Wang, Hao; Feng, Zhitao; Zhu, Junqing; Li, Juan

2014-05-01

To investigate the effect of oral administration of Zaocys type II collagen (ZCII) on the percentages of Treg/Th17 cells in mesenteric lymph node lymphocytes (MLNLs) in mice with collagen-induced arthritis (CIA). CIA was induced in male C57BL/6 mice by immunization with chicken type II collagen. Three weeks later, ZCII, purified by pepsin digestion, was orally administered in the mice for 7 consecutive days (daily dose of 10, 20, or 40 µg/kg). The severity of arthritis in each limb was evaluated using a macroscopic scoring system, and histopathological changes of the joint were observed microscopically with HE staining. The percentages of Treg and Th17 cells in MLNLs was detected by flow cytometry, and the levels of transforming growth factor-β (TGF-β) and interleukin-17 (IL-17) in the supernatant of MLNLs were measured by enzyme-linked immunosorbent assay. Compared with normal control mice, the mice with CIA had significantly higher scores for arthritis and histopathological changes, with also significantly increased percentages of Treg and Th17 cells in MLNLs and elevated levels of TGF-β and IL-17 in MLNL supernatant (P<0.05). In ZCII peptide-treated mice, the scores for arthritis and histopathological changes were significantly lower than those in CIA model group (P<0.05), and Treg cell percentage in MLNLs was up-regulated while Th17 cell percentage lowered; the level of TGF-β was increased but IL-17 was decreased significantly (P<0.05). Oral administration of ZCII improves CIA in mice by regulating the percentages of Treg/Th17 cells and the cytokine levels in MLNLs, suggesting the value of ZCII as a promising candidate agent for treatment of rheumatoid arthritis.

N-acetylglucosamine increases symptoms and fungal burden in a murine model of oral candidiasis.

Science.gov (United States)

Ishijima, Sanae A; Hayama, Kazumi; Takahashi, Miki; Holmes, Ann R; Cannon, Richard D; Abe, Shigeru

2012-04-01

The amino sugar N-acetylglucosamine (GlcNAc) is an in vitro inducer of the hyphal mode of growth of the opportunistic pathogen Candida albicans. The development of hyphae by C. albicans is considered to contribute to the pathogenesis of mucosal oral candidiasis. GlcNAc is also a commonly used nutritional supplement for the self-treatment of conditions such as arthritis. To date, no study has investigated whether ingestion of GlcNAc has an effect on the in vivo growth of C. albicans or the pathogenesis of a C. albicans infection. Using a murine model of oral candidiasis, we have found that administration of GlcNAc, but not glucose, increased oral symptoms of candidiasis and fungal burden. Groups of mice were given GlcNAc in either water or in a viscous carrier, i.e., 1% methylcellulose. There was a dose-dependent relationship between GlcNAc concentration and the severity of oral symptoms. Mice given the highest dose of GlcNAc, 45.2 mM, also showed a significant increase in fungal burden, and increased histological evidence of infection compared to controls given water alone. We propose that ingestion of GlcNAc, as a nutritional supplement, may have an impact on oral health in people susceptible to oral candidiasis.

An oral Na(V)1.8 blocker improves motor function in mice completely deficient of myelin protein P-0

DEFF Research Database (Denmark)

Rosberg, Mette R.; Alvarez Herrero, Susana; Krarup, Christian

2016-01-01

Mice deficient of myelin protein P0 are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Dysmyelination in these mice is associated with an ectopic expression of the sensory neuron specific sodium channel isoform NaV1.8 on motor axons. We reported that in P0+/−, a model of CMT......1B, the membrane dysfunction could be acutely improved by a novel oral NaV1.8 blocker referred to as Compound 31 (C31, Bioorg. Med. Chem. Lett. 2010, 20, 6812; AbbVie Inc.). The aim of this study was to investigate the extent to which C31 treatment could also improve the motor axon function in P0......-of-concept that treatment with oral subtype-selective NaV1.8 blockers could be used to improve the motor function in severe forms of demyelinating CMT....

Sugar-induced cephalic-phase insulin release is mediated by a T1r2+T1r3-independent taste transduction pathway in mice.

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Glendinning, John I; Stano, Sarah; Holter, Marlena; Azenkot, Tali; Goldman, Olivia; Margolskee, Robert F; Vasselli, Joseph R; Sclafani, Anthony

2015-09-01

Sensory stimulation from foods elicits cephalic phase responses, which facilitate digestion and nutrient assimilation. One such response, cephalic-phase insulin release (CPIR), enhances glucose tolerance. Little is known about the chemosensory mechanisms that activate CPIR. We studied the contribution of the sweet taste receptor (T1r2+T1r3) to sugar-induced CPIR in C57BL/6 (B6) and T1r3 knockout (KO) mice. First, we measured insulin release and glucose tolerance following oral (i.e., normal ingestion) or intragastric (IG) administration of 2.8 M glucose. Both groups of mice exhibited a CPIR following oral but not IG administration, and this CPIR improved glucose tolerance. Second, we examined the specificity of CPIR. Both mouse groups exhibited a CPIR following oral administration of 1 M glucose and 1 M sucrose but not 1 M fructose or water alone. Third, we studied behavioral attraction to the same three sugar solutions in short-term acceptability tests. B6 mice licked more avidly for the sugar solutions than for water, whereas T1r3 KO mice licked no more for the sugar solutions than for water. Finally, we examined chorda tympani (CT) nerve responses to each of the sugars. Both mouse groups exhibited CT nerve responses to the sugars, although those of B6 mice were stronger. We propose that mice possess two taste transduction pathways for sugars. One mediates behavioral attraction to sugars and requires an intact T1r2+T1r3. The other mediates CPIR but does not require an intact T1r2+T1r3. If the latter taste transduction pathway exists in humans, it should provide opportunities for the development of new treatments for controlling blood sugar. Copyright © 2015 the American Physiological Society.

Tissue and subcellular localizations of 3H-cyclosporine A in mice

International Nuclear Information System (INIS)

Baeckman, L.; Brandt, I.; Appelkvist, E.-L.; Dallner, G.

1988-01-01

The tissue and subcellular localizations of 3 H-cyclosporine A after administration to mice were determined with whole-body autoradiography and scintillation counting of lipid extracts of tissues and subcellular fractions. The radioactivity was widely distributed in the body and the pattern of distribution after oral or parenteral administration was the same, except that tissue levels were generatlly lower after oral administration. Pretreatment of the animals with a diet containing cyclosporine A for 30 days before the injection of radioactive cyclosporine A did not change the pattern of distribution substantially. No significant radioactivity was found in the central nervous system, except for the choroidal plexus and the area postrema region of the brain. In pregnant mice no passage of radioactivity from the placentas to fetuses was observed after a single injection. 3 H-cyclosporine A and/or its metabolites showed a high affinity for the lympho-myeloid tissues, with a marked long-term retention in bone marrow and lymph nodes. There was massive excretion in the intestinal tract after parenteral administration, and the liver, bile, pancreas and salivary glands contained high levels of radioactivity. In the kidney radioactivity was confined to the outer zone of the outer kidney medulla. In liver homogenates no quantitatively significant binding of 3 H-cyclosporine A and/or its metabolites to cellular molecules such as proteins, DNA, phospho- or neutral lipids was found. After lipid extraction with organic solvents, almost all radioactivity was recovered in the organic phase. (author)

Cognitive and behavioural effects induced by social stress plus MDMA administration in mice.

Science.gov (United States)

García-Pardo, M P; Roger-Sánchez, C; Rodríguez-Arias, M; Miñarro, J; Aguilar, M A

2017-02-15

Adverse life experiences such as social stress may make an individual more vulnerable to drug addiction and mental disorders associated with drug consumption. The present work aimed to evaluate the effects of stress induced by acute social defeat combined with the administration of 3,4-methylenedioxymethamphetamine (MDMA) on depression-like behaviour, memory function and motor response to drug in late adolescent male mice. Two groups of mice were exposed to social defeat (SD) during four encounters with an aggressive co-specific, which took place on alternate days. Immediately after defeat, animals were treated with saline or MDMA 10mg/kg (SD+SAL and SD+MDMA). In control groups, mice were placed in a neutral cage without an opponent (Control+SAL, Control+MDMA). Corticosterone levels and temperature were measured on the last day of this phase. During the following days, the behaviour of the animals was evaluated in the tail suspension test (an animal model of depression), memory tasks (passive avoidance and object recognition) and, after administration of 5mg/kg of MDMA, in the open-field test. Exposure of adult mice to acute social defeat plus MDMA increased immobility in the tail suspension test (depression-like behaviour), produced cognitive impairment, and reduced the motor response to MDMA. An increase in corticosterone levels and a decrease of temperature were also observed. As hypothesised, a combination of social stress and consumption of MDMA increases the risk of developing mental and cognitive disorders. Our results support the idea that stress is a common contributing factor to the high rate of comorbidity between substance abuse and mental disease. Copyright © 2016 Elsevier B.V. All rights reserved.

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