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Sample records for orally administered inhibitor

  1. Phase I and pharmacokinetic study of XR11576, an oral topoisomerase I and II inhibitor, administered on days 1-5 of a 3-weekly cycle in patients with advanced solid tumours

    NARCIS (Netherlands)

    M.J.A. de Jonge (Maja); S.B. Kaye (Stan); J. Verweij (Jaap); C. Brock (C.); S. Reade (Sarah); M. Scurr (M.); L. van Doorn (Leni); C. Verheij (Coleta); W.J. Loos (Walter); C. Brindley (C.); H.D. Mistry; M. Cooper (Meghan); I.R. Judson (Ian)

    2004-01-01

    textabstractXR11576 is an oral topoisomerase I and II inhibitor. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR11576 when administered orally on days 1-5 every 3 w

  2. Phase I and pharmacokinetic study of XR11576, an oral topoisomerase I and II inhibitor, administered on days 1-5 of a 3-weekly cycle in patients with advanced solid tumours

    NARCIS (Netherlands)

    M.J.A. de Jonge (Maja); S.B. Kaye (Stan); J. Verweij (Jaap); C. Brock (C.); S. Reade (Sarah); M. Scurr (M.); L. van Doorn (Leni); C. Verheij (Coleta); W.J. Loos (Walter); C. Brindley (C.); H.D. Mistry; M. Cooper (Meghan); I.R. Judson (Ian)

    2004-01-01

    textabstractXR11576 is an oral topoisomerase I and II inhibitor. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR11576 when administered orally on days 1-5 every 3 w

  3. Contraceptive Efficacy of Oral and Transdermal Hormones When Co-Administered With Protease Inhibitors in HIV-1–Infected Women: Pharmacokinetic Results of ACTG Trial A5188

    Science.gov (United States)

    Vogler, Mary A.; Patterson, Kristine; Kamemoto, Lori; Park, Jeong-Gun; Watts, Heather; Aweeka, Francesca; Klingman, Karin L.; Cohn, Susan E.

    2014-01-01

    Background Pharmacokinetic (PK) interactions between lopinavir/ritonavir (LPV/r) and transdermally delivered ethinyl estradiol (EE) and norelgestromin (NGMN) are unknown. Methods Using a standard noncompartmental PK analysis, we compared EE area under the time–concentration curve (AUC) and NGMN AUC during transdermal contraceptive patch administration in HIV-1–infected women on stable LPV/r to a control group of women not on highly active antiretroviral therapy (HAART). In addition, EE AUC after a single dose of a combination oral contraceptive pill including EE and norethindrone was measured before patch placement and was compared with patch EE AUC in both groups. Contraceptive effects on LPV/r PKs were estimated by measuring LPV/r AUC at baseline and during week 3 of patch administration. Results Eight women on LPV/r, and 24 women in the control group were enrolled. Patch EE median AUC0–168 h was 45% lower at 6010.36 pg·h·mL−1 in those on LPV/r versus 10911.42 pg·h·mL−1 in those on no HAART (P = 0.064). Pill EE median AUC0–48 hours was similarly 55% lower at 344.67 pg·h·mL−1 in those on LPV/r versus 765.38 pg·h·mL−1 in those on no HAART (P = 0.003). Patch NGMN AUC0–168 h however, was 138.39 ng·h·mL−1, 83% higher in the LPV/r group compared with the control AUC of 75.63 ng·h·mL−1 (P = 0.036). After 3 weeks on the patch, LPVAUC0–8 h decreased by 19%, (P = 0.156). Conclusions Although PKs of contraceptive EE and NGMN are significantly altered with LPV/r, the contraceptive efficacy of the patch is likely to be maintained. Larger studies are indicated to fully assess contraceptive efficacy versus risks of the transdermal contraceptive patch when co-administered with protease inhibitors. PMID:20842042

  4. Urinary metabolites of daidzin orally administered in rats.

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    Yasuda, T; Ohsawa, K

    1998-09-01

    In a study on the metabolism of flavonoids, the isoflavone glycoside daidzin was orally administered to rats. Urine samples were collected and treated with beta-glucuronidase and arylsulfatase. Aglycone daidzein (M3) and other three metabolites, 3',4',7-trihydroxyisoflavone (M1), 4',7-dihydroxyisoflavanone (M2) and 4',7-dihydroxyisoflavan (M4) were isolated from the urine following treatment with enzymes. The structures of M1, M2 and M4 were determined on the basis of chemical and spectral data.

  5. Human metabolism of orally administered radioactive cobalt chloride.

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    Holstein, H; Ranebo, Y; Rääf, C L

    2015-05-01

    This study investigated the human gastrointestinal uptake (f1) and subsequent whole-body retention of orally administered inorganic radioactive cobalt. Of eight adult volunteers aged between 24 and 68 years, seven were given solutions of (57)Co (T1/2 = 272 d) containing a stable cobalt carrier, and six were given carrier-free (58)Co (T1/2 = 71 d). The administered activities ranged between 25 and 103 kBq. The observed mean f1, based on 6 days accumulated urinary excretion sampling and whole-body counting, was 0.028 ± 0.0048 for carrier-free (58)Co, and 0.016 ± 0.0021 for carrier-associated (57)Co. These values were in reasonable agreement with values reported from previous studies involving a single intake of inorganic cobalt. The time pattern of the total retention (including residual cobalt in the GI tract) included a short-term component with a biological half-time of 0.71 ± 0.03 d (average ± 1 standard error of the mean for the two nuclides), an intermediate component with a mean half-time of 32 ± 8.5 d, and a long-term component (observed in two volunteers) with half-times ranging from 80 to 720 d for the two isotopes. From the present data we conclude that for the short-lived (57)Co and (58)Co, more than 95% of the internal absorbed dose was delivered within 7 days following oral intake, with a high individual variation influenced by the transit time of the unabsorbed cobalt through the gastro-intestinal tract. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Toxicity and biodistribution of orally administered casein nanoparticles.

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    Gil, Ana Gloria; Irache, Juan Manuel; Peñuelas, Iván; González Navarro, Carlos Javier; López de Cerain, Adela

    2017-08-01

    In the last years, casein nanoparticles have been proposed as carriers for the oral delivery of biologically active compounds. However, till now, no information about their possible specific hazards in vivo was available. The aim of this work was to assess the safety of casein nanoparticles when administered orally to animals through a 90 days dose-repeated toxicity study (OECD guideline 408), that was performed in Wistar rats under GLP conditions. After 90 days, no evidences of significant alterations in animals treated daily with 50, 150 or 500 mg/kg bw of nanoparticles were found. This safety agrees well with the fact that nanoparticles were not absorbed and remained within the gut as observed by radiolabelling in the biodistribution study. After 28 days, there was a generalized hyperchloremia in males and females treated with the highest dose of 500 mg/kg bw, that was coupled with hypernatremia in the females. These effects were related to the presence of mannitol which was used as excipient in the formulation of casein nanoparticles. According to these results, the No Observed Adverse Effect Level (NOAEL) could be established in 150 mg/kg bw/day and the Lowest Observed Effect Level (LOEL) could be established in 500 mg/kg bw/day. Copyright © 2017. Published by Elsevier Ltd.

  7. Bioequivalence in dogs of a meloxicam formulation administered as a transmucosal oral mist with an orally administered pioneer suspension product.

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    Lees, P; Cheng, Z; Keefe, T J; Weich, E; Bryd, J; Cedergren, R; Cozzi, E

    2013-02-01

    A mucosal mist formulation of meloxicam, administered as a spray into the mouth (test article), was compared for bioequivalence to a pioneer meloxicam suspension for oral administration (reference article). Pharmacokinetic profiles and average bioequivalence were investigated in 20 dogs. The study design comprised a two-period, two-sequence, two-treatment cross-over design, with maximum concentration (C(max)) and area under plasma concentration-time curve to last sampling time (AUC(last)) used as pivotal bioequivalence variables. Bioequivalence of the products was confirmed, based on relative ratios of geometric mean concentrations (and 90% confidence intervals within the range 0.80-1.25) for C(max) of 101.9 (97.99-106.0) and for AUC(last) of 97.24 (94.44-100.1). The initial absorption of meloxicam was more rapid for the test article, despite virtually identical C(max) values for the two products. Mean elimination half-lives were 29.6 h (test article) and 30.0 h (reference article). The meloxicam plasma concentration-time profiles were considered in relation to published data on the inhibition of the cyclooxygenase-1 (COX-1) and COX-2 isoenzymes by meloxicam.

  8. Effects of orally self-administered bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice.

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    Gannon, Brenda M; Russell, Lauren N; Modi, Meet S; Rice, Kenner C; Fantegrossi, William E

    2017-10-01

    Synthetic cathinones in bath salts products are psychostimulant drugs of abuse, and 3,4-methylenedioxypyrovalerone (MDPV) is a common constituent of these products. Oral MDPV has been show to stimulate locomotor activity but reinforcing, locomotor and appetitive stimulus effects of oral MDPV are unknown. Choice procedures evaluated preference for 0.03, 0.10, 0.30, and 1.00mg/mL MDPV solutions versus 0.10mg/mL quinine solution or water. To verify that oral MDPV produced pharmacological effects, locomotor activity was monitored during and after consumption of water, quinine, or MDPV solutions. Conditioned place preference (CPP) tested the apparent appetitive effects of a preferred concentration of oral MDPV with locomotor stimulant effects (0.30mg/mL), using water as a control, and compared with results from intraperitoneally-administered MDPV. Consumption of MDPV solutions (0.03-1.00mg/mL) was low when the alternative fluid was water, but a history of MDPV consumption increased MDPV choice. When paired with a quinine control solution, MDPV solutions (0.03-0.30mg/mL) were almost exclusively preferred, and treatment with the catecholamine synthesis inhibitor αMPT decreased MDPV choice. Consumption of MDPV concentrations (0.1-1.0mg/mL) stimulated locomotor activity. Chronic (10day) access to 0.30mg/mL MDPV resulted in escalated consumption, but locomotor effects did not systematically change across the access period. Finally, consumption of 0.30mg/mL MDPV elicited CPP with a magnitude similar to the preference observed following intraperitoneal administration of MDPV. Consistent with human abuse patterns, oral MDPV has reinforcing effects in the mouse which are most likely related to its psychostimulant-like pharmacological profile. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Therapeutic effect of orally administered microencapsulated oxaliplatin for colorectal cancer.

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    Urbanska, Aleksandra M; Karagiannis, Emmanouil D; Guajardo, Gonzalo; Langer, Robert S; Anderson, Daniel G

    2012-06-01

    Colorectal cancer is a significant source of morbidity and mortality in the United States and other Western countries. Oral delivery of therapeutics remains the most patient accepted form of medication. The development of an oral delivery formulation for local delivery of chemotherapeutics in the gastrointestinal tract can potentially alleviate the adverse side effects including systemic cytotoxicity, as well as focus therapy to the lesions. Here we develop an oral formulation of the chemotherapeutic drug oxaliplatin for the treatment of colorectal cancer. Oxaliplatin was encapsulated in pH sensitive, mucoadhesive chitosan-coated alginate microspheres. The microparticles were formulated to release the chemotherapeutics after passing through the acidic gastric environment thus targeting the intestinal tract. In vivo, these particles substantially reduced the tumor burden in an orthotopic mouse model of colorectal cancer, and reduced mortality.

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

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    Yaron, A; Samoiloff, V; Benzioni, A

    1982-03-01

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

  11. MRI of colorectal cancer liver metastases: comparison of orally administered manganese with intravenously administered gadobenate dimeglumine

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    Brismar, Torkel B.; Kartalis, Nikolaos; Albiin, Nils [Karolinska Institutet, Division of Medical Imaging and Technology, Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden); Kylander, Christian [Karolinska Institutet, Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden)

    2012-03-15

    To compare the sensitivity of MRI to detect colorectal cancer liver metastases (CRLM) after ingestion of manganese-based contrast agent (CMC-001) with that of a comprehensive intravenous gadobenate dimeglumine protocol, and to assess the safety and acceptability of oral manganese. 20 patients suspected of having 1-6 CRLM were included prospectively in this randomised cross-over study. Liver MRI was performed with a one-week interval at 1.5 T and included T1-w VIBE and T2-HASTE, before and after administration of 1.6 g CMC-001 or 0.1 mmol/kg gadobenate dimeglumine. The metastasis-to-liver signal intensity (SI) ratio was calculated. Standard of reference was histopathology after surgery, or combination of other imaging studies and/or follow up. Adverse events (AE) and clinicolaboratory tests were monitored. Of 44 metastases, 41 were detected after CMC-001 (93%) and 42 after gadobenate dimeglumine (95%). Fifteen false-positive lesions were found after CMC-001 and 2 after gadobenate dimeglumine. The metastasis-to-liver SI ratio was significantly higher after CMC-001 than after gadobenate dimeglumine (0.51 and 0.21 respectively, P < 0.0001). More AE occurred after manganese compared to gadobenate dimeglumine. CMC-001 is as sensitive as an extensive intravenous gadobenate dimeglumine protocol in detecting CRLM. It was relatively well tolerated but had higher rates of gastrointestinal AE. (orig.)

  12. Techniques to administer oral, inhalational, and IV sedation in dentistry

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    Diana Krystyna Harbuz

    2016-02-01

    Full Text Available Background Sedation in dentistry is a controversial topic given the variety of opinions regarding its safe practice. Aims This article evaluates the various techniques used to administer sedation in dentistry and specific methods practiced to form a recommendation for clinicians. Methods An extensive literature search was performed using PubMed, Medline, Google Scholar, Google, and local library resources. Results Most of the literature revealed a consensus that light sedation on low-risk American Society of Anesthesiologists (ASA groups, that is ASA I, and possibly II, is the safest method for sedation in a dental outpatient setting. Conclusion Formal training is essential to achieve the safe practice of sedation in dentistry or medicine. The appropriate setting for sedation should be determined as there is an increased risk outside the hospital setting. Patients should be adequately assessed and medication titrated appropriately, based on individual requirements.

  13. Disposition of flunixin meglumine injectable preparation administered orally to healthy horses.

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    Pellegrini-Masini, A; Poppenga, R H; Sweeney, R W

    2004-06-01

    An injectable preparation of flunixin meglumine was administered orally and intravenously at a dose of 1.1 mg/kg to six healthy adult horses in a cross-over design. Flunixin meglumine was detected in plasma within 15 min of administration and peak plasma concentrations were observed 45-60 min after oral administration. Mean bioavailability of the oral drug was 71.9 +/- 26.0%, with an absorption half-life of 0.76 h. The apparent elimination half-life after oral administration was 2.4 h. The injectable preparation of flunixin meglumine is suitable for oral administration to horses.

  14. Penetration of orally administered prulifloxacin into human prostate tissue.

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    Giberti, Claudio; Gallo, Fabrizio; Rosignoli, Maria T; Ruggieri, Alessandro; Barattè, Simona; Picollo, Rossella; Dionisio, Paolo

    2009-01-01

    Prulifloxacin, a fluoroquinolone antibacterial agent, may be a useful addition to the antimicrobial armamentarium against prostatitis once the ability of its active metabolite, ulifloxacin, to penetrate prostatic tissue has been determined. This study set out to evaluate ulifloxacin penetration into the prostate following administration of the oral fluoroquinolone prodrug prulifloxacin in patients undergoing transurethral resection of the prostate (TURP). This was a phase I, randomized, open-label, single-centre study involving 20 male Caucasian patients (mean age 63.1 years) requiring TURP for treatment of benign prostatic hyperplasia. Sixteen patients were randomized to receive prulifloxacin; the other four patients were not treated (controls) in order to validate the bioanalytical method. Patients in the active treatment groups were randomized to receive one or three once-daily doses of prulifloxacin 600 mg, with the last administration 3 hours prior to surgery. Central/transitional and peripheral zone prostatic tissue samples were obtained from the 6 o'clock and 9 o'clock positions in the prostate, and blood samples were collected concurrently. Ulifloxacin concentrations were determined in the tissue samples and plasma using liquid chromatography-tandem mass spectrometry. Safety was also assessed. Prostatic tissue concentrations of ulifloxacin always exceeded those in plasma. Mean ulifloxacin concentrations measured in samples collected from the 6 o'clock central/transitional zone of the prostate were higher in patients who received prulifloxacin for 3 days than in those who received a single dose. Mean prostatic tissue/plasma ulifloxacin concentration ratios after single and repeated prulifloxacin administration ranged from 3.8 to 7.1 and from 3.9 to 9.5, respectively. The highest mean ratio was found in the 6 o'clock central/transitional zone after repeated dosing. Prostatic levels of ulifloxacin were above the minimum inhibitory concentrations for the most

  15. Efficacy of recombinant factor VIIa administered by continuous infusion to haemophilia patients with inhibitors

    NARCIS (Netherlands)

    Mauser-Bunschoten, EP; Koopman, MMW; Goede-Bolder, ADE; Leebeek, FWG; Van der Meer, J; Kooij, GMV; Van der Linden, PWG

    2002-01-01

    We have prospectively monitored treatment of haemophilia patients with inhibitors by recombinant factor VIIa (rFVIIa) administered by continuous infusion to obtain more insight in the underlying factors of the clinical efficacy of this administration method. At present, 43 treatment episodes of 14 d

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

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

    2008-07-01

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

  17. 30 CFR 250.1508 - What must I do when MMS administers written or oral tests?

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 2 2010-07-01 2010-07-01 false What must I do when MMS administers written or oral tests? 250.1508 Section 250.1508 Mineral Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Well Control...

  18. Patients with Advanced Ovarian Cancer Administered Oral Etoposide following Taxane as Maintenance Chemotherapy

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    Hiroaki Nagano

    2016-03-01

    Full Text Available Introduction: The concept of maintenance therapy is one of the highly relevant approaches in the management of advanced ovarian cancer. The fundamental goal of maintenance therapy is to improve survival outcomes. We attempted to reinforce maintenance chemotherapy by adding oral etoposide following taxane administration. Cases: We retrospectively evaluated 14 patients with advanced ovarian cancer who had achieved clinically defined complete response to a primary platinum/taxane chemotherapy regimen and who were administered oral etoposide (50 mg/day × 21 days per cycle monthly for 3-5 cycles following paclitaxel or docetaxel administration as maintenance chemotherapy. With regard to oral etoposide toxicity, grade 2 oral mucositis and grade 3 anemia were observed in 1 patient each. Three to five cycles of etoposide were administered to all patients, though daily dosage was reduced to 25 mg in 2 patients due to toxicity. The median progression-free survival was 43.5 months, the median overall survival was 86 months, and 5-year overall survival was 77.1%. Conclusion: The results from this ovarian cancer treatment evaluation suggest that oral etoposide may be administered safely following paclitaxel or docetaxel as maintenance chemotherapy. We expect this regimen to contribute to the improvement in the survival outcomes of patients with advanced ovarian cancer.

  19. Orally administered DTPA penta-ethyl ester for the decorporation of inhaled (241)Am.

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    Sueda, Katsuhiko; Sadgrove, Matthew P; Huckle, James E; Leed, Marina G D; Weber, Waylon M; Doyle-Eisele, Melanie; Guilmette, Raymond A; Jay, Michael

    2014-05-01

    Diethylenetriaminepentaacetic acid (DTPA) is an effective decorporation agent to facilitate the elimination of radionuclides from the body, but its permeability-limited oral bioavailability limits its utility in mass-casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester form of DTPA is under investigation. Pharmacokinetic and biodistribution studies were conducted in rats by orally administering [(14) C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared with a previous reporting of intravenously administered DTPA, the oral administration of this prodrug resulted in a sustained plasma concentration profile with higher plasma exposure and lower clearance. An assessment of the urine composition revealed that the bioactivation was extensive but incomplete, with no detectable levels of the penta- or tetra-ester forms. Tissue distribution at 12 h was limited, with approximately 73% of the administered dose being associated with the gastrointestinal tract. In the efficacy study, rats were exposed to aerosols of (241) Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of (241) Am was found to be 19% higher than with the control. Consistent with prior reports of DTPA, the prodrug was most effective when the treatment delays were minimized. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  20. Orally administered DTPA penta-ethyl ester for the decorporation of inhaled 241Am

    Science.gov (United States)

    Sueda, Katsuhiko; Sadgrove, Matthew P.; Huckle, James E.; Leed, Marina G. D.; Weber, Waylon M.; Doyle-Eisele, Melanie; Guilmette, Raymond A.; Jay, Michael

    2014-01-01

    Diethylenetriaminepentaacetic acid (DTPA) is an effective decorporation agent to facilitate the elimination of radionuclides from the body, but its permeability-limited oral bioavailability limits its utility in mass-casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester form of DTPA is under investigation. Pharmacokinetic and biodistribution studies were conducted in rats by orally administering [14C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared to a previous reporting of intravenously administered DTPA, the oral administration of this prodrug resulted in a sustained plasma concentration profile with higher plasma exposure and lower clearance. An assessment of the urine composition revealed that the bioactivation was extensive but incomplete, with no detectable levels of the penta- or tetra-ester forms. Tissue distribution at 12 h was limited, with approximately 73% of the administered dose being associated with the gastrointestinal tract. In the efficacy study, rats were exposed to aerosols of 241Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of 241Am was found to be 19% higher than with the control. Consistent with prior reports of DTPA, the prodrug was most effective when the treatment delays were minimized. PMID:24619514

  1. Orally administered misoprostol for induction of labor with prelabor rupture of membranes at term.

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    Radoff, Kari A

    2014-01-01

    Prelabor rupture of membranes (PROM) occurs in approximately 8% to 10% of women with term pregnancies. The management of PROM continues to be controversial. Approaches include expectant management and immediate induction of labor. The use of orally administered misoprostol for the management of women with PROM may provide significant advantages when they choose immediate induction of labor. This literature review presents current evidence that supports the use of oral misoprostol for women with PROM, including the benefits of a decreased interval time from PROM to vaginal birth, good safety profile, and reductions in the use of oxytocin augmentation and epidural anesthesia. In addition to clinically proven benefits to women of oral misoprostol for PROM, it also has the potential to reduce chorioamnionitis by reducing the number of sterile vaginal examinations performed thereby reducing the risk of ascending bacteria. Women have also reported acceptability and satisfaction when using oral misoprostol for immediate induction of labor. This review of literature discusses what is known about the use of orally administered misoprostol for the management of term PROM and makes recommendations for clinical use.

  2. Orally administered melatonin prevents lipopolysaccharide-induced neural tube defects in mice.

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    Lin Fu

    Full Text Available Lipopolysaccharide (LPS has been associated with adverse pregnant outcomes, including fetal demise, intra-uterine growth restriction (IUGR, neural tube defects (NTDs and preterm delivery in rodent animals. Previous studies demonstrated that melatonin protected against LPS-induced fetal demise, IUGR and preterm delivery. The aim of the present study was to investigate the effects of melatonin on LPS-induced NTDs. All pregnant mice except controls were intraperitoneally injected with LPS (25 µg/kg daily from gestational day (GD8 to GD12. Some pregnant mice were orally administered with melatonin (MT, 50 mg/kg before each LPS injection. A five-day LPS injection resulted in 27.5% of fetuses with anencephaly, exencephaly or encephalomeningocele. Additional experiment showed that maternal LPS exposure significantly down-regulated placental proton-coupled folate transporter (pcft and disturbed folate transport from maternal circulation through the placentas into the fetus. Interestingly, melatonin significantly attenuated LPS-induced down-regulation of placental pcft. Moreover, melatonin markedly improved the transport of folate from maternal circulation through the placentas into the fetus. Correspondingly, orally administered melatonin reduced the incidence of LPS-induced anencephaly, exencephaly or encephalomeningocele. Taken together, these results suggest that orally administered melatonin prevents LPS-induced NTDs through alleviating LPS-induced disturbance of folate transport from maternal circulation through the placenta into the fetus.

  3. Biorelevant in vitro performance testing of orally administered dosage forms-workshop report.

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    Reppas, Christos; Friedel, Horst-Dieter; Barker, Amy R; Buhse, Lucinda F; Cecil, Todd L; Keitel, Susanne; Kraemer, Johannes; Morris, J Michael; Shah, Vinod P; Stickelmeyer, Mary P; Yomota, Chikako; Brown, Cynthia K

    2014-07-01

    Biorelevant in vitro performance testing of orally administered dosage forms has become an important tool for the assessment of drug product in vivo behavior. An in vitro performance test which mimics the intraluminal performance of an oral dosage form is termed biorelevant. Biorelevant tests have been utilized to decrease the number of in vivo studies required during the drug development process and to mitigate the risk related to in vivo bioequivalence studies. This report reviews the ability of current in vitro performance tests to predict in vivo performance and generate successful in vitro and in vivo correlations for oral dosage forms. It also summarizes efforts to improve the predictability of biorelevant tests. The report is based on the presentations at the 2013 workshop, Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms, in Washington, DC, sponsored by the FIP Dissolution/Drug Release Focus Group in partnership with the American Association of Pharmaceutical Scientists (AAPS) and a symposium at the AAPS 2012 Annual meeting on the same topic.

  4. Orally administered bisphenol a in rainbow trout (Oncorhynchus mykiss): estrogenicity, metabolism, and retention.

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    Bjerregaard, Poul; Andersen, Sidsel B; Pedersen, Knud L; Pedersen, Søren N; Korsgaard, Bodil

    2007-09-01

    The estrogenic effect of orally administered bisphenol A (BPA) was investigated in a rainbow trout (Oncorhynchus mykiss) test system. Bisphenol A was administered orally to sexually immature rainbow trout every second day for up to 12 d in doses between 1.8 and 258 mg/kg every second day (/2d). Plasma vitellogenin was measured before and during the exposures, and the concentrations of BPA in plasma, liver, and muscle and the plasma concentrations of BPA glucuronic acid (BPAGA) were determined at the end of the experiments. Increases in average plasma vitellogenin levels were seen at oral exposure to 24 mg BPA/kg/2d; the most sensitive fish responded to 9.3 mg/kg/2d. At day 12, the 10, 50, and 90% effective doses for increase in vitellogenin synthesis were 13, 19, and 25 mg/kg/2d, respectively. Bisphenol A could be detected in liver, muscle, and plasma at the end of the exposure, generally in increasing concentrations with increasing doses; liver concentrations generally were higher than muscle concentrations. Four to five hours after the last feeding of doses between 3.6 and 24 mg BPA/kg, plasma BPA concentrations ranged between 400 and 1,200 nM, whereas BPAGA concentrations were between 2- and 10-fold higher. The difference between BPA and BPAGA concentrations increased with increasing BPA dose. Bisphenol A showed little tendency to bioaccumulate in rainbow trout; less than 1% of the total amount of BPA administered orally at doses between 1.8 and 258 mg/ kg/2d over the 10- or 12-d experimental period was retained in muscle and liver at 5 or 24 h after the end of the experiments.

  5. Effect of Orally Administered Glutathione-Montmorillonite Hybrid Systems on Tissue Distribution

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    Miri Baek

    2012-01-01

    Full Text Available An ubiquitous tripeptide, glutathione (GSH, is assigned a role in detoxification, activation of immune system, intermediary metabolism, transport, and protection of cells against free radicals or reactive oxygen species. However, instability of orally administered GSH in gastrointestinal (GI tract leads to low absorption and low bioavailability in tissues. In this study, we attempted to synthesize GSH-montmorillonite (MMT hybrid systems by intercalating GSH into the interlayers of a cationic clay delivery carrier, MMT, to improve GSH bioavailability at the systemic level. Polymer coating of the hybrid with polyvinylacetal diethylaminoacetate (AEA was further performed to obtain better stability. Synthetic condition of both GSH-MMT and AEA-GSH-MMT hybrids was optimized, and then GSH-delivery efficiency was evaluated in various organs after oral administration in normal as well as GSH-deficient mice. The present GSH-MMT hybrids remarkably enhanced GSH concentration in the plasma, heart, kidney, and liver, especially when AEA-GSH-MMT hybrid was administered under GSH-deficient condition. Moreover, both hybrids did not induce acute oral toxicity up to 2000 mg/kg, suggesting their great potential for pharmaceutical application.

  6. Tolerability assessment of a lectin fraction from Tepary bean seeds (Phaseolus acutifolius orally administered to rats

    Directory of Open Access Journals (Sweden)

    Roberto Ferriz-Martínez

    2015-01-01

    Full Text Available Our previous studies have shown that a lectin rich fraction (TBLF extracted from Tepary bean seeds differentially inhibits cancer cells proliferation in vitro. Before testing the in vivo anticancer effect, the acute and subchronic toxicological assays in rats were conducted, where an oral dose of 50 mg/body weight kg was determined as the NOAEL. This study evaluated the resistance to digestion and complete blood count (CBC after 24 h of the orally administered 50 mg/kg TBLF. The digestion resistance test showed lectins activity retention after 72 h and the CBC study showed a high level of eosinophils, suggesting an allergic-like response. Tolerability was assayed after 6 weeks of treatment by dosing with an intragastric cannula every third day per week. It was observed a transient reduction in food intake and body weight in the first weeks, resulting in body weight gain reduction of 10% respect to the control group at the end of the study. Additionally, organs weight, histopathological analysis and blood markers for nutritional status and for liver, pancreas and renal function were not affected. Our results suggest that 50 mg/kg TBLF administered by oral route, exhibit no toxicity in rats and it was well tolerated. Further studies will focus on long-term studies.

  7. Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat).

    NARCIS (Netherlands)

    Furlan, A.; Monzani, V.; Reznikov, L.L.; Leoni, F.; Fossati, G.; Modena, D.; Mascagni, P.; Dinarello, C.A.

    2011-01-01

    ITF2357 (givinostat) is a histone deacetylase inhibitor with antiinflammatory properties at low nanomolar concentrations. We report here a phase I safety and pharmacokinetics trial in healthy males administered 50, 100, 200, 400 or 600 mg orally. After 50 mg, mean maximal plasma concentrations reach

  8. Application of the yeast-surface-display system for orally administered salmon calcitonin and safety assessment.

    Science.gov (United States)

    Sun, Ping-Nan; Zhang, Xue-Cheng; Chen, Yun-Song; Zang, Xiao-Nan

    2010-01-01

    High manufacturing costs and oral delivery are the constraints in clinical application of calcitonin. We selected surface-displayed Saccharomyces cerevisiae as a low-cost and safe carrier for oral delivery of salmon calcitonin (sCT). The sCT DNA fragment, optimized according to the codon preference of S. cerevisiae, was synthesized and cloned into the plasmid M-pYD1 to yield recombinant yAGA2-sCT, which was induced to express sCT by galactose for 0, 12, and 24 h. sCT expression was detected on the cell surface by indirect immunofluorescence and peaked at 12 h. About 65% recombinants expressed sCT on flow cytometry. The in vivo and in vitro activity of recombinant sCT was determined by detecting bioactivity of antiosteoclastic absorption on bone wafers and orally administering yAGA2-sCT to Wistar rats, respectively. For safety assessment of yAGA2-sCT, we observed abnormalities, morbidity, and mortality and determined body weight, serum chemistry parameters, hematological parameters, and organ weight. In vitro bioactivity of the recombinant sCT was similar to that of commercial sCT, Miacalcic; oral administration of 5 g/kg yAGA2-sCT induced a long-term hypocalcemic effect in Wistar rats and no adverse effects. This study demonstrates that yAGA2-sCT anchoring sCT protein on a S. cerevisiae surface has potential for low-cost and safe oral delivery of sCT.

  9. Polyamine inhibitors for treatment of feline oral squamous cell carcinoma: a proof-of-concept study.

    Science.gov (United States)

    Lewis, John R; O'Brien, Thomas G; Skorupski, Katherine A; Krick, Erika L; Reiter, Alexander M; Jennings, Michael W; Jurney, Carrie H; Shofer, F S

    2013-01-01

    This study assessed proof-of-concept for use of polyamine inhibitor 2-diluoromethylornithine (DFMO) as a treatment for oral squamous cell carcinoma (SCC) in client-owned cats. Polyamine levels in tumor tissue and normal oral mucosa were quantified before and after treatment. DFMO was administered orally to 14 client-owned cats with histologically confirmed oral SCC. Patients were monitored for gastrointestinal, dermatologic, auditory, hematological, and biochemical abnormalities. Total polyamine levels in tumor tissue decreased after treatment, as did the specific polyamine putrescine in both tumor tissue and normal mucosa. Ototoxicity was observed in 5 of 6 cats receiving pre- and post-treatment brainstem auditory evoked potential tests. Subclinical thrombocytopenia was observed in 6 of 14 cats. One cat showed mild post-anesthetic tremors that resolved without treatment. Oral administration of DFMO at doses used in this study resulted in significantly decreased tumor polyamine levels without life-threatening clinical or hematological toxicities. Further studies are warranted to explore pathophysiology of polyamine biochemistry and use of polyamine inhibitors in treatment of cats with oral SCC.

  10. Safety evaluation of orally administered afoxolaner and milbemycin oxime in eight-week-old dogs.

    Science.gov (United States)

    Drag, M; Saik, J; Harriman, J; Letendre, L; Yoon, S; Larsen, D

    2016-11-27

    The safety profile of afoxolaner (an isoxazoline molecule) when combined with milbemycin oxime (a macrocyclic lactone) was evaluated according to the regulatory requirements when administered six times orally in a soft chewable formulation at a dose of at least 1×, 3×, or 5× the maximum exposure dose in 8-week-old Beagle dogs. Thirty-two healthy puppies (16 males and 16 females) were enrolled and allocated randomly to one of four treatment groups. Three doses were administered at 28-day intervals (Days 0, 28, and 56), followed by three additional doses administered with 14-day intervals (Days 84, 98, and 112). The study ended on Day 126. Treatment groups were as follows: Group 1: untreated, sham-dosed control; Group 2: afoxolaner/milbemycin oxime chews administered at a dose of at least 5 and 1 mg/kg, respectively (1×); Group 3: afoxolaner/milbemycin oxime chews administered at a dose of at least 15 and 3 mg/kg, respectively (3); and Group 4: afoxolaner/milbemycin oxime chews administered at a dose of at least 25 and 5 mg/kg, respectively (5×). All dogs were examined for general health twice a day beginning on Day -14. Physical examinations, and blood collections for clinical pathology analysis and afoxolaner and milbemycin oxime plasma concentrations, were performed throughout the study. No afoxolaner/milbemycin oxime treatment-related changes were observed in growth, physical variables, clinical pathology variables, or tissues examined histologically. No clinically relevant or statistically significant health abnormalities related to the administration of afoxolaner/milbemycin oxime were observed. No signs of macrocyclic lactone sensitivity were observed at any time during the study. Vomiting and diarrhea were observed sporadically across all groups including the controls. Based upon the results of this study, afoxolaner/milbemycin oxime soft chewables were shown to be safe when administered repeatedly at up to 5× the maximum exposure dose in dogs as

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

    Science.gov (United States)

    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.

  12. Implications of Dabigatran, a direct thrombin inhibitor, for oral surgery practice.

    Science.gov (United States)

    Davis, Clayton; Robertson, Chad; Shivakumar, Sudeep; Lee, Min

    2013-01-01

    Direct thrombin inhibitors, specifically orally administered dabigatran etexilate, are emerging as alternatives to warfarin for anticoagulation in the management of atrial fibrillation and venous thromboembolism. The risk associated with bleeding events while taking dabigatran has been documented in multiple randomized controlled trials, but to date, no studies have focused on the risk of bleeding after dental extraction. Extraction of teeth is one of the most common surgical procedures and may cause significant bleeding, so a thorough understanding of the pharmacology of anticoagulant medications is required to prevent complications. With the increasing use of direct thrombin inhibitors, the safe management of patients taking these anticoagulants must be delineated. This review compares dabigatran and warfarin, especially in terms of their effects on dental and oral surgery practice, and examines best management of these patients in light of the existing literature.

  13. Safety evaluation of orally administered afoxolaner in 8-week-old dogs.

    Science.gov (United States)

    Drag, Marlene; Saik, Judith; Harriman, Jay; Larsen, Diane

    2014-04-02

    The safety profile of afoxolaner, a new isoxazoline molecule, was evaluated following the regulatory requirements when administered six times orally in a soft chewable formulation at a dose of at least 1×, 3× or 5× the maximum exposure dose (6.3mg/kg) in 8-week-old Beagle dogs. Thirty-two healthy puppies (16 males and 16 females) were enrolled and allocated randomly to one of four treatment groups. Treatments were administered at three, one-month dose intervals (Days 0, 28 and 56) followed by three, 2-week dose intervals (Days 84, 98 and 112). The study ended at Day 126. The groups were: Group 1: non-treated control; Group 2: afoxolaner chews administered at a dosage of at least 6.3mg/kg (1×); Group 3: afoxolaner chews administered at a dosage of at least 18.9 mg/kg (3×); and Group 4: afoxolaner chews administered at a dosage of at least 31.5mg/kg (5×). All dogs were examined for general health twice a day beginning on at least Day-14. Physical examinations, and blood collections for clinical pathology analysis and afoxolaner plasma concentrations, were performed throughout the study. On Day 126, 2 weeks following the last treatment, all dogs were humanely euthanized prior to the conduction of a full necropsy with tissue collection. No afoxolaner-related changes were observed in growth, physical variables, clinical pathology variables, or tissues examined histologically. No clinically or statistically significant health abnormalities related to the administration of afoxolaner were observed. Vomiting and diarrhea were observed sporadically across all groups including the controls. The kinetics of afoxolaner plasma concentrations was linear following 6 doses of 6.3, 18.9 and 31.5mg/kg and dose proportionality was demonstrated. There were no statistical differences (pafoxolaner was shown to be safe when administered repeatedly in a soft chewable formulation at up to 5× the maximum exposure dose in dogs as young as 8 weeks of age.

  14. Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

    Directory of Open Access Journals (Sweden)

    Lee JA

    2014-12-01

    Full Text Available Jeong-A Lee,1 Mi-Kyung Kim,1 Hee-Jeong Paek,1 Yu-Ri Kim,2 Meyoung-Kon Kim,2 Jong-Kwon Lee,3 Jayoung Jeong,3 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women’s University, Seoul, Republic of Korea; 2Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Republic of Korea; 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk–do, Republic of Korea Purpose: The effects of particle size on the tissue distribution and excretion kinetics of silica nanoparticles and their biological fates were investigated following a single oral administration to male and female rats. Methods: Silica nanoparticles of two different sizes (20 nm and 100 nm were orally administered to male and female rats, respectively. Tissue distribution kinetics, excretion profiles, and fates in tissues were analyzed using elemental analysis and transmission electron microscopy. Results: The differently sized silica nanoparticles mainly distributed to kidneys and liver for 3 days post-administration and, to some extent, to lungs and spleen for 2 days post-administration, regardless of particle size or sex. Transmission electron microscopy and energy dispersive spectroscopy studies in tissues demonstrated almost intact particles in liver, but partially decomposed particles with an irregular morphology were found in kidneys, especially in rats that had been administered 20 nm nanoparticles. Size-dependent excretion kinetics were apparent and the smaller 20 nm particles were found to be more rapidly eliminated than the larger 100 nm particles. Elimination profiles showed 7%–8% of silica nanoparticles were excreted via urine, but most nanoparticles were excreted via feces, regardless of particle size or sex. Conclusion: The kidneys, liver, lungs, and spleen were found to be the target organs of orally-administered silica nanoparticles in rats, and this organ

  15. Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin.

    Science.gov (United States)

    Apgar, James M; Wilkening, Robert R; Greenlee, Mark L; Balkovec, James M; Flattery, Amy M; Abruzzo, George K; Galgoci, Andrew M; Giacobbe, Robert A; Gill, Charles J; Hsu, Ming Jo; Liberator, Paul; Misura, Andrew S; Motyl, Mary; Nielsen Kahn, Jennifer; Powles, Maryann; Racine, Fred; Dragovic, Jasminka; Habulihaz, Bahanu; Fan, Weiming; Kirwan, Robin; Lee, Shu; Liu, Hao; Mamai, Ahmed; Nelson, Kingsley; Peel, Michael

    2015-12-15

    The clinical success of the echinocandins, which can only be administered parentally, has validated β-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency. Installing an aminotetrazole at C2 in conjunction with an N-alkylated aminoether at C3 produced derivatives with significantly improved GS and antifungal potency that exhibited robust oral efficacy in a murine model of disseminated candidiasis.

  16. Pharmacokinetics of oral gabapentin alone or co-administered with meloxicam in ruminant beef calves.

    Science.gov (United States)

    Coetzee, Johann F; Mosher, Ruby A; Kohake, Laura E; Cull, Charley A; Kelly, Lindsey L; Mueting, Stacy L; KuKanich, Butch

    2011-10-01

    Gabapentin is a γ-aminobutyric acid (GABA) analogue indicated for treatment of neuropathic pain. This study determined the pharmacokinetics of oral (PO) gabapentin alone or in combination with meloxicam in ruminant calves. Gabapentin capsules at 10mg/kg or gabapentin powder (from capsules at 15mg/kg) and meloxicam tablets (0.5mg/kg) were administered PO to six beef calves. Plasma drug concentrations were determined over 48h post-administration by liquid chromatography/mass spectrometry followed by non-compartmental pharmacokinetic analysis. The mean (± standard deviation, SD) C(max), T(max) and elimination half-life (t(½)λz) for gabapentin (10mg/kg) alone was 2.97 ± 0.40μg/mL, 9.33 ± 2.73h and 11.02 ± 3.68h, respectively. The mean (± SD) C(max), T(max) and t(½)λz for gabapentin (15mg/kg) co-administered with meloxicam was 3.57±1.04μg/mL, 7.33 ± 1.63h and 8.12±2.11h, respectively. The mean (±SD) C(max), T(max) and t(½)λz for meloxicam was 2.11± 0.19μg/mL, 11.67 ± 3.44h and 20.47 ± 9.22h, respectively. Plasma gabapentin concentrations >2μg/mL were maintained for up to 15h and meloxicam concentrations >0.2μg/mL for up to 48h. The pharmacokinetic profile of oral gabapentin and meloxicam supported clinical evaluation of these compounds for management of neuropathic pain in cattle.

  17. Curative and preventive efficacy of orally administered afoxolaner against Ctenocephalides canis infestation in dogs.

    Science.gov (United States)

    Dumont, Pascal; Gale, Boyd; Chester, Theodore S; Larsen, Diane L

    2014-04-02

    The efficacy of orally administered afoxolaner against adult dog fleas, Ctenocephalides canis, was evaluated in a controlled, blinded study. A total of 32 dogs were infested with 100 adult unfed fleas approximately 24h prior to treatment and then at weekly intervals for 5 weeks after treatment. Live fleas were counted upon removal at 12h (for 16 dogs) and 24h (for the remaining 16 dogs) after treatment (for counts performed the first week) or after infestation (for counts performed on subsequent weeks). In addition, flea eggs were collected from each pen and counted for the dogs with flea removal at 24h. Dosing of individual dogs was achieved using a combination of the chewable tablets to be as close as possible to the minimum effective dose of 2.5mg/kg. The percent efficacy of the afoxolaner treatment was ≥ 99.0% for all 24-h flea counts. For flea counts performed 12h after treatment or infestations, the percent efficacy was ≥ 94.1% up to Day 21. After Day 1, no flea eggs were recovered from the afoxolaner treated group, providing 100% reduction in numbers of flea eggs recovered versus untreated control group. This study confirmed that a single oral treatment with afoxolaner provided excellent efficacy against infestations by C. canis within 12-24h after treatment, prevented re-infestations, and completely prevented egg production from new flea infestations for up to 5 weeks.

  18. Recovery of Cognitive Dysfunction via Orally Administered Redox-Polymer Nanotherapeutics in SAMP8 Mice.

    Directory of Open Access Journals (Sweden)

    Pennapa Chonpathompikunlert

    Full Text Available Excessively generated reactive oxygen species are associated with age-related neurodegenerative diseases. We investigated whether scavenging of reactive oxygen species in the brain by orally administered redox nanoparticles, prepared by self-assembly of redox polymers possessing antioxidant nitroxide radicals, facilitates the recovery of cognition in 17-week-old senescence-accelerated prone (SAMP8 mice. The redox polymer was delivered to the brain after oral administration of redox nanoparticles via a disintegration of the nanoparticles in the stomach and absorption of the redox polymer at small intestine to the blood. After treatment for one month, levels of oxidative stress in the brain of SAMP8 mice were remarkably reduced by treatment with redox nanoparticles, compared to that observed with low-molecular-weight nitroxide radicals, resulting in the amelioration of cognitive impairment with increased numbers of surviving neurons. Additionally, treatment by redox nanoparticles did not show any detectable toxicity. These findings indicate the potential of redox polymer nanotherapeutics for treatment of the neurodegenerative diseases.

  19. Urinary excretion of orally administered oxalic acid in saccharin and o-phenylphenol-fed NMRI mice.

    Science.gov (United States)

    Salminen, E; Salminen, S

    1986-01-01

    Both saccharin and o-phenylphenol have been suggested to be carcinogenic to the urinary bladder in experimental animals, but the mechanism has remained unclear. The aim of this study was to investigate the effects of dietary saccharin and o-phenylphenol on the urinary excretion of dietary oxalic acid. Male NMRI mice were gradually adapted to either 3% o-phenylphenol or 5% saccharin in their diet. Having being adapted to these diets for 1 week or after consuming them for 3 months, the animals were fasted for 6 h and given a 2.5-microCi oral dose of U-14C-oxalic acid. Dosed animals were kept in metabolism cages for 48 h to monitor urinary and fecal excretion of the label. Adaptation to dietary o-phenylphenol appeared to increase the urinary excretion of orally administered U-14C-oxalic acid when food and water were available during urinary and fecal collections. Adaptation to dietary saccharin had little effect on urinary oxalate levels when compared to control animals. These results indicate that changes in urinary oxalate levels should be more carefully studied in connection with potential urinary bladder carcinogens to avoid the possibility of bladder irritation by increased urinary oxalate excretion.

  20. Effects of orally administered yeast-derived beta-glucans: a review.

    Science.gov (United States)

    Samuelsen, Anne Berit C; Schrezenmeir, Jürgen; Knutsen, Svein H

    2014-01-01

    Yeast-derived beta-glucans (Y-BG) are considered immunomodulatory compounds suggested to enhance the defense against infections and exert anticarcinogenic effects. Specific preparations have received Generally Recognized as Safe status and acceptance as novel food ingredients by European Food Safety Authority. In human trials, orally administered Y-BG significantly reduced the incidence of upper respiratory tract infections in individuals susceptible to upper respiratory tract infections, whereas significant differences were not seen in healthy individuals. Increased salivary IgA in healthy individuals, increased IL-10 levels in obese subjects, beneficial changes in immunological parameters in allergic patients, and activated monocytes in cancer patients have been reported following Y-BG intake. The studies were conducted with different doses (7.5-1500 mg/day), using different preparations that vary in their primary structure, molecular weight, and solubility. In animal models, oral Y-BG have reduced the incidence of bacterial infections and levels of stress-induced cytokines and enhanced antineoplastic effects of cytotoxic agents. Protective effects toward drug intoxication and ischemia/reperfusion injury have also been reported. In conclusion, additional studies following good clinical practice principles are needed in which well-defined Y-BG preparations are used and immune markers and disease endpoints are assessed. Since optimal dosing may depend on preparation characteristics, dose-response curves might be assessed to find the optimal dose for a specific preparation. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Effect of Mesalamine and Prednisolone on TNBS Experimental Colitis, following Various Doses of Orally Administered Iron

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    John K. Triantafillidis

    2014-01-01

    Full Text Available Background. Experimental data suggest that oral iron (I. supplementation can worsen colitis in animals. Aim. To investigate the influence of various concentrations of orally administered I. in normal gut mucosa and mucosa of animals with TNBS colitis, as well as the influence of Mesalamine (M. and Prednisolone (P. on the severity of TNBS colitis following orally administered I. Methods and Materials. 156 Wistar rats were allocated into 10 groups. Colitis was induced by TNBS. On the 8th day, all animals were euthanatized. Activity of colitis and extent of tissue damage were assessed histologically. The levels of tissue tumor necrosis factor-α (t-TNF-α and tissue malondialdehyde (t-MDA were estimated in all animal groups. Results. Moderate and high I. supplementation induced inflammation in the healthy colon and increased the activity of the experimentally induced TNBS colitis. Administration of M. on TNBS colitis following moderate iron supplementation (0.3 g/Kg diet resulted in a significant improvement in the overall histological score as well as in two individual histological parameters. M. administration, however, did not significantly reduce the t-TNF-α levels (17.67±4.92 versus 14.58±5.71, P=0.102, although it significantly reduced the t-MDA levels (5.79±1.55 versus 3.67±1.39, P=0.000. Administration of M. on TNBS colitis following high iron supplementation (3.0 g/Kg diet did not improve the overall histological score and the individual histological parameters, neither reduced the levels of t-TNF-α (16.57 ± 5.61 versus 14.65±3.88, P=0.296. However, M. significantly reduced the t-MDA levels (5.99±1.37 versus 4.04±1.41, P=0.000. Administration of P. on TNBS colitis after moderate iron supplementation resulted in a significant improvement in the overall histological score as well as in three individual histological parameters. P. also resulted in a significant reduction in the t-TNF-α levels (17.67±4.92 versus 12.64±3

  2. Optimization of orally bioavailable alkyl amine renin inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Zhenrong; Cacatian, Salvacion; Yuan, Jing; Simpson, Robert D.; Jia, Lanqi; Zhao, Wei; Tice, Colin M.; Flaherty, Patrick T.; Guo, Joan; Ishchenko, Alexey; Singh, Suresh B.; Wu, Zhongren; McKeever, Brian M.; Scott, Boyd B.; Bukhtiyarov, Yuri; Berbaum, Jennifer; Mason, Jennifer; Panemangalore, Reshma; Cappiello, Maria Grazia; Bentley, Ross; Doe, Christopher P.; Harrison, Richard K.; McGeehan, Gerard M.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A. (Vitae); (GSKPA)

    2010-09-17

    Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC{sub 50} of 0.83 nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10 mg/kg resulted in >20 h reduction of blood pressure in a double transgenic rat model of hypertension.

  3. Barriers to administering non-oral formulations in a paediatric population: A semi-structured interview study.

    Science.gov (United States)

    Venables, Rebecca; Batchelor, Hannah; Stirling, Heather; Marriott, John

    2016-01-30

    There is a paucity of research exploring barriers to non-oral medicines administration in paediatric patients; however, these undoubtedly influence medicines adherence. Studies conducted with healthcare professionals have identified various issues with the administration and acceptance of non-oral medicines and devices (Venables et al., 2012; Walsh et al., 2015). EMA (2014) guidelines specify that formulation teams should demonstrate 'acceptability' of paediatric formulations when developing pharmaceutical formulations. Semi-structured interviews exploring barriers to administering non-oral medicines were conducted with young persons and the parents/legal guardians of children (0-17 years) with chronic conditions at the University Hospital of Coventry and Warwickshire, UK. 90 children prescribed a total of 148 non-oral medicines were recruited to the study; 88 barriers to administering non-oral medicines were reported. The most commonly reported barriers were: poor acceptance of face mask/difficulties with spacer for inhaled formulations (38% of reports); disliking parenteral/preferring alternative formulations (38% of reports); greasy texture of topical preparations; difficulty with administering an ocular ointment and the large dose volume of a nasal preparation. Formulation teams should consider the use of child-friendly, age-appropriate designs to improve usability and acceptance, thus medicines adherence. These findings should be used to inform future development of non-oral formulations and devices, suitable in terms of safety, efficacy and acceptability to paediatric patients.

  4. Oral candidiasis in HIV+ patients under treatment with protease inhibitors.

    Science.gov (United States)

    Witzel, Andréa Lusvarghi; Silveira, Fernando Ricardo Xavier da; Pires, Maria de Fátima Costa; Lotufo, Mônica Andrade

    2008-01-01

    The purpose of this work was to evaluate the influence of Protease Inhibitors (PI) on the occurrence of oral candidiasis in 111 HIV+ patients under PI therapy (Group A). The controls consisted of 56 patients that were not using PI drugs (Group B) and 26 patients that were not using any drugs for HIV therapy (Group C). The patient's cd4 cell counts were taken in account for the correlations. One hundred and ninety three patients were evaluated. The PI did not affect the prevalence of oral candidiasis (p = 0.158) or the frequency of C. albicans isolates (p = 0.133). Patients with lower cd4 cell counts showed a higher frequency of C. albicans isolates (p = 0.046) and a greater occurrence of oral candidiasis (p = 0.036).

  5. Gene delivery to dendritic cells by orally administered recombinant Saccharomyces cerevisiae in mice.

    Science.gov (United States)

    Kiflmariam, Meron G; Yang, Hanjiang; Zhang, Zhiying

    2013-02-27

    DNA vaccination has caught the attention of many for triggering humoral as well as cellular immune responses. And delivering DNA into the antigen presenting cells (APCs) in order to induce efficient immunoresponse has become the backbone of this field. It has been confirmed that Saccharomyces cerevisiae, though non-pathogenic, is being engulfed by the dendritic cells and macrophages and delivers not only proteins, but also DNA materials (already confirmed in vitro). In this research, S. cerevisiae is used to deliver green fluorescent protein (GFP) reporter gene controlled under cytomegalovirus (CMV) promoter in living organism (mice). The recombinant yeast, transfected with the plasmid containing the GFP gene, was heat killed and orally administered to mice. After 60 h of yeast administration, mice were sacrificed and intestine was separated, washed and frozen in liquid nitrogen. Tissues were cut at the size of 10 μm using Cryostat machine, and GFP expression was successfully detected under a fluorescence microscope. After 45 days Western blot was able to detect GFP antibody in the blood of mice. These results imply that S. cerevisiae, being non-pathogenic, cheap, and easy to culture could be a good candidate to deliver DNA materials to the immune cells for vaccination.

  6. Evaluation of ATC as an Orally Administered Drug in Treatment of Cadmium Toxicity of Rat Organs

    Directory of Open Access Journals (Sweden)

    S. Nabilaldine Fatemi

    2009-01-01

    Full Text Available The effect of N-tetramethylene dithiocarbamate (ATC as a chelating agent on the excretion of cadmium was evaluated in cadmium-poisoned Wistar rats following administration through food and drink. The present research aimed to characterize the potential efficiency of ATC as an orally administered chelator drug after cadmium administration for 60 days. This chelator significantly enhanced the urinary and biliary excretion of cadmium and restored the altered levels of iron. Cadmium and iron concentrations in different tissues were determined by graphite furnace and flame atomic absorption spectrometry (GF AAS and F AAS methods, respectively. The chelation therapy results show that ATC is able to remove cadmium ions from different tissues while iron concentration returned to the normal level and the clinical symptoms were also reduced. In summary, we conclude that ATC is able to mobilize and promote the excretion of cadmium in rat organs and reduce the side effects and general symptoms of toxicity caused by cadmium and might be useful for preliminary testing of the efficacy of chelating agents in human body. However, these results should be confirmed in different experimental models before extrapolation to other systems. This testing procedure of course does not provide all the relevant answers for evaluating the efficiency of chelating agents in cadmium toxicity.

  7. Identification and quantification of metabolites of orally administered naringenin chalcone in rats.

    Science.gov (United States)

    Yoshimura, Mineka; Sano, Atsushi; Kamei, Jun-Ichi; Obata, Akio

    2009-07-22

    Naringenin chalcone is the main active component of tomato skin extract, which has an antiallergic activity. In this study, naringenin chalcone was orally administered to rats, and the chemical structures and levels of the major metabolites in the plasma and urine of rats were determined. HPLC analysis indicated the presence of three major metabolites in the urine. LC-MS and NMR analyses tentatively identified these as naringenin chalcone-2'-O-beta-D-glucuronide, naringenin-7-O-beta-D-glucuronide, and naringenin-4'-O-beta-D-glucuronide. Naringenin chalcone-2'-O-beta-D-glucuronide was the only metabolite detected in the plasma, and its peak plasma level was observed 1 h after naringenin chalcone administration. Naringenin chalcone-2'-O-beta-D-glucuronide also inhibited histamine release from rat peritoneal mast cells stimulated with compound 48/80. This activity might contribute to the antiallergic activity of naringenin chalcone in vivo. To the best of the authors' knowledge, this study is the first to report determination of naringenin chalcone metabolites in rat plasma and urine.

  8. Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor

    Directory of Open Access Journals (Sweden)

    Upreti VV

    2013-04-01

    Full Text Available Vijay V Upreti,1 Yan Song,1 Jessie Wang,2 Wonkyung Byon,3 Rebecca A Boyd,3 Janice M Pursley,4 Frank LaCreta,1 Charles E Frost1 1Clinical Pharmacology and Pharmacometrics, Discovery Medicine and Clinical Pharmacology, 2Exploratory Development Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, 3Primary Care Clinical Pharmacology, Pfizer, Groton, CT, 4Analytical and Bioanalytical Department, Bristol-Myers Squibb, Princeton, NJ, USA Background: Apixaban is an oral, selective, direct factor Xa inhibitor approved for thromboprophylaxis after orthopedic surgery and stroke prevention in patients with atrial fibrillation, and under development for treatment of venous thromboembolism. This study investigated the effect of a gastric acid suppressant, famotidine (a histamine H2-receptor antagonist, on the pharmacokinetics of apixaban in healthy subjects. Methods: This two-period, two-treatment crossover study randomized 18 healthy subjects to receive a single oral dose of apixaban 10 mg with and without a single oral dose of famotidine 40 mg administered 3 hours before dosing with apixaban. Plasma apixaban concentrations were measured up to 60 hours post-dose and pharmacokinetic parameters were calculated. Results: Famotidine did not affect maximum apixaban plasma concentration (Cmax or area under the plasma concentration-time curve from zero to infinite time (AUC∞. Point estimates for ratios of geometric means with and without famotidine were close to unity for Cmax (0.978 and AUC∞ (1.007, and 90% confidence intervals were entirely contained within the 80%–125% no-effect interval. Administration of apixaban alone and with famotidine was well tolerated. Conclusion: Famotidine does not affect the pharmacokinetics of apixaban, consistent with the physicochemical properties of apixaban (lack of an ionizable group and pH-independent solubility. Apixaban pharmacokinetics would not be affected by an increase in gastrointestinal pH due to

  9. Orally administered extract from Prunella vulgaris attenuates spontaneous colitis in mdr1a-/-mice

    Institute of Scientific and Technical Information of China (English)

    Kelley; MK; Haarberg; Meghan; J; Wymore; Brand; Anne-Marie; C; Overstreet; Catherine; C; Hauck; Patricia; A; Murphy; Jesse; M; Hostetter; Amanda; E; Ramer-Tait; Michael; J; Wannemuehler

    2015-01-01

    AIM: To investigate the ability of a Prunella vulgaris(P. vulgaris) ethanolic extract to attenuate spontaneous typhlocolitis in mdr1a-/- mice. METHODS: Vehicle(5% ethanol) or P. vulgaris ethanolic extract(2.4 mg/d) were administered daily by oral gavage to mdr1a-/- or wild type FVBWT mice from 6 wk of age up to 20 wk of age. Clinical signs of disease were noted by monitoring weight loss. Mice experiencingweight loss in excess of 15% were removed from the study. At the time mice were removed from the study, blood and colon tissue were collected for analyses that included histological evaluation of lesions, inflammatory cytokine levels, and myeloperoxidase activity. RESULTS: Administration of P. vulgaris extracts to mdr1a-/- mice delayed onset of colitis and reduced severity of mucosal inflammation when compared to vehicle-treated mdr1a-/- mice. Oral administration of the P. vulgaris extract resulted in reduced(P < 0.05) serum levels of IL-10(4.6 ± 2 vs 19.4 ± 4), CXCL9(1319.0 ± 277 vs 3901.0 ± 858), and TNFα(9.9 ± 3 vs 14.8 ± 1) as well as reduced gene expression by more than two-fold for Ccl2, Ccl20, Cxcl1, Cxcl9, IL-1 α, Mmp10, VCAM-1, ICAM, IL-2, and TNFα in the colonic mucosa of mdr1a-/- mice compared to vehicle-treated mdr1a-/-mice. Histologically, several microscopic parameters were reduced(P < 0.05) in P. vulgaris-treated mdr1a-/-mice, as was myeloperoxidase activity in the colon(2.49 ± 0.16 vs 3.36 ± 0.06, P < 0.05). The numbers of CD4+ T cells(2031.9 ± 412.1 vs 5054.5 ± 809.5) and germinal center B cells(2749.6 ± 473.7 vs 4934.0 ± 645.9) observed in the cecal tonsils of P. vulgaris-treated mdr1a-/- were significantly reduced(P < 0.05) from vehicle-treated mdr1a-/- mice. Vehicle-treated mdr1a-/- mice were found to produce serum antibodies to antigens derived from members of the intestinal microbiota, indicative of severe colitis and a loss of adaptive tolerance to the members of the microbiota. These serum antibodies were greatly reduced or

  10. Orally administered tylosin for the control of pneumonia in neonatal calves.

    Science.gov (United States)

    Matsuoka, T; Muenster, O A; Ose, E E; Tonkinson, L

    1980-08-16

    The effectiveness of orally administered tylosin tartrate for the control of naturally occurring pneumonia was determined in 287 neonatal calves. Tylosin tartrate was mixed with reconstituted milk replacer at the time of feeding. Daily doses of 1.0 g (0.5 g BID), 2.0 g (1.0 g BID) and 4.0 g (2.0 g BID) were evaluated for periods ranging from seven to 28 days. Tylosin at the optimum dose of 2.0 g daily reduced mortality to 12 out of 95 (12.6 per cent) compared to 38 out of 89 (42.7 per cent) in the non-medicated control calves. The 1.0 g daily dose did not reduce mortality. The number of calves with moderate to severe lung lesions was also reduced by treatment at 2.0 g daily to 13 out of 95 (13.7 per cent) compared to 45 out of 89 (50.6 per cent) in the control group. All dose levels had a similar effect in reducing the severity of clinical signs indicative of respiratory disease. Tylosin treatment at all dose levels reduced the number of Pasteurella multocida isolations from lung tissue to 15/146 (10.3 per cent) compared to 61/141 (43.3 per cent) for the controls. However, there were no differences between treated and controls in the number of P haemolytica isolations. The frequency of mycoplasma isolations from lung tissue were reduced significantly by tylosin treatment at the 4.0 g and 2.0 g dose levels to 36/93 (38.7 per cent) compared to 61/86 (70.9 per cent) for the control calves.

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

    Science.gov (United States)

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

    1997-12-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  13. Multiple-dose pharmacokinetics and tolerability of gemifloxacin administered orally to healthy volunteers.

    Science.gov (United States)

    Allen, A; Bygate, E; Vousden, M; Oliver, S; Johnson, M; Ward, C; Cheon, A; Choo, Y S; Kim, I

    2001-02-01

    Gemifloxacin mesylate (SB-265805-S, LB-20304a) is a potent, novel fluoroquinolone agent with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were characterized in two parallel group studies in healthy male volunteers after doses of 160, 320, 480, and 640 mg once daily for 7 days. Multiple serum or plasma and urine samples were collected on days 1 and 7 and were analyzed for gemifloxacin by high-performance liquid chromatography (HPLC)-fluorescence (study 1) or HPLC-mass spectrometry (study 2). Safety assessments included vital signs, 12-lead electrocardiogram (ECG) readings, hematology, clinical chemistry, urinalysis, and adverse experience monitoring. Gemifloxacin was rapidly absorbed, with a time to maximum concentration of approximately 1 h after dosing followed by a biexponential decline in concentration. Generally, maximum concentration and area under the concentration-time curve (AUC) increased linearly with dose after either single or repeat doses. Mean +/- standard deviation values of AUC(0-tau) on day 7 were 4.92 +/- 1.08, 9.06 +/- 2.20, 12.2 +/- 3.69, and 20.1 +/- 3.67 microg x h/ml following 160-, 320-, 480-, and 640-mg doses, respectively. The terminal-phase half-life was approximately 7 to 8 h, independent of dose, and was similar following single and repeated administrations. There was minimal accumulation of gemifloxacin after multiple dosing. Approximately 20 to 30% of the administered dose was excreted unchanged in the urine. The renal clearance was 160 ml/min on average after single and multiple doses, which was slightly greater than the accepted glomerular filtration rate (approximately 120 ml/min). These data show that the pharmacokinetics of gemifloxacin are linear and independent of dose. Gemifloxacin was generally well tolerated, although one subject was withdrawn from the study after 6 days at 640 mg for mild, transient elevations of alanine aminotransferase and aspartate

  14. Pharmacokinetics of orally administered ibuprofen in African and Asian elephants (Loxodonta africana and Elephas maximus).

    Science.gov (United States)

    Bechert, Ursula; Christensen, J Mark

    2007-06-01

    The pharmacokinetic parameters of S(+) and R(-) ibuprofen were determined in 20 elephants after oral administration of preliminary 4-, 5-, and 6-mg/kg doses of racemic ibuprofen. Following administration of 4 mg/kg ibuprofen, serum concentrations of ibuprofen peaked at 5 hr at 3.9 +/- 2.07 microg/ml R(-) and 10.65 +/- 5.64 microg/ml S(+) (mean +/- SD) in African elephants (Loxodonta africana) and at 3 hr at 5.14 +/- 1.39 microg/ml R(-) and 13.77 +/- 3.75 microg/ml S(+) in Asian elephants (Elephas maximus), respectively. Six-milligram/kilogram dosages resulted in peak serum concentrations of 5.91 +/- 2.17 microg/ml R(-) and 14.82 +/- 9.71 microg/ml S(+) in African elephants, and 5.72 +/- 1.60 microg/ml R(-) and 18.32 +/- 10.35 microg/ml S(+) in Asian elephants. Ibuprofen was eliminated with first-order kinetics characteristic of a single-compartment model with a half-life of 2.2-2.4 hr R(-) and 4.5-5.1 hr S(+) in African elephants and 2.4-2.9 hr R(-) and 5.9-7.7 hr S(+) in Asian elephants. Serum concentrations of R(-) ibuprofen were undetectable at 24 hr, whereas S(+) ibuprofen decreased to below 5 microg/ml 24 hr postadministration in all elephants. The volume of distribution was estimated to be between 322 and 356 ml/kg R(-) and 133 and 173 ml/kg S(+) in Asian elephants and 360-431 ml/kg R(-) and 179-207 ml/kg S(+) in African elephants. Steady-state serum concentrations of ibuprofen ranged from 2.2 to 10.5 microg/ml R(-) and 5.5 to 32.0 microg/ml S(+) (mean: 5.17 +/- 0.7 R(-) and 13.95 +/- 0.9 S(+) microg/ml in African elephants and 5.0 +/- 1.09 microg/ml R(-) and 14.1 +/- 2.8 microg/ml S(+) in Asian elephants). Racemic ibuprofen administered at 6 mg/kg/12 hr for Asian elephants and at 7 mg/kg/12 hr for African elephants results in therapeutic serum concentrations of this antiinflammatory agent.

  15. A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors

    NARCIS (Netherlands)

    U. Banerji (Udai); L. van Doorn (Leni); D. Papadatos-Pastos (Dionysis); R.S. Kristeleit (R.); P.M. Debnam (Phillip); A.R. Tall (Alan); A. Stewart (Alison); P. Raynaud (Philippe); J.M. Garrett; M. Toal (Martin); L. Hooftman (Leon); J.S. de Bono (Johann); J. Verweij (Jaap); F.A.L.M. Eskens (Ferry)

    2012-01-01

    textabstractPurpose: This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor. Patients and Methods: CHR-3996 was administered orally once a day. This phase I trial used a 3+3

  16. Vagally mediated inhibition of acoustic stress-induced cortisol release by orally administered kappa-opioid substances in dogs.

    Science.gov (United States)

    Bueno, L; Gue, M; Fargeas, M J; Alvinerie, M; Junien, J L; Fioramonti, J

    1989-04-01

    The effects of oral vs. iv administration of kappa- and mu-opioid agonists on plasma cortisol release induced by acoustic stress (AS) were evaluated in fasted dogs with an implanted jugular catheter. AS was induced by 1 h of music (less than or equal to 86 decibels) played through earphones and was accompanied by a 382% maximal rise in plasma cortisol after 15-30 min. Administered orally 30 min before the AS session, both U-50488 (0.1 mg/kg) and PD 117-302 (0.05 mg/kg) significantly (P less than or equal to 0.01) decreased (by 71.2% and 80.9%, respectively) the maximal increase in plasma cortisol induced by AS, while bremazocine, morphine, as well as iv administration of U-50488 at similar doses were ineffective. The effects of U-50488 and PD 117-302 orally administered (0.1 mg/kg) on the hypercortisolemia induced by AS were abolished by pretreatment with iv naloxone (0.1 mg/kg) or MR 2266 (0.1 mg/kg). Naloxone given alone significantly (P less than 0.01) increased basal plasma cortisol, without affecting cortisol increase induced by AS. Vagotomy abolished the effects of orally administered U-50488 on the AS-induced increase in plasma cortisol. Neither U-50488 nor PD 117302 (0.1 mg/kg, orally) reduced the increase in plasma cortisol induced by intracerebroventricular administration of ovine CRF (100 ng/kg). It is concluded that kappa- but not mu-opioid agonists are able to inhibit the stimulation of the hypothalamo-pituitary-adrenocortical axis induced by AS by acting selectively on peripheral kappa-receptors located in the wall of the proximal gut. This action is neurally mediated through afferent vagal fibers affecting central nervous system release of CRF induced by a centrally acting stressor.

  17. Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia.

    Science.gov (United States)

    Suh, Sang Won; Aoyama, Koji; Chen, Yongmei; Garnier, Philippe; Matsumori, Yasuhiko; Gum, Elizabeth; Liu, Jialing; Swanson, Raymond A

    2003-11-19

    Severe hypoglycemia causes neuronal death and cognitive impairment. Evidence suggests that hypoglycemic neuronal death involves excitotoxicity and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) normally functions in DNA repair, but promotes cell death when extensively activated by DNA damage. Cortical neuron cultures were subjected to glucose deprivation to assess the role of PARP-1 in hypoglycemic neuronal death. PARP-1-/- neurons and wild-type, PARP-1+/+ neurons treated with the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone both showed increased resistance to glucose deprivation. A rat model of insulin-induced hypoglycemia was used to assess the therapeutic potential of PARP inhibitors after hypoglycemia. Rats subjected to severe hypoglycemia (30 min EEG isoelectricity) accumulated both nitrotyrosine and the PARP-1 product, poly(ADP-ribose), in vulnerable neurons. Treatment with PARP inhibitors immediately after hypoglycemia blocked production of poly(ADP-ribose) and reduced neuronal death by >80% in most brain regions examined. Increased neuronal survival was also achieved when PARP inhibitors were administered up to 2 hr after blood glucose correction. Behavioral and histological assessments performed 6 weeks after hypoglycemia confirmed a sustained salutary effect of PARP inhibition. These results suggest that PARP-1 activation is a major factor mediating hypoglycemic neuronal death and that PARP-1 inhibitors can rescue neurons that would otherwise die after severe hypoglycemia.

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

    Science.gov (United States)

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

    2016-01-01

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

  19. Toxicity of colloidal silica nanoparticles administered orally for 90 days in rats

    Directory of Open Access Journals (Sweden)

    Kim YR

    2014-12-01

    Full Text Available Yu-Ri Kim,1,* Seung-Young Lee,3,* Eun Jeong Lee,1 Sung Ha Park,4 Nak-won Seong,3 Heung-Sik Seo,3 Sung-Sup Shin,3 Seon-Ju Kim,3 Eun-Ho Meang,3 Myeong-Kyu Park,3 Min-Seok Kim,3 Cheol-Su Kim,5 Soo-Ki Kim,5 Sang Wook Son,2 Young Rok Seo,6 Boo Hyon Kang,7 Beom Seok Han,8 Seong Soo A An,9 Beom-Jun Lee,10 Meyoung-Kon Kim1 1Department of Biochemistry and Molecular Biology, 2Department of Dermatology, Korea University Medical School and College, 3General Toxicology Team, Korea Testing and Research Institute, Seoul, Republic of Korea; 4Department of Biochemistry, University of Bath, Bath, UK; 5Department of Microbiology, Wonju College of Medicine, Yonsei University, Gangwon, 6Department of Life Science, Institute of Environmental Medicine for Green Chemistry, Dongguk University, Seoul, 7Nonclinical Research Institute, Chemon Inc, Gyeonggi, 8Toxicological Research Center, Hoseo University, Chungnam, 9Department of Bionanotechnology, Gachon University, Gyeonggi, 10College of Veterinary Medicine, Chungbuk National University, Chungbuk, Republic of Korea *These authors contributed equally to this work Abstract: This study was undertaken to investigate the potential toxicity and establish the no observed adverse effect level (NOAEL and target organ(s of negatively charged colloidal silica particles of different sizes, ie, SiO2EN,20(- (20 nm or SiO2EN,100(- (100 nm, administered by gavage in Sprague-Dawley rats. After verification of the physicochemical properties of the SiO2 particles to be tested, a preliminary dose range-finding study and 90-day repeated dose study were conducted according to the Organisation for Economic Cooperation and Development test guideline. Based on the results of the 14-day dose range-finding study, a high dose was determined to be 2,000 mg/kg, and middle and low doses were set at 1,000 and 500 mg/kg, respectively. In the 90-day toxicity study, there were no animal deaths in relation to administration of SiO2 particles of

  20. Strain-dependent induction of cytokine profiles in the gut by orally administered Lactobacillus strains

    NARCIS (Netherlands)

    Maassen, C.B.M.; Holten-Neelen, C. van; Balk, F.; Bak-Glashouwer, M.-J.H. den; Leer, R.J.; Laman, J.D.; Boersma, W.J.A.; Claassen, E.

    2000-01-01

    Different Lactobacillus strains are frequently used in consumer food products. In addition, recombinant lactobacilli which contain novel expression vectors can now be used in immunotherapeutic applications such as oral vaccination strategies and in T cell tolerance induction approaches for

  1. Strain-dependent induction of cytokine profiles in the gut by orally administered Lactobacillus strains

    NARCIS (Netherlands)

    Maassen, C.B.M.; Holten-Neelen, C. van; Balk, F.; Bak-Glashouwer, M.-J.H. den; Leer, R.J.; Laman, J.D.; Boersma, W.J.A.; Claassen, E.

    2000-01-01

    Different Lactobacillus strains are frequently used in consumer food products. In addition, recombinant lactobacilli which contain novel expression vectors can now be used in immunotherapeutic applications such as oral vaccination strategies and in T cell tolerance induction approaches for autoimmun

  2. Strain-dependent induction of cytokine profiles in the gut by orally administered Lactobacillus strains

    NARCIS (Netherlands)

    Maassen, C.B.M.; Holten-Neelen, C. van; Balk, F.; Bak-Glashouwer, M.-J.H. den; Leer, R.J.; Laman, J.D.; Boersma, W.J.A.; Claassen, E.

    2000-01-01

    Different Lactobacillus strains are frequently used in consumer food products. In addition, recombinant lactobacilli which contain novel expression vectors can now be used in immunotherapeutic applications such as oral vaccination strategies and in T cell tolerance induction approaches for autoimmun

  3. Bioavailability of ketoprofen from orally administered ketoprofen-dextran ester prodrugs in the pig

    DEFF Research Database (Denmark)

    Larsen, C.; Jensen, Bodil Hamborg; Olesen, H. P.

    1991-01-01

    The bioavailability of ketoprofen after oral administration of aqueous solutions of various ketoprofen-dextran ester prodrugs in pigs was assessed. Conjugates derived from dextran fractions in the molecular weight range 10,000-500,000 were employed. Compared to the administration of an oral......-dextran esters. Thus, the present study adds support to a more versatile application of the dextran ester prodrug approach to providing selective colon delivery of drugs possessing a carboxylic acid functional group....

  4. Effectiveness and safety of orally administered immunotherapy for food allergies: a systematic review and meta-analysis.

    Science.gov (United States)

    Nurmatov, Ulugbek; Devereux, Graham; Worth, Allison; Healy, Laura; Sheikh, Aziz

    2014-01-14

    The aim of using oral and sublingual immunotherapy with food allergies is to enable the safe consumption of foods containing these allergens in patients with food allergies. In the present study, a systematic review of intervention studies was undertaken; this involved the searching of eleven international databases for controlled clinical trials. We identified 1152 potentially relevant papers, from which we selected twenty-two reports of twenty-one eligible trials (i.e. eighteen randomised controlled trials and three controlled clinical trials). The meta-analysis revealed a substantially lower risk of reactions to the relevant food allergen in those receiving orally administered immunotherapy (risk ratios (RR) 0·21, 95 % CI 0·12, 0·38). The meta-analysis of immunological data demonstrated that skin prick test responses to the relevant food allergen significantly decreased with immunotherapy (mean difference - 2·96 mm, 95 % CI - 4·48, - 1·45), while allergen-specific IgG4 levels increased by an average of 19·9 (95 % CI 17·1, 22·6) μg/ml. Sensitivity analyses excluding studies at the highest risk of bias and subgroup analyses in relation to specific food allergens and treatment approaches generated comparable summary estimates of effectiveness and immunological changes. Pooling of the safety data revealed an increased risk of local (i.e. minor oropharyngeal/gastrointestinal) adverse reactions with immunotherapy (RR 1·47, 95 % CI 1·11, 1·95); there was a non-significant increased average risk of systemic adverse reactions with immunotherapy (RR 1·08, 95 % CI 0·97, 1·19). There is strong evidence that orally administered immunotherapy can induce immunomodulatory changes and thereby promote desensitisation to a range of foods. However, given the paucity of evidence on longer-term safety, effectiveness and cost-effectiveness, orally administered immunotherapy should not be used outside experimental conditions presently.

  5. Esomeprazole administered through a nasogastric tube provides bioavailability similar to oral dosing.

    Science.gov (United States)

    Sostek, M B; Chen, Y; Skammer, W; Winter, H; Zhao, J; Andersson, T

    2003-09-15

    To determine if nasogastric tube administration of the enteric-coated pellets from an opened esomeprazole capsule provides bioavailability similar to oral dosing with the intact capsule. A randomized, single-centre, open-label, two-period crossover pharmacokinetic study consisting of two 5-day dosing periods separated by a 7- to 14-day washout period was conducted. Healthy subjects between the ages of 18 and 50 years received esomeprazole 40 mg once daily either orally as an intact capsule, or as a suspension of the enteric-coated pellets from an opened capsule in water through a nasogastric tube. In 47 evaluable subjects, the 90% confidence intervals were 0.87-1.08 and 0.93-1.25 for the geometric mean of the ratio of nasogastric tube administration relative to administration of the intact capsule for the area under the plasma concentration-time curve and for maximum plasma concentration, respectively, on day 1, demonstrating bioequivalence. Oral and nasogastric administration also demonstrated similar bioavailabilities on day 5. Esomeprazole was well tolerated regardless of the mode of administration. Nasogastric tube administration of the enteric-coated pellets from an opened esomeprazole 40 mg capsule provides bioavailability similar to oral dosing. Administration of the contents of an opened esomeprazole 40 mg capsule in water through a nasogastric tube is a practical alternative for patients with feeding tubes who require effective gastric acid suppression, but cannot swallow an oral preparation.

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

    Science.gov (United States)

    Lean, Qi Ying; Eri, Rajaraman D.; Randall-Demllo, Sarron; Sohal, Sukhwinder Singh; Stewart, Niall; Peterson, Gregory M.; Gueven, Nuri; Patel, Rahul P.

    2015-01-01

    Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS). Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8), colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis. PMID:26218284

  7. Effect of Orally Administered Enterococcus faecium EF1 on Intestinal Cytokines and Chemokines Production of Suckling Piglets

    Directory of Open Access Journals (Sweden)

    Yi Huang§, Ya-li Li, Qin Huang, Zhi-wen Cui, Dong-you Yu, Imran Rashid Rajput, Cai-hong Hu and Wei-fen Li*

    2012-01-01

    Full Text Available The objective of this study was to determine the effect of orally administered Enterococcus faecium EF1 on intestinal cytokines and chemokines production in piglets. Twenty-four newborn piglets were randomly divided into two groups. The treatment group (T1, orally administered sterilized (110 ºC for 30 min skim milk 10% (2 ml/piglet/day with addition of viable E. faecium EF1 (5~6×108 cfu/ml on 1st, 3rd and 5th day after birth. The control group (T0, were fed the same volume of sterilized skim milk without addition of probiotics. Feeding trial was conducted for 25 days of suckling age. At the end of trail six piglets were randomly selected from each group to collect the samples of jejunum and ileum mucosa to observe the cytokines and chemokines production. The results showed that concentrations of IL-10 and TGF-β1 significantly increased in T1 group. Whereas, production of IL-1β, IL-6, IL-12, IFN-γ and IL-8 decreased in T1 compared to T0. Levels of TNF-α were increased in jejunal mucosa, while decreased in ileal mucosa comparatively in T1 group. Our findings revealed that oral administration of E. faecium EF1 induced a strong anti-inflammatory response in the small intestine. These immunomodulatory effects of this bacterium might contribute to maintenance of immune homeostasis in the intestine of piglets.

  8. Orally administered Lactobacillus strains differentially affect the direction and efficacy of the immune response

    NARCIS (Netherlands)

    Maassen, C.B.M.; Holten, J.C.A.M. van; Balk, F.; Heijne den Bak-Glashouwer, M.J.; Leer, R.; Laman, J.D.; Boersma, W.J.A.; Claassen, E.

    1998-01-01

    In mice, strain dependent cytokine production profiles are induced after oral administration of Lactobacillus. Such a cytokine profile seems to determine the direction and efficacy of the humoral response. In SJL mice lactobacilli are able to enhance or inhibit the development of disease after

  9. Rat adipose tissue rapidly accumulates and slowly releases an orally-administered high vitamin D dose

    NARCIS (Netherlands)

    Brouwer, DAJ; van Beek, J; Ferwerda, H; Brugman, AM; van der Klis, FRM; Muskiet, FAJ

    1998-01-01

    We investigated the effect of oral high-dose cholecalciferol on plasma and adipose tissue cholecalciferol and its subsequent release, and on plasma 25-hydroxyvitamin D (25(OH)D). Female Wistar rats (n 126) received 37.5 mu g cholecalciferol/d for 14 d and were subsequently studied for a further 88 d

  10. EFFECTS OF ORALLY OR VAGINALLY ADMINISTERED LEVONOGESTREL TABLET ON LIPID METABOLISM

    Institute of Scientific and Technical Information of China (English)

    HEChang-Hai; YANGPei-Juan; GUIYou-Lun; LILa-Mei; SHIYONG-En

    1989-01-01

    Twenty healthy female volunteers of reproductive age were recruited and randomized into two groups with ten cases in each group. In Group A, each subject took five pills orally containing 0.75rag levonorgestrel (LNG)in each for postcoital contraception in each

  11. Differential impact of glucose administered intravenously or orally on bone turnover markers in healthy male subjects

    DEFF Research Database (Denmark)

    Westberg-Rasmussen, Sidse; Starup-Linde, Jakob; Hermansen, Kjeld

    2017-01-01

    BACKGROUND: Patients with type-1 (T1D) and type-2 diabetes mellitus (T2D) have an increased risk of hip fracture. The underlying mechanisms may involve disturbances in the incretin hormones. Our aim was to clarify if glucose administration i.e. orally or intravenously differentially affects bone ...

  12. A D-octapeptide drug efflux pump inhibitor acts synergistically with azoles in a murine oral candidiasis infection model.

    Science.gov (United States)

    Hayama, Kazumi; Ishibashi, Hiroko; Ishijima, Sanae A; Niimi, Kyoko; Tansho, Shigeru; Ono, Yasuo; Monk, Brian C; Holmes, Ann R; Harding, David R K; Cannon, Richard D; Abe, Shigeru

    2012-03-01

    Clinical management of patients undergoing treatment of oropharyngeal candidiasis with azole antifungals can be impaired by azole resistance. High-level azole resistance is often caused by the overexpression of Candida albicans efflux pump Cdr1p. Inhibition of this pump therefore represents a target for combination therapies that reverse azole resistance. We assessed the therapeutic potential of the D-octapeptide derivative RC21v3, a Cdr1p inhibitor, in the treatment of murine oral candidiasis caused by either the azole-resistant C. albicans clinical isolate MML611 or its azole-susceptible parental strain MML610. RC21v3, fluconazole (FLC), or a combination of both drugs were administered orally to immunosuppressed ICR mice at 3, 24, and 27 h after oral inoculation with C. albicans. FLC protected the mice inoculated with MML610 from oral candidiasis, but was only partially effective in MML611-infected mice. The co-application of RC21v3 (0.02 μmol per dose) potentiated the therapeutic performance of FLC for mice infected with either strain. It caused a statistically significant decrease in C. albicans cfu isolated from the oral cavity of the infected mice and reduced oral lesions. RC21v3 also enhanced the therapeutic activity of itraconazole against MML611 infection. These results indicate that RC21v3 in combination with azoles has potential as a therapy against azole-resistant oral candidiasis.

  13. Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance

    Directory of Open Access Journals (Sweden)

    Li HH

    2016-09-01

    Full Text Available Huamin Henry Li Institute for Asthma and Allergy, Chevy Chase, MD, USA Abstract: Hereditary angioedema (HAE is a rare genetic disease characterized by episodic subcutaneous or submucosal swelling. The primary cause for the most common form of HAE is a deficiency in functional C1 esterase inhibitor (C1-INH. The swelling caused by HAE can be painful, disfiguring, and life-threatening. It reduces daily function and compromises the quality of life of affected individuals and their caregivers. Among different treatment strategies, replacement with C1-INH concentrates is employed for on-demand treatment of acute attacks and long-term prophylaxis. Three human plasma-derived C1-INH preparations are approved for HAE treatment in the US, the European Union, or both regions: Cinryze®, Berinert®, and Cetor®; however, only Cinryze is approved for long-term prophylaxis. Postmarketing studies have shown that home therapy (self-administered or administered by a caregiver is a convenient and safe option preferred by many HAE patients. In this review, we summarize the role of self-administered plasma-derived C1-INH concentrate therapy with Cinryze at home in the prophylaxis of HAE. Keywords: C1-INH concentrate, hereditary angioedema, disease management, first line, prophylaxis, self-administration 

  14. Modulation of human humoral immune response through orally administered bovine colostrum.

    Science.gov (United States)

    He, F; Tuomola, E; Arvilommi, H; Salminen, S

    2001-08-01

    Eighteen healthy volunteers were randomized into two treatment groups and consumed liquid prepackaged bovine colostrum whey and placebo for 7 days. On days 1, 3 and 5, an attenuated Salmonella typhi Ty21a oral vaccine was given to all subjects to mimic an enteropathogenic infection. The circulating antibody secreting cells and the expression of phagocytosis receptors of the subjects before and after oral immunization were measured with the ELISPOT assay and flow cytometry. All subjects responded well to the vaccine. No significant differences were observed in ELISPOT values for IgA, IgG, IgM, Fcgamma and CR receptor expression on neutrophils and monocytes between the two groups. There was a trend towards greater increase in specific IgA among the subjects receiving their vaccine with bovine colostrum. These results suggest that bovine colostrum may possess some potential to enhance human special immune responses.

  15. Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model

    OpenAIRE

    Chun-Yan Yeung; Wai-Tao Chan; Chun-Bin Jiang; Mei-Lien Cheng; Chia-Yuan Liu; Szu-Wen Chang; Jen-Shiu Chiang Chiau; Hung-Chang Lee

    2015-01-01

    Background and Aims Intestinal mucositis is a frequently encountered side effect in oncology patients undergoing chemotherapy. No well-established or up to date therapeutic strategies are available. To study a novel way to alleviate mucositis, we investigate the effects and safety of probiotic supplementation in ameliorating 5-FU-induced intestinal mucositis in a mouse model. Methods Seventy-two mice were injected saline or 5-Fluorouracil (5-FU) intraperitoneally daily. Mice were either orall...

  16. Orally administered S-1 suppresses circulating endothelial cell counts in metastatic breast cancer patients.

    OpenAIRE

    2013-01-01

    [Background]S-1 is an oral cytotoxic preparation that contains tegafur. Gamma-butyrolactone (GBL) is a metabolite of tegafur that is known to suppress vascular endothelial growth factor (VEGF)-mediated angiogenic activity. The aim of this study was to determine the change in circulating endothelial cell (CEC) counts, GBL levels, and angiogenesis-related factors during S-1 administration in metastatic breast cancer (MBC) patients. [Methods]Patients with HER2-negative MBC were eligible. S-1 was...

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

    Science.gov (United States)

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

    1985-07-01

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

  18. Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel.

    Science.gov (United States)

    Furuta, Takahisa; Sugimoto, Mitsushige; Kodaira, Chise; Nishino, Masafumi; Yamade, Mihoko; Uotani, Takahiro; Sahara, Shu; Ichikawa, Hitomi; Kagami, Takuma; Iwaizumi, Moriya; Hamaya, Yasushi; Osawa, Satoshi; Sugimoto, Ken; Umemura, Kazuo

    2017-04-01

    Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 ± 21.1%, 43.2 ± 20.2%, 46.4 ± 18.8%, and 47.3 ± 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps clopidogrel with rabeprazole administered at lunchtime was 51.6%, which was markedly similar to that of clopidogrel alone (p = 0.114). All tested PPIs reduce the efficacy of clopidogrel when administered concomitantly. Our preliminary data suggest that administration of rabeprazole 4 h following clopidogrel may minimize potential drug-drug interactions.

  19. PHARMACOKINETICS OF ORALLY ADMINISTERED VORICONAZOLE IN AFRICAN PENGUINS (SPHENISCUS DEMERSUS) AFTER SINGLE AND MULTIPLE DOSES.

    Science.gov (United States)

    Hyatt, Michael W; Wiederhold, Nathan P; Hope, William W; Stott, Katharine E

    2017-06-01

    Aspergillosis is a common respiratory fungal disease in African penguins ( Spheniscus demersus ) under managed care, and treatment failures with itraconazole due to drug resistance are increasingly common, leading to recent use of voriconazole. Empirical dosing with voriconazole based on other avian studies has resulted in adverse clinical drug effects in penguins. The objective of this study was to determine oral voriconazole pharmacokinetics (PK) in African penguins (n = 18). Single and once daily multiple oral doses of 5 mg/kg voriconazole were evaluated with a 4-mo washout period between trials. Plasma voriconazole concentrations were determined via high-performance liquid chromatography. Data was modeled using 3-compartamental population methodologies that supported first-order elimination. Observed mean peak concentration (1.89 μg/ml) after single dosing PK analysis was determined within the first hour following voriconazole administration. In the multiple-dose trial average plasma voriconazole concentrations were significantly higher on days 4 and 7 as compared with day 2. The mean estimates for volume of distribution (V/F) and clearance (Cl/F) for the multiple-dose study were 3.34 L and 0.18 L/hr, respectively. Monte Carlo simulations determined the median area under the curve (AUC0-24) at 84 hr was 37.7 μg·h/ml. As this assessment was comparable with the average AUC in humans receiving the recommended human oral dosage 200 mg b.i.d., it suggests that 5 mg/kg p.o. s.i.d. could be a safe and effective regimen in African penguins for treatment of aspergillosis. However, due to potential drug accumulation and subsequent toxicity, therapeutic drug monitoring with dosage adjustments is recommended to individualize dosing.

  20. Viper and cobra venom neutralization by alginate coated multicomponent polyvalent antivenom administered by the oral route.

    Science.gov (United States)

    Bhattacharya, Sourav; Chakraborty, Mousumi; Mukhopadhyay, Piyasi; Kundu, P P; Mishra, Roshnara

    2014-08-01

    Snake bite causes greater mortality than most of the other neglected tropical diseases. Snake antivenom, although effective in minimizing mortality in developed countries, is not equally so in developing countries due to its poor availability in remote snake infested areas as, and when, required. An alternative approach in this direction could be taken by making orally deliverable polyvalent antivenom formulation, preferably under a globally integrated strategy, for using it as a first aid during transit time from remote trauma sites to hospitals. To address this problem, multiple components of polyvalent antivenom were entrapped in alginate. Structural analysis, scanning electron microscopy, entrapment efficiency, loading capacity, swelling study, in vitro pH sensitive release, acid digestion, mucoadhesive property and venom neutralization were studied in in vitro and in vivo models. Results showed that alginate retained its mucoadhesive, acid protective and pH sensitive swelling property after entrapping antivenom. After pH dependent release from alginate beads, antivenom (ASVS) significantly neutralized phospholipaseA2 activity, hemolysis, lactate dehydrogenase activity and lethality of venom. In ex vivo mice intestinal preparation, ASVS was absorbed significantly through the intestine and it inhibited venom lethality which indicated that all the components of antivenom required for neutralization of venom lethality were retained despite absorption across the intestinal layer. Results from in vivo studies indicated that orally delivered ASVS can significantly neutralize venom effects, depicted by protection against lethality, decreased hemotoxicity and renal toxicity caused by russell viper venom. Alginate was effective in entrapping all the structural components of ASVS, which on release and intestinal absorption effectively reconstituted the function of antivenom in neutralizing viper and cobra venom. Further research in this direction can strategize to

  1. Viper and Cobra Venom Neutralization by Alginate Coated Multicomponent Polyvalent Antivenom Administered by the Oral Route

    Science.gov (United States)

    Bhattacharya, Sourav; Chakraborty, Mousumi; Mukhopadhyay, Piyasi; Kundu, P. P.; Mishra, Roshnara

    2014-01-01

    Background Snake bite causes greater mortality than most of the other neglected tropical diseases. Snake antivenom, although effective in minimizing mortality in developed countries, is not equally so in developing countries due to its poor availability in remote snake infested areas as, and when, required. An alternative approach in this direction could be taken by making orally deliverable polyvalent antivenom formulation, preferably under a globally integrated strategy, for using it as a first aid during transit time from remote trauma sites to hospitals. Methodology/Principal Findings To address this problem, multiple components of polyvalent antivenom were entrapped in alginate. Structural analysis, scanning electron microscopy, entrapment efficiency, loading capacity, swelling study, in vitro pH sensitive release, acid digestion, mucoadhesive property and venom neutralization were studied in in vitro and in vivo models. Results showed that alginate retained its mucoadhesive, acid protective and pH sensitive swelling property after entrapping antivenom. After pH dependent release from alginate beads, antivenom (ASVS) significantly neutralized phospholipaseA2 activity, hemolysis, lactate dehydrogenase activity and lethality of venom. In ex vivo mice intestinal preparation, ASVS was absorbed significantly through the intestine and it inhibited venom lethality which indicated that all the components of antivenom required for neutralization of venom lethality were retained despite absorption across the intestinal layer. Results from in vivo studies indicated that orally delivered ASVS can significantly neutralize venom effects, depicted by protection against lethality, decreased hemotoxicity and renal toxicity caused by russell viper venom. Conclusions/Significance Alginate was effective in entrapping all the structural components of ASVS, which on release and intestinal absorption effectively reconstituted the function of antivenom in neutralizing viper and cobra

  2. Discovery of sarolaner: A novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs.

    Science.gov (United States)

    McTier, Tom L; Chubb, Nathan; Curtis, Michael P; Hedges, Laura; Inskeep, Gregory A; Knauer, Christopher S; Menon, Sanjay; Mills, Brian; Pullins, Aleah; Zinser, Erich; Woods, Debra J; Meeus, Patrick

    2016-05-30

    The novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3μg/mL against C. felis and an LC100 of 0.003μg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs≥8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration

  3. Effect of papaverine and atropine on pharmacokinetics of paracetamol administered orally.

    Science.gov (United States)

    Wójcicki, J; Kaźmierczyk, J; Gawrońska-Szklarz, B; Samochowiec, L

    1979-01-01

    The effect of intramuscular injection of atropine and papaverine on the pharmacokinetics of a single oral dose of paracetamol in healthy men was investigated. The open two-compartment model was applied and the calculations were performed using a program for the Hewlett-Packard 9830 B system. An increase of the extent of bioavailability of paracetamol was observed after the atropine administration, however the absorption of the drug was delayed. The administration of papaverine did not change the AUC and Cmax, but tmax was significantly longer.

  4. Fate of orally administered {sup 15}N-labeled polyamines in rats bearing solid tumors

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Masaki; Samejima, Keijiro; Goda, Hitomi; Niitsu, Masaru [Josai Univ., Sakado, Saitama (Japan). Faculty of Pharmaceutical Sciences; Xu Yongji [Qingdao Univ. of Science and Technology (China). Inst. of Chemical and Molecular Technology; Takahashi, Masakazu [Sasaki Inst., Tokyo (Japan); Hashimoto, Yoshiyuki [Kyoritsu Coll. of Pharmacy, Tokyo (Japan)

    2003-03-01

    We studied absorption, distribution, metabolism, and excretion of polyamines (putrescine, spermidine, and spermine) in the gastrointestinal tract using {sup 15}N-labeled polyamines as tracers and ionspray ionization mass spectrometry (IS-MS). The relatively simple protocol using rats bearing solid tumors provided useful information. Three {sup 15}N-labeled polyamines that were simultaneously administered were absorbed equally from gastrointestinal tract, and distributed within tissues at various concentrations. The uptake of {sup 15}N-spermidine seemed preferential to that of {sup 15}N-spermine since the concentrations of {sup 15}N-spermidine in the liver and tumors were higher, whereas those of {sup 15}N-spermine were higher in the kidney, probably due to the excretion of excess extracellular spermine. Most of the absorbed {sup 15}N-putrescine seemed to be lost, suggesting blood and tissue diamine oxidase degradation. Concentrations of {sup 15}N-spermidine and {sup 15}N-spermine in the tumor were low. We also describe the findings from two rats that were administered with {sup 15}N-spermine. The tissue concentrations of {sup 15}N-spermine were unusually high, and significant levels of {sup 15}N-spermidine were derived from {sup 15}N-spermine in these animals. (author)

  5. Assessment of the efficacy of orally administered afoxolaner against Rhipicephalus sanguineus sensu lato.

    Science.gov (United States)

    Kunkle, Bruce; Daly, Sean; Dumont, Pascal; Drag, Marlene; Larsen, Diane

    2014-04-02

    Two studies were conducted to confirm that a single oral dose of the novel insecticide/acaricide afoxolaner is efficacious against existing infestations of Rhipicephalus sanguineus sensu lato in dogs and can control re-infestation for up to 35 days. Each study utilized 16 purpose bred adult dogs using a controlled randomized block design. One or two days prior to treatment, all dogs were infested with 50 unfed adult ticks. On Day 0 one group was treated with an oral chewable formulation of afoxolaner at a dose as close as possible to the minimum dose of 2.5mg/kg. Weekly re-infestations with 50 adult unfed ticks were repeated for five weeks. Forty-eight hours after treatment and after each re-infestation, the number of remaining live ticks on each dog was counted. Treatment with afoxolaner resulted in efficacies of 98.8-100% within 48 h on existing tick infestations, while the efficacy against new tick infestations was >95.7% over five weeks.

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

    Science.gov (United States)

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

    2000-01-01

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

  7. Pharmacokinetic drug-drug interaction between ethinyl estradiol and gestodene, administered as a transdermal fertility control patch, and two CYP3A4 inhibitors and a CYP3A4 substrate.

    Science.gov (United States)

    Winkler, Julia; Goldammer, Mark; Ludwig, Matthias; Rohde, Beate; Zurth, Christian

    2015-12-01

    Pharmacokinetic (PK) interactions between the cytochrome P450 3A4 (CYP3A4) pathway and transdermally administered ethinyl estradiol (EE) and gestodene (GSD) were investigated. This paper reports the findings of three open-label, intra-individual, one-way crossover, Phase I trials. In two studies, women used a novel contraceptive patch for 3 weeks during two 4-week study periods; in the second period, the CYP3A4 inhibitors erythromycin (Study 1) or ketoconazole (Study 2) were administered concurrently. In a third study, women received single doses of the CYP3A4 model substrate midazolam, alone and after 3 weeks of concurrent patch application. In each period, the EE/GSD patch (delivering low EE and GSD doses resulting in the same systemic exposure as a combined oral contraceptive containing 0.02 mg EE and 0.06 mg GSD) was applied once weekly for 3 weeks, with one patch-free week. Erythromycin, ketoconazole, and midazolam were administered orally. Main outcome measures were area under the curves (AUCs) and maximum plasma concentration (C max) of EE, and total and unbound GSD (Studies 1 and 2). AUC and C max of midazolam (Study 3). Co-administration of CYP3A4 inhibitors did not affect EE metabolism, and had only weak effects on the PK of total and unbound GSD. The patch had no clinically relevant effect on metabolism of the CYP3A4 substrate midazolam.

  8. The effects of food on the bioavailability of fenofibrate administered orally in healthy volunteers via sustained-release capsule.

    Science.gov (United States)

    Yun, Hwi-Yeol; Joo Lee, Eun; Youn Chung, Soo; Choi, Sun-Ok; Kee Kim, Hyung; Kwon, Jun-Tack; Kang, Wonku; Kwon, Kwang-Il

    2006-01-01

    To examine the effects of food on plasma concentration and bioavailability of fenofibrate administered as a sustained-release capsule. Twenty-four healthy Korean volunteers were enrolled in a randomised, open-label, balanced, three-treatment, three-period, three-sequence, single oral dose, crossover pharmacokinetic study. A single dose of fenofibrate (250 mg sustained-release capsule) was administered on three occasions -- after overnight fasting, after consumption of a standard breakfast and after a high-fat breakfast. Serial blood samples were collected for the next 72 hours. Plasma fenofibric acid concentrations were measured by high-performance liquid chromatography, and pharmacokinetic parameters were calculated. The pharmacokinetic parameters were significantly affected by food intake. The high-fat breakfast affected the rate of absorption of fenofibrate more than the standard breakfast and fasted conditions. Specifically, the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and peak plasma concentration (C(max)) increased 2.45-fold and 2.89-fold, respectively, between the fasted and standard-fed conditions (p fenofibric acid. In healthy volunteers, AUC(infinity) and C(max) of fenofibrate, when administered via sustained-release capsules immediately after the consumption of food, was increased significantly from the fasting conditions (p < 0.01). The greatest AUC(infinity) and C(max) occurred when the capsules were taken after a high-fat breakfast.

  9. Survival and digestibility of orally-administered immunoglobulin preparations containing IgG through the gastrointestinal tract in humans.

    Science.gov (United States)

    Jasion, Victoria S; Burnett, Bruce P

    2015-03-07

    Oral immunoglobulin (Ig) preparations are prime examples of medicinal nutrition from natural sources. Plasma products containing Ig have been used for decades in animal feed for intestinal disorders to mitigate the damaging effects of early weaning. These preparations reduce overall mortality and increase feed utilization in various animal species leading to improved growth. Oral administration of Ig preparations from human serum as well as bovine colostrum and serum have been tested and proven to be safe as well as effective in human clinical trials for a variety of enteric microbial infections and other conditions which cause diarrhea. In infants, children, and adults, the amount of intact IgG recovered in stool ranges from trace amounts up to 25% of the original amount ingested. It is generally understood that IgG can only bind to antigens within the GI tract if the Fab structure is intact and has not been completely denatured through acidic pH or digestive proteolytic enzymes. This is a comprehensive review of human studies regarding the survivability of orally-administered Ig preparations, with a focus on IgG. This review also highlights various biochemical studies on IgG which potentially explain which structural elements are responsible for increased stability against digestion.

  10. Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model

    Science.gov (United States)

    Jiang, Chun-Bin; Cheng, Mei-Lien; Liu, Chia-Yuan; Chang, Szu-Wen; Chiang Chiau, Jen-Shiu; Lee, Hung-Chang

    2015-01-01

    Background and Aims Intestinal mucositis is a frequently encountered side effect in oncology patients undergoing chemotherapy. No well-established or up to date therapeutic strategies are available. To study a novel way to alleviate mucositis, we investigate the effects and safety of probiotic supplementation in ameliorating 5-FU-induced intestinal mucositis in a mouse model. Methods Seventy-two mice were injected saline or 5-Fluorouracil (5-FU) intraperitoneally daily. Mice were either orally administrated daily saline, probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35) or Lactobacillus acidophilus and Bifidobacterium bifidum (LaBi). Diarrhea score, pro-inflammatory cytokines serum levels, intestinal villus height and crypt depth and total RNA from tissue were assessed. Samples of blood, liver and spleen tissues were assessed for translocation. Results Marked diarrhea developed in the 5-FU groups but was attenuated after oral Lcr35 and LaBi administrations. Diarrhea scores decreased significantly from 2.64 to 1.45 and 0.80, respectively (Pprobiotics administration. We also found TNF-α, IL-1β and IL-6 mRNA expressions were up-regulated in intestinal mucositis tissues following 5-FU treatment (TNF-α: 4.35 vs. 1.18, IL-1β: 2.29 vs. 1.07, IL-6: 1.49 vs. 1.02) and that probiotics treatment suppressed this up-regulation (Pprobiotics Lcr35 and LaBi can ameliorate chemotherapy-induced intestinal mucositis in a mouse model. This suggests probiotics may serve as an alternative therapeutic strategy for the prevention or management of chemotherapy-induced mucositis in the future. PMID:26406888

  11. Triple Recycling Processes Impact Systemic and Local Bioavailability of Orally Administered Flavonoids.

    Science.gov (United States)

    Dai, Peimin; Zhu, Lijun; Luo, Feifei; Lu, Linlin; Li, Qiang; Wang, Liping; Wang, Ying; Wang, Xinchun; Hu, Ming; Liu, Zhongqiu

    2015-05-01

    Triple recycling (i.e., enterohepatic, enteric and local recycling) plays a central role in governing the disposition of phenolics such as flavonoids, resulting in low systemic bioavailability but higher gut bioavailability and longer than expected apparent half-life. The present study aims to investigate the coexistence of these recycling schemes using model bioactive flavonoid tilianin and a four-site perfused rat intestinal model in the presence or absence of a lactase phlorizin hydrolase (LPH) inhibitor gluconolactone and/or a glucuronidase inhibitor saccharolactone. The result showed that tilianin could be metabolized into tilianin glucuronide, acacetin, and acacetin glucuronide, which are excreted into the bile and luminal perfusate (highest in the duodenum and lowest in the colon). Gluconolactone (20 mM) significantly reduced the absorption of tilianin and the enteric and biliary excretion of acacetin glucuronide. Saccharolactone (0.1 mM) alone or in combination of gluconolactone also remarkably reduced the biliary and intestinal excretion of acacetin glucuronide. Acacetin glucuronides from bile or perfusate were rapidly hydrolyzed by bacterial β-glucuronidases to acacetin, enabling enterohepatic and enteric recycling. Moreover, saccharolactone-sensitive tilianin disposition and glucuronide deconjugation, which was more active in the small intestine than the colon, points to the small intestinal origin of the deconjugation enzyme and supports the presence of local recycling scheme. In conclusion, our studies have demonstrated triple recycling of a bioactive phenolic (i.e., a model flavonoid), and this recycling may have an impact on the site and duration of polyphenols pharmacokinetics in vivo.

  12. Antithrombotic properties of SSR182289A, a new, orally active thrombin inhibitor.

    Science.gov (United States)

    Lorrain, J; Millet, L; Lechaire, I; Lochot, S; Ferrari, P; Visconte, C; Sainte-Marie, M; Lunven, C; Berry, C N; Schaeffer, P; Herbert, J-M; O'Connor, S E

    2003-02-01

    N-[3-[[[(1S)-4-(5-Amino-2-pyridinyl)-1-[[4-difluoromethylene)-1-piperidinyl]carbonyl]butyl]amino]sulfonyl][1,1'-biphenyl]-2-yl]acetamide hydrochloride (SSR182289A) is a novel, potent, and selective thrombin inhibitor. We have examined the antithrombotic properties of SSR182289A administered by i.v. and p.o. routes in several different animal thrombosis models in comparison with reference antithrombotic agents. Oral administration of SSR182289A produced dose-related antithrombotic effects in the following models; rat venous thrombosis (ED(50) 0.9 mg/kg p.o.), rat silk thread arterio-venous (AV) shunt (ED(50) 3.8 mg/kg p.o.), rat thromboplastin-induced AV shunt (ED(50) 3.1 mg/kg p.o.), rat carotid artery thrombosis (ED(200) 5.9 mg/kg p.o.), and rabbit venous thrombosis (ED(50) 7.5 mg/kg p.o.). Administered as an i.v. bolus, SSR182289A showed antithrombotic activity in the above models with ED(50)/ED(200) values in the range of 0.2 to 1.9 mg/kg i.v. SSR182289A increased rat tail transection bleeding time at doses > or =10 mg/kg p.o. In the rat thromboplastin-induced AV shunt model, SSR182289A 10 mg/kg p.o. produced marked antithrombotic effects at 30, 60, 120, and 240 min after administration. Hence, SSR182289A demonstrates potent oral antithrombotic properties in animal venous, AV-shunt, and arterial thrombosis models.

  13. Decorporation of systemically distributed americium by a novel orally administered diethylenetriaminepentaacetic acid (DTPA) formulation in beagle dogs.

    Science.gov (United States)

    Wilson, James P; Cobb, Ronald R; Dungan, Nathanael W; Matthews, Laura L; Eppler, Bärbel; Aiello, Kenneth V; Curtis, Shiro; Boger, Teannetta; Guilmette, Raymond A; Weber, Waylon; Doyle-Eisele, Melanie; Talton, James D

    2015-03-01

    Novel decorporation agents are being developed to protect against radiological accidents and terrorists attacks. Radioactive americium is a significant component of nuclear fallout. Removal of large radioactive materials, such as 241Am, from exposed persons is a subject of significant interest due to the hazards they pose. The objective of this study was to evaluate the dose-related efficacy of daily doses of NanoDTPA™ Capsules for decorporating Am administered intravenously as a soluble citrate complex to male and female beagle dogs. In addition, the efficacy of the NanoDTPA™ Capsules for decorporating 241Am was directly compared to intravenously administered saline and DTPA. Animals received a single IV administration of 241Am(III)-citrate on Day 0. One day after radionuclide administration, one of four different doses of NanoDTPA™ Capsules [1, 2, or 6 capsules d(-1) (30 mg, 60 mg, or 180 mg DTPA) or 2 capsules BID], IV Zn-DTPA (5 mg kg(-1) pentetate zinc trisodium) as a positive control, or IV saline as a placebo were administered. NanoDTPA™ Capsules, IV Zn-DTPA, or IV saline was administered on study days 1-14. Animals were euthanized on day 21. A full necropsy was conducted, and liver, spleen, kidneys, lungs and trachea, tracheobronchial lymph nodes (TBLN), muscle samples (right and left quadriceps), gastrointestinal (GI) tract (stomach plus esophagus, upper and lower intestine), gonads, two femurs, lumbar vertebrae (L1-L4), and all other soft tissue remains were collected. Urinary and fecal excretion profiles were increased approximately 10-fold compared to those for untreated animals. Tissue contents were decreased compared to untreated controls. In particular, liver content was decreased by approximately eightfold compared to untreated animals. The results from this study further demonstrate that oral NanoDTPA™ Capsules are equally efficient compared to IV Zn-DTPA in decorporation of actinides.

  14. Pharmacokinetics, safety, and hydrolysis of oral pyrroloquinazolinediamines administered in single and multiple doses in rats.

    Science.gov (United States)

    Li, Qigui; Kozar, Michael P; Shearer, Todd W; Xie, Lisa H; Lin, Ai J; Smith, Kirsten S; Si, Yuanzheng; Anova, Lalaine; Zhang, Jing; Milhous, Wilbur K; Skillman, Donald R

    2007-08-01

    Pyrroloquinazolinediamine (PQD) derivatives such as tetra-acetamide PQD (PQD-A4) and bis-ethylcarbamyl PQD (PQD-BE) were much safer (with therapeutic indices of 80 and 32, respectively) than their parent compound, PQD (therapeutic index, 10). Further evaluation of PQD-A4 and PQD-BE in single and multiple pharmacokinetic (PK) studies as well as corresponding toxicity studies was conducted with rats. PQD-A4 could be converted to two intermediate metabolites (monoacetamide PQD and bisacetamide PQD) first and then to the final metabolite, PQD, while PQD-BE was directly hydrolyzed to PQD without precursor and intermediate metabolites. Maximum tolerant doses showed that PQD-A4 and PQD-BE have only 1/12 and 1/6, respectively, of the toxicity of PQD after a single oral dose. Compared to the area under the concentration-time curve for PQD alone (2,965 ng.h/ml), values measured in animals treated with PQD-A4 and PQD-BE were one-third (1,047 ng.h/ml) and one-half (1,381 ng.h/ml) as high, respectively, after an equimolar dosage, suggesting that PQD was the only agent to induce the toxicity. Similar results were also shown in multiple treatments; PQD-A4 and PQD-BE generated two-fifths and three-fifths, respectively, of PQD concentrations, with 8.8-fold and 3.8-fold safety margins, respectively, over the parent drug. PK data indicated that the bioavailability of oral PQD-A4 was greatly limited at high dose levels, that PQD-A4 was slowly converted to PQD via a sequential three-step process of conversion, and that PQD-A4 was significantly less toxic than the one-step hydrolysis drug, PQD-BE. It was concluded that the slow and smaller release of PQD was the main reason for the reduction in toxicity and that the active intermediate metabolites can still maintain antimalarial potency. Therefore, the candidate with multiple-step hydrolysis of PQD could be developed as a safer potential agent for malaria treatment.

  15. Assessment of the effects of orally administered ferrous sulfate on Oncopeltus fasciatus (Heteroptera: Lygaeidae).

    Science.gov (United States)

    Ferrero, Amparo; Torreblanca, Amparo; Garcerá, María Dolores

    2017-03-01

    Iron is an essential nutrient needed for multiple biological processes, but it is also an effective pro-oxidant in its reduced form. Environmental sources of iron toxic species include reduced soils from rice plantations, polluted natural areas from metal industry waste, or iron oxides used in soil bioremediation. Few studies have been conducted to assess the toxicity of iron species in insects. The present work aims to assess the oxidative stress effects of ferrous sulfate administered in drinking water after acute exposure (96 h) to adults of the insect model Oncopeltus fasciatus (Dallas). Mortality was higher in exposed groups and significantly associated with iron treatment (OR [95% CI]; 11.8 [6.1-22.7]). Higher levels of body iron content were found in insects exposed to ferrous sulfate, with an increase of 5-6 times with respect to controls. Catalase activity and lipid peroxidation (TBARS content), but not glutathione S-transferase activity, were significantly higher in exposed insects and significantly correlated with body iron content (Pearson coefficient of 0.68 and 0.74, respectively) and between them (0.78). The present work demonstrates that, despite the disruption in water and food intake caused by iron administration, this metal is accumulated by insect causing lipid peroxidation and eliciting an antioxidant response mediated by catalase.

  16. Quantitative Evaluation of Compliance with Recommendation for Sulfonylurea Dose Co-Administered with DPP-4 Inhibitors in Japan

    Directory of Open Access Journals (Sweden)

    Motonobu Sakaguchi

    2012-09-01

    Full Text Available After the launch of dipeptidyl peptidase-4 (DPP-4, a new oral hypoglycemic drug (OHD, in December 2009, severe hypoglycemia cases were reported in Japan. Although the definite cause was unknown, co-administration with sulfonylureas (SU was suspected as one of the potential risk factors. The Japan Association for Diabetes Education and Care (JADEC released a recommendation in April 2010 to lower the dose of three major SUs (glimepiride, glibenclamide, and gliclazide when adding a DPP-4 inhibitor. To evaluate the effectiveness of this risk minimization action along with labeling changes, dispensing records for 114,263 patients prescribed OHDs between December 2008 and December 2010 were identified in the Nihon-Chouzai pharmacy claims database. The adherence to the recommended dosing of SU co-prescribed with DPP-4 inhibitors increased from 46.3% before to 63.8% after the JADEC recommendation (p < 0.01 by time-series analysis, while no change was found in those for SU monotherapy and SU with other OHD co-prescriptions. The adherence was significantly worse for those receiving a glibenclamide prescription. The JADEC recommendation, along with labeling changes, appeared to have a favorable effect on the risk minimization action in Japan. In these instances, a pharmacy claims database can be a useful tool to evaluate risk minimization actions.

  17. Improving the prediction of the brain disposition for orally administered drugs using BDDCS

    DEFF Research Database (Denmark)

    Broccatelli, Fabio; Larregieu, Caroline A.; Cruciani, Gabriele;

    2012-01-01

    In modeling blood–brain barrier (BBB) passage, in silico models have yielded ~80% prediction accuracy, and are currently used in early drug discovery. Being derived from molecular structural information only, these models do not take into account the biological factors responsible for the in vivo...... were found to markedly distribute throughout the brain; this includes a number of BDDCS class 1 drugs shown to be Pgp substrates. This new perspective provides a further interpretation of how Pgp influences the sedative effects of H1-histamine receptor antagonists.......In modeling blood–brain barrier (BBB) passage, in silico models have yielded ~80% prediction accuracy, and are currently used in early drug discovery. Being derived from molecular structural information only, these models do not take into account the biological factors responsible for the in vivo...... outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB...

  18. Fate of orally administered radioactive fatty acids in the late-pregnant rat.

    Science.gov (United States)

    López-Luna, Pilar; Ortega-Senovilla, Henar; López-Soldado, Iliana; Herrera, Emilio

    2016-03-01

    To investigate the biodisponibility of placental transfer of fatty acids, rats pregnant for 20 days were given tracer amounts of [(14)C]palmitic (PA), oleic (OA), linoleic (LA), α-linolenic (LNA), or docosahexaenoic acid (DHA) orally and euthanized at 0.5, 1.0, 2.0, or 8.0 h thereafter. Maternal plasma radioactivity in lipids initially increased only to decline at later times. Most of the label appeared first as triacylglycerols (TAG); later, the proportion in phospholipids (PhL) increased. The percentage of label in placental lipids was also always highest shortly after administration and declined later; again, PhL increased with time. Fetal plasma radioactivity increased with time, with its highest value at 8.0 h after DHA or LNA administration. DHA initially appeared primarily in the nonesterified fatty acids (NEFA) and PA, OA, LA, and LNA as TAG followed by NEFA; in all cases, there was an increase in PhL at later times. Measurement of fatty acid concentrations allowed calculation of specific (radio)activities, and the ratio (fetal/maternal) of these in the plasmas gave an index of placental transfer activity, which was LNA > LA > DHA = OA > PA. It is proposed that a considerable proportion of most fatty acids transferred through the placenta are released into the fetal circulation in the form of TAG.

  19. Corn oil and milk enhance the absorption of orally administered allyl isothiocyanate in rats.

    Science.gov (United States)

    Ippoushi, Katsunari; Ueda, Hiroshi; Takeuchi, Atsuko

    2013-11-15

    Allyl isothiocyanate, a chief component of mustard oil, exhibits anticancer effects in both cultured cancer cells and animal models. The accumulation of the N-acetylcysteine conjugate of allyl isothiocyanate, the final metabolite of allyl isothiocyanate, in urine was evaluated in rats that were orally coadministered allyl isothiocyanate with fluids (e.g., water, green tea, milk, and 10% ethanol) or corn oil. The N-acetylcysteine conjugate of allyl isothiocyanate content in urine when allyl isothiocyanate (2 or 4μmol) was coadministered with corn oil or milk showed a greater increase (1.4±0.22 or 2.7±0.34μmol or 1.2±0.32 or 2.5±0.36μmol, 1.6- to 1.8-fold or 1.5-fold, respectively) than when allyl isothiocyanate (2 or 4μmol) was coadministered with water (0.78±0.10 or 1.7±0.17μmol). This result demonstrates that corn oil and milk enhance the absorption of allyl isothiocyanate in rats.

  20. Orally administered whole egg demonstrates antidepressant-like effects in the forced swimming test on rats.

    Science.gov (United States)

    Nagasawa, Mao; Otsuka, Tsuyoshi; Ogino, Yumi; Yoshida, Junki; Tomonaga, Shozo; Yasuo, Shinobu; Furuse, Mitsuhiro

    2014-08-01

    Several studies have reported that vegetarian diets are associated with a higher prevalence of major depression. Therefore, we hypothesised that the consumption of animal products, especially eggs, may have positive effects on mental health, especially on major depression, because a previous study reported that egg consumption produces numerous beneficial effects in humans. The purpose of the present study was to evaluate the effects of chronic whole-egg treatment on depression-like behaviours in Wistar rats, a control strain, and Wistar Kyoto rats, an animal model of depression. In both the rats, either whole-egg solution (5 ml/kg) or distilled water (5 ml/kg) was orally administrated for 35 days. During these periods, the open-field test (OFT) was conducted on the 21st day, and a forced swimming test (FST) was enforced on the 27th and 28th days. On the 36th day, the plasma and brain were collected. Chronic whole-egg treatment did not affect line crossing in the OFT, whereas it reduced the total duration of immobility in the FST on both strains. Furthermore, interestingly, the results indicated the possibility that whole-egg treatment elevated the incorporation of tryptophan into the brain, and the tryptophan concentration in the prefrontal cortex was actually increased by the treatment. This study demonstrated that whole-egg treatment exerts an antidepressant-like effect in the FST. It is suggested that whole egg may be an excellent food for preventing and alleviating the conditions of major depression.

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

    Science.gov (United States)

    Vogt, Josef A; Denzer, Christian

    2013-04-01

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

  2. Effectiveness of orally administered cupric oxide needles in alleviating hypocupraemia in sheep and cattle.

    Science.gov (United States)

    Suttle, N F

    1981-05-09

    The oral administration of a small dose of cupric oxide "needles" (CuOn), providing 0.5 g copper, to hypocupraemic ewes maintained on a copper-deficient diet alleviated hypocupraemia for 111 days when the diet was supplemented with molybdenum and sulphate and for 301 days when the diet was not supplemented. The same amount of copper given as cupric sulphate was approximately half as effective. The administration of a large dose of CuOn, providing 40 g copper, to hypocupraemic steers and heifers alleviated hypocupraemia for not less than 41 days, at which time a substantial reserve of copper (428 mg) remained in the liver. The absorbability of copper in CuOn was estimated to be 8.3 per cent and 3.8 per cent (depending on diet) for sheep. It was calculated that enough absorbable copper could be provided in a single dose to meet the net copper requirements of ewes for several years. This new form of copper therapy demands a totally different approach from that associated with parenteral copper usage.

  3. Antiosteoporotic effect of orally administered yolk-derived peptides on bone mass in women.

    Science.gov (United States)

    Abdou, Adham M; Watabe, Kazuya; Yamane, Tetsuro; Isono, Tadayuki; Okamura, Yoshitaka; Kawahito, Seiji; Takeshima, Kazuhito; Masuda, Kazuyuki; Kim, Mujo

    2014-05-01

    The main objective of this study was to verify the effect of oral intake of a yolk-derived peptide preparation (HYP) obtained by enzymatic hydrolysis of yolk water-soluble protein on bone markers and bone density in 65 perimenopausal women with an average age of 47.6 ± 5.2 years. Subjects were divided into three groups, and then enrolled in a 6-month, randomized, double-blind clinical trial. Bone formation and resorption markers were measured at 0, 3, and 6 months, while bone mineral density (BMD) in the lumbar spines was measured at 0 and 6 months. Although the bone formation marker levels showed the similarity changes among the groups, bone resorption markers in the test HYP group were significantly decreased after 3 and 6 months in comparison to other groups (P < 0.05). After 6 months, BMD in the test HYP group maintained at healthy numerical values whereas BMD values were decreased in other groups. Hence HYP would be an antiosteoporotic agent originated from natural food to maintain bone health, especially for women.

  4. The pharmacokinetics of orally administered ivermectin in African elephants (Loxodonta africana): implications for parasite elimination.

    Science.gov (United States)

    Gandolf, A Rae; Lifschitz, A; Stadler, C; Watson, B; Galvanek, L; Ballent, M; Lanusse, C

    2009-03-01

    Loxodonta africana are susceptible to a wide variety of parasites that are often treated with the broad spectrum antiparasitic ivermectin (IVM) based on empirical knowledge. The objectives of this study were to 1) measure plasma IVM levels following administration of 0.1 mg/kg IVM p.o., 2) compare plasma IVM levels following administration with regular versus restricted feed rations, 3) measure IVM excretion in feces, and 4) use these findings to generate dosing recommendations for this species. Using a crossover design, six African elephants were divided into two groups. Ivermectin was administered and typical grain rations were either provided or withheld for 2 hr. Blood and fecal samples were collected for 7 days following drug administration. After a 5-wk washout period, groups were switched and the procedure repeated. Plasma and fecal IVM were analyzed using high-performance liquid chromatography. There was no statistically significant difference detected in the pharmacokinetic data between the fed and fasted groups. Peak plasma concentration, area under the curve, and half-life for plasma ranged between 5.41-8.49 ng/ml, 17.1-20.3 ng x day/ml, and 3.12-4.47 day, respectively. High IVM concentrations were detected in feces. The peak concentration values in feces were between 264-311-fold higher than those obtained in plasma. The comparatively large area under the curve and short time to maximum concentration in feces indicate elimination prior to absorption of much of the drug. Plasma IVM concentrations were low when compared to other species. Based on these findings, administration of 0.2-0.4 mg/kg p.o. should be appropriate for eliminating many types of parasites in elephants, and could minimize development of parasite resistance.

  5. Assessment of vitamin B(12) absorption based on the accumulation of orally administered cyanocobalamin on transcobalamin.

    Science.gov (United States)

    Hardlei, Tore Forsingdal; Mørkbak, Anne Louise; Bor, Mustafa Vakur; Bailey, Lynn B; Hvas, Anne-Mette; Nexo, Ebba

    2010-03-01

    Vitamin B(12), or cobalamin (Cbl), is absorbed in the intestine and transported to the cells bound to transcobalamin (TC). We hypothesize that cyanocobalamin (CNCbl) is absorbed unchanged, thereby allowing measurement of the complex of CNCbl bound to TC (TC-CNCbl) to be used for studying the absorption of the vitamin. TC was immunoprecipitated from serum samples obtained from healthy donors at baseline and at 24 h after oral administration of three 9-microg CNCbl doses over 1 day. Cbl was released by treatment with subtilisin Carlsberg. The different forms of Cbl were isolated by HPLC and subsequently quantified with an ELISA-based Cbl assay. At baseline, the median TC-CNCbl concentration was 1 pmol/L (range, 0-10 pmol/L); the intraindividual variation (SD) was 1.6 pmol/L (n = 31). After CNCbl administration, the TC-CNCbl concentration increased significantly (P = 0.0003, paired t-test), whereas no major changes were observed in any of the other Cbl forms bound to TC (n = 10). Only a moderate additional increase in TC-CNCbl was observed with prolonged (5 days) CNCbl administration (n = 10). We designed an absorption test based on measuring TC-CNCbl at baseline and 24 h after CNCbl intake and established a reference interval for the increase in TC-CNCbl (n = 78). The median absolute increase was 23 pmol/L (range, 6-64 pmol/L), and the relative increase was >3-fold. Our data demonstrate that CNCbl is absorbed unchanged and accumulates on circulating TC. We suggest that measuring TC-CNCbl will improve the assessment of vitamin B(12) absorption.

  6. Orally administered novel cyclic pentapeptide P-317 alleviates symptoms of diarrhoea-predominant irritable bowel syndrome.

    Science.gov (United States)

    Zielińska, Marta; Chen, Chunqiu; Mokrowiecka, Anna; Cygankiewicz, Adam I; Zakrzewski, Piotr K; Sałaga, Maciej; Małecka-Panas, Ewa; Wlaź, Piotr; Krajewska, Wanda M; Fichna, Jakub

    2015-02-01

    The aim of our study was to characterize the effect of P-317, a novel cyclic derivative of morphiceptin, on gastrointestinal (GI) motility and abdominal pain in mouse models mimicking symptoms of diarrhoea-predominant irritable bowel syndrome (IBS-D). The effect of P-317 on mouse intestinal motility was characterized in vitro and in vivo in physiological and pathophysiological conditions. The antinociceptive action of P-317 was characterized in the mustard oil-induced abdominal pain model and the writhing test. Locomotor activity and grip-strength tests were used to evaluate the effect of P-317 in the central nervous system (CNS). To translate our study to clinical conditions, the semi-quantitative expression of μ-opioid receptors (MOP) and κ-opioid receptors (KOP) messenger RNA (mRNA) in human colonic samples from IBS-D patients was quantified. In vitro, P-317 (10(-10) -10(-6) M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent, β-funaltrexamine and nor-binaltorphimine-reversible manner. In vivo, P-317 (0.1 mg/kg, i.p. and 1 mg/kg, p.o.) inhibited GI transit, displayed a potent antinociceptive action in abdominal pain tests and did not influence the CNS. P-317 produced a potent analgesic and antidiarrhoeal action in the mouse GI tract after oral administration. Given lower expression of MOP and KOP mRNA in IBS-D patients, P-317 is a promising peptide-based drug candidate for IBS-D therapy. © 2014 Royal Pharmaceutical Society.

  7. Plasma Drug Concentrations of Orally Administered Rosuvastatin in Hispaniolan Amazon Parrots (Amazona ventralis).

    Science.gov (United States)

    Beaufrère, Hugues; Papich, Mark G; Brandão, João; Nevarez, Javier; Tully, Thomas N

    2015-03-01

    Atherosclerotic diseases are common in pet psittacine birds, in particular Amazon parrots. While hypercholesterolemia and dyslipidemia have not definitely been associated with increased susceptibility to atherosclerosis in parrots, these are important and well-known risk factors in humans. Therefore statin drugs such as rosuvastatin constitute the mainstay of human treatment of dyslipidemia and the prevention of atherosclerosis. No pharmacologic studies have been performed in psittacine birds despite the high prevalence of atherosclerosis in captivity. Thirteen Hispaniolan Amazon parrots were used to test a single oral dose of 10 mg/kg of rosuvastatin with blood sampling performed according to a balanced incomplete block design over 36 hours. Because low plasma concentrations were produced in the first study, a subsequent pilot study using a dose of 25 mg/kg in 2 Amazon parrots was performed. Most plasma samples for the 10 mg/kg dose and all samples for the 25 mg/kg dose had rosuvastatin concentration below the limits of quantitation. For the 10 mg/kg study, the median peak plasma concentration and time to peak plasma concentration were 0.032 μg/mL and 2 hours, respectively. Our results indicate that rosuvastatin does not appear suitable in Amazon parrots as compounded and used at the dose in this study. Pharmacodynamic studies investigating lipid-lowering effects of statins rather than pharmacokinetic studies may be more practical and cost effective in future studies to screen for a statin with more ideal properties for potential use in psittacine dyslipidemia and atherosclerotic diseases.

  8. Pharmacokinetics of orally administered phenylbutazone in African and Asian elephants (Loxodonta africana and Elephas maximus).

    Science.gov (United States)

    Bechert, Ursula; Christensen, J Mark; Nguyen, C; Neelkant, R; Bendas, E

    2008-06-01

    The pharmacokinetic parameters of phenylbutazone were determined in 18 elephants (Loxodonta africana and Elephas maximus) after single-dose oral administration of 2, 3, and 4 mg/kg phenylbutazone, as well as multiple-dose administrations with a 4-wk washout period between trials. After administration of 2 mg/kg phenylbutazone, mean serum concentrations peaked in approximately 7.5 hr at 4.3 +/- 2.02 microg/ml and 9.7 hr at 7.1 +/- 2.36 microg/ml for African and Asian elephants, respectively, while 3 mg/kg dosages resulted in peak serum concentrations of 7.2 +/- 4.06 microg/ml in 8.4 hr and 12.1 +/- 3.13 microg/ml in 14 hr. The harmonic mean half-life was long, ranging between 13 and 15 hr and 39 and 45 hr for African and Asian elephants, respectively. There was evidence of enterohepatic cycling of phenylbutazone in Asian elephants. Significant differences (P < 0.0001) in pharmacokinetic values occurred between African and Asian elephants for clearance (27.9 and 7.6 ml/hr/kg, respectively), terminal half-life (15.0 and 38.7 hr, respectively), and mean residence time (22.5 and 55.5 hr, respectively) using 2-mg/kg dosages as an example. This suggests that different treatment regimens for Asian and African elephants should be used. There were no apparent gender differences in these parameters for either elephant species.

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

    Directory of Open Access Journals (Sweden)

    J.J. Fourie

    2005-06-01

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

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

    Science.gov (United States)

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

    2006-01-01

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

  11. Attenuation of obesity-induced inflammation in mice orally administered with salmon cartilage proteoglycan, a prophylactic agent.

    Science.gov (United States)

    Hirose, Shouhei; Asano, Krisana; Nakane, Akio

    2017-03-11

    Obesity is associated with chronic inflammation of adipose tissue and causes development of type 2 diabetes. M1 macrophage population was increased in adipose tissue of obese mouse. M1 macrophages induce insulin resistance through the secretion of proinflammatory cytokines. Our previous studies demonstrated that salmon cartilage proteoglycan (PG) suppresses excess inflammation in various mouse inflammatory diseases. In this study, we examined the effect of PG on type 2 diabetes using high-fat-diet (HFD) induced obese mouse model. Oral PG administration enhanced the population of small adipocytes (area less than 1000 μm(2)) without body and tissue weight gain. In addition, PG administration suppressed mRNA expression of TNF-α, IL-6 and CXCL2 in adipose tissue. The proportion of M1 macrophages was decreased by PG administration. In addition, PG administration suppressed hyperglycemia after intraperitoneal glucose injection. Fasted serum insulin level was decreased in PG-administered mice. Moreover, insulin-stimulated phosphorylation of Akt was enhanced in the liver and gastrocnemius skeletal muscle of PG-administered mice. These data suggested that PG administration improves hyperglycemia and insulin sensitivity in obese mice by modulation of M1 macrophages which secrete proinflammatory cytokines in adipose tissue and activation of Akt in liver and skeletal muscle.

  12. Orally administered P22 phage tailspike protein reduces salmonella colonization in chickens: prospects of a novel therapy against bacterial infections.

    Directory of Open Access Journals (Sweden)

    Shakeeba Waseh

    Full Text Available One of the major causes of morbidity and mortality in man and economically important animals is bacterial infections of the gastrointestinal (GI tract. The emergence of difficult-to-treat infections, primarily caused by antibiotic resistant bacteria, demands for alternatives to antibiotic therapy. Currently, one of the emerging therapeutic alternatives is the use of lytic bacteriophages. In an effort to exploit the target specificity and therapeutic potential of bacteriophages, we examined the utility of bacteriophage tailspike proteins (Tsps. Among the best-characterized Tsps is that from the Podoviridae P22 bacteriophage, which recognizes the lipopolysaccharides of Salmonella enterica serovar Typhimurium. In this study, we utilized a truncated, functionally equivalent version of the P22 tailspike protein, P22sTsp, as a prototype to demonstrate the therapeutic potential of Tsps in the GI tract of chickens. Bacterial agglutination assays showed that P22sTsp was capable of agglutinating S. Typhimurium at levels similar to antibodies and incubating the Tsp with chicken GI fluids showed no proteolytic activity against the Tsp. Testing P22sTsp against the three major GI proteases showed that P22sTsp was resistant to trypsin and partially to chymotrypsin, but sensitive to pepsin. However, in formulated form for oral administration, P22sTsp was resistant to all three proteases. When administered orally to chickens, P22sTsp significantly reduced Salmonella colonization in the gut and its further penetration into internal organs. In in vitro assays, P22sTsp effectively retarded Salmonella motility, a factor implicated in bacterial colonization and invasion, suggesting that the in vivo decolonization ability of P22sTsp may, at least in part, be due to its ability to interfere with motility… Our findings show promise in terms of opening novel Tsp-based oral therapeutic approaches against bacterial infections in production animals and potentially in

  13. RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase.

    Science.gov (United States)

    Amin, D; Rutledge, R Z; Needle, S N; Galczenski, H F; Neuenschwander, K; Scotese, A C; Maguire, M P; Bush, R C; Hele, D J; Bilder, G E; Perrone, M H

    1997-05-01

    Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation of other products of the isoprenoid pathway, such as dolichol and ubiquinone. RPR 107393 [3-hydroxy-3-[4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane dihydrochloride] and its R and S enantiomers are potent inhibitors of rat liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM. One hour after oral administration to rats, RPR 107393 inhibited de novo [14C]cholesterol biosynthesis from [14C]mevalonate in the liver with an ED50 value of 5 mg/kg. Diacid metabolites of [14C]farnesyl pyrophosphate were identified after acid treatment of the livers of these animals. These results support in vitro data demonstrating that these compounds are inhibitors of squalene synthase. In rats, RPR 107393 (30 mg/kg p.o. b.i.d. for 2 days) reduced total serum cholesterol by RPR 107393 (20 mg/kg b.i.d.) reduced plasma cholesterol concentration by 50% after 1 week of administration; this was greater than the reduction observed with lovastatin or pravastatin, neither of which produced > 31% reduction in plasma cholesterol when administered for 1 week at a dose of 50 mg/kg b.i.d. The R and S enantiomers of RPR 107393 (20 mg/kg p.o. q.d. for 7 days) reduced plasma low density lipoprotein cholesterol by 50% and 43%, respectively, whereas high density lipoprotein cholesterol was unchanged. In summary, RPR 107393 is a potent inhibitor of squalene synthase. It is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset.

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

    Science.gov (United States)

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

    2013-07-01

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

  15. The fate of calcium carbonate nanoparticles administered by oral route: absorption and their interaction with biological matrices

    Directory of Open Access Journals (Sweden)

    Lee JA

    2015-03-01

    Full Text Available Jeong-A Lee,1,* Mi-Kyung Kim,1,* Hyoung-Mi Kim,2,* Jong Kwon Lee,3 Jayoung Jeong,4 Young-Rok Kim,5 Jae-Min Oh,2 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women’s University, Seoul, Republic of Korea; 2Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Republic of Korea; 3Hazard Substances Analysis Division, Gwangju Regional Food and Drug Administration, Ministry of Food and Drug Safety, Gwangju, Republic of Korea; 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, Republic of Korea; 5Department of Food Science and Biotechnology, Kyung Hee University, Yongin, Republic of Korea *These authors contributed equally to this work Background: Orally administered particles rapidly interact with biological fluids containing proteins, enzymes, electrolytes, and other biomolecules to eventually form particles covered by a corona, and this corona potentially affects particle uptake, fate, absorption, distribution, and elimination in vivo. This study explored relationships between the biological interactions of calcium carbonate particles and their biokinetics.Methods: We examined the effects of food grade calcium carbonates of different particle size (nano [N-Cal] and bulk [B-Cal]: specific surface areas of 15.8 and 0.83 m2/g, respectively on biological interactions in in vitro simulated physiological fluids, ex vivo biofluids, and in vivo in gastrointestinal fluid. Moreover, absorption and tissue distribution of calcium carbonates were evaluated following a single dose oral administration to rats.Results: N-Cal interacted more with biomatrices than bulk materials in vitro and ex vivo, as evidenced by high fluorescence quenching ratios, but it did not interact more actively with biomatrices in vivo. Analysis of coronas revealed that immunoglobulin, apolipoprotein, thrombin, and fibrinogen

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

    Science.gov (United States)

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

    2012-01-01

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

  17. Effect of orally administered collagen hydrolysate on gene expression profiles in mouse skin: a DNA microarray analysis.

    Science.gov (United States)

    Oba, Chisato; Ito, Kyoko; Ichikawa, Satomi; Morifuji, Masashi; Nakai, Yuji; Ishijima, Tomoko; Abe, Keiko; Kawahata, Keiko

    2015-08-01

    Dietary collagen hydrolysate has been hypothesized to improve skin barrier function. To investigate the effect of long-term collagen hydrolysate administration on the skin, we evaluated stratum corneum water content and skin elasticity in intrinsically aged mice. Female hairless mice were fed a control diet or a collagen hydrolysate-containing diet for 12 wk. Stratum corneum water content and skin elasticity were gradually decreased in chronologically aged control mice. Intake of collagen hydrolysate significantly suppressed such changes. Moreover, we used DNA microarrays to analyze gene expression in the skin of mice that had been administered collagen hydrolysate. Twelve weeks after the start of collagen intake, no significant differences appeared in the gene expression profile compared with the control group. However, 1 wk after administration, 135 genes were upregulated and 448 genes were downregulated in the collagen group. This suggests that gene changes preceded changes of barrier function and elasticity. We focused on several genes correlated with functional changes in the skin. Gene Ontology terms related to epidermal cell development were significantly enriched in upregulated genes. These skin function-related genes had properties that facilitate epidermal production and differentiation while suppressing dermal degradation. In conclusion, our results suggest that altered gene expression at the early stages after collagen administration affects skin barrier function and mechanical properties. Long-term oral intake of collagen hydrolysate improves skin dysfunction by regulating genes related to production and maintenance of skin tissue.

  18. Roles of secretory leukocyte protease inhibitor amniotic membrane in oral wound healing

    Directory of Open Access Journals (Sweden)

    Elly Munadziroh

    2006-12-01

    Full Text Available Secretory Leukocyte Protease Inhibitor (SLPI is serine protease inhibitor. Secretory Leukocyte Protease Inhibitor is a protein found in secretions such as whole saliva, seminal fluid, cervical mucus, synovial fluid, breast milk, tears, and cerebral spinal fluid, as in secretions from the nose and bronchi, amniotic fluid and amniotic membrane etc. These findings demonstrate that SLPI function as a potent anti protease, anti inflammatory, bactericidal, antifungal, tissue repair, extra cellular synthesis. Impaired healing states are characterized by excessive proteolysis and often bacterial infection, leading to the hypothesis that SLPI may have a role in the process. The objectives of this article are to investigate the role of SLPI in oral inflammation and how it contributes to tissue repair in oral mucosa. The oral wound healing responses are impaired in the SLPI sufficient mice and matrix synthesis and collagen deposition are delayed. This study indicated that SLPI is a povital factor necessary for optimal wound healing.

  19. A novel protocol allowing oral delivery of a protein complement inhibitor that subsequently targets to inflamed colon mucosa and ameliorates murine colitis.

    Science.gov (United States)

    Elvington, M; Blichmann, P; Qiao, F; Scheiber, M; Wadsworth, C; Luzinov, I; Lucero, J; Vertegel, A; Tomlinson, S

    2014-08-01

    While there is evidence of a pathogenic role for complement in inflammatory bowel disease, there is also evidence for a protective role that relates to host defence and protection from endotoxaemia. There is thus concern regarding the use of systemic complement inhibition as a therapeutic strategy. Local delivery of a complement inhibitor to the colon by oral administration would ameliorate such concerns, but while formulations exist for oral delivery of low molecular weight drugs to the colon, they have not been used successfully for oral delivery of proteins. We describe a novel pellet formulation consisting of cross-linked dextran coated with an acrylic co-polymer that protects the complement inhibitor CR2-Crry from destruction in the gastrointestinal tract. CR2-Crry containing pellets administered by gavage, were characterized using a therapeutic protocol in a mouse model of dextran sulphate sodium (DSS)-induced colitis. Oral treatment of established colitis over a 5-day period significantly reduced mucosal inflammation and injury, with similar therapeutic benefit whether or not the proton pump inhibitor, omeprazole, was co-administered. Reduction in injury was associated with the targeting of CR2-Crry to the mucosal surface and reduced local complement activation. Treatment had no effect on systemic complement activity. This novel method for oral delivery of a targeted protein complement inhibitor will reduce systemic effects, thereby decreasing the risk of opportunistic infection, as well as lowering the required dose and treatment cost and improving patient compliance. Furthermore, the novel delivery system described here may provide similar benefits for administration of other protein-based drugs, such as anti-tumour necrosis factor-α antibodies.

  20. A randomized controlled trial of the efficacy and safety of CCX282-B, an orally-administered blocker of chemokine receptor CCR9, for patients with Crohn's disease

    DEFF Research Database (Denmark)

    Keshav, Satish; Vaňásek, Tomáš; Niv, Yaron;

    2013-01-01

    CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 pat...... this clinical trial led to initiation of Phase 3 clinical trials in Crohn's disease....

  1. Factors Influencing Adherence in Cancer Patients Taking Oral Tyrosine Kinase Inhibitors: A Qualitative Study.

    Science.gov (United States)

    Verbrugghe, Mathieu; Duprez, Veerle; Beeckman, Dimitri; Grypdonck, Mieke; Quaghebeur, Marijke; Verschueren, Caroline; Verhaeghe, Sofie; Van Hecke, Ann

    2016-01-01

    Nonadherence in cancer patients taking oral anticancer drugs is common. Reasons for nonadherence are still not really understood as influencing factors are often complex, dynamic, and interrelated. A qualitative study was conducted to gain insight into (non-)adherence behavior in patients taking oral tyrosine kinase inhibitors by exploring (1) processes and factors influencing (non-)adherence and (2) their interrelatedness. Semistructured interviews were held with 30 patients of different ages and with different types of cancer. A grounded theory approach was used. Three foci were found when dealing with oral tyrosine kinase inhibitors: (1) a focus on survival, (2) a focus on quality of life, and (3) a balance between survival and quality of life. The process of adherence was determined by a set of complex and interrelated influencing factors: treatment-related side effects, hope, anxiety, trust, and feedback mechanisms. This qualitative study gives insight into processes and factors influencing (non-)adherence behavior in patients taking oral tyrosine kinase inhibitors. The results of this study can help healthcare professionals understand why patients taking oral tyrosine kinase inhibitors do not always adhere to their therapy. Conditions should be created by which patients get maximum opportunity to establish a balance between survival and quality of life. An open climate and a trust-based relationship should be established in which patients feel comfortable to openly discuss their therapy and the difficulties they experience.

  2. Preliminary efficacy investigations of oral fipronil against Anopheles arabiensis when administered to Zebu cattle (Bos indicus) under field conditions.

    Science.gov (United States)

    Poché, Richard M; Githaka, Naftaly; van Gool, Frans; Kading, Rebekah C; Hartman, Daniel; Polyakova, Larisa; Abworo, Edward Okoth; Nene, Vishvanath; Lozano-Fuentes, Saul

    2017-12-01

    Globally, malaria remains one of the most important vector-borne diseases despite the extensive use of vector control, including indoor residual spraying (IRS) and insecticide-treated nets (ITNs). These control methods target endophagic vectors, whereas some malaria vectors, such as Anopheles arabiensis, preferentially feed outdoors on cattle, making it a complicated vector to control using conventional strategies. Our study evaluated whether treating cattle with a capsule containing the active ingredient (AI) fipronil could reduce vector density and sporozoite rates, and alter blood feeding behavior, when applied in a small-scale field study. A pilot field study was carried out in the Samia District, Western Kenya, from May to July 2015. Four plots, each comprised of 50 huts used for sleeping, were randomly designated to serve as control or treatment. A week before cattle treatment, baseline mosquito collections were performed inside the houses using mechanical aspirators. Animals in the treatment (and buffer) were administered a single oral application of fipronil at ∼0.5mg/kg of body weight. Indoor mosquito collections were performed once a week for four weeks following treatment. Female mosquitoes were first identified morphologically to species complex, followed by PCR-based methods to obtain species identity, sporozoite presence, and the host source of the blood meal. All three species of anophelines found in the study area (An. gambiae s.s., An. arabiensis, An. funestus s.s.) were actively transmitting Plasmodium falciparum during the study period. The indoor resting density of An. arabiensis was significantly reduced in treatment plot one at three weeks post-treatment (T1) (efficacy=89%; T1 density=0.08, 95% credibility intervals [0.05, 0.10]; control plot density=0.78 [0.22, 0.29]) and at four weeks post-treatment (efficacy=64%; T1 density=0.16 [0.08, 0.14]; control plot density=0.48 [0.17, 0.22]). The reduction of An. arabiensis mosquitoes captured in

  3. A phase I and pharmacokinetic study of oral lapatinib administered once or twice daily in patients with solid malignancies.

    Science.gov (United States)

    Burris, Howard A; Taylor, Charles W; Jones, Suzanne F; Koch, Kevin M; Versola, Melissa J; Arya, Niki; Fleming, Ronald A; Smith, Deborah A; Pandite, Lini; Spector, Neil; Wilding, George

    2009-11-01

    This study determined the range of tolerable doses, clinical safety, pharmacokinetics, and preliminary evidence of clinical activity following once or twice daily administration of lapatinib in patients with solid malignancies. Cancer patients (n = 81) received oral doses of lapatinib ranging from 175 to 1,800 mg once daily or 500 to 900 mg twice daily. Clinical assessments of safety and antitumor activity were recorded and blood was sampled for pharmacokinetic assessments. The effect of a low-fat meal on lapatinib pharmacokinetics was assessed in a subset of patients. Lapatinib was well tolerated, such that dose escalation was limited at 1,800 mg once daily only by pill burden. Twice-daily dosing was implemented to further explore tolerability, and was limited by diarrhea to 500 mg twice daily. The most commonly reported adverse events with once-daily dosing were diarrhea (48%), nausea (40%), rash (40%), and fatigue (38%) and with twice-daily dosing were diarrhea (85%), rash (54%), and nausea (34%). Lapatinib serum concentrations accumulated upon repeated dosing, increasing nearly in proportion with dose, and were significantly increased when dosed with food or administered twice daily. One patient with head and neck cancer achieved a confirmed complete response and 22 patients had stable disease of >or=8 weeks including three patients with stable disease of >10 months (renal, lung, and salivary gland cancers). Lapatinib was well tolerated following once and twice daily administration. Systemic exposure to lapatinib was dependent on the dose, duration and frequency of dosing, and prandial state. Clinical activity was observed.

  4. In Vivo Curative and Protective Potential of Orally Administered 5-Aminolevulinic Acid plus Ferrous Ion against Malaria

    Science.gov (United States)

    Suzuki, Shigeo; Hikosaka, Kenji; Balogun, Emmanuel O.; Komatsuya, Keisuke; Niikura, Mamoru; Kobayashi, Fumie; Takahashi, Kiwamu; Tanaka, Tohru; Nakajima, Motowo

    2015-01-01

    5-Aminolevulinic acid (ALA) is a naturally occurring amino acid present in diverse organisms and a precursor of heme biosynthesis. ALA is commercially available as a component of cosmetics, dietary supplements, and pharmaceuticals for cancer diagnosis and therapy. Recent reports demonstrated that the combination of ALA and ferrous ion (Fe2+) inhibits the in vitro growth of the human malaria parasite Plasmodium falciparum. To further explore the potential application of ALA and ferrous ion as a combined antimalarial drug for treatment of human malaria, we conducted an in vivo efficacy evaluation. Female C57BL/6J mice were infected with the lethal strain of rodent malaria parasite Plasmodium yoelii 17XL and orally administered ALA plus sodium ferrous citrate (ALA/SFC) as a once-daily treatment. Parasitemia was monitored in the infected mice, and elimination of the parasites was confirmed using diagnostic PCR. Treatment of P. yoelii 17XL-infected mice with ALA/SFC provided curative efficacy in 60% of the mice treated with ALA/SFC at 600/300 mg/kg of body weight; no mice survived when treated with vehicle alone. Interestingly, the cured mice were protected from homologous rechallenge, even when reinfection was attempted more than 230 days after the initial recovery, indicating long-lasting resistance to reinfection with the same parasite. Moreover, parasite-specific antibodies against reported vaccine candidate antigens were found and persisted in the sera of the cured mice. These findings provide clear evidence that ALA/SFC is effective in an experimental animal model of malaria and may facilitate the development of a new class of antimalarial drug. PMID:26324278

  5. Seromucosal transport of intravenously administered carbamazepine is not enhanced by oral doses of activated charcoal in rats.

    Science.gov (United States)

    Eyer, Florian; Jung, Nicole; Neuberger, Heidi; Witte, Andreas; Poethko, Thorsten; Henke, Julia; Zilker, Thomas

    2008-03-01

    The fate of carbamazepine after intravenous injection in rats (n = 24) and the influence of activated charcoal on the kinetics was investigated. After randomization to four groups (n = 6, each), plasma concentration and the quantities of carbamazepine and metabolites excreted into bile, urine and intestine were determined using an in situ perfusion model of the small intestine (Ringer's solution) with or without orally administered activated charcoal (AC+; AC-) and with or without bile duct cannulation (BD+; BD-). The cumulative amount of carbamazepine and metabolites exsorbed into the small intestine within 3.5 hr after intravenous injection was about 15% in BD- animals and about 3% in BD+ animals. About 20% of the dose was detected in the externalized bile. Activated charcoal did not influence the amount exsorbed into the small intestine. Terminal half-life in plasma ranged from 159 min. to 194 min. within the four treatment groups without statistical significant difference (P = 0.751). Correspondingly, the area under the curve did not vary significantly and ranged between 1.13 and 1.41 g/min./l (P = 0.378). Excretion of carbamazepine and metabolites into urine varied between 3% and 6% of dose within all groups and showed close correlation with diuresis. In an identical experimental approach using a 2-fold intestinal perfusion rate (50 ml/hr; n = 8), no fundamental changes compared to the main experiment regarding pharmacokinetics of carbamazepine were observed. The lack of effect of activated charcoal on the elimination of carbamazepine and metabolites must be contributed to the small amount of the drug being exsorbed into the intestine and may be further influenced by reduced intestinal permeability of carbamazepine and metabolites or inadequate luminal stirring.

  6. An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities.

    Science.gov (United States)

    Cheng, Yuan; Brown, James; Judd, Ted C; Lopez, Patricia; Qian, Wenyuan; Powers, Timothy S; Chen, Jian Jeffrey; Bartberger, Michael D; Chen, Kui; Dunn, Robert T; Epstein, Oleg; Fremeau, Robert T; Harried, Scott; Hickman, Dean; Hitchcock, Stephen A; Luo, Yi; Minatti, Ana Elena; Patel, Vinod F; Vargas, Hugo M; Wahl, Robert C; Weiss, Matthew M; Wen, Paul H; White, Ryan D; Whittington, Douglas A; Zheng, Xiao Mei; Wood, Stephen

    2015-02-12

    BACE1 inhibition to prevent Aβ peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aβ levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.

  7. Novel, potent, selective, and orally bioavailable human betaII-tryptase inhibitors.

    Science.gov (United States)

    Sperandio, David; Tai, Vincent W-F; Lohman, Julia; Hirschbein, Bernie; Mendonca, Rohan; Lee, Chang-Sun; Spencer, Jeffrey R; Janc, James; Nguyen, Margaret; Beltman, Jerlyn; Sprengeler, Paul; Scheerens, Heleen; Lin, Tong; Liu, Liang; Gadre, Ashwini; Kellogg, Alisha; Green, Michael J; McGrath, Mary E

    2006-08-01

    The synthesis of novel [1,2,4]oxadiazoles and their structure-activity relationship (SAR) for the inhibition of tryptase and related serine proteases is presented. Elaboration of the P'-side afforded potent, selective, and orally bioavailable tryptase inhibitors.

  8. Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF-03084014, an Oral Gamma Secretase Inhibitor.

    Science.gov (United States)

    Villalobos, Victor Manuel; Hall, Francis; Jimeno, Antonio; Gore, Lia; Kern, Kenneth; Cesari, Rossano; Huang, Bo; Schowinsky, Jeffrey T; Blatchford, Patrick Judson; Hoffner, Brianna; Elias, Anthony; Messersmith, Wells

    2017-09-08

    Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in β-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral gamma secretase inhibitor, PF-03084014. PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated. Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0-96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5-21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily. PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0-96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation.

  9. Bioavailability of orally administered rhGM-CSF: a single-dose, randomized, open-label, two-period crossover trial.

    Directory of Open Access Journals (Sweden)

    Wenping Zhang

    Full Text Available BACKGROUND: Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF is usually administered by injection, and its oral administration in a clinical setting has been not yet reported. Here we demonstrate the bioavailability of orally administered rhGM-CSF in healthy volunteers. The rhGM-CSF was expressed in Bombyx mori expression system (BmrhGM-CSF. METHODS AND FINDINGS: Using a single-dose, randomized, open-label, two-period crossover clinical trial design, 19 healthy volunteers were orally administered with BmrhGM-CSF (8 microg/kg and subcutaneously injected with rhGM-CSF (3.75 microg/kg respectively. Serum samples were drawn at 0.0h, 0.5h ,0.75h,1.0h,1.5h,2.0h ,3.0h,4.0h,5.0h,6.0h,8.0h,10.0h and 12.0h after administrations. The hGM-CSF serum concentrations were determined by ELISA. The AUC was calculated using the trapezoid method. The relative bioavailability of BmrhGM-CSF was determined according to the AUC ratio of both orally administered and subcutaneously injected rhGM-CSF. Three volunteers were randomly selected from 15 orally administrated subjects with ELISA detectable values. Their serum samples at the 0.0h, 1.0h, 2.0h, 3.0h and 4.0h after the administrations were analyzed by Q-Trap MS/MS TOF. The different peaks were revealed by the spectrogram profile comparison of the 1.0h, 2.0h, 3.0h and 4.0h samples with that of the 0.0h sample, and further analyzed using both Enhanced Product Ion (EPI scanning and Peptide Mass Fingerprinting Analysis. The rhGM-CSF was detected in the serum samples from 15 of 19 volunteers administrated with BmrhGM-CSF. Its bioavailability was observed at an average of 1.0%, with the highest of 3.1%. The rhGM-CSF peptide sequences in the serum samples were detected by MS analysis, and their sizes ranging from 2,039 to 7,336 Da. CONCLUSIONS: The results demonstrated that the oral administered BmrhGM-CSF was absorbed into the blood. This study provides an approach for an oral administration of

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

    Science.gov (United States)

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

    2014-10-01

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

  11. Hyperprolactinemia contributes to reproductive deficit in male rats chronically administered PDE5 inhibitors (sildenafil and tadalafil and opioid (tramadol

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    V.U. Nna

    2016-09-01

    Conclusion: Serum prolactin concentration correlated negatively with male reproductive hormones and may play a major role in reproductive deficits associated with chronic use of PDE5 inhibitors and opioids.

  12. Oral voclosporin: novel calcineurin inhibitor for treatment of noninfectious uveitis

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    Roesel M

    2011-09-01

    Full Text Available Martin Roesel1, Christoph Tappeiner2, Arnd Heiligenhaus1,3, Carsten Heinz1,31Department of Ophthalmology, St Franziskus-Hospital, Muenster, Germany; 2Department of Ophthalmology, Inselspital, University of Bern, Switzerland; 3University Duisburg-Essen, GermanyAbstract: Voclosporin, a novel immunomodulatory drug inhibiting the calcineurin enzyme, was developed to prevent organ graft rejection and to treat autoimmune diseases. The chemical structure of voclosporin is similar to that of cyclosporine A, with a difference in one amino acid, leading to superior calcineurin inhibition and less variability in plasma concentration. Compared with placebo, voclosporin may significantly reduce inflammation and prevent recurrences of inflammation in patients with noninfectious uveitis. Future studies have to show if these advantages are accompanied by greater clinical efficacy and fewer side effects compared with the classic calcineurin inhibitors.Keywords: uveitis, immunosuppression, voclosporin

  13. Quantification of secretory leukocyte protease inhibitor (SLPI) in oral gargle specimens collected using mouthwash

    Science.gov (United States)

    Pierce Campbell, Christine M.; Guan, Wei; Sprung, Robert; Koomen, John M.; O’Keefe, Michael T.; Ingles, Donna J.; Abrahamsen, Martha; Giuliano, Anna R.

    2014-01-01

    Background Secretory leukocyte protease inhibitor (SLPI) is an innate immunity-associated protein known to inhibit HIV transmission, and is thought to inhibit a variety of infectious agents, including human papillomaviruses (HPVs). We aimed to optimize an established ELISA-based SLPI quantification assay for use with oral gargle specimens collected using mouthwash, and to assess preliminary associations with age, smoking status, and alcohol intake. Methods Oral gargle supernatants from 50 individuals were used to optimize the Human SLPI Quantikine ELISA Kit. Sample suitability was assessed and quality control analyses were conducted. Results Salivary SLPI was successfully recovered from oral gargles with low intra-assay and high inter-individual variability. Initial measurements showed that salivary SLPI varied considerably across individuals, and that SLPI was inversely associated with age. Conclusions This optimized assay can be used to examine the role of SLPI in the acquisition of oral HPV and other infections. PMID:24140751

  14. New oral antithrombotics: focus on dabigatran, an oral, reversible direct thrombin inhibitor for the prevention and treatment of venous and arterial thromboembolic disorders

    Directory of Open Access Journals (Sweden)

    Dahl OE

    2012-01-01

    Full Text Available Ola E Dahl1,21Department of Orthopaedics, Innlandet Hospital Trust, Elverum Central Hospital, Elverum, Norway; 2Thrombosis Research Institute, London, UKAbstract: Venous thromboembolism, presenting as deep vein thrombosis or pulmonary embolism, is a major challenge for health care systems. It is the third most common vascular disease after coronary heart disease and stroke, and many hospitalized patients have at least one risk factor. In particular, patients undergoing hip or knee replacement are at risk, with an incidence of asymptomatic deep vein thrombosis of 40%–60% without thromboprophylaxis. Venous thromboembolism is associated with significant mortality and morbidity, with patients being at risk of recurrence, post-thrombotic syndrome, and chronic thromboembolic pulmonary hypertension. Arterial thromboembolism is even more frequent, and atrial fibrillation, the most common embolic source (cardiac arrhythmia, is associated with a five-fold increase in the risk of stroke. Strokes due to atrial fibrillation tend to be more severe and disabling and are more often fatal than strokes due to other causes. Currently, recommended management of both venous and arterial thromboembolism involves the use of anticoagulants such as coumarin and heparin derivatives. These agents are effective, although have characteristics that prevent them from providing optimal anticoagulation and convenience. Hence, new improved oral anticoagulants are being investigated. Dabigatran is a reversible, direct thrombin inhibitor, which is administered as dabigatran etexilate, the oral prodrug. Because it is the first new oral anticoagulant that has been licensed in many countries worldwide for thromboprophylaxis following orthopedic surgery and for stroke prevention in patients with atrial fibrillation, this compound will be the main focus of this review. Dabigatran has been investigated for the treatment of established venous thromboembolism and prevention of

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

    Science.gov (United States)

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

    2012-06-01

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

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

    Science.gov (United States)

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

    2015-01-22

    Anti-inflammatory effects of oral administration of the glucosamine oligomers (chito-oligosaccharides: COS) were evaluated in an experimental model of inflammatory bowel disease (IBD). Oral administration of COS improved shortening of colon length and tissue injury (as assessed by histology) in mice. Oral administration of COS inhibited inflammation in the colonic mucosa by suppression of myeloperoxidase activation in inflammatory cells, as well as activation of nuclear factor-kappa B, cyclooxygenase-2, and inducible nitric oxide synthase. Oral administration of COS also reduced serum levels of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6). Moreover, it prolonged survival time in mice. These data suggest that COS have anti-inflammatory effects in an experimental model of IBD, and could be new functional foods for IBD patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. A single, low dose oral antigen exposure in newborn piglets primes mucosal immunity if administered with CpG oligodeoxynucleotides and polyphosphazene adjuvants.

    Science.gov (United States)

    Pasternak, J Alex; Ng, Siew Hon; Wilson, Heather L

    2014-10-15

    By definition, soluble antigens ingested orally trigger mucosal tolerance such that any subsequent re-exposure by a systemic route results in suppression of immunity. We propose that antigens introduced in extreme early life can readily traverse the gut wall and therefore circumvent induction of mucosal tolerance and instead induce immunity. Piglets were drenched with low-doses of ovalbumin (OVA; 5mg or 0.05 mg) alone, OVA plus adjuvants (CpG oligodeoxynucleotides and PCEP polyphosphazene) or saline within 6h of birth. At 28 days of age, they were administered 10mg OVA plus 1:1 Montanide adjuvant (or saline) via the intraperitoneal (i.p.) route or via the oral route. Serum was obtained on day 28 and day 49 to measure OVA-specific antibodies titres. All piglets boosted orally with OVA plus Montanide, regardless of prior OVA exposure, failed to induce immunity. As expected, piglets drenched with saline but boosted via the i.p. route with OVA plus Montanide showed significant induction of anti-OVA IgA, IgG, IgG1 and IgG2 relative to saline control piglets. Newborn animals drenched with 5mg or 0.05 mg OVA failed to induce oral immunity. A second intramuscular injection in adulthood triggered immunity in the piglets that were drenched with 0.05 mg OVA and boosted initially by the i.p. route suggesting that some systemic lymphocytes were primed despite initial lack of induction of humoral immunity. In contrast, piglets orally immunized with 5mg or 0.05 mg OVA plus adjuvants resulted in significant induction of anti-OVA IgA (5mg only), IgM, IgG, IgG1 and IgG2 in serum relative to saline control piglets as well as significant induction of anti-OVA IgA, IgM (5mg only) IgG, IgG1 (5mg only) or IgG2 relative to piglets drenched with OVA alone. These data clearly show that the response was sensitive to the oral vaccine components and was not simply a response to the i.p. immunization at day 28. This work demonstrates that newborn piglets respond to oral antigens with immunity

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

    Science.gov (United States)

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

    2009-11-01

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

  19. Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance

    OpenAIRE

    Li HH

    2016-01-01

    Huamin Henry Li Institute for Asthma and Allergy, Chevy Chase, MD, USA Abstract: Hereditary angioedema (HAE) is a rare genetic disease characterized by episodic subcutaneous or submucosal swelling. The primary cause for the most common form of HAE is a deficiency in functional C1 esterase inhibitor (C1-INH). The swelling caused by HAE can be painful, disfiguring, and life-threatening. It reduces daily function and compromises the quality of life of affected individuals and their caregivers....

  20. The efficacy and plasma profiles of abamectin plus levamisole combination anthelmintics administered as oral and pour-on formulations to cattle.

    Science.gov (United States)

    Leathwick, D M; Miller, C M; Sauermann, C W; Candy, P M; Ganesh, S; Fraser, K; Waghorn, T S

    2016-08-30

    In phase I, faecal egg count reduction tests (FECRT) were conducted on six commercial cattle farms to compare the performance of two pour-on and one oral combination anthelmintic. Groups of 12-15 calves were sampled for faecal nematode egg count (FEC) before treatment with either abamectin oral, levamisole oral, an abamectin+levamisole oral combination or one of two abamectin+levamisole combination pour-ons. Samples were collected again 14days after treatment to calculate the percentage reduction in FEC. The proportions of infective stage larvae (L3) in faecal cultures were used to apportion egg counts to, and calculate efficacy against, the main parasite genera. Abamectin oral was effective against Ostertagia except on one farm where resistance was indicated, but had reduced efficacy against Cooperia on four farms. Levamisole oral was effective against Cooperia on all farms, but had variable efficacy against Ostertagia. The abamectin+levamisole oral was effective against both species on all farms. The abamectin+levamisole pour-ons were effective on some farms but not on others. In particular, pour-on 2 failed to achieve 95% efficacy in 45% of evaluations, 4/6 against Cooperia and 1/5 against Ostertagia. On some farms the combination pour-ons were less effective than their constituent actives administered alone as orals. In phase II, 8 groups of 6 calves, grazing parasite-free pasture, were infected with putatively ML-resistant isolates of Cooperia oncophora and Ostertagia ostertagi. Once infections were patent groups were treated with oral or pour-on formulations of abamectin alone, levamisole alone, abamectin+levamisole (two pour-ons) or remained untreated. Blood samples were collected for analysis and after 8days all calves were euthanized and abomasa and intestines recovered for worm counts. All treatments were effective against O. ostertagi and all treatments containing levamisole were effective against C. oncophora. Animals treated with the oral combination

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

    Science.gov (United States)

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

    2014-10-13

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

  2. A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions

    NARCIS (Netherlands)

    Blanquet, S.; Zeijdner, E.; Beyssac, E.; Meunier, J.-P.; Denis, S.; Havenaar, R.; Alric, M.

    2004-01-01

    Purpose. The purpose of this study was to demonstrate the potential of a dynamic, multicompartmental in vitro system simulating the human stomach and small intestine (TIM-1) for studying the behavior of oral drug dosage forms under various physiological gastrointestinal conditions. Methods. Two mode

  3. Bacterial antigen expression is an important component in inducing an immune response to orally administered Salmonella-delivered DNA vaccines.

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    Michelle E Gahan

    Full Text Available BACKGROUND: The use of Salmonella to deliver heterologous antigens from DNA vaccines is a well-accepted extension of the success of oral Salmonella vaccines in animal models. Attenuated S. typhimurium and S. typhi strains are safe and efficacious, and their use to deliver DNA vaccines combines the advantages of both vaccine approaches, while complementing the limitations of each technology. An important aspect of the basic biology of the Salmonella/DNA vaccine platform is the relative contributions of prokaryotic and eukaryotic expression in production of the vaccine antigen. Gene expression in DNA vaccines is commonly under the control of the eukaryotic cytomegalovirus (CMV promoter. The aim of this study was to identify and disable putative bacterial promoters within the CMV promoter and evaluate the immunogenicity of the resulting DNA vaccine delivered orally by S. typhimurium. METHODOLOGY/PRINCIPAL FINDINGS: The results reported here clearly demonstrate the presence of bacterial promoters within the CMV promoter. These promoters have homology to the bacterial consensus sequence and functional activity. To disable prokaryotic expression from the CMV promoter a series of genetic manipulations were performed to remove the two major bacterial promoters and add a bacteria transcription terminator downstream of the CMV promoter. S. typhimurium was used to immunise BALB/c mice orally with a DNA vaccine encoding the C-fragment of tetanus toxin (TT under control of the original or the modified CMV promoter. Although both promoters functioned equally well in eukaryotic cells, as indicated by equivalent immune responses following intramuscular delivery, only the original CMV promoter was able to induce an anti-TT specific response following oral delivery by S. typhimurium. CONCLUSIONS: These findings suggest that prokaryotic expression of the antigen and co-delivery of this protein by Salmonella are at least partially responsible for the successful

  4. Effect of orally administered betel leaf (Piper betle Linn.) on digestive enzymes of pancreas and intestinal mucosa and on bile production in rats.

    Science.gov (United States)

    Prabhu, M S; Platel, K; Saraswathi, G; Srinivasan, K

    1995-10-01

    The influence of two varieties of betel leaf (Piper betle Linn.) namely, the pungent Mysore and non-pungent Ambadi, was examined on digestive enzymes of pancreas and intestinal mucosa and on bile secretion in experimental rats. The betel leaves were administered orally at two doses which were either comparable to human consumption level or 5 times this. The results indicated that while these betel leaves do not influence bile secretion and composition, they have a significant stimulatory influence on pancreatic lipase activity. Besides, the Ambadi variety of betel leaf has a positive stimulatory influence on intestinal digestive enzymes, especially lipase, amylase and disaccharidases. A slight lowering in the activity of these intestinal enzymes was seen when Mysore variety of betel leaf was administered, and this variety also had a negative effect on pancreatic amylase. Further, both the betel leaf varieties have shown decreasing influence on pancreatic trypsin and chymotrypsin activities.

  5. p38 MAPK Inhibitor Insufficiently Attenuates HSC Senescence Administered Long-Term after 6 Gy Total Body Irradiation in Mice

    Directory of Open Access Journals (Sweden)

    Lu Lu

    2016-06-01

    Full Text Available Senescent hematopoietic stem cells (HSCs accumulate with age and exposure to stress, such as total-body irradiation (TBI, which may cause long-term myelosuppression in the clinic. However, the methods available for long-term myelosuppression remain limited. Previous studies have demonstrated that sustained p38 mitogen-activated protein kinases (p38 MAPK activation in HSCs following exposure to TBI in mice and the administration of its inhibitor twenty-four hours after TBI may partially prevent long-term myelosuppression. However, long-term myelosuppression is latent and identified long after the administration of radiation. In this study, we investigated the effects of SB203580 (a small molecule inhibitor of p38 MAPK on long-term myelosuppression induced by TBI. Mice with hematopoietic injury were injected intraperitoneally with SB203580 every other day five times beginning 70 days after 6 Gy of 137Cs γ ray TBI. Our results at 80 days demonstrated that SB203580 did not significantly improve the TBI-induced long-term reduction of peripheral blood cell and bone marrow nucleated cell (BMNC counts, or defects in hematopoietic progenitor cells (HPCs and HSC clonogenic function. SB203580 reduced reactive oxygen species (ROS production and p-p38 expression; however, SB203580 had no effect on p16 expression in the HSCs of mice. In conclusion, these findings suggest that treatment with SB203580 70 days after TBI in mice inhibits the ROS-p38 oxidative stress pathway; however, it has no therapeutic effect on long-term myelosuppression induced by TBI.

  6. Selective serotonin reuptake inhibitors and oral bleeding complications after invasive dental treatment.

    Science.gov (United States)

    Napeñas, Joel J; Hong, Catherine H L; Kempter, Eric; Brennan, Michael T; Furney, Scott L; Lockhart, Peter B

    2011-10-01

    The purpose of this study was to examine the frequency of oral bleeding complications after invasive dental procedures in patients taking selective serotonin reuptake inhibitor (SSRI) medications. In this retrospective cohort study, we included dental patients who had invasive dental treatment and were taking an SSRI medication. Data collected included demographics, medical history, dental visits and procedures, and use of adjunctive measures to control bleeding. Primary outcomes included documentation of return visits or phone calls to the dental clinic or emergency department (ED) for oral bleeding, and oral bleeding or use of blood products for inpatients. There were 92 patients taking SSRIs who had 145 invasive procedure visits, consisting of extractions, implant surgery, alveoloplasty, periodontal surgery, subgingival scaling and root planning, and biopsy. There were 110 extraction visits yielding a total of 167 extractions. Among all patients, there was 1 return visit to the clinic and 1 telephone call with a chief complaint of oral bleeding. The frequency of oral bleeding complications after invasive dental treatment is low to negligible in patients on SSRI medications. Copyright © 2011 Mosby, Inc. All rights reserved.

  7. Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma.

    Science.gov (United States)

    Vail, D M; Husbands, B D; Kamerling, S G; Simpson, H; Kurzman, I D; McDonnell, A

    2012-01-01

    Idarubicin, a PO bioavailable anthracycline antibiotic-class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery. The primary objective of this study was to determine the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD. Client-owned dogs with measurable lymphoma. Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines. The MTD in dogs > 15 kg body weight was 22 mg/m(2) . Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol. PO administered idarubicin was generally well-tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated-dose, randomized clinical trials. Copyright © 2012 by the American College of Veterinary Internal Medicine.

  8. Orally administered DTPA di-ethyl ester for decorporation of (241)Am in dogs: Assessment of safety and efficacy in an inhalation-contamination model.

    Science.gov (United States)

    Huckle, James E; Sadgrove, Matthew P; Pacyniak, Erik; Leed, Marina G D; Weber, Waylon M; Doyle-Eisele, Melanie; Guilmette, Raymond A; Agha, Bushra J; Susick, Robert L; Mumper, Russell J; Jay, Michael

    2015-07-01

    Currently two injectable products of diethylenetriaminepentaacetic acid (DTPA) are U.S. Food and Drug Administration (FDA)-approved for decorporation of (241)Am; however, an oral product is considered more amenable in a mass casualty situation. The di-ethyl ester of DTPA, named C2E2, is being developed as an oral drug for treatment of internal radionuclide contamination. Single-dose decorporation efficacy of C2E2 administered 24-h post contamination was determined in beagle dogs using a (241)Am nitrate inhalation contamination model. Single and multiple dose toxicity studies in beagle dogs were performed as part of an initial safety assessment program. In addition, the genotoxic potential of C2E2 was evaluated by the in vitro bacterial reverse mutation Ames test, mammalian cell chromosome aberration cytogenetic assay and an in vivo micronucleus test. Oral administration of C2E2 significantly increased (241)Am elimination over untreated controls and significantly reduced the retention of (241)Am in tissues, especially liver, kidney, lung and bone. Daily dosing of 200 mg/kg/day for 10 days was well tolerated in dogs. C2E2 was found to be neither mutagenic or clastogenic. The di-ethyl ester of DTPA (C2E2) was shown to effectively enhance the elimination of (241)Am after oral administration in a dog inhalation-contamination model and was well tolerated in toxicity studies.

  9. Orally Administered DTPA Di-ethyl Ester for Decorporation of 241Am in dogs: Assessment of Safety and Efficacy in an Inhalation-Contamination Model

    Science.gov (United States)

    Huckle, James E.; Sadgrove, Matthew P.; Pacyniak, Erik; Leed, Marina G. D.; Weber, Waylon M.; Doyle-Eisele, Melanie; Guilmette, Raymond A.; Agha, Bushra J.; Susick, Robert L.; Mumper, Russell J.; Jay, Michael

    2016-01-01

    Purpose Currently two injectable products of diethylenetriaminepentaacetic acid (DTPA) are U.S. Food and Drug Administration (FDA) approved for decorporation of 241Am, however, an oral product is considered more amenable in a mass casualty situation. The diethyl ester of DTPA, named C2E2, is being developed as an oral drug for treatment of internal radionuclide contamination. Materials and methods Single dose decorporation efficacy of C2E2 administered 24-hours post contamination was determined in beagle dogs using a 241Am nitrate inhalation contamination model. Single and multiple dose toxicity studies in beagle dogs were performed as part of an initial safety assessment program. In addition, the genotoxic potential of C2E2 was evaluated by the in vitro bacterial reverse mutation Ames test, mammalian cell chromosome aberration cytogenetic assay and an in vivo micronucleus test. Results Oral administration of C2E2 significantly increased 241Am elimination over untreated controls and significantly reduced the retention of 241Am in tissues, especially liver, kidney, lung and bone. Daily dosing of 200 mg/kg/day for 10 days was well tolerated in dogs. C2E2 was found to be neither mutagenic or clastogenic. Conclusions The di-ethyl ester of DTPA (C2E2) was shown to effectively enhance the elimination of 241Am after oral administration in a dog inhalation-contamination model and was well tolerated in toxicity studies. PMID:25912343

  10. Effects of Orally Administered Lactoferrin and Lactoperoxidase-Containing Tablets on Clinical and Bacteriological Profiles in Chronic Periodontitis Patients

    Directory of Open Access Journals (Sweden)

    Eiju Shimizu

    2011-01-01

    Full Text Available This study was undertaken to evaluate the effect of oral administration of lactoferrin (LF and lactoperoxidase-(LPO-containing tablet on periodontal condition. Seventy-two individuals with chronic periodontitis were randomly assigned to take either bovine LF and LPO-containing tablets (test group, n=37 or control tablets (control group, n=35 every day for 12 weeks. Periodontal parameters and levels of subgingival plaque bacteria, human and bovine LF, and endotoxin in gingival crevicular fluid (GCF were evaluated at baseline, 1 week, 4 weeks, and 12 weeks. Significant differences were observed in GCF levels of bovine LF between the test and control groups throughout the study (P<.05. However, clinical and bacteriological parameter values proved comparable between the two groups at 1 week to 12 weeks. Therefore, the effect of oral administration of LF and LPO-containing tablets might be weak on periodontal and bacteriological profile in this study.

  11. Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Cutolo M

    2013-11-01

    Full Text Available Maurizio Cutolo, Marianna Meroni Research Laboratories and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy Abstract: Immune/inflammatory cells act in rheumatoid arthritis (RA-affected patients by synthesizing several inflammatory mediators, including cytokines that initiate intracellular signaling. Recently, small molecule inhibitors of transduction and transcription signals that influence the intracellular pathways (such as the Janus kinase [JAK] family of tyrosine kinases have been tested for RA treatment. Four members of the JAK family are known: JAK1, JAK2, JAK3, and TyK2. JAK1/JAK3 constitutively binds to the cytoplasmic portion of the cytokine receptor – the common gamma chain – that represents a common subunit of several cytokines involved in T-cell and natural killer cell development, as well as in B-cell activation. Tofacitinib is an oral JAK inhibitor that is now available and effective in RA treatment, as shown in multiple Phase II and Phase III clinical trials. However, long-term safety data and comparisons with other disease-modifying antirheumatic drugs and small molecule inhibitors are necessary to better determine the role of tofacitinib in RA. Keywords: Janus kinase inhibitors, tofacitinib, rheumatoid arthritis, kinases, small molecules inhibitors, intracellular signaling

  12. International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and Differences

    OpenAIRE

    Davit, Barbara; Braddy, April C.; Conner, Dale P.; Yu, Lawrence X.

    2013-01-01

    The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Assoc...

  13. Eficacia antihelmíntica de tres endectocidas administrados por vía oral en caballos Anthelmintic efficacy of three endectocides administered by oral route in horses

    Directory of Open Access Journals (Sweden)

    L. RUBILAR

    2001-01-01

    Full Text Available Con el propósito de evaluar la eficacia antihelmíntica de los endectocidas ivermectina, doramectina y moxidectina sobre el control del parasitismo gastrointestinal en equinos, se seleccionaron 20 caballos clínicamente sanos con recuentos fecales positivos a huevos de nemátodos. Los caballos fueron distribuidos homogéneamente considerando el peso vivo y el recuento fecal de huevos en 4 grupos de 5 animales cada uno. Grupo 1: control, sin tratamiento antihelmíntico; Grupo 2: tratados con ivermectina en dosis de 0,2 mg/kg vía oral; Grupo 3 tratados con doramectina inyectable , en dosis 0.2 mg/kg, reformulado mediante caolín y miel de abejas para la administración vía oral; Grupo 4: tratados con moxidectina , en dosis 0,4 mg/kg vía oral. De cada uno de los caballos se obtuvieron muestras de heces para recuento de huevos y coprocultivos, antes del tratamiento y a los 3, 6, 10, 20, 40, 60,90, 105, 125, 145 y 175 días post tratamiento. Los resultados obtenidos indican una reducción significativa (pIn naturally gastrointestinal nematodes infected horses the anthelmintic efficacy of the endectocides ivermectin (IVM, doramectin (DRM and moxidectin (MXD was evaluated. Animals were evenly distributed to 4 experimental groups: Group I, non treated horses, control; Group II treated with an oral dose of 0.2 mg/kg of IVM by oral route; Group III treated with a reformulated oral dose of 0,2 mg/kg of DRM; Group IV treated with an oral dose of 0.4 mg/kg of MXD. Faecal samples for parasites eggs count and larval cultures were collected before treatment at 3,6,10,20,40,60,90,105,125,145 and 175 days postreatment. Results obtained showed a significant reduction (p <0,05 in the faecal eggs count in treated group, from day 3 to day 145 post treatment. This level of significance remained until day 175 post treatment only in the group treated with moxidectin

  14. Efficacy of bath and orally administered praziquantel and fenbendazole against Lepidotrema bidyana Murray, a monogenean parasite of silver perch, Bidyanus bidyanus (Mitchell).

    Science.gov (United States)

    Forwood, J M; Harris, J O; Deveney, M R

    2013-11-01

    We investigated the efficacy of praziquantel (PZQ) and fenbendazole (FBZ), each administered by bath and orally, against the monogenean Lepidotrema bidyana Murray, a gill parasite of the freshwater fish silver perch, Bidyanus bidyanus (Mitchell). PZQ and FBZ were each administered by bath at 10 mg L⁻¹ for 48 h and on surface-coated feed pellets at 75 mg kg⁻¹ per body weight (BW) per day for 6 days. Bath treatments of PZQ and FBZ had an efficacy of 99% and 91%, respectively, against adult L. bidyana. Oral treatments of PZQ and FBZ had an efficacy of 79% and 95%, respectively, against adult L. bidyana. Fish rejected feed pellets surface-coated with PZQ, suggesting that palatability of surface-coated PZQ-medicated feed is poor, which undermined efficacy. In all trials, some juvenile parasites were present on fish after treatment during efficacy assessment, indicating that efficacy may be lower against juvenile parasites or that recruitment occurred post-treatment, demonstrating that repeat treatments are necessary to effectively control L. bidyana in aquaculture.

  15. Fecal Excretion of Orally Administered Collagen-Like Peptides in Rats: Contribution of the Triple-Helical Conformation to Their Stability.

    Science.gov (United States)

    Koide, Takaki; Yamamoto, Naoyuki; Taira, Kazuma B; Yasui, Hiroyuki

    2016-01-01

    Orally ingested peptides are generally digested in the gastrointestinal (GI) tract and absorbed in the form of oligopeptides. We previously reported that intravenously administered collagen-like triple-helical peptides circulated in the bloodstream and were excreted in their intact forms in urine nearly quantitatively. In the present study, we investigated the fates of orally administered collagen-like peptides in rats. (Pro-Hyp-Gly)10 (Hyp: 4-hydroxyproline), which formed a stable triple-helical structure, was stable in the GI tract, and 72.3±13.0% of the peptide was excreted in the feces. Its recovery ratio was similar to that of all-D-(Pro-Pro-Gly)10 (75.1±15.7%), the indigestible control. In contrast, (Pro-Hyp-Gly)5 and (Pro-Pro-Gly)10, the random coil conformations of which were dominant at body temperature, were not detected in fecal samples, indicating that they were digested by proteases. The high stability of the triple-helical conformation in mammalian bodies suggests the potential use of collagen-like peptides as novel scaffolds of peptide drugs.

  16. Effects of Long-term Use of Polyphenols on the Absorption and Tissue Distribution of Orally Administered Metformin and Atenolol in Rats

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    Saad Abdulrahman Hussain

    2013-06-01

    Full Text Available Aim: To evaluate the effect of long-term use of silibinin, epigallocatechin (ECGC, quercetin and rutin on the absorption and tissue distribution of metformin and atenolol. Materials and Methods: Thirty male rats were used, allocated into 5 groups and treated as follow: 1st group treated with olive oil and served as control; the other 4 groups were treated with either silibinin, EPGC, quercetin or rutin, administered orally as oily solutions for 30 days. At day 30, a 300mg/kg metformin and 50mg/kg atenolol were administered orally; 3.0 hrs later, the animals were sacrificed and blood samples, tissues of brain, kidney and liver were obtained for evaluation of the drugs level. Results: The polyphenols increased both serum and tissue levels of metformin compared with controls. This effect was relatively varied according to the structural differences among flavonoids. Conclusion: Long-term use of supraphysiological doses of flavonoids increase absorption of Zn, Cu and Fe and their tissue availability in brain, kidney and liver; this effect seems to be different with variations in structural features. [J Intercult Ethnopharmacol 2013; 2(3.000: 147-154

  17. Disposition of intravenously or orally administered silver nanoparticles in pregnant rats and the effect on the biochemical profile in urine.

    Science.gov (United States)

    Fennell, Timothy R; Mortensen, Ninell P; Black, Sherry R; Snyder, Rodney W; Levine, Keith E; Poitras, Eric; Harrington, James M; Wingard, Christopher J; Holland, Nathan A; Pathmasiri, Wimal; Sumner, Susan C J

    2017-05-01

    Few investigations have been conducted on the disposition and fate of silver nanoparticles (AgNP) in pregnancy. The distribution of a single dose of polyvinylpyrrolidone (PVP)-stabilized AgNP was investigated in pregnant rats. Two sizes of AgNP, 20 and 110 nm, and silver acetate (AgAc) were used to investigate the role of AgNP diameter and particle dissolution in tissue distribution, internal dose and persistence. Dams were administered AgNP or AgAc intravenously (i.v.) (1 mg kg(-1) ) or by gavage (p.o.) (10 mg kg(-1) ), or vehicle alone, on gestation day 18 and euthanized at 24 or 48 h post-exposure. The silver concentration in tissues was measured using inductively-coupled plasma mass spectrometry. The distribution of silver in dams was influenced by route of administration and AgNP size. The highest concentration of silver (μg Ag g(-1) tissue) at 48 h was found in the spleen for i.v. administered AgNP, and in the lungs for AgAc. At 48 h after p.o. administration of AgNP, the highest concentration was measured in the cecum and large intestine, and for AgAc in the placenta. Silver was detected in placenta and fetuses for all groups. Markers of cardiovascular injury, oxidative stress marker, cytokines and chemokines were not significantly elevated in exposed dams compared to vehicle-dosed control. NMR metabolomics analysis of urine indicated that AgNP and AgAc exposure impact the carbohydrate, and amino acid metabolism. This study demonstrates that silver crosses the placenta and is transferred to the fetus regardless of the form of silver. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Pharmacokinetics of a single dose of voriconazole administered orally with and without food to red-tailed hawks (Buteo jamaicensus).

    Science.gov (United States)

    Parsley, Ruth A; Tell, Lisa A; Gehring, Ronette

    2017-04-01

    OBJECTIVE To determine the pharmacokinetics of voriconazole administered PO with or without food to red-tailed hawks (Buteo jamaicensus) and whether any observed variability could be explained by measured covariates to inform dose adjustments. ANIMALS 7 adult red-tailed hawks. PROCEDURES In a crossover study design, hawks were randomly assigned to first receive voriconazole (15 mg/kg, PO) injected into a dead mouse (n = 3; fed birds) or without food (4; unfed birds). Sixteen days later, treatments were reversed. Blood samples were collected at various points to measure plasma voriconazole concentrations by ultraperformance liquid chromatography. Pharmacokinetic data were analyzed by noncompartmental methods and fit to a compartmental model through nonlinear mixed-effects regression, with feeding status and body weight investigated as covariates. RESULTS Voriconazole was well absorbed, with quantifiable plasma concentrations up to 24 hours after administration. Mean plasma half-life was approximately 2 hours in fed and unfed birds. Administration of the voriconazole in food delayed absorption, resulting in a significant delay in time to maximum plasma concentration. The final compartmental model included a categorical covariate to account for this lag in absorption as well as body weight as a covariate of total body clearance (relative to unknown bioavailability). CONCLUSIONS AND CLINICAL RELEVANCE A single dose of voriconazole (15 mg/kg) administered PO to red-tailed hawks resulted in mean plasma voriconazole concentrations greater than the targeted value (1 μg/mL). Additional studies with larger sample sizes and multidose regimens are required before the model developed here can be applied in clinical settings.

  19. The effects of orally administered Beta-glucan on innate immune responses in humans, a randomized open-label intervention pilot-study.

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    Jenneke Leentjens

    Full Text Available RATIONALE: To prevent or combat infection, increasing the effectiveness of the immune response is highly desirable, especially in case of compromised immune system function. However, immunostimulatory therapies are scarce, expensive, and often have unwanted side-effects. β-glucans have been shown to exert immunostimulatory effects in vitro and in vivo in experimental animal models. Oral β-glucan is inexpensive and well-tolerated, and therefore may represent a promising immunostimulatory compound for human use. METHODS: We performed a randomized open-label intervention pilot-study in 15 healthy male volunteers. Subjects were randomized to either the β -glucan (n = 10 or the control group (n = 5. Subjects in the β-glucan group ingested β-glucan 1000 mg once daily for 7 days. Blood was sampled at various time-points to determine β-glucan serum levels, perform ex vivo stimulation of leukocytes, and analyze microbicidal activity. RESULTS: β-glucan was barely detectable in serum of volunteers at all time-points. Furthermore, neither cytokine production nor microbicidal activity of leukocytes were affected by orally administered β-glucan. CONCLUSION: The present study does not support the use of oral β-glucan to enhance innate immune responses in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT01727895.

  20. Lipoprotein lipase expression, serum lipid and tissue lipid deposition in orally-administered glycyrrhizic acid-treated rats

    Directory of Open Access Journals (Sweden)

    Ton So

    2009-07-01

    Full Text Available Abstract Background The metabolic syndrome (MetS is a cluster of metabolic abnormalities comprising visceral obesity, dyslipidaemia and insulin resistance (IR. With the onset of IR, the expression of lipoprotein lipase (LPL, a key regulator of lipoprotein metabolism, is reduced. Increased activation of glucocorticoid receptors results in MetS symptoms and is thus speculated to have a role in the pathophysiology of the MetS. Glycyrrhizic acid (GA, the bioactive constituent of licorice roots (Glycyrrhiza glabra inhibits 11β-hydroxysteroid dehydrogenase type 1 that catalyzes the activation of glucocorticoids. Thus, oral administration of GA is postulated to ameliorate the MetS. Results In this study, daily oral administration of 50 mg/kg of GA for one week led to significant increase in LPL expression in the quadriceps femoris (p p > 0.05 of the GA-treated rats compared to the control. Decrease in adipocyte size (p > 0.05 in both the visceral and subcutaneous adipose tissue depots accompanies such selective induction of LPL expression. Consistent improvement in serum lipid parameters was also observed, with decrease in serum free fatty acid, triacylglycerol, total cholesterol and LDL-cholesterol but elevated HDL-cholesterol (p > 0.05. Histological analysis using tissue lipid staining with Oil Red O showed significant decrease in lipid deposition in the abdominal muscle and quadriceps femoris (p p > 0.05. Conclusion Results from this study may imply that GA could counteract the development of visceral obesity and improve dyslipidaemia via selective induction of tissue LPL expression and a positive shift in serum lipid parameters respectively, and retard the development of IR associated with tissue steatosis.

  1. Aggression behaviour induced by oral administration of the Janus-kinase inhibitor tofacitinib, but not oclacitinib, under stressful conditions.

    Science.gov (United States)

    Fukuyama, Tomoki; Tschernig, Thomas; Qi, Yulin; Volmer, Dietrich A; Bäumer, Wolfgang

    2015-10-05

    Janus kinase (JAK) inhibitors have recently been developed for allergic diseases. We focused on the 2 different JAK inhibitors, tofacitinib (selective for JAK3) and oclacitinib (selective for JAK1 and 2), to clarify the mechanism of anti-inflammatory and anti-itching potency of these drugs. In the process of detecting anti-itching potency, we observed that tofacitinib treated mice showed aggression behaviour. The objective of the study reported here was to investigate the aggressive behaviour induced by tofacitinib by using a mouse model of allergic dermatitis and the resident-intruder test. For the allergic dermatitis model, female BALB/c mice were sensitised and challenged topically with toluene-2,4-diisocyanate (TDI). Vehicle, tofacitinib or oclacitinib, was administered orally 30 min before TDI challenge. Scratching, aggression and standing behaviours were monitored in the 60 min period immediately following challenge of TDI. Another group of male BALB/c mice treated with vehicle, tofacitinib or oclacitinib was evaluated in the resident-intruder test and brains were obtained to determine blood brain barrier penetration. In the allergic dermatitis model, a significant increase in aggression and standing behaviour was only obvious in the tofacitinib treatment group. There was no effect in non-sensitised mice, but similar aggression was also induced by tofacitinib in male resident-intruder test. Penetration of blood-brain barrier was observed both in tofacitinib and oclacitinib treated mice. These results suggest that aggression was induced by tofacitinib under some kind of stressful environment. This study indicates a possible role of the JAK-STAT pathway in modulation of aggression behaviour.

  2. Ability of Saudi mothers to appropriately and accurately use dosing devices to administer oral liquid medications to their children

    Directory of Open Access Journals (Sweden)

    Almazrou S

    2014-12-01

    Full Text Available Saja Almazrou, Hind Alsahly, Huda Alwattar, Lamya Alturki, Mona Alamri Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia Background: Most liquid medications are packaged with administration devices, which may be used inappropriately or inaccurately, and sometimes are not used at all. Because of the importance of their proper use for children's health, this study was designed to assess Saudi mothers' experiences with measuring cups, syringes, and droppers for oral liquid medications; to compare accuracy of dosing across these devices; and to determine the effects of mothers' education statuses and pharmacist counseling on dosing accuracy. Methods: This was a cross-sectional study in which mothers were observed as they used a set of commonly available dosing devices which are a dosing cup, syringe, and dropper. Interviews were conducted in the outpatient pharmacy waiting area in several tertiary hospitals and primary clinics in Riyadh, Saudi Arabia between March and April 2013. Saudi women who were mothers of children aged 12 years old or younger and who gave their consent were eligible. Caregivers other than mothers and subjects with vision problems or cognitive/physical disabilities were excluded. We gathered demographic information such as age, number of children, and education status. Subjects were asked if they had had counseling on how to use measuring devices and which device they preferred. Then, the mothers were required to demonstrate how to measure 5 mL of paracetamol (acetaminophen syrup using a cup and a syringe and 1 mL of paracetamol syrup using a dropper. Dosing errors were evaluated visually as overdosing, underdosing, or no error (if the dose was accurate. The data were entered into Microsoft Excel and evaluated using Stata 11.1. Logistic regression was employed to determine relationships. Results: The results revealed that 58% of participants measured an accurate dose of paracetamol

  3. Effect of orally administered L. fermentum NCIMB 5221 on markers of metabolic syndrome: an in vivo analysis using ZDF rats.

    Science.gov (United States)

    Tomaro-Duchesneau, Catherine; Saha, Shyamali; Malhotra, Meenakshi; Jones, Mitchell L; Labbé, Alain; Rodes, Laetitia; Kahouli, Imen; Prakash, Satya

    2014-01-01

    Metabolic syndrome, encompassing type 2 diabetes mellitus and cardiovascular disease, is a growing health concern of industrialized countries. Ferulic acid (FA) is a phenolic acid found in foods normally consumed by humans that has demonstrated antioxidant activity, cholesterol-lowering capabilities, and anti-tumorigenic properties. Select probiotic bacteria, including Lactobacillus fermentum NCIMB 5221, produce FA due to intrinsic ferulic acid esterase activity. The aim of the present research was to investigate a FA-producing probiotic, L. fermentum NCIMB 5221, as a biotherapeutic for metabolic syndrome. The probiotic formulation was administered daily for 8 weeks to Zucker diabetic fatty (ZDF) rats, a model of hyperlipidemia and hyperglycemia. Results show that the probiotic formulation reduced fasting insulin levels and insulin resistance, significantly reduced serum triglycerides (p = 0.016), lowered serum low-density lipoprotein cholesterol levels (p = 0.008), and significantly reduced the atherogenic (p = 0.016) and atherosclerosis (p = 0.012) index as compared to the control animals. In addition, the probiotic formulation significantly increased high-density lipoprotein cholesterol levels (p = 0.041) as compared to the control animals. This research indicates that administration of the FA-producing L. fermentum NCIMB 5221 has the potential to reduce insulin resistance, hyperinsulinemia, hypercholesterolemia, and other markers involved in the pathogenesis of metabolic syndrome. Further studies are required to investigate the human clinical potential of the probiotic formulation in affecting the markers and pathogenesis of metabolic syndrome.

  4. Orally administered betaine reduces photodamage caused by UVB irradiation through the regulation of matrix metalloproteinase-9 activity in hairless mice.

    Science.gov (United States)

    Im, A-Rang; Lee, Hee Jeong; Youn, Ui Joung; Hyun, Jin Won; Chae, Sungwook

    2016-01-01

    Betaine is widely distributed in plants, microorganisms, in several types of food and in medical herbs, including Lycium chinense. The administration of 100 mg betaine/kg body weight/day is an effective strategy for preventing ultraviolet irradiation‑induced skin damage. The present study aimed to determine the preventive effects of betaine on ultraviolet B (UVB) irradiation‑induced skin damage in hairless mice. The mice were divided into three groups: Control (n=5), UVB‑treated vehicle (n=5) and UVB‑treated betaine (n=5) groups. The level of irradiation was progressively increased between 60 mJ/cm2 per exposure at week 1 (one minimal erythematous dose = 60 mJ/cm2) and 90 mJ/cm2 per exposure at week 7. The formation of wrinkles significantly increased following UVB exposure in the UVB‑treated vehicle group. However, treatment with betaine suppressed UVB‑induced wrinkle formation, as determined by the mean length, mean depth, number, epidermal thickness and collagen damage. Furthermore, oral administration of betaine also inhibited the UVB‑induced expression of mitogen‑activated protein kinase kinase (MEK), extracellular signal‑regulated kinase (ERK), and matrix metalloproteinase‑9 (MMP‑9). These findings suggested that betaine inhibits UVB‑induced skin damage by suppressing increased expression of MMP‑9 through the inhibition of MEK and ERK.

  5. Multicenter randomized prospective clinical evaluation of meloxicam administered via transmucosal oral spray in client-owned dogs.

    Science.gov (United States)

    Cozzi, E M; Spensley, M S

    2013-12-01

    The clinical safety and efficacy of a transmucosal oral spray (TMOS) formulation of meloxicam was evaluated for the control of pain and inflammation associated with osteoarthritis in dogs. A total of 280 client-owned dogs were enrolled at fourteen veterinary clinics: there were 187 dogs in the meloxicam TMOS group and 93 in the placebo control group. Dogs received placebo or treatment spray once daily for twenty-eight days. Improvement in signs of osteoarthritis was measured using client-specific outcome measures (CSOM) made at days 14 and 28 and veterinary assessments of lameness and pain on palpation made at day 28. A significantly higher number of dogs in the meloxicam TMOS group were treatment successes at 28 days (72.6%) compared with the placebo group (46.9%), based on CSOM scores. Total CSOM scores were significantly lower in the meloxicam TMOS-treated group compared with the placebo group at both 14 and 28 days. Differences between treatment groups were not observed in veterinary assessments. Gastrointestinal effects of meloxicam were observed in some animals. Meloxicam TMOS was found to be safe and effective in dogs for the control of pain and inflammation associated with osteoarthritis.

  6. International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences.

    Science.gov (United States)

    Davit, Barbara; Braddy, April C; Conner, Dale P; Yu, Lawrence X

    2013-10-01

    The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association, Japan, Mexico, Singapore, South Korea, Switzerland, the USA, and the World Health Organization. We began with a comparison of how the various jurisdictions and organizations define a generic product and its corresponding reference product. We then compared the following bioequivalence approaches: recommended bioequivalence study designs, method of pharmacokinetic calculations and bioequivalence acceptance limits, recommendations for modifying bioequivalence study designs and limits for highly variable drugs and narrow therapeutic index drugs, provisions for waiving bioequivalence study requirements (granting biowaivers), and implementation of the Biopharmaceutics Classification System. We observed that, overall, there are more similarities than differences in bioequivalence approaches among the regulatory authorities surveyed.

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

    Science.gov (United States)

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

    2015-01-01

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

  8. Potent quinoxaline-based inhibitors of PDGF receptor tyrosine kinase activity. Part 2: the synthesis and biological activities of RPR127963 an orally bioavailable inhibitor.

    Science.gov (United States)

    He, Wei; Myers, Michael R; Hanney, Barbara; Spada, Alfred P; Bilder, Glenda; Galzcinski, Helen; Amin, Dilip; Needle, Saul; Page, Ken; Jayyosi, Zaid; Perrone, Mark H

    2003-09-15

    RPR127963 demonstrates an excellent pharmacokinetic profile in several species and was found to be efficacious in the prevention of restenosis in a Yucatan mini-pig model upon oral administration of 1-5 mg/kg. The in vitro selectivity profile and SAR of the highly optimized PDGF-R tyrosine kinase inhibitor are highlighted.

  9. Metabolism of orally administered (/sup 3/H)ergocalciferol and (/sup 3/H)cholecalciferol by dairy calves

    Energy Technology Data Exchange (ETDEWEB)

    Sommerfeldt, J.L.; Napoli, J.L.; Littledike, E.T.; Beitz, D.C.; Horst, R.L.

    1983-12-01

    Concentrations of ergocalciferol, cholecalciferol, and their metabolites in plasma were determined after a single oral dose of (/sup 3/H)ergocalciferol or (/sup 3/H)cholecalciferol was given to 95- to 105-kg Jersey bull calves. One group (three calves) was given 365 muCi of (/sup 3/H)ergocalciferol (1.2 Ci/mmol) per calf, and the other group (three calves) was given 365 muCi of (/sup 3/H)cholecalciferol (1.2 Ci/mmol) per calf. Fourteen blood samples were taken from each calf during the 3 weeks after administration. Total plasma radioactivity was highest at 80 hours in both groups (8400 dpm/ml and 4600 dpm/ml in the (/sup 3/H)cholecalciferol- and (/sup 3/H)ergocalciferol-treated calves, respectively). For determination of the time-dependent appearance and disappearance of plasma vitamin D and vitamin D metabolites, the plasma /sup 3/H-labeled steroids were extracted and separated by high-performance liquid chromatography. In both groups, (/sup 3/H)vitamin D peaked at 24-48 hours and was the predominant radioactive form in plasma 10-15 hours after dosing. After 15 hours, 25-(/sup 3/H)hydroxyvitamin D became the predominant labeled metabolite, reaching its maximal concentration between 48 and 96 hours. Concentrations of 25-(/sup 3/H)hydroxycholecalciferol were about twice those of 25-(/sup 3/H)hydroxyergocalciferol. The appearance/disappearance profile of 25,26-(/sup 3/H)dihydroxycholecalciferol and 1,25(/sup 3/H)hydroxycholecalciferol resembled that of 25-(/sup 3/H)hydroxycholecalciferol.

  10. Orally Active and Selective Tubulin Inhibitors as Anti-Trypanosome Agents.

    Directory of Open Access Journals (Sweden)

    Vishal Nanavaty

    Full Text Available There is an urgent need to develop a safe, effective, orally active, and inexpensive therapy for African trypanosomiasis due to the drawbacks of current drugs. Selective tubulin inhibitors have the potential to be promising drug candidates for the treatment of this disease, which is based on the tubulin protein structural difference between mammalian and trypanosome cells. We propose to identify novel tubulin inhibitors from a compound library developed based on the lead compounds that selectively target trypanosomiasis.We used Trypanosoma brucei brucei as the parasite model, and human normal kidney cells and mouse microphage cells as the host model. Growth rates of both trypanosomes and mammalian cells were determined as a means to screen compounds that selectively inhibit the proliferation of parasites. Furthermore, we examined the cell cycle profile of the parasite and compared tubulin polymerization dynamics before and after the treatment using identified compounds. Last, in vivo anti-parasite activities of these compounds were determined in T. brucei-infected mice.Three compounds were selected that are 100 fold more effective against the growth of T. brucei cells than mammalian cells. These compounds caused cell cycle progression defects in T. brucei cells. Western analyses indicated that these compounds decreased tubulin polymerization in T. brucei cells. The in vivo investigation revealed that these compounds, when admitted orally, inhibited T. brucei cell proliferation in mouse blood. However, they were not potent enough to clear up the infection completely.These compounds are promising lead compounds as orally active agents for drug development of anti-trypanosome agents. A more detail structure activity relationship (SAR was summarized that will be used to guide future lead optimization to improve the selectivity and potency of the current compounds.

  11. Sex-differential effect on infant mortality of oral polio vaccine administered with BCG at birth in Guinea-Bissau. A natural experiment

    DEFF Research Database (Denmark)

    Benn, Christine Stabell; Fisker, Ane Baerent; Rodrigues, Amabelia

    2008-01-01

    was not available during several periods. We took advantage of this "natural experiment" to test the effect on mortality of receiving OPV at birth. METHODOLOGY: Between 2002 and 2004, the VAS trial randomised normal-birth-weight infants to 50,000 IU VAS or placebo administered with BCG. Provision of OPV at birth......BACKGROUND: The policy to provide oral polio vaccine (OPV) at birth was introduced in low-income countries to increase coverage. The effect of OPV at birth on overall child mortality was never studied. During a trial of vitamin A supplementation (VAS) at birth in Guinea-Bissau, OPV...... was not part of the trial, but we noted whether the infants received OPV or not. OPV was missing during several periods in 2004. We used Cox proportional hazards models to compute mortality rate ratios (MRR) of children who had received or not received OPV at birth. PRINCIPAL FINDINGS: A total of 962 (22...

  12. Genistein administered as a once-daily oral supplement had no beneficial effect on the tibia in rat models for postmenopausal bone loss.

    Science.gov (United States)

    Turner, Russell T; Iwaniec, Urszula T; Andrade, Juan E; Branscum, Adam J; Neese, Steven L; Olson, Dawn A; Wagner, Lindsay; Wang, Victor C; Schantz, Susan L; Helferich, William G

    2013-06-01

    Estrogen deficiency after menopause results in rapid bone loss, predisposing women to osteoporotic fractures. Genistein, a phytoestrogen present in high concentrations in soy, is an ingredient in dietary supplements aggressively marketed for bone health. However, in a recent long-duration clinical trial in postmenopausal women, the efficacy of soy extracts in reducing bone loss was disappointing. To better understand the failure of soy extracts to consistently induce a robust skeletal response in women, we investigated the long-term (5 mo) efficacy of genistein, administered as a daily oral supplement, (1) in preventing cancellous bone loss in skeletally mature virgin Long-Evans rats ovariectomized at 7 months of age and (2) in improving cancellous bone mass and architecture in aged retired-breeder rats ovariectomized at 16 or 22 months of age. Rats within each age group were randomly assigned into one of three treatment groups (n = 7-12 rats/group): (1) vehicle control, (2) genistein 485 μg/day, or (3) genistein 970 μg/day, resulting in mean (SE) serum genistein levels of 0.18 (0.10), 0.76 (0.15), and 1.48 (0.31) μM, respectively. Total tibia bone mass and density were evaluated using dual-energy x-ray absorptiometry, whereas cancellous bone mass and architecture in the tibial metaphysis, as well as cortical bone mass and architecture in the tibial diaphysis, were evaluated by micro-CT. Oral genistein administered as a dietary supplement did not influence the cumulative effects of ovariectomy, aging, and/or reproductive history on cancellous and cortical bone mass and architecture. Serum levels of genistein similar to those in women consuming a high-soy diet are ineffective in preventing or treating bone loss in rat models for postmenopausal osteoporosis.

  13. The effects of orally administered Bacillus coagulans and inulin on prevention and progression of rheumatoid arthritis in rats

    Directory of Open Access Journals (Sweden)

    Khadijeh Abhari

    2016-07-01

    groups (P < 0.001, which was similar to the anti-inflammatory effect of indomethacin. Furthermore, no significant anti-inflammatory effects were observed following different treatments using α1 AGp as an RA indicator. Pretreatment with all supplied diets significantly inhibited the development of paw swelling induced by CFA (P < 0.001. Conclusion: The results of this study indicate that the oral intake of probiotic B. coagulans and prebiotic inulin can improve the biochemical and clinical parameters of induced RA in rat.

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

    Science.gov (United States)

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

    2015-03-01

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

  15. Once-daily oral administration of cyclosporine in a lung transplant patient with a history of renal toxicity of calcineurin inhibitors.

    Science.gov (United States)

    Matsuda, Yuya; Chen, Fengshi; Miyata, Hitomi; Date, Hiroshi

    2014-07-01

    Cyclosporine is usually administered orally in two divided doses every 12 h in transplant patients. However, some patients have difficulty in achieving therapeutic levels after transplantation. In fact, cyclosporine is reportedly administered once daily in renal and liver transplantation cases, but not in lung transplantation cases. We report a patient with a history of calcineurin inhibitor-induced renal toxicity who successfully underwent living-donor lobar lung transplantation (LDLLT) with the novel immunosuppressive strategy of once-daily administration of cyclosporine. An 18-year old man with progressive respiratory insufficiency after bone marrow transplantation was referred to our hospital for lung transplantation. He had a history of renal toxicity due to calcineurin inhibitors. Based on his history of tacrolimus- and cyclosporine-induced renal toxicity, we decided to initiate basiliximab as induction therapy, followed by once-daily cyclosporine administration to obtain high enough blood cyclosporine concentrations at 2 h post-dose (C2) and lowered trough blood concentrations (C0) for protection of renal function as maintenance therapy. LDLLT was successfully performed, and the postoperative course was uneventful and free of rejection episodes. Cyclosporine dosing was adjusted with intensive therapeutic drug monitoring of blood cyclosporine levels. One year after LDLLT, the patient is alive and well with no problems with daily life activities. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

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

    Science.gov (United States)

    Bains, Rasneer S; Ebenezer, Ivor S

    2013-01-01

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

  17. Flavonoids and polymer derivatives as CYP3A4 inhibitors for improved oral drug bioavailability.

    Science.gov (United States)

    Fasinu, Pius; Choonara, Yahya E; Khan, Riaz A; Du Toit, Lisa C; Kumar, Pradeep; Ndesendo, Valence M K; Pillay, Viness

    2013-02-01

    Molecular modeling computations were utilized to generate pharmaceutical grade CYP3A4-enzyme inhibitors. In vitro metabolism of felodipine in human intestinal and liver microsomes (HLM and HIM) was optimized yielding a Michaelis-Menten plot from where the K(m) and V(max) values were estimated by nonlinear regression. The flavonoids, naringin, naringenin, and quercetin, were subsequently incubated with felodipine at the determined K(m) value in HLM. Comparing results obtained from a known CYP3A4 inhibitor, verapamil, the flavonoids inhibited felodipine metabolism. In-depth computational analysis of these flavonoids in terms of CYP3A4 binding, sequencing, and affinity, computational biomimetism was employed to validate the potential CYP3A4 inhibitors. The modeled compounds were comparatively evaluated by incubation with felodipine in both HLM and HIM. Results showed that the polymers 8-arm-PEG, o-(2-aminoethyl)-o-methyl-PEG, 4-arm-PEG (molecular weight = 10,000 g/mol and 20,000 g/mol, respectively), and poly(l-lysine) were able to inhibit the felodipine metabolism with the half maximal inhibitory concentration (IC(50)) values ranging from 7.22 to 30.0 μM (HLM) and 5.78 to 41.03 μM (HIM). Molecular docking confirmed drug-enzyme interactions by computing the free energies of binding (ΔE) and inhibition constants (K(i)) of the docked compounds utilizing a Lamarckian Genetic Algorithm. Comparative correlations between the computed and experimental K(i) values were obtained. Computational modeling of CYP3A4 inhibitors provided a suitable strategy to screen pharmaceutical grade compounds that may potentially inhibit presystemic CYP3A4-dependent drug metabolism with the prospect of improving oral drug bioavailability. Copyright © 2012 Wiley Periodicals, Inc.

  18. Design and synthesis of a novel, orally active, brain penetrant, tri-substituted thiophene based JNK inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Bowers, Simeon; Truong, Anh P.; Neitz, R. Jeffrey; Neitzel, Martin; Probst, Gary D.; Hom, Roy K.; Peterson, Brian; Galemmo, Jr., Robert A.; Konradi, Andrei W.; Sham, Hing L.; Tóth, Gergley; Pan, Hu; Yao, Nanhua; Artis, Dean R.; Brigham, Elizabeth F.; Quinn, Kevin P.; Sauer, John-Michael; Powell, Kyle; Ruslim, Lany; Ren, Zhao; Bard, Frédérique; Yednock, Ted A.; Griswold-Prenner, Irene (Elan)

    2012-02-28

    The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction.

  19. Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206

    OpenAIRE

    Mohd Rehan; Beg, Mohd A.; Shadma Parveen; Ghazi A Damanhouri; Galila F Zaher

    2014-01-01

    The AKT signaling pathway has been identified as an important target for cancer therapy. Among small-molecule inhibitors of AKT that have shown tremendous potential in inhibiting cancer, MK-2206 is a highly potent, selective and orally active allosteric inhibitor. Promising preclinical anticancer results have led to entry of MK-2206 into Phase I/II clinical trials. Despite such importance, the exact binding mechanism and the molecular interactions of MK-2206 with human AKT are not available. ...

  20. New Strategy That Delays Progression of Amyotrophic Lateral Sclerosis in G1H-G93A Transgenic Mice: Oral Administration of Xanthine Oxidoreductase Inhibitors That Are Not Substrates for the Purine Salvage Pathway.

    Science.gov (United States)

    Kato, Shinsuke; Kato, Masako; Kusano, Teruo; Nishino, Takeshi

    2016-12-01

    Amyotrophic lateral sclerosis (ALS), Lou Gehrig's disease, is a progressive fatal neurodegenerative disease that involves both upper and lower motor neurons. We orally administered 4 xanthine oxidoreductase (XOR) inhibitors to G1H-G93A mice carrying 25 transgene copy numbers of human mutant G93A superoxide dismutase 1, from 80 days of age. Three nonpurine-analogue inhibitors (TEI-6720: Febuxostat, Y-700 and FYX-051), but not allopurinol with a purine analogue ring (pyrazolo pyrimidine ring), significantly delayed disease onset, prolonged survival and the duration of disease stages, improved clinical signs, and alleviated weight loss. Exercise testing (extension reflex, inclined plane, footprint, rotarod, and beam balance tests) showed significantly improved motor function in the G1H-G93A mice treated with these 3 inhibitors. Significant amelioration of disease was seen even when TEI-6720 or Y-700 was administered after the appearance of early signs. Histopathological evaluation in the late stage revealed that G1H-G93A mice treated with TEI-6720 had well-preserved motor neurons and fewer inclusion bodies, compared with mice treated with placebo or with allopurinol. Our results indicate that these 3 nonpurine-analogue XOR inhibitors might increase the supply of high-energy compounds via the purine salvage pathway, thereby protecting motor neurons against death. This strategy may be applicable for oral therapy of ALS patients. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  1. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action.

    Science.gov (United States)

    Fletcher, Graham C; Brokx, Richard D; Denny, Trisha A; Hembrough, Todd A; Plum, Stacy M; Fogler, William E; Sidor, Carolyn F; Bray, Mark R

    2011-01-01

    ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC(50) values ranging from 0.025 to 0.7 μmol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinum-resistant ovarian cancer. ©2010 AACR.

  2. Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral cancer.

    Science.gov (United States)

    Samal, Sabindra K; Routray, Samapika; Veeramachaneni, Ganesh Kumar; Dash, Rupesh; Botlagunta, Mahendran

    2015-04-28

    DDX3 belongs to DEAD box RNA helicase family and is involved in the progression of several types of cancer. In this work, we employed a High Throughput Virtual screening approach to identify bioactive compounds against DDX3 from ZINC natural database. Ketorolac salt was selected based on its binding free energy less than or equals to -5 Kcal/mol with reference to existing synthetic DDX3 inhibitors and strong hydrogen bond interactions as similar to crystallized DDX3 protein (2I4I). The anti-cancer activity of Ketorolac salt against DDX3 was tested using oral squamous cell carcinoma (OSCC) cell lines. This compound significantly down regulated the expression of DDX3 in human OSCC line (H357) and the half maximal growth inhibitory concentration (IC50) of Ketorolac salt in H357 cell line is 2.6 µM. Ketorolac salt also inhibited the ATP hydrolysis by directly interacting with DDX3. More importantly, we observed decreased number of neoplastic tongue lesions and reduced lesion severity in Ketorolac salt treated groups in a carcinogen induced tongue tumor mouse model. Taken together, our result demonstrates that Ketorolac salt is a newly discovered bioactive compound against DDX3 and this compound can be used as an ideal drug candidate to treat DDX3 associated oral cancer.

  3. SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models

    Directory of Open Access Journals (Sweden)

    Xin Chen

    2013-07-01

    Full Text Available Background: Melanoma is considered as one of the most aggressive and deadliest cancers and current targeted therapies of melanoma often suffer limited efficacy or drug resistance. Discovery of novel multikinase inhibitors as anti-melanoma drug candidates is still needed. Methods: In this investigation, we assessed the in vitro and in vivo anti-melanoma activities of SC-535, which is a novel small molecule multikinase inhibitor discovered by us recently. We analyzed inhibitory effects of SC-535 on various melanoma cell lines and human umbilical vascular endothelial cells (HUVEC in vitro. Tumor xenografts in athymic mice were used to examine the in vivo activity of SC-535. Results: SC-535 could efficiently inhibit vascular endothelial growth factor receptor (VEGFR 1/2/3, B-RAF, and C-RAF kinases. It showed significant antiangiogenic potencies both in vitro and in vivo and considerable anti-proliferative ability against several melanoma cell lines. Oral administration of SC-535 resulted in dose-dependent suppression of tumor growth in WM2664 and C32 xenograft mouse models. Studies of mechanisms of action indicated that SC-535 suppressed the tumor angiogenesis and induced G2/M phase cell cycle arrest in human melanoma cells. SC-535 possesses favorable pharmacokinetic properties. Conclusion: All of these results support SC-535 as a potential candidate for clinical studies in patients with melanoma.

  4. Effect of food on the pharmacokinetics of oral MMI270B (CGS 27023A), a novel matrix metalloproteinase inhibitor

    NARCIS (Netherlands)

    F.A.L.M. Eskens (Ferry); N.C. Levitt; A. Sparreboom (Alex); L. Choi; R. Mather; J. Verweij (Jaap); A.L. Harris

    2000-01-01

    textabstractMMI270B is a matrix metalloproteinase inhibitor (MMPI) with in vitro and in vivo activity. To exert optimal target inhibition, MMPI must be given chronically, and therefore, oral bioavailability is important. We analyzed the effect of food intake on AUC0-8

  5. Preclinical Metabolism and Disposition of SB939 (Pracinostat), an Orally Active Histone Deacetylase Inhibitor, and Prediction of Human Pharmacokinetics

    NARCIS (Netherlands)

    Jayaraman, Ramesh; Reddy, Venkatesh Pilla; Pasha, Mohammed Khalid; Wang, Haishan; Sangthongpitag, Kanda; Yeo, Pauline; Hu, Chang Yong; Wu, Xiaofeng; Xin, Liu; Goh, Evelyn; New, Lee Sun; Ethirajulu, Kantharaj

    2011-01-01

    The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokin

  6. 3-Amido-3-aryl-piperidines: A Novel Class of Potent, Selective, and Orally Active GlyT1 Inhibitors.

    Science.gov (United States)

    Pinard, Emmanuel; Alberati, Daniela; Alvarez-Sanchez, Ruben; Brom, Virginie; Burner, Serge; Fischer, Holger; Hauser, Nicole; Kolczewski, Sabine; Lengyel, Judith; Mory, Roland; Saladin, Christian; Schulz-Gasch, Tanja; Stalder, Henri

    2014-04-10

    3-Amido-3-aryl-piperidines were discovered as a novel structural class of GlyT1 inhibitors. The structure-activity relationship, which was developed, led to the identification of highly potent compounds exhibiting excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo activity after oral administration.

  7. Antitumor Activity of IMC-038525, a Novel Oral Tubulin Polymerization Inhibitor.

    Science.gov (United States)

    Tuma, Maria Carolina; Malikzay, Asra; Ouyang, Xiaohu; Surguladze, David; Fleming, James; Mitelman, Stan; Camara, Margarita; Finnerty, Bridget; Doody, Jacqueline; Chekler, Eugene L P; Kussie, Paul; Tonra, James R

    2010-10-01

    Microtubules are a well-validated target for anticancer therapy. Molecules that bind tubulin affect dynamic instability of microtubules causing mitotic arrest of proliferating cells, leading to cell death and tumor growth inhibition. Natural antitubulin agents such as taxanes and Vinca alkaloids have been successful in the treatment of cancer; however, several limitations have encouraged the development of synthetic small molecule inhibitors of tubulin function. We have previously reported the discovery of two novel chemical series of tubulin polymerization inhibitors, triazoles (Ouyang et al. Synthesis and structure-activity relationships of 1,2,4-triazoles as a novel class of potent tubulin polymerization inhibitors. Bioorg Med Chem Lett. 2005; 15:5154-5159) and oxadiazole derivatives (Ouyang et al. Oxadiazole derivatives as a novel class of antimitotic agents: synthesis, inhibition of tubulin polymerization, and activity in tumor cell lines. Bioorg Med Chem Lett. 2006; 16:1191-1196). Here, we report on the anticancer effects of a lead oxadiazole derivative in vitro and in vivo. In vitro, IMC-038525 caused mitotic arrest at nanomolar concentrations in epidermoid carcinoma and breast tumor cells, including multidrug-resistant cells. In vivo, IMC-038525 had a desirable pharmacokinetic profile with sustained plasma levels after oral dosing. IMC-038525 reduced subcutaneous xenograft tumor growth with significantly greater efficacy than the taxane paclitaxel. At efficacious doses, IMC-038525 did not cause substantial myelosuppression or peripheral neurotoxicity, as evaluated by neutrophil counts and changes in myelination of the sciatic nerve, respectively. These data indicate that IMC-038525 is a promising candidate for further development as a chemotherapeutic agent.

  8. Orally Administered Salacia reticulata Extract Reduces H1N1 Influenza Clinical Symptoms in Murine Lung Tissues Putatively Due to Enhanced Natural Killer Cell Activity

    Science.gov (United States)

    Romero-Pérez, Gustavo A.; Egashira, Masayo; Harada, Yuri; Tsuruta, Takeshi; Oda, Yuriko; Ueda, Fumitaka; Tsukahara, Takamitsu; Tsukamoto, Yasuhiro; Inoue, Ryo

    2016-01-01

    Influenza is a major cause of respiratory tract infection. Although most cases do not require further hospitalization, influenza periodically causes epidemics in humans that can potentially infect and kill millions of people. To countermeasure this threat, new vaccines need to be developed annually to match emerging influenza viral strains with increased resistance to existing vaccines. Thus, there is a need for finding and developing new anti-influenza viral agents as alternatives to current treatments. Here, we tested the antiviral effects of an extract from the stems and roots of Salacia reticulata (SSRE), a plant rich in phytochemicals, such as salacinol, kotalanol, and catechins, on H1N1 influenza virus-infected mice. Following oral administration of 0.6 mg/day of SSRE, the incidence of coughing decreased in 80% of mice, and only one case of severe pulmonary inflammation was detected. Moreover, when compared with mice given Lactobacillus casei JCM1134, a strain previously shown to help increase in vitro natural killer (NK) cell activity, SSRE-administered mice showed greater and equal NK cell activity in splenocytes and pulmonary cells, respectively, at high effector cell:target cell ratios. Next, to test whether or not SSRE would exert protective effects against influenza in the absence of gut microbiota, mice were given antibiotics before being inoculated influenza virus and subsequently administered SSRE. SSRE administration induced an increase in NK cell activity in splenocytes and pulmonary cells at levels similar to those detected in mice not treated with antibiotics. Based on our results, it can be concluded that phytochemicals in the SSRE exerted protective effects against influenza infection putatively via modulation of the immune response, including enhancement of NK cell activity, although some protective effects were not necessarily through modulation of gut microbiota. Further investigation is necessary to elucidate the molecular mechanisms

  9. PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE AND ITS METABOLITE O-DESMETHYLTRAMADOL FOLLOWING A SINGLE, ORALLY ADMINISTERED DOSE IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    Science.gov (United States)

    Boonstra, Jennifer L; Barbosa, Lorraine; Van Bonn, William G; Johnson, Shawn P; Gulland, Frances M D; Cox, Sherry K; Martin-Jimenez, Tomas

    2015-09-01

    Tramadol is a synthetic, centrally acting, opiate-like analgesic that is structurally related to codeine and morphine. The objective of this study was to determine the pharmacokinetics of tramadol hydrochloride and its major active metabolite O-desmethyltramadol (M1) in the California sea lion (Zalophus californianus). A single dose of tramadol was administered orally in fish at 2 mg/kg to a total of 15 wild California sea lions admitted for rehabilitation. Twenty-four total blood samples were collected post drug administration at 10, 20, 30, and 45 min and at 1, 3, 5, 6, 8, 12, and 24 hr. Blood plasma was separated and stored at -80°C until analysis with high-performance liquid chromatography was performed to determine levels of tramadol and M1, the major active metabolite. The results indicate that the plasma levels of parent tramadol are low or negligible during the first 30-45 min and then reach the predicted mean maximum plasma concentration of 358 ng/ml at 1.52 hr. The M1 metabolite was not detectable in 21 of 24 plasma samples, below the level of quantification of 5 ng/ml in one sample, and detectable at 11 and 17 ng/ml in two of the samples. This study suggests that a 2 mg/kg dose would need to be administered every 6-8 hr to maintain concentrations of tramadol above the minimum human analgesic level for mild to moderate pain. Based on dosing simulations, a dose of 4 mg/kg q8 hr or q12 hr, on average, may represent an adequate compromise, but further studies are needed using a larger sample size. Pharmacodynamic studies are warranted to determine if tramadol provides analgesic effects in this species. The potential for tramadol toxicosis at any dose also has not been determined in this species.

  10. Orally administered Salacia reticulata extract reduces H1N1 influenza clinical symptoms in murine lung tissues putatively due to enhanced natural killer cell activity

    Directory of Open Access Journals (Sweden)

    Gustavo Adolfo Romero-Pérez

    2016-03-01

    Full Text Available Influenza is a major cause of respiratory tract infection. Although most cases do not require further hospitalization, influenza periodically causes epidemics in humans that can potentially infect and kill millions of people. To countermeasure this threat, new vaccines need to be developed annually to match emerging influenza viral strains with increased resistance to existing vaccines. Thus, there is a need for finding and developing new anti-influenza viral agents as alternatives to current treatments. Here, we tested the antiviral effects of an extract from the stems and roots of Salacia reticulata (SSRE, a plant rich in phytochemicals such as salacinol, kotalanol and catechins, on H1N1 influenza virus-infected mice. Following oral administration of 0.6 mg/day of SSRE, the incidence of coughing decreased in 80% of mice, and only one case of severe pulmonary inflammation was detected. Moreover, when compared with mice given Lactobacillus casei JCM1134, a strain previously shown to help increase in vitro NK cell activity, SSRE-administered mice showed greater and equal NK cell activity in splenocytes and pulmonary cells, respectively, at high effector cell:target cell ratios. Next, to test whether or not SSRE would exert protective effects against influenza in the absence of gut microbiota, mice were given antibiotics before being inoculated influenza virus and subsequently administered SSRE. SSRE administration induced an increase in NK cell activity in splenocytes and pulmonary cells at levels similar to those detected in mice not treated with antibiotics. Based on our results, it can be concluded that phytochemicals in the SSRE exerted protective effects against influenza infection putatively via modulation of the immune response including enhancement of NK cell activity, although some protective effects were not necessarily through modulation of gut microbiota. Further investigation is necessary to elucidate the molecular mechanisms

  11. Time-and pH-dependent colon-specific drug delivery for orally administered diclofenac sodium and 5-aminosalicylic acid

    Institute of Scientific and Technical Information of China (English)

    Gang Cheng; Feng An; Mei-Juan Zou; Jin Sun; Xiu-Hua Hao; Yun-Xia He

    2004-01-01

    AIM: To investigate Time- and pH-dependent colon-specific drug delivery systems (CDDS) for orally administered diclofenac sodium (DS) and 5-aminosalicylic acid (5-ASA), respectively.METHODS: DS tablets and 5-ASA pellets were coated by ethylcellulose (EC) and methacrylic acid copolymers (Eudragit[] L100 and S100), respectively. The in vitro release behavior of the DS coated tablets and 5-ASA coated pellets were examined, and then in vivo absorption kinetics of DS coated tablets in dogs were further studied.RESULTS: Release profile of time-dependent DS coated tablets was not influenced by pH of the dissolution medium,but the lag time of DS release was primarily controlled by the thickness of the coating layer. The thicker the coating layer, the longer the lag time of DS release is. On the contrary, in view of the pH-dependent 5-ASA coated pellets,5-ASA release was significantly governed by pH. Moreover,the 5-ASA release features from the coated pellets depended upon both the combination ratio of the Eudragit[] L100 and S100 pH-sensitive copolymers in the coating formulation and the thickness of the coating layer. The absorption kinetic studies of the DS coated tablets in dogs demonstrated that in vivo lag time of absorption was in a good agreement with in vitro lag time of release.CONCLUSION: Two types of CDDS, prepared herein by means of the regular coating technique, are able to achieve site-specific drug delivery targeting at colon following oral administration, and provide a promising strategy to control drug release targeting the desired lower gastrointestinal region.

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

    Science.gov (United States)

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

    2010-09-01

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

  13. Effects of SiC nanoparticles orally administered in a rat model: Biodistribution, toxicity and elemental composition changes in feces and organs

    Energy Technology Data Exchange (ETDEWEB)

    Lozano, Omar, E-mail: omar.lozanogarcia@fundp.ac.be [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Research Centre for the Physics of Matter and Radiation (PMR-LARN), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Laloy, Julie; Alpan, Lütfiye [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Mejia, Jorge [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Research Centre for the Physics of Matter and Radiation (PMR-LARN), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Rolin, Stéphanie [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Toussaint, Olivier [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Laboratory of Biochemistry and Cellular Biology (URBC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Dogné, Jean-Michel [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); and others

    2012-10-15

    Background: Silicon carbide (SiC) presents noteworthy properties as a material such as high hardness, thermal stability, and photoluminescent properties as a nanocrystal. However, there are very few studies in regard to the toxicological potential of SiC NPs. Objectives: To study the toxicity and biodistribution of silicon carbide (SiC) nanoparticles in an in vivo rat model after acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 600 mg·kg{sup −1}, while the subacute doses were 0.5 and 50 mg·kg{sup −1}. Results: SiC biodistribution and elemental composition of feces and organs (liver, kidneys, and spleen) have been studied by Particle-Induced X-ray Emission (PIXE). SiC and other elements in feces excretion increased by the end of the subacute assessment. SiC did not accumulate in organs but some elemental composition modifications were observed after the acute assessment. Histopathological sections from organs (stomach, intestines, liver, and kidneys) indicate the absence of damage at all applied doses, in both assessments. A decrease in the concentration of urea in blood was found in the 50 mg·kg{sup −1} group from the subacute assessment. No alterations in the urine parameters (sodium, potassium, osmolarity) were found. Conclusion: This is the first study that assesses the toxicity, biodistribution, and composition changes in feces and organs of SiC nanoparticles in an in vivo rat model. SiC was excreted mostly in feces and low traces were retrieved in urine, indicating that SiC can cross the intestinal barrier. No sign of toxicity was however found after oral administration. -- Highlights: ► SiC nanoparticles were orally administered to rats in acute and subacute doses. ► SiC was found in low traces in urine. It is mostly excreted in feces within 5 days. ► SiC excretion rate, feces and organ elemental composition change with time. ► No morphological alteration were found on GI tract, liver, kidneys

  14. Distribution of intravenously administered acetylcholinesterase inhibitor and acetylcholinesterase activity in the adrenal gland: 11C-donepezil PET study in the normal rat.

    Directory of Open Access Journals (Sweden)

    Tadashi Watabe

    Full Text Available PURPOSE: Acetylcholinesterase (AChE inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered (11C-Donepezil (DNP and the AChE activity in the normal rat, with special focus on the adrenal glands. METHODS: The distribution of (11C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight  = 220 ± 8.9 g. A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of (11C-DNP (45.0 ± 10.7 MBq. The whole-body distribution of the (11C-DNP PET was evaluated based on the Vt (total distribution volume by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs. RESULTS: The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of (11C-DNP in the body (following the liver (13.33 ± 1.08 and 19.43 ± 1.29 ml/cm(3, respectively, indicating that the distribution of (11C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach (24.9 ± 1.6, 83.1 ± 3.0, and 38.5 ± 8.1 mU/mg, respectively, indicating high activity of AChE in the adrenal glands. CONCLUSIONS: We demonstrated the whole-body distribution of (11C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of (11C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.

  15. Distribution of intravenously administered acetylcholinesterase inhibitor and acetylcholinesterase activity in the adrenal gland: 11C-donepezil PET study in the normal rat.

    Science.gov (United States)

    Watabe, Tadashi; Naka, Sadahiro; Ikeda, Hayato; Horitsugi, Genki; Kanai, Yasukazu; Isohashi, Kayako; Ishibashi, Mana; Kato, Hiroki; Shimosegawa, Eku; Watabe, Hiroshi; Hatazawa, Jun

    2014-01-01

    Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered (11)C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands. The distribution of (11)C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight  = 220 ± 8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of (11)C-DNP (45.0 ± 10.7 MBq). The whole-body distribution of the (11)C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs. The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of (11)C-DNP in the body (following the liver) (13.33 ± 1.08 and 19.43 ± 1.29 ml/cm(3), respectively), indicating that the distribution of (11)C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9 ± 1.6, 83.1 ± 3.0, and 38.5 ± 8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands. We demonstrated the whole-body distribution of (11)C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of (11)C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.

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

    Science.gov (United States)

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

    2015-12-01

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

  17. Comparison of oral psoralen-UV-A with a portable tanning unit at home vs hospital-administered bath psoralen-UV-A in patients with chronic hand eczema - An open-label randomized controlled trial of efficacy

    NARCIS (Netherlands)

    van Coevorden, AM; Kamphof, WG; van Sonderen, E; Bruynzeel, DP; Coenraads, PJ

    2004-01-01

    Objective: To study whether oral psoralen-UV-A (PUVA) with a portable tanning unit at home is as effective as hospital-administered bath PUVA in patients with chronic hand eczema. Design: Open-label randomized controlled trial, with a 10-week treatment period and an 8-week follow-up period. Setting:

  18. Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase

    Science.gov (United States)

    Palencia, Andrés; Li, Xianfeng; Bu, Wei; Choi, Wai; Ding, Charles Z.; Easom, Eric E.; Feng, Lisa; Hernandez, Vincent; Houston, Paul; Liu, Liang; Meewan, Maliwan; Mohan, Manisha; Rock, Fernando L.; Sexton, Holly; Zhang, Suoming; Zhou, Yasheen; Wan, Baojie; Wang, Yuehong; Franzblau, Scott G.; Woolhiser, Lisa; Gruppo, Veronica; Lenaerts, Anne J.; O'Malley, Theresa; Parish, Tanya; Cooper, Christopher B.; Waters, M. Gerard; Ma, Zhenkun; Ioerger, Thomas R.; Sacchettini, James C.; Rullas, Joaquín; Angulo-Barturen, Iñigo; Pérez-Herrán, Esther; Mendoza, Alfonso; Barros, David; Cusack, Stephen; Plattner, Jacob J.

    2016-01-01

    The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis. Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid. PMID:27503647

  19. 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

  20. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren.

    Science.gov (United States)

    Stanton, Alice; Jensen, Chris; Nussberger, Juerg; O'Brien, Eoin

    2003-12-01

    Inhibition of the first and rate-limiting step of the renin-angiotensin system has long been an elusive therapeutic goal. Aliskiren, the first known representative of a new class of completely nonpeptide, orally active, renin inhibitors, has been shown to inhibit the production of angiotensin I and II in healthy volunteers and to reduce blood pressure (BP) in sodium-depleted marmosets. The aim of this randomized, double-blind, active comparator trial study was to assess the BP-lowering efficacy and safety of aliskiren. Two hundred twenty-six patients, 21 to 70 years of age, with mild to moderate hypertension, were randomly assigned to receive 37.5 mg, 75 mg, 150 mg, or 300 mg aliskiren or 100 mg losartan daily for 4 weeks. Dose-dependent reductions in daytime ambulatory systolic pressure (mean change, mm Hg [SD of change]; -0.4 [11.7], -5.3 [11.3], -8.0 [11.0], and -11.0 [11.0], P=0.0002) and in plasma renin activity (median change % [interquartile range]; -55 [-64, -11], -60 [-82, -46], -77 [-86, -72], and -83 [-92, -71], P=0.0008) were observed with 37.5, 75, 150, and 300 mg aliskiren. The change in daytime systolic pressure with 100 mg losartan (-10.9 [13.8]) was not significantly different from the changes seen with 75, 150, and 300 mg aliskiren. Aliskiren was well tolerated at all doses studied. This study demonstrates that aliskiren, through inhibition of renin, is an effective and safe orally active BP-lowering agent. Whether renin inhibition results in protection from heart attack, stroke, and nephropathy, similar to angiotensin-converting enzyme inhibition and angiotensin receptor blockade, needs to be researched.

  1. Management of major bleedings during anticoagulant treatment with the oral direct thrombin inhibitor ximelagatran or warfarin.

    Science.gov (United States)

    Fernlöf, Gunilla; Sjöström, Britta M; Lindell, Klas M; Wall, Ulrika E

    2009-12-01

    Several new oral anticoagulants are currently investigated in phase III programmes, mainly with inhibition of factor Xa or thrombin as their pharmacological target. Advantages are expected with these new drugs compared with vitamin K antagonists, but one potential drawback is the lack of specific antidotes. During the clinical studies with ximelagatran, an oral direct thrombin inhibitor withdrawn due to hepatic side effects, investigators were instructed to manage bleedings with routine measures. We have retrospectively tried to assess whether this was sufficient or whether there was a need for reversal strategies. The study population consisted of patients with major bleedings in three long-term studies (104 ximelagatran, 155 warfarin). All individual patient narratives were reviewed with respect to management of the bleeding. Complementary data were retrieved from the data-based case report forms. Approximately, two of three of the patients in both groups were subject to some kind of treatment. One-third (1/3) in both groups had transfusions documented and/or received specific medication. Vitamin K was given more often to warfarin patients. Two ximelagatran patients received prothrombin complex (four-factor concentrate), but one was a patient with a severe hepatopathy suspected to be drug-induced. Overall, the case descriptions did not reveal any apparent differences in the course of events between groups. We found no indications that the lack of an antidote posed a clinical problem in patients treated with ximelagatran as compared with warfarin. The relatively short half-life of melagatran, the active metabolite of ximelagatran, may have contributed to these results.

  2. Effect of the hepatitis C virus protease inhibitor faldaprevir on the pharmacokinetics of an oral contraceptive containing ethinylestradiol and levonorgestrel in healthy female volunteers.

    Science.gov (United States)

    Sabo, John P; Lang, Benjamin; Elgadi, Mabrouk; Huang, Fenglei

    2015-01-01

    Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor. Faldaprevir is known to inhibit P-glycoprotein, CYP3A4, and UDP-glucuronosyltransferase 1A1. This study evaluated the effect of steady-state 240 mg faldaprevir on the pharmacokinetics (PK) of an oral contraceptive containing ethinylestradiol (EE) and levonorgestrel (LNG) in healthy premenopausal women. In period 1, subjects received EE/LNG once daily (QD) for 14 days. Blood samples were taken on days 1, 11, and 12, with intensive PK blood sampling for EE and LNG on day 13. In period 2, subjects received EE-LNG QD and 240 mg faldaprevir QD on days 14 to 21 (240 mg faldaprevir twice daily on day 14). Blood samples were taken on days 14, 19, and 20, with PK profiling samples obtained for EE and LNG on day 21. A total of 15/16 subjects completed the study. Overall, EE and LNG exposure (assessed by the area under the curve) was approximately 1.4-fold higher when EE and LNG were coadministered with faldaprevir than when administered alone. Median t1/2 (terminal half-life in plasma at steady state) values were prolonged for both EE (2.4 h longer) and LNG (4.7 h longer) when EE and LNG were coadministered with faldaprevir. The mean oral clearance and apparent volume of distribution of both EE and LNG were lower (∼ 30%) when EE and LNG were coadministered with faldaprevir. Coadministration of faldaprevir and an oral contraceptive resulted in a moderate increase in exposure to both EE and LNG. However, this increase was not considered clinically meaningful, and no dose adjustment of oral contraceptives was deemed necessary. (This study has been registered at ClinicalTrials.gov under registration number NCT01570244.).

  3. A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors.

    Science.gov (United States)

    Kristeleit, Rebecca; Shapiro, Geoffrey I; Burris, Howard A; Oza, Amit M; LoRusso, Patricia; Patel, Manish R; Domchek, Susan M; Balmaña, Judith; Drew, Yvette; Chen, Lee-May; Safra, Tamar; Montes, Ana; Giordano, Heidi; Maloney, Lara; Goble, Sandra; Isaacson, Jeff; Xiao, Jim; Borrow, Jen; Rolfe, Lindsey; Shapira-Frommer, Ronnie

    2017-08-01

    Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I-II study was the first to evaluate single-agent oral rucaparib at multiple doses.Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1.Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately dose-proportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2-mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression).Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2-mutated HGOC. Clin Cancer Res; 23(15); 4095-106. ©2017 AACR. ©2017 American Association for Cancer Research.

  4. Discovery of potent imidazole and cyanophenyl containing farnesyltransferase inhibitors with improved oral bioavailability.

    Science.gov (United States)

    Tong, Yunsong; Lin, Nan-Horng; Wang, Le; Hasvold, Lisa; Wang, Weibo; Leonard, Nicholas; Li, Tongmei; Li, Qun; Cohen, Jerry; Gu, Wen-Zhen; Zhang, Haiying; Stoll, Vincent; Bauch, Joy; Marsh, Kennan; Rosenberg, Saul H; Sham, Hing L

    2003-05-05

    A pyridyl moiety was introduced into a previously developed series of farnesyltransferase inhibitors containing imidazole and cyanophenyl (such as 4), resulting in potent inhibitors with improved pharmacokinetics.

  5. Combining oral contraceptives with a natural nuclear factor-kappa B inhibitor for the treatment of endometriosis-related pain

    Science.gov (United States)

    Maia, Hugo; Haddad, Clarice; Casoy, Julio

    2014-01-01

    Endometriosis is a chronic disease in which a persistent state of heightened inflammation is maintained by nuclear factor-kappa B (NF-κB) activation. The progestins present in oral contraceptives are potent inhibitors of NF-κB translocation to cell nuclei, while Pycnogenol® (Pinus pinaster) acts by blocking post-translational events. In this study, the effects of Pycnogenol on pain scores were investigated in patients with endometriosis using oral contraceptives containing either gestodene or drospirenone in extended regimens. Pain scores were determined using a visual analog scale before and after 3 months of treatment. Oral contraceptives, used alone (groups 1 and 3) or in association with Pycnogenol (groups 2 and 4), resulted in significant decreases in pain scores after 3 months of treatment; however, this reduction was significantly greater in the groups using oral contraceptives + Pycnogenol (groups 2 and 4) compared with those using oral contraceptives alone (groups 1 and 3). In the groups using oral contraceptives alone, 50% of patients became pain-free by the end of the third month of treatment. These results suggest that Pycnogenol increases the efficacy of oral contraceptives for the treatment of endometriosis-related pain. PMID:24379702

  6. Identification of a novel boronic acid as a potent, selective, and orally active hormone sensitive lipase inhibitor.

    Science.gov (United States)

    Ogiyama, Tomoko; Yamaguchi, Mitsuhiro; Kurikawa, Nobuya; Honzumi, Shoko; Yamamoto, Yuka; Sugiyama, Daisuke; Inoue, Shinichi

    2016-08-15

    Hormone sensitive lipase (HSL) is an attractive therapeutic target of dyslipidemia. We designed and synthesized several compounds as reversible HSL inhibitors with a focus on hydrophobic interactions, which was thought to be effective upon the HSL inhibitory activity. In these efforts, we identified boronated compound 12 showing a potent HSL inhibitory activity with an IC50 value of 7nM and a high selectivity against cholinesterases. Furthermore, compound 12 is the first boron containing HSL inhibitor that has shown an antilipolytic effect in rats after oral administration at 3mg/kg. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Targeting kynurenine aminotransferase II in psychiatric diseases: promising effects of an orally active enzyme inhibitor.

    Science.gov (United States)

    Wu, Hui-Qiu; Okuyama, Masahiro; Kajii, Yasushi; Pocivavsek, Ana; Bruno, John P; Schwarcz, Robert

    2014-03-01

    Increased brain levels of the tryptophan metabolite kynurenic acid (KYNA) have been linked to cognitive dysfunctions in schizophrenia and other psychiatric diseases. In the rat, local inhibition of kynurenine aminotransferase II (KAT II), the enzyme responsible for the neosynthesis of readily mobilizable KYNA in the brain, leads to a prompt reduction in extracellular KYNA levels, and secondarily induces an increase in extracellular glutamate, dopamine, and acetylcholine levels in several brain areas. Using microdialysis in unanesthetized, adult rats, we now show that the novel, systemically active KAT II inhibitor BFF-816, applied orally at 30 mg/kg in all experiments, mimics the effects of local enzyme inhibition. No tolerance was seen when animals were treated daily for 5 consecutive days. Behaviorally, daily injections of BFF-816 significantly decreased escape latency in the Morris water maze, indicating improved performance in spatial and contextual memory. Thus, systemically applied BFF-816 constitutes an excellent tool for studying the neurobiology of KYNA and, in particular, for investigating the mechanisms linking KAT II inhibition to changes in glutamatergic, dopaminergic, and cholinergic function in brain physiology and pathology.

  8. Managing patients taking novel oral anticoagulants (NOAs) in dentistry: a discussion paper on clinical implications

    OpenAIRE

    Costantinides, Fulvia; Rizzo, Roberto; Pascazio, Lorenzo; Maglione, Michele

    2016-01-01

    Background The aim of this paper is to contribute to the discussion on how to approach patients taking new orally administered anticoagulants (NOAs) dabigatran etexilate (a direct thrombin inhibitor), rivaroxaban and apixaban (factor Xa inhibitors), before, during and after dental treatment in light of the more recent knowledges. Discussion In dentistry and oral surgery, the major concerns in treatment of patients taking direct thrombin inhibitors and factor Xa inhibitors is the risk of haemo...

  9. Orally-effective, long-acting sorbitol dehydrogenase inhibitors: synthesis, structure-activity relationships, and in vivo evaluations of novel heterocycle-substituted piperazino-pyrimidines.

    Science.gov (United States)

    Chu-Moyer, Margaret Y; Ballinger, William E; Beebe, David A; Berger, Richard; Coutcher, James B; Day, Wesley W; Li, Jiancheng; Mylari, Banavara L; Oates, Peter J; Weekly, R Matthew

    2002-01-17

    Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED(90) < or = 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED(90) values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for approximately 17 h, when administered orally at a single dose of 2 mg/kg/day.

  10. Sex-differential effect on infant mortality of oral polio vaccine administered with BCG at birth in Guinea-Bissau. A natural experiment.

    Directory of Open Access Journals (Sweden)

    Christine Stabell Benn

    Full Text Available BACKGROUND: The policy to provide oral polio vaccine (OPV at birth was introduced in low-income countries to increase coverage. The effect of OPV at birth on overall child mortality was never studied. During a trial of vitamin A supplementation (VAS at birth in Guinea-Bissau, OPV was not available during several periods. We took advantage of this "natural experiment" to test the effect on mortality of receiving OPV at birth. METHODOLOGY: Between 2002 and 2004, the VAS trial randomised normal-birth-weight infants to 50,000 IU VAS or placebo administered with BCG. Provision of OPV at birth was not part of the trial, but we noted whether the infants received OPV or not. OPV was missing during several periods in 2004. We used Cox proportional hazards models to compute mortality rate ratios (MRR of children who had received or not received OPV at birth. PRINCIPAL FINDINGS: A total of 962 (22.1% of the 4345 enrolled children did not receive OPV at birth; 179 children died within the first year of life. Missing OPV at birth was associated with a tendency for decreased mortality (adjusted MRR = 0.69 (95% CI = 0.46-1.03, the effect being similar among recipients of VAS and placebo. There was a highly significant interaction between OPV at birth and sex (p = 0.006. Not receiving OPV at birth was associated with a weak tendency for increased mortality in girls (1.14 (0.70-1.89 but significantly decreased mortality in boys (0.35 (0.18-0.71. CONCLUSIONS: In our study OPV at birth had a sex-differential effect on mortality. Poliovirus is almost eradicated and OPV at birth contributes little to herd immunity. A randomised study of the effect of OPV at birth on overall mortality in both sexes is warranted.

  11. Orally administered fructose increases the numbers of peripheral lymphocytes reduced by exposure of mice to gamma or SPE-like proton radiation

    Science.gov (United States)

    Romero-Weaver, A. L.; Ni, J.; Lin, L.; Kennedy, A. R.

    2014-07-01

    Exposure of the whole body or a major portion of the body to ionizing radiation can result in Acute Radiation Sickness (ARS), which can cause symptoms that range from mild to severe, and include death. One of the syndromes that can occur during ARS is the hematopoietic syndrome, which is characterized by a reduction in bone marrow cells as well as the number of circulating blood cells. Doses capable of causing this syndrome can result from conventional radiation therapy and accidental exposure to ionizing radiation. It is of concern that this syndrome could also occur during space exploration class missions in which astronauts could be exposed to significant doses of solar particle event (SPE) radiation. Of particular concern is the reduction of lymphocytes and granulocytes, which are major components of the immune system. A significant reduction in their numbers can compromise the immune system, causing a higher risk for the development of infections which could jeopardize the success of the mission. Although there are no specific countermeasures utilized for the ARS resulting from exposure to space radiation(s), granulocyte colony-stimulating factor (G-CSF) has been proposed as a countermeasure for the low number of neutrophils caused by SPE radiation, but so far no countermeasure exists for a reduced number of circulating lymphocytes. The present study demonstrates that orally administered fructose significantly increases the number of peripheral lymphocytes reduced by exposure of mice to 2 Gy of gamma- or SPE-like proton radiation, making it a potential countermeasure for this biological end-point.

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

    Science.gov (United States)

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

    2015-01-01

    Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10mg oral doses of delta-9-tetrahydocannibinol (THC); and 0mg, 10mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10mg THC+0mg, 10mg, and 40 mg MPH=89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of "Feel Drug," "Good Effects," and "Take Drug Again." THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

    Directory of Open Access Journals (Sweden)

    David G Warnock

    Full Text Available Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT with either agalsidase alfa (Replagal or agalsidase beta (Fabrazyme. Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%. Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.ClinicalTrials.gov NCT01196871.

  14. Effect of mefloquine administered orally at single, multiple, or combined with artemether, artesunate, or praziquantel in treatment of mice infected with Schistosoma japonicum.

    Science.gov (United States)

    Xiao, Shu-hua; Mei, Jing-yan; Jiao, Pei-ying

    2011-02-01

    The purpose of the study is to explore the efficacy of mefloquine administered orally at single, multiple doses, or in combination with artesuante, artemether, or praziquantel in mouse--Schistosoma japonicum model. A total of 205 mice were divided into 4 batches and each batch of mice was infected percutaneously with 40 S. japonicum cercariae for 35 days. The infected mice were treated orally with mefloquine at single doses, multiple daily doses, or combined with artesunate, artemether, or praziquantel, while infected but untreated mice served as control. All treated animals were killed 4 weeks post-treatment for assessment of effect. When infected mice were treated orally with mefloquine at single or multiple daily doses under the same total dose levels, the tendency to decrease the efficacy was seen. Particularly, when a lower single dose of 100 mg/kg was divided equally into five daily doses of 20 mg/kg, the efficacy decreased statistically significant (Pmefloquine or artesuante at a single dose of 100 mg/kg, a moderate effect against schistosomes was observed. No further significant reduction of total and female worm burdens was seen, when the two drugs combined together at the same dose level. On the other hand, administration of mefloquine combined with artesunate at single dose of 50 mg/kg, which exhibited no effect against schistosomes, resulted in significant reduction of total and female worm burdens in comparison with the groups treated with mefloquine and artesunate alone at the same dose level. Similar results were observed in treatment of infected mice with mefloquine in combination with artemether at the smaller dose of 50 mg/kg. The total worm burden was significantly lower than that of control and the female worm burden was also significant lower than that of groups treated with mefloquine and artemether alone. Interestingly, in administration of mefloquine 100 mg/kg combined with artemether 100 mg/kg to the infected mice, all female worms were

  15. Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats

    Energy Technology Data Exchange (ETDEWEB)

    Li, Li, E-mail: li1.li@novartis.com [Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States); Vashisht, Kapil; Boisclair, Julie [Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States); Li, Wenkui; Lin, Tsu-han [Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States); Schmid, Herbert A. [Novartis Oncology Development, Basel (Switzerland); Kluwe, William; Schoenfeld, Heidi; Hoffmann, Peter [Preclinical Safety, Novartis Institutes for BioMedical Research, East Hanover, NJ (United States)

    2015-08-01

    The somatostatin analog pasireotide and the 11β-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of pasireotide (0.3 mg/kg/day, subcutaneously), osilodrostat (20 mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03 mg/kg/day; mid-dose, 5/0.1 mg/kg/day; or high dose, 20/0.3 mg/kg/day), or vehicle for 13 weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. C{sub max} and AUC{sub 0–24h} of osilodrostat and pasireotide increased in an approximately dose-proportional manner. In conclusion, the pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy. - Highlights: • We examined the target organ toxicity of SOM230

  16. Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer.

    Science.gov (United States)

    Arcaroli, John; Quackenbush, Kevin; Dasari, Arvind; Powell, Rebecca; McManus, Martine; Tan, Aik-Choon; Foster, Nathan R; Picus, Joel; Wright, John; Nallapareddy, Sujatha; Erlichman, Charles; Hidalgo, Manuel; Messersmith, Wells A

    2012-10-01

    Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] "top scoring pairs" polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3' untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible.

  17. Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors

    DEFF Research Database (Denmark)

    Artang, Ramin; Rome, Eric; Nielsen, Jørn Dalsgaard;

    2013-01-01

    . To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention......Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI...... trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely...

  18. Structure-based design of novel guanidine/benzamidine mimics: potent and orally bioavailable factor Xa inhibitors as novel anticoagulants.

    Science.gov (United States)

    Lam, Patrick Y S; Clark, Charles G; Li, Renhua; Pinto, Donald J P; Orwat, Michael J; Galemmo, Robert A; Fevig, John M; Teleha, Christopher A; Alexander, Richard S; Smallwood, Angela M; Rossi, Karen A; Wright, Matthew R; Bai, Stephen A; He, Kan; Luettgen, Joseph M; Wong, Pancras C; Knabb, Robert M; Wexler, Ruth R

    2003-10-09

    As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K(i) of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.

  19. Use of the oral platelet inhibitors dipyridamole and acetylsalicylic acid is associated with increased risk of fracture

    DEFF Research Database (Denmark)

    Vestergaard, Peter; Steinberg, Thomas H; Schwarz, P

    2012-01-01

    ). Clopidogrel is the most widely used, and in combination with acetylsalicylic acid it is the standard of care for acute coronary syndromes and percutaneous coronary interventions. However, the modes of action involve pathways that are involved in the metabolic activity in bone cells and pharmacologic...... modulation of these pathways may therefore have effects on bone. METHODS: In the current study, we assessed the association between platelet inhibitor use and fracture incidence in a population-based epidemiological study performed within the Danish population consisting of approximately 5.3million...... is not associated with increased fracture risk. CONCLUSIONS: Use of some oral platelet inhibitors is associated with increased risk of fractures, and more studies are warranted to determine the potential effect of platelet inhibitors on bone metabolism in vivo....

  20. Oral administration of Bruton's tyrosine kinase inhibitors impairs GPVI-mediated platelet function.

    Science.gov (United States)

    Rigg, Rachel A; Aslan, Joseph E; Healy, Laura D; Wallisch, Michael; Thierheimer, Marisa L D; Loren, Cassandra P; Pang, Jiaqing; Hinds, Monica T; Gruber, András; McCarty, Owen J T

    2016-03-01

    The Tec family kinase Bruton's tyrosine kinase (Btk) plays an important signaling role downstream of immunoreceptor tyrosine-based activation motifs in hematopoietic cells. Mutations in Btk are involved in impaired B-cell maturation in X-linked agammaglobulinemia, and Btk has been investigated for its role in platelet activation via activation of the effector protein phospholipase Cγ2 downstream of the platelet membrane glycoprotein VI (GPVI). Because of its role in hematopoietic cell signaling, Btk has become a target in the treatment of chronic lymphocytic leukemia and mantle cell lymphoma; the covalent Btk inhibitor ibrutinib was recently approved by the US Food and Drug Administration for treatment of these conditions. Antihemostatic events have been reported in some patients taking ibrutinib, although the mechanism of these events remains unknown. We sought to determine the effects of Btk inhibition on platelet function in a series of in vitro studies of platelet activation, spreading, and aggregation. Our results show that irreversible inhibition of Btk with two ibrutinib analogs in vitro decreased human platelet activation, phosphorylation of Btk, P-selectin exposure, spreading on fibrinogen, and aggregation under shear flow conditions. Short-term studies of ibrutinib analogs administered in vivo also showed abrogation of platelet aggregation in vitro, but without measurable effects on plasma clotting times or on bleeding in vivo. Taken together, our results suggest that inhibition of Btk significantly decreased GPVI-mediated platelet activation, spreading, and aggregation in vitro; however, prolonged bleeding was not observed in a model of bleeding. Copyright © 2016 the American Physiological Society.

  1. Phase I and pharmacologic study of oral ZD9331, a novel nonpolyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors.

    NARCIS (Netherlands)

    Jonge, M.J.A. de; Punt, C.J.A.; Sparreboom, A.; Planting, A.S.T.; Peters, M.E.W.J.; Schraaf, J. van de; Jackman, A.; Smith, R.J.H.; Mulder, P.H.M. de; Verweij, J.

    2002-01-01

    PURPOSE: To assess the toxicity profile and dose-limiting toxicities (DLTs), to determine the maximum-tolerated dose, and to study the pharmacokinetics of ZD9331 when administered orally to patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with oral ZD9331 given once d

  2. Phase I/II clinical trial of 2-Difluoromethylornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma

    OpenAIRE

    Skorupski, Katherine A.; O'Brien, Thomas G; Guerrero, Teri; Rodriguez, Carlos O.; Burns, Mark R.

    2011-01-01

    Polyamines are essential for cell proliferation. Their production is dysregulated in many cancers and polyamine depletion leads to tumor regression in mouse models of SCC. The purpose of this study was to determine the maximally tolerated dose of the polyamine transport inhibitor, MQT 1426, when combined with the ornithine decarboxylase inhibitor, DFMO, and to determine whether this therapy results in reduction in tumor polyamine levels. Thirteen cats with oral SCC received both drugs orally ...

  3. Orally administered Lactobacillus rhamnosus modulates the respiratory immune response triggered by the viral pathogen-associated molecular pattern poly(I:C

    Directory of Open Access Journals (Sweden)

    Villena Julio

    2012-09-01

    Full Text Available Abstract Background Some studies have shown that probiotics, including Lactobacillus rhamnosus CRL1505, had the potential to beneficially modulate the outcome of certain bacterial and viral respiratory infections. However, these studies did not determine the mechanism(s by which probiotics contribute to host defense against respiratory viruses. Results In this work we demonstrated that orally administered Lactobacillus rhamnosus CRL1505 (Lr1505 was able to increase the levels of IFN-γ, IL-10 and IL-6 in the respiratory tract and the number of lung CD3+CD4+IFN-γ+ T cells. To mimic the pro-inflammatory and physiopathological consecuences of RNA viral infections in the lung, we used an experimental model of lung inflammation based on the administration of the artificial viral pathogen-associated molecular pattern poly(I:C. Nasal administration of poly(I:C to mice induced a marked impairment of lung function that was accompanied by the production of pro-inflammatory mediators and inflammatory cell recruitment into the airways. The preventive administration of Lr1505 reduced lung injuries and the production of TNF-α, IL-6, IL-8 and MCP-1 in the respiratory tract after the challenge with poly(I:C. Moreover, Lr1505 induced a significant increase in lung and serum IL-10. We also observed that Lr1505 was able to increase respiratory IFN-γ levels and the number of lung CD3+CD4+IFN-γ+ T cells after poly(I:C challenge. Moreover, higher numbers of both CD103+ and CD11bhigh dendritic cells and increased expression of MHC-II, IL-12 and IFN-γ in these cell populations were found in lungs of Lr1505-treated mice. Therefore, Lr1505 treatment would beneficially regulate the balance between pro-inflammatory mediators and IL-10, allowing an effective inflammatory response against infection and avoiding tissue damage. Conclusions Results showed that Lr1505 would induce a mobilization of cells from intestine and changes in cytokine profile that would be able to

  4. Absorptive constituents and their metabolites in drug-containing urine samples from Wuzhishan miniature pigs orally administered with Buyang Huanwu decoction.

    Science.gov (United States)

    Yang, Dong-Hui; Ren, Xiang-Liang; Xu, Feng; Ma, Xiao-Qing; Liu, Guang-Xue; Li, Cang-Hai; Li, Chen; Cai, Shao-Qing

    2014-01-01

    Buyang Huanwu decoction (BYHWD), a famous traditional Chinese medicine prescription for the treatment of cerebrovascular diseases, is composed of seven commonly used Chinese herbs--Astragali Radix, Angelicae Sinensis Radix, Paeoniae Radix Rubra, Chuanxiong Rhizoma, Carthami Flos, Persicae Semen and Pheretima. To determine the main absorptive constituents and the metabolites of BYHWD in vivo, urine samples from Wuzhishan (WZS) miniature pigs orally administered with BYHWD (13.6 g crude drugs/kg) were collected to investigate the characteristic compounds. By comparing the high-performance liquid chromatography of a drug-containing urine sample with that of a drug-free sample, 17 characteristic compounds were isolated from the methanol extract of a drug-containing urine sample by column chromatography. Their structures, including 11 isoflavanoids, 2 pterocarpanoids and 4 isoflavonoids, were identified by spectroscopic means. Of the 17 compounds, 8 (1-8) were new compounds with the following structures: 3S-7,3',4'-trihydroxyisoflavan-3'-O-β-D-glucuronide (1), 3S-7,3',4'-trihydroxyisoflavan-4'-O-β-D-glucuronide (2), 3S-7,2',4'-trihydroxyisoflavan-2'-O-β-D-glucuronide (3), 3R-7,2'-dihydroxy-3',4'-dimethoxyisoflavan-2'-O-β-D-glucuronide (4), 3R-7,2'-dihydroxy-3',4'-dimethoxyisoflavan-2'-O-β-D-glucuronide-6"-methyl ester (5), 3R-7,2'-dihydroxy-3',4'-dimethoxyisoflavan-7-O-β-D-glucuronide-6"-methyl ester (6), 3R-7,2',3'-trihydroxy-4'-methoxyisoflavan-3'-O-β-D-glucuronide-6"-methyl ester (7), and 3S-7,4',5'-trihydroxy-2',3'-dimethoxyisoflavan-5'-O-β-D-glucuronide (8). Based on the possible relationship and metabolic pathways of the 17 compounds in vivo, 3R-7,2'-dihydroxy-3',4'-dimethoxyisoflavan (isomucronulatol, 11), 6aR,11aR-3-hydroxy-9,10-dimethoxypterocarpan (methylnissolin, astrapterocarpan, 13), 7,3'-dihydroxy-4'-methoxyisoflavone (calycosin, 16) and 7-hydroxy-4'-methoxyisoflavone (formononetin, 17) were thought to be the most important absorptive original

  5. Orally administered fatty acids enhance anorectic potential but do not activate central fatty acid sensing in Senegalese sole post-larvae.

    Science.gov (United States)

    Velasco, Cristina; Bonacic, Kruno; Soengas, José L; Morais, Sofia

    2017-02-15

    Studies in fish have reported the presence and function of fatty acid (FA)-sensing systems comparable in many aspects to those known in mammals. Such studies were carried out in juvenile and adult fish, but the presence of FA-sensing systems and control of food intake have never been evaluated in early life stages, despite the importance of establishing when appetite regulation becomes functional in larval fish. In this study, we aimed to elucidate the possible effects of different specific FAs on neural FA-sensing systems and neuropeptides involved in the control of food intake in Senegalese sole post-larvae. To achieve this, we orally administered post-larvae with different solutions containing pure FA - oleate (OA), linoleate (LA), α-linolenate (ALA) or eicosapentaenoate (EPA) - and evaluated changes in mRNA abundance of neuropeptides involved in the control of food intake and of transcripts related to putative FA-sensing systems, 3 and 6 h post-administration. The changes in neuropeptide gene expression were relatively consistent with the activation of anorectic pathways (enhanced cart4 and pomcb) and a decrease in orexigenic factors (npy) following intake of FA. Even though there were a few differences depending on the nature of the FA, the observed changes appear to suggest the existence of a putative anorectic response in post-larvae fish to the ingestion of all four tested FAs. However, changes in neuropeptides cannot be explained by the integration of metabolic information regarding FAs in circulation through FA-sensing mechanisms in the brain. Only the reduction in mRNA levels of the FA metabolism gene acc in OA-treated (6 h), ALA-treated (3 h) and EPA-treated (3 and 6 h) post-larvae could be indicative of the presence of a FA-sensing system, but most genes either were not significantly regulated (fat/cd36-lmp2, acly, kir6.x, srebp1c) or were affected in a way that was inconsistent with FA-sensing mechanisms (fat/cd36-pg4l, fas, cpt1.1, cpt1

  6. Combining oral contraceptives with a natural nuclear factor-kappa B inhibitor for the treatment of endometriosis-related pain

    Directory of Open Access Journals (Sweden)

    Maia H Jr

    2013-12-01

    Full Text Available Hugo Maia Jr,1–3 Clarice Haddad,3 Julio Casoy3 1Department of Gynecology and Obstetrics, School of Medicine, Federal University of Bahia, 2Itaigara Memorial Day Hospital, 3Centro de Pesquisas e Assistência em Reprodução Humana (CEPARH, Salvador, Bahia, Brazil Abstract: Endometriosis is a chronic disease in which a persistent state of heightened inflammation is maintained by nuclear factor-kappa B (NF-κB activation. The progestins present in oral contraceptives are potent inhibitors of NF-κB translocation to cell nuclei, while Pycnogenol® (Pinus pinaster acts by blocking post-translational events. In this study, the effects of Pycnogenol on pain scores were investigated in patients with endometriosis using oral contraceptives containing either gestodene or drospirenone in extended regimens. Pain scores were determined using a visual analog scale before and after 3 months of treatment. Oral contraceptives, used alone (groups 1 and 3 or in association with Pycnogenol (groups 2 and 4, resulted in significant decreases in pain scores after 3 months of treatment; however, this reduction was significantly greater in the groups using oral contraceptives + Pycnogenol (groups 2 and 4 compared with those using oral contraceptives alone (groups 1 and 3. In the groups using oral contraceptives alone, 50% of patients became pain-free by the end of the third month of treatment. These results suggest that Pycnogenol increases the efficacy of oral contraceptives for the treatment of endometriosis-related pain. Keywords: Pycnogenol®, aromatase, endometriosis, nuclear factor-kappa B

  7. To fast or not to fast? How food could impact on the absorption of kinase inhibitors and its economical value

    Directory of Open Access Journals (Sweden)

    Camillo Porta

    2011-12-01

    Full Text Available Presently, cancer patients receiving oral kinase inhibitors are suggested to take the drug with an empty stomach or, in the case of drugs such as Sorafenib which are administered twice daily, at least following a lowfat meal...

  8. No significant effects of single intravenous, single oral and subchronic oral administration of acetylcholinesterase inhibitors on striatal [{sup 123}I]FP-CIT binding in rats

    Energy Technology Data Exchange (ETDEWEB)

    Knol, R.J.J.; Booij, J. [University of Amsterdam, Department of Nuclear Medicine, Academic Medical Center, Amsterdam (Netherlands); Graduate School of Neurosciences, Amsterdam (Netherlands); Bruin, K. de; Eck-Smit, B.L.F. van [University of Amsterdam, Department of Nuclear Medicine, Academic Medical Center, Amsterdam (Netherlands)

    2008-03-15

    [{sup 123}I]FP-CIT SPECT is a valuable diagnostic tool to discriminate Lewy body dementia from Alzheimer's dementia. To date, however, it is uncertain whether the frequently used acetylcholinesterase inhibitors (AChEIs) by demented patients, have an effect on [{sup 123}I]FP-CIT binding to dopamine transporters (DATs). Earlier animal studies showed a decline of DAT availability after acute intravenous injection of AChEIs. The aim of this study was to investigate effects of single intravenous, single oral and subchronic oral administration of AChEIs on DAT availability in the rat brain as measured by [{sup 123}I]FP-CIT. Biodistribution studies were performed in Wistar rats (n = 5-16 per group). Before [{sup 123}I]FP-CIT injection, rats were injected intravenously with a single dose of the AChEI rivastigmine (2.5 mg/kg body weight) or donepezil (0.5 mg/kg), the DAT-blocker methylphenidate (10 mg/kg) or saline. A second group was orally treated with a single dose of rivastigmine or donepezil (2.5 mg/kg), methylphenidate (10 mg/kg) or saline before injection of [{sup 123}I]FP-CIT. Studies were also performed in rats that were orally treated during 14 consecutive days with either rivastigmine (1 mg/kg daily), donepezil (1.5 mg/kg daily), methylphenidate (2.5 mg/kg) or saline. Brain parts were assayed in a gamma counter, and specific striatum/cerebellum ratios were calculated for the [{sup 123}I]FP-CIT binding to DATs. No significant effects of either single intravenous, single oral or subchronic oral administration of AChEIs on striatal FP-CIT binding could be detected. Single pretreatment with methylphenidate resulted in an expected significantly lower striatal FP-CIT binding. We conclude that in rats, single intravenous and single or subchronic oral administration of the tested AChEIs does not lead to an important alteration of [{sup 123}I]FP-CIT binding to striatal DATs. Therefore, it is unlikely that these drugs will induce large effects on the interpretation of

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

    Science.gov (United States)

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

    1998-01-01

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

  10. Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1

    DEFF Research Database (Denmark)

    Migoya, E M; Bergeron, R; Miller, J L

    2010-01-01

    The aim of the study was to investigate the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP-4 activity, and preproglucagon (...

  11. Pharmacological profile of AW-814141, a novel, potent, selective and orally active inhibitor of p38 MAP kinase

    DEFF Research Database (Denmark)

    Chopra, Puneet; Kulkarni, Onkar; Gupta, Shashank

    2010-01-01

    -inflammatory activity of a p38 MAPK inhibitor, AW-814141. AW-814141 inhibited enzymatic activity of recombinant p38-alpha and beta isoforms with IC(50) value of 100nM and 158nM, respectively. AW-814141 also inhibited the release of tumor necrosis factor (TNF)-alpha by lipopolysaccharide (LPS) treated human peripheral...... blood mononuclear cells with an IC(50) value of 212nM and demonstrated selectivity against a panel of few kinases. Oral administration of AW-814141 (10mpk) in LPS-injected mice resulted in a significant reduction in TNF-alpha production in the circulation. In a carrageenan-induced rat paw edema model...

  12. Aliskiren – an orally active renin inhibitor. Review of pharmacology, pharmacodynamics, kinetics, and clinical potential in the treatment of hypertension

    Directory of Open Access Journals (Sweden)

    Kristina Allikmets

    2008-01-01

    Full Text Available Kristina AllikmetsDepartment of Drug Development and Medical Affairs, Nycomed Group, Roskilde, DenmarkAbstract: The importance of renin-angiotensin-aldosterone system (RAAS in diseases such as hypertension, congestive heart failure and chronic renal failure has long ago been recognized. It has also been established that inhibition of RAAS, using inhibitors of the angiotensin-converting enzyme (ACE or angiotensin II receptor blockers (ARB, is an effective way to intervene with the pathogenesis of these disorders. Renin inhibitors block the RAAS at the highest level, at its origin, and might thus offer a new exciting approach for pharmacotherapy of arterial hypertension. Aliskiren is the first in a new class of orally active, non-peptide, low molecular weight renin inhibitors, and so far the only renin inhibitor that has progressed to phase III clinical trials. This review summarizes the available data on the pharmacokinetic and pharmacodynamic properties of aliskiren and its clinical development for treatment of arterial hypertension.Keywords: aliskiren, hypertension, renin-angiotensin-aldosterone system, renin inhibition, essential hypertension

  13. Cediranib, an Oral Inhibitor of Vascular Endothelial Growth Factor Receptor Kinases, Is an Active Drug in Recurrent Epithelial Ovarian, Fallopian Tube, and Peritoneal Cancer

    Science.gov (United States)

    Matulonis, Ursula A.; Berlin, Suzanne; Ivy, Percy; Tyburski, Karin; Krasner, Carolyn; Zarwan, Corrine; Berkenblit, Anna; Campos, Susana; Horowitz, Neil; Cannistra, Stephen A.; Lee, Hang; Lee, Julie; Roche, Maria; Hill, Margaret; Whalen, Christin; Sullivan, Laura; Tran, Chau; Humphreys, Benjamin D.; Penson, Richard T.

    2009-01-01

    Purpose Angiogenesis is important for epithelial ovarian cancer (EOC) growth, and blocking angiogenesis can lead to EOC regression. Cediranib is an oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) -1, VEGFR-2, VEGFR-3, and c-kit. Patients and Methods We conducted a phase II study of cediranib for recurrent EOC or peritoneal or fallopian tube cancer; cediranib was administered as a daily oral dose, and the original dose was 45 mg daily. Because of toxicities observed in the first 11 patients, the dose was lowered to 30 mg. Eligibility included ≤ two lines of chemotherapy for recurrence. End points included response rate (via Response Evaluation Criteria in Solid Tumors [RECIST] or modified Gynecological Cancer Intergroup CA-125), toxicity, progression-free survival (PFS), and overall survival (OS). Results Forty-seven patients were enrolled; 46 were treated. Clinical benefit rate (defined as complete response [CR] or partial response [PR], stable disease [SD] > 16 weeks, or CA-125 nonprogression > 16 weeks), which was the primary end point, was 30%; eight patients (17%; 95% CI, 7.6% to 30.8%) had a PR, six patients (13%; 95% CI, 4.8% to 25.7%) had SD, and there were no CRs. Eleven patients (23%) were removed from study because of toxicities before two cycles. Grade 3 toxicities (> 20% of patients) included hypertension (46%), fatigue (24%), and diarrhea (13%). Grade 2 hypothyroidism occurred in 43% of patients. Grade 4 toxicities included CNS hemorrhage (n = 1), hypertriglyceridemia/hypercholesterolemia/elevated lipase (n = 1), and dehydration/elevated creatinine (n = 1). No bowel perforations or fistulas occurred. Median PFS was 5.2 months, and median OS has not been reached; median follow-up time is 10.7 months. Conclusion Cediranib has activity in recurrent EOC, tubal cancer, and peritoneal cancer with predictable toxicities observed with other TKIs. PMID:19826113

  14. A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors

    Science.gov (United States)

    Deutsch, Eric; Moyal, Elizabeth Cohen-Jonathan; Gregorc, Vanesa; Zucali, Paolo Andrea; Menard, Jean; Soria, Jean-Charles; Kloos, Ioana; Hsu, Jeff; Luan, Ying; Liu, Emily; Vezan, Remus; Graef, Thorsten; Rivera, Sofia

    2017-01-01

    Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions. PMID:28915584

  15. A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors.

    Science.gov (United States)

    Deutsch, Eric; Cohen-Jonathan Moyal, Elizabeth; Gregorc, Vanesa; Zucali, Paolo Andrea; Menard, Jean; Soria, Jean-Charles; Kloos, Ioana; Hsu, Jeff; Luan, Ying; Liu, Emily; Vezan, Remus; Graef, Thorsten; Rivera, Sofia

    2016-12-24

    Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions.

  16. Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

    Science.gov (United States)

    Parvathy, Subramanian S.

    2016-01-01

    Background There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP. Methods The reaction latency to thermal stimuli (hot plate test; at 55 °C) and cold stimuli (cold plate test; at 4 °C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min. Results The coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h. Conclusions These results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711’s antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors

  17. CGP 53437, an orally bioavailable inhibitor of human immunodeficiency virus type 1 protease with potent antiviral activity.

    Science.gov (United States)

    Alteri, E; Bold, G; Cozens, R; Faessler, A; Klimkait, T; Lang, M; Lazdins, J; Poncioni, B; Roesel, J L; Schneider, P

    1993-10-01

    CGP 53437 is a peptidomimetic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease containing a hydroxyethylene isostere. The compound inhibited recombinant HIV-1 protease with a Ki of 0.2 nM. The inhibition constant versus human cathepsin D and human cathepsin E was 4 nM. Human pepsin and gastricsin were inhibited with Kis of 8 and 500 nM, respectively, and human renin was inhibited with a Ki of 190 microM. The replication of HIV-1/LAV, HIV-1/Z-84, and HIV-1/pLAI was inhibited with a 90% effective dose of 0.1 microM in acutely infected MT-2 cells. The 50% cytotoxic dose was 100 microM. Similar antiviral activity was observed when the compound was added up to 10 h after infection. At the effective concentration, processing of Gag precursor protein p55 was greatly reduced, confirming an action on the late stage of the virus life cycle, as expected. The efficacy of the inhibitor was also demonstrated by using primary human peripheral blood lymphocytes infected with the HIV-1/LAV strain, low-passage clinical isolates obtained from HIV-1-seropositive individuals (including a zidovudine-resistant strain), and HIV-2/ROD. In these cells, CGP 53437 delayed the onset of HIV replication in a dose-dependent fashion (substantial effects with concentrations of > or = 0.1 microM) as long as the inhibitor was maintained in the culture. CGP 53437 was orally bioavailable in mice. Concentrations in plasma 10-fold in excess of the in vitro antiviral 90% effective dose could be sustained for several hours after oral application of 120 mg/kg. Therefore, CGP 53437 has the potential to be a therapeutically useful anti-HIV agent for the treatment of AIDS.

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

    Science.gov (United States)

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

    1989-06-01

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

  19. N-benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors.

    Science.gov (United States)

    Atkinson, Karen A; Beretta, Elena E; Brown, Janice A; Castrodad, Mayda; Chen, Yue; Cosgrove, Judith M; Du, Ping; Litchfield, John; Makowski, Michael; Martin, Kelly; McLellan, Thomas J; Neagu, Constantin; Perry, David A; Piotrowski, David W; Steppan, Claire M; Trilles, Richard

    2011-03-15

    A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

    DEFF Research Database (Denmark)

    Le Gall, Maud; Gallois, Mélanie; Sève, Bernard;

    2009-01-01

    Sodium butyrate (SB) provided orally favours body growth and maturation of the gastrointestinal tract (GIT) in milk-fed pigs. In weaned pigs, conflicting results have been obtained. Therefore, we hypothesised that the effects of SB (3 g/kg DM intake) depend on the period (before v. after weaning......) of its oral administration. From the age of 5 d, thirty-two pigs, blocked in quadruplicates within litters, were assigned to one of four treatments: no SB (control), SB before (for 24 d), or after (for 11-12 d) weaning and SB before and after weaning (for 35-36 d). Growth performance, feed intake...... and various end-point indices of GIT anatomy and physiology were investigated at slaughter. The pigs supplemented with SB before weaning grew faster after weaning than the controls (P intake was higher in pigs supplemented with SB before or after weaning (P

  1. Effects of alpha-amylase and its inhibitors on acid production from cooked starch by oral streptococci.

    Science.gov (United States)

    Aizawa, S; Miyasawa-Hori, H; Nakajo, K; Washio, J; Mayanagi, H; Fukumoto, S; Takahashi, N

    2009-01-01

    This study evaluated acid production from cooked starch by Streptococcus mutans, Streptococcus sobrinus, Streptococcus sanguinis and Streptococcus mitis, and the effects of alpha-amylase inhibitors (maltotriitol and acarbose) and xylitol on acid production. Streptococcal cell suspensions were anaerobically incubated with various carbohydrates that included cooked potato starch in the presence or absence of alpha-amylase. Subsequently, the fall in pH and the acid production rate at pH 7.0 were measured. In addition, the effects of adding alpha-amylase inhibitors and xylitol to the reaction mixture were evaluated. In the absence of alpha-amylase, both the fall in pH and the acid production rate from cooked starch were small. On the other hand, in the presence of alpha-amylase, the pH fell to 3.9-4.4 and the acid production rate was 0.61-0.92 micromol per optical density unit per min. These values were comparable to those for maltose. When using cooked starch, the fall in pH by S. sanguinis and S. mitis was similar to that by S. mutans and S. sobrinus. For all streptococci, alpha-amylase inhibitors caused a decrease in acid production from cooked starch, although xylitol only decreased acid production by S. mutans and S. sobrinus. These results suggest that cooked starch is potentially acidogenic in the presence of alpha-amylase, which occurs in the oral cavity. In terms of the acidogenic potential of cooked starch, S. sanguinis and S. mitis were comparable to S. mutans and S. sobrinus. Alpha-amylase inhibitors and xylitol might moderate this activity.

  2. Discovery of orally active pyrrolopyridine- and aminopyridine-based Met kinase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Zhen-Wei; Wei, Donna; Schroeder, Gretchen M.; Cornelius, Lyndon A.M.; Kim, Kyoung; Chen, Xiao-Tao; Schmidt, Robert J.; Williams, David K.; Tokarski, John S.; An, Yongmi; Sack, John S.; Manne, Veeraswamy; Kamath, Amrita; Zhang, Yueping; Marathe, Punit; Hunt, John T.; Lombardo, Louis J.; Fargnoli, Joseph; Borzilleri, Robert M. (BMS)

    2008-09-10

    A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.

  3. Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity

    NARCIS (Netherlands)

    Baugh, Mark; Black, Darcey; Westwood, Paul; Kinghorn, Emma; McGregor, Kieran; Bruin, John; Hamilton, William; Dempster, Maureen; Claxton, Christopher; Cai, Jiaqiang; Bennett, Jonathan; Long, Clive; Mckinnon, Heather; Vink, Paul; den Hoed, Leontien; Gorecka, Monika; Vora, Kalpit; Grant, Ethan; Percival, M. David; Boots, A. Mieke H.; van Lierop, Marie-Jose; Boots, Annemieke

    2011-01-01

    The purpose of the study was to examine the potential of inhibition of cathepsin S as a treatment for autoimmune diseases. A highly selective cathepsin S inhibitor, CSI-75, was shown to upregulate levels of the cathepsin S substrate, invariant chain Lip10, in vitro as well as in vivo in C57Bl/6 mice

  4. Evolving uses of oral reverse transcriptase inhibitors in the HIV-1 epidemic: From treatment to prevention

    NARCIS (Netherlands)

    R.K. Gupta (Ravindra); D.A.M.C. van de Vijver (David); S. Manicklal (Sheetal); M.A. Wainberg (Mark)

    2013-01-01

    textabstractThe HIV epidemic continues unabated, with no highly effective vaccine and no cure. Each new infection has significant economic, social and human costs and prevention efforts are now as great a priority as global antiretroviral therapy (ART) scale up. Reverse transcriptase inhibitors, the

  5. Capromorelin oral solution (ENTYCE®) increases food consumption and body weight when administered for 4 consecutive days to healthy adult Beagle dogs in a randomized, masked, placebo controlled study.

    Science.gov (United States)

    Zollers, Bill; Rhodes, Linda; Heinen, Ernst

    2017-01-05

    Dogs can suffer from inappetence caused by a variety of medical conditions. This may present as anorexia (complete loss of appetite), hyporexia (decreased appetite) or dysrexia (change in food preferences). A drug with a new mechanism of action, capromorelin, has potential to stimulate appetite in dogs. Capromorelin is a ghrelin receptor agonist, which mimics the action of endogenous ghrelin. It is a member of the growth hormone secretagogue (GHS) class of drugs. Capromorelin oral solution (ENTYCE®) was tested in healthy adult male and female Beagle dogs (n = 6 males and 6 females per group) for its effect on food consumption and body weight. A randomized, masked, placebo controlled study was conducted to measure the effects of a daily 3 mg/kg oral dose given over 4 days. Dogs were observed for clinical signs, physical examinations were completed prior to and at the end of treatment, and blood was drawn before and after treatment for evaluation of serum chemistry and hematology parameters. Capromorelin was well-tolerated, with no abnormalities seen on physical examination or clinical pathology. Some dogs showed increased salivation. Capromorelin treated dogs had increased mean (±SD) food consumption compared to placebo treated dogs (60.55 ± 39.87% versus -11.15 ± 14.23% respectively, P dogs also had increased mean body weights compared to placebo treated dogs (5.96 ± 1.76% versus 0.053 ± 1.14% respectively, P dogs. Treatment with the oral solution resulted in dramatic increases in appetite, as measured by food consumption, of over 60% compared to placebo. The drug was well tolerated. Capromorelin is the first ghrelin receptor agonist developed for appetite stimulation in any species, and represents a novel mechanism of action for this clinical use.

  6. A multiple-dose, double-blind comparison of intramuscularly and orally administered ketorolac tromethamine and Ketogan in patients with pain following orthopaedic surgery

    DEFF Research Database (Denmark)

    Gebuhr, Peter Henrik; Soelberg, M; Strauss, W

    1994-01-01

    In this multiple-dose, double-blind study 100 patients with moderate, severe or very severe pain following orthopaedic surgery were randomly assigned to receive ketorolac, a non-steroidal anti-inflammatory drug with potent analgesic properties (10 mg), or the standard regimen of Ketogan (a......-mg doses of oral ketorolac are as effective as Ketogan for the treatment of pain following orthopaedic surgery. Ketorolac appears to be better tolerated than Ketogan since significantly fewer patients reported adverse events (P = 0.004) when taking ketorolac....

  7. Correlation between the Serum Pepsinogen I Level and the Symptom Degree in Proton Pump Inhibitor-Users Administered with a Probiotic

    Directory of Open Access Journals (Sweden)

    Muneki Igarashi

    2014-06-01

    Full Text Available In patients with functional upper gastrointestinal disorders such as gastroesophageal reflux disease and functional dyspepsia, the presence of symptoms is thought to occur in the absence of any organic diseases and the mechanisms behind this remain unclear. We therefore examined the relationship between stomach-related biomarker levels and symptoms. Twenty-four outpatients who had taken proton-pump inhibitors every day were enrolled in this study. The subjects consumed yogurt containing 109 colony-forming units of Lactobacillus gasseri OLL2716 (LG21 every day for three months. They underwent four clinical examinations in total. Each examination consisted of answering a questionnaire with a frequency scale for the symptoms of GERD (FSSG, and included measurements of the serum gastrin, ghrelin, and pepsinogens I and II levels. As a result, the FSSG score and the PGI value showed a decrease and an increase, respectively, after LG21 treatment when analyzed without age adjustment. A multiple regression analysis with additional adjustments for gender and age revealed a strong association between the PGI value and the FSSG symptom scores. Therefore either the PGI level itself or the factors regulating the PGI level might be involved in the etiology of these symptoms.

  8. Pharmacological and safety evaluation of CIGB-300, a casein kinase 2 inhibitor peptide, administered intralesionally to patients with cervical cancer stage IB2/II

    Directory of Open Access Journals (Sweden)

    Soriano-García JL

    2013-08-01

    Full Text Available CIGB-300 is a pro-apoptotic casein kinase 2 inhibitor peptide with potential anticancer action. An open-label and dose scaling Phase I trial was carried out to investigate the peptide tumor uptake, pharmacokinetics, toxicity, and levels of a CIGB-300 response biomarker in patients with cervical cancer stage IB2/II. Fourteen patients were included; six of them received 35 mg, 6 received 70 mg and the two remaining patients received 245 mg of CIGB-300 prior chemoradiotherapy. CIGB-300 was applied by intratumor injections during 5-consecutive days. For pharmacokinetic and biodistribution studies, the peptide was radiolabeled with 99mTc in the first administration and whole body gammagraphy and plasma testing were done during 48 h. Data showed that the maximum tolerated dose was 70 mg for CIGB-300 in this clinical setting. Furthermore, an allergic-like syndrome was identified as the dose limiting toxicity, which was well-correlated with plasmatic histamine levels. Importantly, the mean tumor uptake was 14.9 mg and 10.4 mg for CIGB-300 doses of 35 and 70 mg, respectively. Also, the kidneys were the main target organ for drug elimination. Finally, treatment with CIGB-300 significantly reduced the B23/nucleophosmin levels in tumor specimens. CIGB-300 meets potentialities to be tested in future trials in a neoadjuvant setting prior to chemoradiotherapy in cervical cancer.

  9. Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar.

    NARCIS (Netherlands)

    Tang, S.C.; Nguyen, L.N.; Sparidans, R.W.; Wagenaar, E.; Beijnen, J.H.; Schinkel, A.H.

    2014-01-01

    Crizotinib is an oral tyrosine kinase inhibitor approved for treating patients with non-small cell lung cancer (NSCLC) containing an anaplastic lymphoma kinase (ALK) rearrangement. We used knockout mice to study the roles of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) in

  10. Allosteric inhibitors of hepatitis C polymerase: discovery of potent and orally bioavailable carbon-linked dihydropyrones.

    Science.gov (United States)

    Li, Hui; Linton, Angelica; Tatlock, John; Gonzalez, Javier; Borchardt, Allen; Abreo, Mel; Jewell, Tanya; Patel, Leena; Drowns, Matthew; Ludlum, Sarah; Goble, Mike; Yang, Michele; Blazel, Julie; Rahavendran, Ravi; Skor, Heather; Shi, Stephanie; Lewis, Cristina; Fuhrman, Shella

    2007-08-23

    The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.

  11. A novel prothrombin time assay for assessing the anticoagulant activity of oral factor Xa inhibitors.

    Science.gov (United States)

    Barrett, Yu Chen; Wang, Zhaoqing; Knabb, Robert M

    2013-09-01

    Conventional prothrombin time (PT) assays have limited sensitivity and dynamic range in monitoring the anticoagulant activity of direct factor Xa inhibitors. Hence, new assays are needed. We modified a PT assay by adding calcium chloride (CaCl2) to the thromboplastin reagent to increase assay dynamic range and improve sensitivity. Effects of calcium and sodium ion concentrations, and sample handling, were evaluated to optimize assay performance. Increasing concentrations of calcium ions produced progressive increases in PT across the factor Xa inhibitor concentrations of 0 to 2500 nmol/L for razaxaban and apixaban. The greatest effect was seen when the thromboplastin reagent was diluted 1:2.25 with 100 mmol/L CaCl2 (thus selected for routine use). The optimized assay showed an interassay precision of 1.5 to 9.3 percentage coefficient of variation (%CV) for razaxaban and 3.1 to 4.6 %CV for apixaban. We conclude that the modified PT assay is likely to be suitable as a pharmacodynamic marker for activity at therapeutic concentrations of factor Xa inhibitors.

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

    Science.gov (United States)

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

    2007-09-01

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

  13. Pharmacokinetics and pharmacodynamics of orally administered acetylenic tricyclic bis(cyanoenone), a highly potent Nrf2 activator with a reversible covalent mode of action

    Energy Technology Data Exchange (ETDEWEB)

    Kostov, Rumen V.; Knatko, Elena V.; McLaughlin, Lesley A.; Henderson, Colin J. [Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, DD1 9SY, Scotland (United Kingdom); Zheng, Suqing [Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY, 11794 (United States); Huang, Jeffrey T.-J. [Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, DD1 9SY, Scotland (United Kingdom); Honda, Tadashi [Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY, 11794 (United States); Dinkova-Kostova, Albena T., E-mail: a.dinkovakostova@dundee.ac.uk [Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, DD1 9SY, Scotland (United Kingdom); Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 (United States); Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 (United States)

    2015-09-25

    The acetylenic tricyclic bis(cyanoenone) TBE-31 is a highly potent cysteine targeting compound with a reversible covalent mode of action; its best-characterized target being Kelch-like ECH-associated protein-1 (Keap1), the cellular sensor for oxidants and electrophiles. TBE-31 reacts with cysteines of Keap1, impairing its ability to target nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) for degradation. Consequently, Nrf2 accumulates and orchestrates cytoprotective gene expression. In this study we investigated the pharmacokinetic and pharmacodynamic properties of TBE-31 in C57BL/6 mice. After a single oral dose of 10 μmol/kg (∼200 nmol/animal), the concentration of TBE-31 in blood exhibited two peaks, at 22.3 nM and at 15.5 nM, 40 min and 4 h after dosing, respectively, as determined by a quantitative stable isotope dilution LC-MS/MS method. The AUC{sub 0–24h} was 195.5 h/nmol/l, the terminal elimination half-life was 10.2 h, and the k{sub el} was 0.068 h{sup −1}. To assess the pharmacodynamics of Nrf2 activation by TBE-31, we determined the enzyme activity of its prototypic target, NAD(P)H:quinone oxidoreductase 1 (NQO1) and found it elevated by 2.4- and 1.5-fold in liver and heart, respectively. Continuous feeding for 18 days with diet delivering the same daily doses of TBE-31 under conditions of concurrent treatment with the immunosuppressive agent azathioprine had a similar effect on Nrf2 activation without any indications of toxicity. Together with previous reports showing the cytoprotective effects of TBE-31 in animal models of carcinogenesis, our results demonstrate the high potency, efficacy and suitability for chronic administration of cysteine targeting reversible covalent drugs. - Highlights: • TBE-31 is a cysteine targeting compound with a reversible covalent mode of action. • After a single oral dose, the blood concentration of TBE-31 exhibits two peaks. • Oral TBE-31 is a potent activator of Nrf2-dependent enzymes in

  14. Safety and preliminary efficacy data of a novel Casein Kinase 2 (CK2 peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies

    Directory of Open Access Journals (Sweden)

    Alonso Daniel F

    2009-05-01

    Full Text Available Abstract Background Cervical cancer is now considered the second leading cause of death among women worldwide, and its incidence has reached alarming levels, especially in developing countries. Similarly, high grade squamous intraepithelial lesion (HSIL, the precursor stage for cervical cancer, represents a growing health problem among younger women as the HSIL management regimes that have been developed are not fully effective. From the etiological point of view, the presence of Human Papillomavirus (HPV has been demonstrated to play a crucial role for developing cervical malignancies, and viral DNA has been detected in 99.7% of cervical tumors at the later stages. CIGB-300 is a novel cyclic synthetic peptide that induces apoptosis in malignant cells and elicits antitumor activity in cancer animal models. CIGB-300 impairs the Casein Kinase (CK2 phosphorylation, by targeting the substrate's phosphoaceptor domain. Based on the perspectives of CIGB-300 to treat cancer, this "first-in-human" study investigated its safety and tolerability in patients with cervical malignancies. Methods Thirty-one women with colposcopically and histologically diagnosed microinvasive or pre-invasive cervical cancer were enrolled in a dose escalating study. CIGB-300 was administered sequentially at 14, 70, 245 and 490 mg by intralesional injections during 5 consecutive days to groups of 7 – 10 patients. Toxicity was monitored daily until fifteen days after the end of treatment, when patients underwent conization. Digital colposcopy, histology, and HPV status were also evaluated. Results No maximum-tolerated dose or dose-limiting toxicity was achieved. The most frequent local events were pain, bleeding, hematoma and erythema at the injection site. The systemic adverse events were rash, facial edema, itching, hot flashes, and localized cramps. 75% of the patients experienced a significant lesion reduction at colposcopy and 19% exhibited full histological regression

  15. Plasma levels of the tissue inhibitor matrix metalloproteinase-3 as a potential biomarker in oral cancer progression

    Science.gov (United States)

    Su, Chun-Wen; Su, Bo-Feng; Chiang, Whei-Ling; Yang, Shun-Fa; Chen, Mu-Kuan; Lin, Chiao-Wen

    2017-01-01

    Oral cancer is the most common malignancy with poor prognosis and is the fourth most common cancer in men in Taiwan. The tissue inhibitor of metalloproteinase-3 (TIMP3) acts as a tumor suppressor gene by inhibiting the growth, angiogenesis, migration, and invasion of cancer cells. However, few studies have examined the association of plasma TIMP3 levels with oral squamous cell carcinoma (OSCC), and the role of plasma TIMP3 levels in OSCC progression is still unclear. We measured the plasma TIMP3 levels of 450 OSCC patients and 64 healthy controls by using a commercial enzyme-linked immunosorbent assay. We also analyzed TIMP3 mRNA levels of 328 OSCC patients and 32 normal tissues from The Cancer Genome Atlas (TCGA) dataset. Our results revealed that plasma TIMP3 levels were significantly lower in patients with OSCC than in healthy controls (p < 0.001). Moreover, plasma TIMP3 levels in patients with OSCC were significantly associated with the tumor stage and tumor status but not with the lymph node status, metastasis, and cell differentiation. To verify our findings, we also examined TCGA bioinformatics database and discovered similar results for the association with the pathological stage of OSCC. In conclusion, our results suggest that plasma TIMP3 is a potential biomarker for predicting the tumor stage and T status in patients with OSCC. PMID:28138307

  16. An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model.

    Science.gov (United States)

    Krumm, Stefanie A; Yan, Dan; Hovingh, Elise S; Evers, Taylor J; Enkirch, Theresa; Reddy, G Prabhakar; Sun, Aiming; Saindane, Manohar T; Arrendale, Richard F; Painter, George; Liotta, Dennis C; Natchus, Michael G; von Messling, Veronika; Plemper, Richard K

    2014-04-16

    Measles virus is a highly infectious morbillivirus responsible for major morbidity and mortality in unvaccinated humans. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets the viral RNA polymerase. Prophylactic oral treatment of ferrets infected intranasally with a lethal CDV dose reduced viremia and prolonged survival. Ferrets infected with the same dose of virus that received post-infection treatment at the onset of viremia showed low-grade viral loads, remained asymptomatic, and recovered from infection, whereas control animals succumbed to the disease. Animals that recovered also mounted a robust immune response and were protected against rechallenge with a lethal CDV dose. Drug-resistant viral recombinants were generated and found to be attenuated and transmission-impaired compared to the genetic parent virus. These findings may pioneer a path toward an effective morbillivirus therapy that could aid measles eradication by synergizing with vaccination to close gaps in herd immunity due to vaccine refusal.

  17. Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis.

    Science.gov (United States)

    Petersen, M; Thorikay, M; Deckers, M; van Dinther, M; Grygielko, E T; Gellibert, F; de Gouville, A C; Huet, S; ten Dijke, P; Laping, N J

    2008-03-01

    Progressive kidney fibrosis precedes end-stage renal failure in up to a third of patients with diabetes mellitus. Elevated intra-renal transforming growth factor-beta (TGF-beta) is thought to underlie disease progression by promoting deposition of extracellular matrix and epithelial-mesenchymal transition. GW788388 is a new TGF-beta type I receptor inhibitor with a much improved pharmacokinetic profile compared with SB431542. We studied its effect in vitro and found that it inhibited both the TGF-beta type I and type II receptor kinase activities, but not that of the related bone morphogenic protein type II receptor. Further, it blocked TGF-beta-induced Smad activation and target gene expression, while decreasing epithelial-mesenchymal transitions and fibrogenesis. Using db/db mice, which develop diabetic nephropathy, we found that GW788388 given orally for 5 weeks significantly reduced renal fibrosis and decreased the mRNA levels of key mediators of extracellular matrix deposition in kidneys. Our study shows that GW788388 is a potent and selective inhibitor of TGF-beta signalling in vitro and renal fibrosis in vivo.

  18. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Herman, Gary A; Bergman, Arthur; Stevens, Catherine;

    2006-01-01

    CONTEXT: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglyce...

  19. Value of Oral Proton Pump Inhibitors in Acute, Nonvariceal Upper Gastrointestinal Bleeding: A Network Meta-Analysis.

    Science.gov (United States)

    Rodriguez, Eduardo A; Donath, Elie; Waljee, Akbar K; Sussman, Daniel A

    2017-09-01

    Intravenous (IV) proton pump inhibitors (PPI) are the standard medical treatment in acute nonvariceal upper gastrointestinal bleeding (ANVGIB). Optimal route of PPI delivery has been questioned. The aim was to perform a systematic review and network meta-analysis for the endpoints of risk of rebleeding, length of stay (LOS), surgery (ROS), mortality, and total units of blood transfused (UBT) among trials evaluating acid suppressive medications in ANVGIB. A total of 39 studies using IV PPI drip, IV scheduled PPI, oral PPI, H2-receptor antagonists, and placebo were identified. Network meta-analysis was used for indirect comparisons and Bayesian Markov Chain Monte Carlo methods for calculation of probability superiority. No difference was observed between IV PPI drip and scheduled IV PPI for mortality (relative risk=1.11; 95% credibility interval, 0.56-2.21), LOS (0.04, -0.49 to 0.44), ROS (1.27, 0.64-2.35) and risk of rebleeding within 72 hours, 1 week, and 1 month [(0.98, 0.48-1.95), (0.59, 0.13-2.03), (0.82, 0.28-2.16)]. Oral PPIs were as effective as IV scheduled PPIs and IV PPI drip for LOS (0.22, -0.61 to 0.79 and 0.16, -0.56 to 0.80) and UBT (-0.25, -1.23 to 0.65 and -0.06, -0.71 to 0.65) and superior to IV PPI drip for ROS (0.30, 0.10 to 0.78). Scheduled IV PPIs were as effective as IV PPI drip for most outcomes. Oral PPIs were comparable to scheduled IV for LOS and UBT and superior to IV PPI drip for ROS. Conclusions should be tempered by low frequency endpoints such as ROS, but question the need for IV PPI drip in ANVGIB.

  20. Evolution of a Novel, Orally Bioavailable Series of PI3Kδ Inhibitors from an Inhaled Lead for the Treatment of Respiratory Disease.

    Science.gov (United States)

    Amour, Augustin; Barton, Nick; Cooper, Anthony W J; Inglis, Graham; Jamieson, Craig; Luscombe, Christopher N; Morrell, Josie; Peace, Simon; Perez, David; Rowland, Paul; Tame, Chris; Uddin, Sorif; Vitulli, Giovanni; Wellaway, Natalie

    2016-08-11

    A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.

  1. Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT-100, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft models.

    Science.gov (United States)

    Ferguson, Debra; Rodriguez, Luis E; Palma, Joann P; Refici, Marion; Jarvis, Kenneth; O'Connor, Jacqueline; Sullivan, Gerard M; Frost, David; Marsh, Kennan; Bauch, Joy; Zhang, Haiying; Lin, Nan-Horng; Rosenberg, Saul; Sham, Hing L; Joseph, Ingrid B J K

    2005-04-15

    To evaluate the preclinical pharmacokinetics, antitumor efficacy, and mechanism of action of a novel orally active farnesyltransferase inhibitor, ABT-100. In vitro sensitivity of a panel of human cell lines was determined using proliferation and clonogenic assays. In vivo efficacy of ABT-100 was evaluated in xenograft models (flank or orthotopic) by assessing angiogenesis, proliferation, and apoptosis in correlation with pharmacokinetics. Efficacy of the racemate of ABT-100 (A-367074) was also compared with R115777 (tipifarnib). ABT-100 inhibited proliferation of cells in vitro carrying oncogenic H-Ras (EJ-1 bladder; IC(50) 2.2 nmol/L), Ki-Ras (DLD-1 colon, MDA-MB-231 breast, HCT-116 colon, and MiaPaCa-2 pancreatic; IC(50) range, 3.8-9.2 nmol/L), and wild-type Ras (PC-3 and DU-145; IC(50), 70 and 818 nmol/L, respectively) as well as clonogenic potential. ABT-100 shows 70% to 80% oral bioavailability in mice. ABT-100 regressed EJ-1 tumors (2-12.5 mg/kg/d s.c., every day for 21 days) and showed significant efficacy in DLD-1, LX-1, MiaPaCa-2, or PC-3 tumor-bearing mice (6.25-50 mg/kg/d s.c. once daily or twice daily orally). A-367074 showed equivalent efficacy to R115777 given at approximately one-fourth the total dose of R115777 for a shorter duration (EJ-1 and LX-1). Antitumor activity was associated with decreased cell proliferation (Ki-67), increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), and decreased angiogenesis. A reduction in tumor angiogenic cytokine levels (vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8) correlated with a reduction in tumor vascularity (CD31). Overall, ABT-100 has an acceptable pharmacokinetic profile, is well tolerated, and possesses broad-spectrum antitumor activity against a series of xenograft models similar to farnesyltransferase inhibitors in clinical development; therefore, it is an attractive candidate for clinical evaluation.

  2. Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9 H -pyrimido[4,5- b ]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yujun; Bai, Longchuan; Liu, Liu; McEachern, Donna; Stuckey, Jeanne A.; Meagher, Jennifer L.; Yang, Chao-Yie; Ran, Xu; Zhou, Bing; Hu, Yang; Li, Xiaoqin; Wen, Bo; Zhao, Ting; Li, Siwei; Sun, Duxin; Wang, Shaomeng (Michigan)

    2017-03-24

    We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, 31 achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of 31 with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that 31 is a highly selective inhibitor of BET proteins. Our data show that 31 is a potent, selective, and orally active BET inhibitor.

  3. Suppression of inhibitor formation against FVIII in a murine model of hemophilia A by oral delivery of antigens bioencapsulated in plant cells.

    Science.gov (United States)

    Sherman, Alexandra; Su, Jin; Lin, Shina; Wang, Xiaomei; Herzog, Roland W; Daniell, Henry

    2014-09-04

    Hemophilia A is the X-linked bleeding disorder caused by deficiency of coagulation factor VIII (FVIII). To address serious complications of inhibitory antibody formation in current replacement therapy, we created tobacco transplastomic lines expressing FVIII antigens, heavy chain (HC) and C2, fused with the transmucosal carrier, cholera toxin B subunit. Cholera toxin B-HC and cholera toxin B-C2 fusion proteins expressed up to 80 or 370 µg/g in fresh leaves, assembled into pentameric forms, and bound to GM1 receptors. Protection of FVIII antigen through bioencapsulation in plant cells and oral delivery to the gut immune system was confirmed by immunostaining. Feeding of HC/C2 mixture substantially suppressed T helper cell responses and inhibitor formation against FVIII in mice of 2 different strain backgrounds with hemophilia A. Prolonged oral delivery was required to control inhibitor formation long-term. Substantial reduction of inhibitor titers in preimmune mice demonstrated that the protocol could also reverse inhibitor formation. Gene expression and flow cytometry analyses showed upregulation of immune suppressive cytokines (transforming growth factor β and interleukin 10). Adoptive transfer experiments confirmed an active suppression mechanism and revealed induction of CD4(+)CD25(+) and CD4(+)CD25(-) T cells that potently suppressed anti-FVIII formation. In sum, these data support plant cell-based oral tolerance for suppression of inhibitor formation against FVIII. © 2014 by The American Society of Hematology.

  4. Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.

    Science.gov (United States)

    Lucas, Matthew C; Bhagirath, Niala; Chiao, Eric; Goldstein, David M; Hermann, Johannes C; Hsu, Pei-Yuan; Kirchner, Stephan; Kennedy-Smith, Joshua J; Kuglstatter, Andreas; Lukacs, Christine; Menke, John; Niu, Linghao; Padilla, Fernando; Peng, Ying; Polonchuk, Liudmila; Railkar, Aruna; Slade, Michelle; Soth, Michael; Xu, Daigen; Yadava, Preeti; Yee, Calvin; Zhou, Mingyan; Liao, Cheng

    2014-03-27

    Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.

  5. Effect of a novel oral chemotherapeutic agent containing a combination of trifluridine, tipiracil and the novel triple angiokinase inhibitor nintedanib, on human colorectal cancer xenografts.

    Science.gov (United States)

    Suzuki, Norihiko; Nakagawa, Fumio; Matsuoka, Kazuaki; Takechi, Teiji

    2016-12-01

    Trifluridine/tipiracil (TFTD) is a combination drug that is used for the treatment of metastatic colorectal cancer and was formerly known as TAS-102. It is a combination of two active pharmaceutical compounds, trifluridine, an antineoplastic thymidine-based nucleoside analog, and tipiracil, which enhances the bioavailability of trifluridine in vivo. TFTD is used for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is resistant to standard therapies. In the present study, the anticancer effects of trifluridine in combination with nintedanib, an oral triple angiokinase inhibitor, on human colorectal cancer cell lines were investigated. The cytotoxicity against DLD-1, HT-29, and HCT116 cell lines was determined by the crystal violet staining method. The combination of trifluridine and nintedanib exerted an additive effect on the growth inhibition of DLD-1 and HT-29 cells and a sub-additive effect on HCT116 cells, as determined by isobologram analyses. Subsequently, the human colorectal cancer cell lines were implanted subcutaneously into nude mice to allow the evaluation of the in vivo tumor growth inhibitory effects of TFTD and nintedanib combination therapy. TFTD (150 mg/kg/day) and/or nintedanib (40 mg/kg/day) were orally administered to the mice twice daily from day 1 to day 14. The tumor growth inhibition with combination therapy was 61.5, 72.8, 67.6 and 67.5% for the DLD-1, DLD-1/5-FU, HT-29, and HCT116 xenografts, respectively. This was significantly (P<0.05) higher than the effects of monotherapy with either TFTD or nintedanib. These results demonstrated the effectiveness of the combination of TFTD and nintedanib in the treatment of colorectal cancer xenografts. The concentration of trifluridine incorporated into DNA in the HT-29 and HCT116 tumors was determined by liquid chromatography-tandem mass spectrometry. The incorporation levels following treatment with TFTD and nintedanib for 14 consecutive days were

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

    Directory of Open Access Journals (Sweden)

    Meera Esvaran

    2016-07-01

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

  7. Response of intestinal cells and macrophages to an orally administered cellulose-PEG based polymer as a potential treatment for intractable edemas.

    Science.gov (United States)

    Esposito, Annaclaudia; Sannino, Alessandro; Cozzolino, Anna; Quintiliano, Sergio Nappo; Lamberti, Monica; Ambrosio, Luigi; Nicolais, Luigi

    2005-07-01

    The elimination of water from the body represents a fundamental therapeutic goal in those diseases in which oedemas occur. Aim of this work is the design of a material able to absorb large amount of water to be used, by oral administration, in those cases in which resistance to diuretics appears. Sorption and mechanical properties of the cellulose based superabsorbent hydrogel acting as a water elimination system have been modulated through the insertion of molecular spacers between the crosslinks. Starting polymers are the sodium salt of carboxymethylcellulose (CMCNa), a polyelectrolyte cellulose derivative, and the hydroxyethylcellulose (HEC), a non-polyelectrolyte derivative. Polyethyleneglycol (PEG) with various molecular weights, has been linked by its free ends at two divinylsulfone (DVS) crosslinker molecules, in order to increase the average distance between two crosslinking sites and thus acting as spacer. Both the effect of concentration and molecular weight of the spacer resulted to significantly affect the hydrogel final sorption properties and thus the efficiency of the body water elimination system. Biocompatibility studies have been performed to test the hydrogel compatibility with respect to intestinal and macrophages cell lines. To investigate the effects of intestinal cells conditioned media after the contact with the gel on macrophages nitric oxide release tests have been carried out.

  8. Protective effects of green tea polyphenols administered by oral intubation against chemical carcinogen-induced forestomach and pulmonary neoplasia in A/J mice.

    Science.gov (United States)

    Katiyar, S K; Agarwal, R; Mukhtar, H

    1993-09-30

    Our studies and others have shown the cancer chemopreventive effects of chronic administration of green tea in several animal tumor models. In this study, the administration of a polyphenolic fraction isolated from green tea (GTP) by oral intubation at a dose of 5 mg in 0.2 ml water 30 min prior to challenge with carcinogen, afforded significant protection against both diethylnitrosamine (DEN)- and benzo(a)pyrene (BP)-induced forestomach and lung tumorigenesis in A/J mice. The protective effects were evident by a decrease in numbers of tumors/mouse in GTP-fed groups compared to non GTP-fed controls. In the forestomach tumorigenesis protocol, GTP afforded 71 and 66% protection against, respectively DEN- and BP-induced tumor multiplicity. In the case of lung tumorigenesis protocol, however, the protective effects of GTP were 41 and 39%, respectively. Histological examination of forestomach tumors showed significantly lesser number of squamous cell carcinoma formation in GTP-fed groups of mice compared to carcinogen alone-treated controls. When pulmonary tumors were examined histologically, no adenocarcinomas were observed in GTP-fed groups compared to 15% mice with adenocarcinomas in DEN and BP alone-treated controls. The results of this study suggest that limited doses of GTP administration by gavage 30 min prior to carcinogen challenge may afford protection against carcinogen-induced tumorigenesis in internal body organs.

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

    Science.gov (United States)

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

    2009-08-15

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

  10. Orally administered lycopene attenuates diethylnitrosamine-induced hepatocarcinogenesis in rats by modulating Nrf-2/HO-1 and Akt/mTOR pathways.

    Science.gov (United States)

    Sahin, Kazim; Orhan, Cemal; Tuzcu, Mehmet; Sahin, Nurhan; Ali, Shakir; Bahcecioglu, Ibrahim H; Guler, Osman; Ozercan, Ibrahim; Ilhan, Necip; Kucuk, Omer

    2014-01-01

    Hepatocarcinogenesis is one of the most prevalent and lethal cancers. We studied the mechanisms underlying the inhibition of diethylnitrosamine (DEN)-induced hepatocarcinogenesis by lycopene in rats. Hepatocarcinogenesis was induced by an intraperitoneal injection of DEN followed by promotion with phenobarbital for 24 successive wk. The rats were given lycopene (20 mg/kg body weight) 3 times a week orally for 4 wk prior to initiation, and the treatment was continued for 24 consecutive wk. Lycopene reduced incidence, number, size, and volume of hepatic nodules. Serum alanine transaminase, aspartate aminotransferase, total bilirubin, and malondialdehyde (MDA) considerably increased and hepatic antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) and glutathione decreased in DEN-treated rats when compared with the control group. Lycopene significantly reversed these biochemical changes and increased the expression of NF-E-2-related factor-2)/heme oxygenase-1, and it decreased NF-κB/cyclooxygenase-2, inhibiting the inflammatory cascade and activating antioxidant signaling (P B (P < 0.05). Lycopene is an active chemopreventive agent that offers protection against DEN-induced hepatocarcinogenesis by inhibiting NF-κB and mTOR pathways.

  11. 86 The Efficacy and Safety of Human Plasma-derived C1-Inhibitor Concentrate Administered for the Treatment of Attacks in Pediatric Patients with Hereditary Angioedema Due to C1-Inhibitor Deficiency

    OpenAIRE

    Farkas, Henriette; Csuka, Dorottya; Zotter, Zsuzsanna; Szabó, Erika; Kelemen, Zsuzsanna; Varga, Lilian; Fejes, János; Harmat, George

    2012-01-01

    Background Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a life-threatening, rare disease characterized by recurrent edematous attacks. In 50% of cases, the initial onset of symptoms occurs between 5 and 11 years of age. There are limited data on the emergency treatment of acute episodes in pediatric patients. Our aim was to analyze the efficacy and safety of human plasma-derived C1-INH concentrate in our pediatric patient population with HAE-C1-INH. Methods 50 pediatri...

  12. Tumorigenic effects in Wistar rats orally administered benzo[a] pyrene for two years (gavage studies). Implications for human cancer risks associated with oral exposure to polycyclic aromatic hydrocarbons

    NARCIS (Netherlands)

    Kroese ED; Muller JJA; Mohn GR; Dortant PM; Wester PW; LEO; LPI; CSR

    2002-01-01

    Humans are exposed via the environment and via food to Polycyclic Aromatic Hydrocarbons (PAH), mixtures considered carcinogenic by IARC. A quantitative cancer risk assessment for oral exposure is hampered by the absence of adequate data. The need for experimental data is substantiated by the fact th

  13. Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Hammond, Marlys; Washburn, David G.; Hoang, Tram H.; Manns, Sharada; Frazee, James S.; Nakamura, Hiroko; Patterson, Jaclyn R.; Trizna, Walter; Wu, Charlene; Azzarano, Leonard M.; Nagilla, Rakesh; Nord, Melanie; Trejo, Rebecca; Head, Martha S.; Zhao, Baoguang; Smallwood, Angela M.; Hightower, Kendra; Laping, Nicholas J.; Schnackenberg, Christine G.; Thompson, Scott K.; (GSKPA)

    2010-09-27

    The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {l_brace}4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl{r_brace}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.

  14. Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors.

    Science.gov (United States)

    Hammond, Marlys; Washburn, David G; Hoang, H Tram; Manns, Sharada; Frazee, James S; Nakamura, Hiroko; Patterson, Jaclyn R; Trizna, Walter; Wu, Charlene; Azzarano, Leonard M; Nagilla, Rakesh; Nord, Melanie; Trejo, Rebecca; Head, Martha S; Zhao, Baoguang; Smallwood, Angela M; Hightower, Kendra; Laping, Nicholas J; Schnackenberg, Christine G; Thompson, Scott K

    2009-08-01

    The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.

  15. Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy

    Science.gov (United States)

    Yang, Yang; Fan, Chun-Mei; He, Xuan; Ren, Ke; Zhang, Jin-Kun; He, Ying-Ju; Yu, Luo-Ting; Zhao, Ying-Lan; Gong, Chang-Yang; Zheng, Yu; Song, Xiang-Rong; Zeng, Jun

    2014-01-01

    Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (Peff) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10−4 mg·min−1·cm−2. The Peff value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates. PMID:24776763

  16. Zilascorb(2H), a new reversible protein synthesis inhibitor: clinical study of an oral preparation.

    Science.gov (United States)

    Semb, K A; Fodstad, O; Klem, B; Bibow, K; Osmundsen, K; Aamdal, S

    1997-03-01

    The new anti-cancer drug zilascorb(2H) has shown promising activity in preclinical models. Its putative mechanism of action is reversible protein synthesis inhibition and long-term treatment is required. As a clinical treatment modality, long-term daily zilascorb(2H) infusions, as used in previous studies, are not regarded feasible. Therefore, an oral formulation of the drug was developed, and pharmacokinetic profile, toxicity and antitumor activity of zilascorb(2H) tablets were studied. Thirteen patients with advanced solid cancer not amenable to established therapy, but with adequate performance status and organ functions, were included. The treatment was given as a daily i.v. zilascorb(2H) infusion for 5 days, followed by zilascorb(2H) tablets twice daily for 3 months. Blood and urine sampling was performed when estimated plasma steady-state level was reached for each formulation, respectively. Analyses of drug concentrations in plasma and urine were performed by high performance liquid chromatography. Zilascorb(2H) in tablet formulation had a bioavailability of 32%, was quickly absorbed and slowly eliminated. Concomitant use of the H2-blocker ranitidine possibly enhanced bioavailability. Zilascorb(2H) was well tolerated. Two patients experienced drug-related fever, disturbing the treatment schedule for one of them. Moderate nausea was reported. One objective response was obtained. The bioavailability of zilascorb(2H) tablets was satisfactory. The principle of oral administration of zilascorb(2H) is feasible for long-term treatment and the side effects are acceptable. The mechanisms of action and the very low toxicity of the drug makes it a candidate for combination with other anticancer agents.

  17. Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Yang Yang

    2014-04-01

    Full Text Available Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR of NCE were estimated in different phosphate buffers. Effective intestinal permeability (Peff of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability and ranitidine (low permeability were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10−4 mg·min−1·cm−2. The Peff value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.

  18. Study on biopharmaceutics classification and oral bioavailability of a novel multikinase inhibitor NCE for cancer therapy.

    Science.gov (United States)

    Yang, Yang; Fan, Chun-Mei; He, Xuan; Ren, Ke; Zhang, Jin-Kun; He, Ying-Ju; Yu, Luo-Ting; Zhao, Ying-Lan; Gong, Chang-Yang; Zheng, Yu; Song, Xiang-Rong; Zeng, Jun

    2014-04-25

    Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (P(eff)) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10⁻⁴ mg·min⁻¹·cm⁻². The P(eff) value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.

  19. In vitro antimicrobial activity and MIC quality control guidelines of RPR 106972 (RPR 112808/RPR106950): a novel orally administered streptogramin combination. The Quality Control Study Group.

    Science.gov (United States)

    Putnam, S D; Jones, R N; Johnson, D M

    1997-07-01

    RPR 106972 is a novel oral streptogramin combination with reported therapeutic potency against Gram-positive and certain respiratory tract pathogens. MICs for RPR 106972, quinupristin/dalfopristin, and seven comparison drugs were determined by the reference methods against 337 strains selected to define spectrum and potency. RPR 106972 demonstrated antimicrobial activity against oxacillin-susceptible and -resistant Staphylococcus aureus (MIC ranges of 0.12 to 2 micrograms/ml and 0.5 to 2 micrograms/ml, respectively), and coagulase-negative staphylococci were also inhibited by RPR 106972 (MIC90, RPR 106972 was highly active with MIC results at RPR 106972 inhibited Corynebacterium jeikeium (MIC90, 0.5 microgram/ml). Moraxella catarrhalis (MIC90, 0.25 microgram/ml), and some Haemophilus influenzae (MIC50, 2 micrograms/ml). RPR 106972 and quinupristin/dalfopristin demonstrated little activity against Enterococcus faecalis (MIC90s, 4 to 32 micrograms/ml) as compared to Enterococcus faecium (MIC90s, 0.5 to 1 microgram/ml) and other Enterococcus ssp. (MIC90s, 1 microgram/ml). Studies to establish MIC quality-control guidelines indicated the following ranges: for E. faecalis ATCC 29212, 0.5 to 4 micrograms/ml; for S. aureus ATCC 29213, 0.25 to 1 microgram/ml; and for Streptococcus pneumoniae ATCC 49619, 0.06 to 0.5 microgram/ml. The results of this study indicate that the in vitro activity of RPR 106972 against Gram-positive bacteria and selected Gram-negative respiratory organisms is promising and warrants additional studies of pharmacokinetics, and in vivo infection model dynamics.

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

    Science.gov (United States)

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

    2012-05-01

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

  1. The immuno-regulatory impact of orally-administered Hypericum perforatum extract on Balb/C mice inoculated with H1n1 influenza A virus.

    Directory of Open Access Journals (Sweden)

    Nan Huang

    Full Text Available Hypericumperforatum (H. perforatum ethanol extract has been found to inhibit lipopolysaccharide-induced production of inflammatory mediators and cytokines in cultured macrophages. Therefore, it may be able to protect the host from excessive inflammation during viral infection. In the current study, the immune-regulatory effect of H. perforatum extract was evaluated in A549 lung epithelial cells and BALB/c mice exposed to Influenza A/PR/8/34 H1N1 virus. In A549 cells, the extract (30 µg/mL significantly inhibited influenza virus induced monocyte chemotactic protein (MCP-1 and interferon-γ induced protein 10 kD (IP-10, but dramatically increased interleukin-6 (IL-6. In mice inoculated intranasally with 10(7.9 EID50 of Influenza A/PR/8/34 H1N1 (high dose, daily oral treatment of H. perforatum extract at a rate of 110 mg/kg of body weight increased lung viral titer, bronchoalveolar lavage (BAL pro-inflammatory cytokine and chemokine levels, and the infiltration of pro-inflammatory cells in the lung 5 days post-inoculation, as compared to ethanol vehicle treated mice. Transcription of suppressor of cytokine signaling 3 (SOCS3 was increased by H. perforatum extract both in A549 cells and BALB/c mice, which could have interrupted anti-viral immune response and thus led to the inefficient viral clearance and increased lung inflammation. H. perforatum treatment resulted in minor reduction in viral titer without affecting body weight when mice were inoculated with a lower dose (~10(5.0 EID50 and H. perforatum was applied in the later phase of infection. Mice challenged intranasally with high dose of influenza virus (10(7.9 EID50 suffered from a higher mortality rate when dosed with H. perforatum extract. In conclusion, the current study showed that SOCS3 elevation by H. perforatum may cause impaired immune defense against influenza virus infection and lead to higher mortality.

  2. ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease.

    Science.gov (United States)

    Kim, Kyungho; Li, Jing; Barazia, Andrew; Tseng, Alan; Youn, Seock-Won; Abbadessa, Giovanni; Yu, Yi; Schwartz, Brian; Andrews, Robert K; Gordeuk, Victor R; Cho, Jaehyung

    2017-02-01

    Previous studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrophils and platelets from sickle cell disease patients in vitro and cell-cell interactions in a mouse model of sickle cell disease. Studies using neutrophils and platelets isolated from sickle cell disease patients revealed that treatment with 50-500 nM ARQ 092 significantly blocks αMβ2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V-mediated agglutination in platelets. Treatment of isolated platelets and neutrophils with ARQ 092 inhibited heterotypic cell-cell aggregation under shear conditions. Intravital microscopic studies demonstrated that short-term oral administration of ARQ 092 or hydroxyurea, a major therapy for sickle cell disease, diminishes heterotypic cell-cell interactions in venules of sickle cell disease mice challenged with tumor necrosis factor-α. Co-administration of hydroxyurea and ARQ 092 further reduced the adhesive function of neutrophils in venules and neutrophil transmigration into alveoli, inhibited expression of E-selectin and intercellular adhesion molecule-1 in cremaster vessels, and improved survival in these mice. Ex vivo studies in sickle cell disease mice suggested that co-administration of hydroxyurea and ARQ 092 efficiently blocks neutrophil and platelet activation and that the beneficial effect of hydroxyurea results from nitric oxide production. Our results provide important evidence that ARQ 092 could be a novel drug for the prevention and treatment of acute vaso-occlusive complications in patients with sickle cell disease.

  3. ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease

    Science.gov (United States)

    Kim, Kyungho; Li, Jing; Barazia, Andrew; Tseng, Alan; Youn, Seock-Won; Abbadessa, Giovanni; Yu, Yi; Schwartz, Brian; Andrews, Robert K.; Gordeuk, Victor R.; Cho, Jaehyung

    2017-01-01

    Previous studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrophils and platelets from sickle cell disease patients in vitro and cell-cell interactions in a mouse model of sickle cell disease. Studies using neutrophils and platelets isolated from sickle cell disease patients revealed that treatment with 50–500 nM ARQ 092 significantly blocks αMβ2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V-mediated agglutination in platelets. Treatment of isolated platelets and neutrophils with ARQ 092 inhibited heterotypic cell-cell aggregation under shear conditions. Intravital microscopic studies demonstrated that short-term oral administration of ARQ 092 or hydroxyurea, a major therapy for sickle cell disease, diminishes heterotypic cell-cell interactions in venules of sickle cell disease mice challenged with tumor necrosis factor-α. Co-administration of hydroxyurea and ARQ 092 further reduced the adhesive function of neutrophils in venules and neutrophil transmigration into alveoli, inhibited expression of E-selectin and intercellular adhesion molecule-1 in cremaster vessels, and improved survival in these mice. Ex vivo studies in sickle cell disease mice suggested that co-administration of hydroxyurea and ARQ 092 efficiently blocks neutrophil and platelet activation and that the beneficial effect of hydroxyurea results from nitric oxide production. Our results provide important evidence that ARQ 092 could be a novel drug for the prevention and treatment of acute vaso-occlusive complications in patients with sickle cell disease. PMID:27758820

  4. COX-2 selective inhibitors: a literature review of analgesic efficacy and safety in oral-maxillofacial surgery.

    Science.gov (United States)

    Cicconetti, Andrea; Bartoli, Adriano; Ripari, Francesca; Ripari, Andrea

    2004-02-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed analgesic agents in surgical outpatients. Major limitations of NSAIDs are their gastrointestinal (GI) adverse events (perforation, ulceration, and bleeding), impairment of hemostatic function, and renal failure (with long-term therapy). A new class of NSAIDs, the COX-2 selective inhibitors (CSIs or Coxibs), have been developed with the aim of reducing the GI adverse events of traditional NSAIDs while maintaining their effective anti-inflammatory and analgesic properties. This is a narrative review of the literature aimed to discuss analgesic efficacy, clinical safety and cost-benefit ratio of CSIs in the treatment of post-oral surgery pain. Relevant drug and clinical studies of analgesic efficacy and safety of CSIs in the management of postoperative dental pain were identified through searches of MEDLINE/PubMed, in peer-reviewed journals of medicine and dentistry. The Food and Drug Administration Web site was searched for data of tolerability. Hand-searching included several dental journals and bibliographies of relevant studies. The last electronic search was conducted in April 2003. Data from well-designed, randomized, controlled trials of CSIs on the management of post-oral surgery pain indicate that these drugs are as well-effective analgesic agents as traditional NSAIDs and offer clinical advantages in terms of GI safety and unimpaired platelet function. CSIs do not offer advantages of renal safety over traditional NSAIDs. Although CSIs display analgesic efficacy similar to that of traditional NSAIDs in the treatment of acute, post-oral surgery pain, there is reasonable evidence that these new drugs are preferable in patients who are at an increased risk of developing serious upper-GI complications, in patients who take aspirin for cardiovascular comorbid conditions, and in those allergic to aspirin. Furthermore, CSIs may be given more safely than NSAIDs in perioperative settings

  5. Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Rosenberg JE

    2012-01-01

    Full Text Available Yasser Rehman1, Jonathan E Rosenberg21Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA, USA; 2Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC, which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17. This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.Keywords: CRPC, abiraterone, CYP17, inhibitors, androgens, castration resistant prostate cancer

  6. Pharmacological and behavioral characterization of D-473, an orally active triple reuptake inhibitor targeting dopamine, serotonin and norepinephrine transporters.

    Directory of Open Access Journals (Sweden)

    Aloke K Dutta

    Full Text Available Major depressive disorder (MDD is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine transporter should provide more efficacious antidepressants activity. This has led to the development of triple reuptake inhibitor D-473 which is a novel pyran based molecule and interacts with all three monoamine transporters. The monoamine uptake inhibition activity in the cloned human transporters expressed in HEK-293 cells (70.4, 9.18 and 39.7 for DAT, SERT and NET, respectively indicates a serotonin preferring triple reuptake inhibition profile for this drug. The drug D-473 exhibited good brain penetration and produced efficacious activity in rat forced swim test under oral administration. The optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated that systemic administration of D-473 elevated extracellular level of the three monoamines DA, 5-HT, and NE efficaciously in the dorsal lateral striatum (DLS and the medial prefrontal cortex (mPFC area, indicating in vivo blockade of all three monoamine transporters by D-473. Thus, the current biological data from D-473 indicate potent antidepressant activity of the molecule.

  7. The novel IκB kinase β inhibitor IMD-0560 prevents bone invasion by oral squamous cell carcinoma

    Science.gov (United States)

    Tada, Yukiyo; Kokabu, Shoichiro; Sugiyama, Goro; Nakatomi, Chihiro; Aoki, Kazuhiro; Fukushima, Hidefumi; Osawa, Kenji; Sugamori, Yasutaka; Ohya, Keiichi; Okamoto, Masato; Fujikawa, Tomoyuki; Itai, Akiko; Matsuo, Kou; Watanabe, Seiji; Jimi, Eijiro

    2014-01-01

    Oral squamous cell carcinoma (OSCC) cells display significantly augmented nuclear factor-κB (NF-κB) activity, and inhibiting this activity suppresses malignant tumor characteristics. Thus, we evaluated the effect of IMD-0560, a novel inhibitor of IκB kinase (IKK) β that is under assessment in a clinical trial of rheumatoid arthritis, on bone invasion by the mouse OSCC cell line SCCVII. We examined the inhibitory effects of IMD-0560 on NF-κB activity and tumor invasion using human OSCC cell lines and SCCVII cells in vitro. Using a mouse model of jaw bone invasion by SCCVII cells, we assessed the inhibitory effect of IMD-0560 on jaw bone invasion, tumor growth, and matrix degradation in vivo. IMD-0560 suppressed the nuclear translocation of NF-κB and the degradation of IκBα in OSCC cells. IMD-0560 also inhibited invasion by suppressing matrix metalloproteinase-9 (MMP-9) production in OSCC cells. IMD-0560 protected against zygoma and mandible destruction by SCCVII cells, reduced the number of osteoclasts by inhibiting receptor activator of NF-κB ligand (RANKL) expression in osteoblastic cells and SCCVII cells, increased SCCVII cell death and suppressed cell proliferation and MMP-9 production in SCCVII cells. Based on these results, IMD-0560 may represent a new therapeutic agent for bone invasion by OSCC cells. PMID:25373602

  8. The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis.

    Science.gov (United States)

    Hodge, Jennifer A; Kawabata, Thomas T; Krishnaswami, Sriram; Clark, James D; Telliez, Jean-Baptiste; Dowty, Martin E; Menon, Sujatha; Lamba, Manisha; Zwillich, Samuel

    2016-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterised by infiltration of immune cells into the affected synovium, release of inflammatory cytokines and degradative mediators, and subsequent joint damage. Both innate and adaptive arms of the immune response play a role, with activation of immune cells leading to dysregulated expression of inflammatory cytokines. Cytokines work within a complex regulatory network in RA, signalling through different intracellular kinase pathways to modulate recruitment, activation and function of immune cells and other leukocytes. As our understanding of RA has advanced, intracellular signalling pathways such as Janus kinase (JAK) pathways have emerged as key hubs in the cytokine network and, therefore, important as therapeutic targets. Tofacitinib is an oral JAK inhibitor for the treatment of RA. Tofacitinib is a targeted small molecule, and an innovative advance in RA therapy, which modulates cytokines critical to the progression of immune and inflammatory responses. Herein we describe the mechanism of action of tofacitinib and the impact of JAK inhibition on the immune and inflammatory responses in RA.

  9. Poor adherence with ACE inhibitors is a risk factor of CVA with oral hypoglycemic agents in diabetic patients.

    Science.gov (United States)

    Aftab, Muhammad Tariq; Dharamshi, Hasnain Abbas; Faraz, Ahmed; Shakeel, Saba; Shakeel, Osama

    2017-03-01

    Poor adherence with medicine declines the clinical outcome of pharmacotherapy. It may carry serious sequelae especially in case of antihypertensive drugs like cerebrovascular accident (CVA). This study has been planned to find the association of poor adherence with anti-hypertensive with CVA in diabetic and non- diabetic patients. One hundred CVA patients who were admitted through Emergency in Abbasi Shaheed hospital, a tertiary care hospital in Karachi, were recruited from Jun 2013 till Dec 2013. The criteria of inclusion was, diagnosed case of CVA, with primary hypertension, availability of patient's therapeutic record, consent of the patient or legal successor/heir. The criteria of exclusion was, secondary hypertension, newly diagnosed primary hypertensive patients and complete adherence with medication. Morisky medication adherence scale was applied. Therapeutic record was accessed. The mean age was 62.15 years with 3:1 male to female ratio. Adherence to medicine was graded 0.05) was seen in any combination (p>0.05). Thus it is concluded that poor adherence with ACE inhibitors may be a risk factor of CVA in diabetic patients using oral hypoglycemic agents.

  10. Oral anticoagulation with vitamin K inhibitors and determinants of successful self-management in primary care.

    Science.gov (United States)

    Tamayo Aguirre, E; Galo-Anza, A; Dorronsoro-Barandiaran, O; Del Burgo, E Uranga-Saez; Ostiza Irigoyen, A; Garcia-Carro, A; Lopez-Fernandez, I; Colera, N; Saez-Garbayo, P; Tamayo-Uria, I

    2016-09-13

    Self-management may be an option to monitor oral anticoagulant therapy in health systems, but before recommending it, we need to assess patients' ability to take on this task. The purpose of the study was to describe patients' ability to self-manage and associated factors. This was a 3-year prospective quasi-experimental study with a control group. Overall, 333 patients on anticoagulant therapy from seven primary care health centres of the Basque Health Service were included in the intervention group and followed up for 6 months after the intervention, assessing their ability to self-test and self-manage. The intervention consisted of a patient training programme, providing detailed information on their condition and its treatment, and practical training in how to use a portable blood coagulation monitor and adjust their anticoagulant dose. Comparisons were made with a control group (333 patients receiving OAT under usual care from the same seven health centres). Outcome variables were ability to self-manage, quality of the outcome (in terms of time in therapeutic range), and quality of life in the intervention group, and general patient characteristics (age and sex), clinical variables (reason for OAT, INR range), and quality of the outcome (in terms of percentage of INR measurements in range and complications) in both groups. Overall, 26.13 % of patients invited to participate in the intervention agreed. Of these, 99 % successfully learned to self-manage their OAT. Just 4.2 % did not complete the follow-up, in all cases for reasons unrelated to self-management, and 4.5 % required additional learning support. Outcomes were better than under usual care in terms of percentage of INR measurements in range (12 %), rate of complications (4 %) and quality of life (9.2 %). Patients were only followed-up period for 6 months and the study was conducted in a single health organization. Though patients eligible to participate were selected randomly, they were not randomly

  11. Phase I/II clinical trial of 2-difluoromethyl-ornithine (DFMO) and a novel polyamine transport inhibitor (MQT 1426) for feline oral squamous cell carcinoma.

    Science.gov (United States)

    Skorupski, K A; O'Brien, T G; Guerrero, T; Rodriguez, C O; Burns, M R

    2011-12-01

    Polyamines are essential for cell proliferation. Their production is dysregulated in many cancers and polyamine depletion leads to tumour regression in mouse models of squamous cell carcinoma (SCC). The purpose of this study was to determine the maximally tolerated dose of the polyamine transport inhibitor, MQT 1426, when combined with the ornithine decarboxylase (ODC) inhibitor, DFMO, and to determine whether this therapy results in reduction in tumour polyamine levels. Thirteen cats with oral SCC received both drugs orally and serial tumour biopsies were obtained for polyamine measurement. Cats were monitored for response to therapy and toxicity. A maximum tolerated dose (MTD) of MQT 1426 when combined with DFMO was determined. Dose-limiting toxicity was vestibular in nature, but was fully reversible. Spermidine and total polyamine levels decreased significantly in tissues, two cats experienced objective tumour regression and six cats had stable disease. These results suggest that further study of polyamine depletion therapies is warranted.

  12. Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 8. Pharmacological optimization of orally bioavailable 2-pyridone-containing peptidomimetics.

    Science.gov (United States)

    Dragovich, Peter S; Prins, Thomas J; Zhou, Ru; Johnson, Theodore O; Hua, Ye; Luu, Hiep T; Sakata, Sylvie K; Brown, Edward L; Maldonado, Fausto C; Tuntland, Tove; Lee, Caroline A; Fuhrman, Shella A; Zalman, Leora S; Patick, Amy K; Matthews, David A; Wu, Ellen Y; Guo, Ming; Borer, Bennett C; Nayyar, Naresh K; Moran, Terence; Chen, Lijian; Rejto, Paul A; Rose, Peter W; Guzman, Mark C; Dovalsantos, Elena Z; Lee, Steven; McGee, Kevin; Mohajeri, Michael; Liese, Andreas; Tao, Junhua; Kosa, Maha B; Liu, Bo; Batugo, Minerva R; Gleeson, Jean-Paul R; Wu, Zhen Ping; Liu, Jia; Meador, James W; Ferre, Rose Ann

    2003-10-09

    The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).

  13. Changes in glucose-induced plasma active glucagon-like peptide-1 levels by co-administration of sodium–glucose cotransporter inhibitors with dipeptidyl peptidase-4 inhibitors in rodents

    OpenAIRE

    Takahiro Oguma; Chiaki Kuriyama; Keiko Nakayama; Yasuaki Matsushita; Kumiko Hikida; Minoru Tsuda-Tsukimoto; Akira Saito; Kenji Arakawa; Kiichiro Ueta; Masabumi Minami; Masaharu Shiotani

    2016-01-01

    We investigated whether structurally different sodium–glucose cotransporter (SGLT) 2 inhibitors, when co-administered with dipeptidyl peptidase-4 (DPP4) inhibitors, could enhance glucagon-like peptide-1 (GLP-1) secretion during oral glucose tolerance tests (OGTTs) in rodents. Three different SGLT inhibitors—1-(β-d-Glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene (GTB), TA-1887, and canagliflozin—were examined to assess the effect of chemical structure. Oral treatment...

  14. Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics--results from single oral dose studies in healthy volunteers.

    Science.gov (United States)

    Stoch, S Aubrey; Zajic, Stefan; Stone, Julie A; Miller, Deborah L; van Bortel, Lucas; Lasseter, Kenneth C; Pramanik, Barnali; Cilissen, Caroline; Liu, Qi; Liu, Lida; Scott, Boyd B; Panebianco, Deborah; Ding, Yu; Gottesdiener, Keith; Wagner, John A

    2013-05-01

    To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction. Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing. © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. British Journal of

  15. Orally Administered Bioadherent Sustained Release Microencapsulated Vaccines

    Science.gov (United States)

    1996-09-01

    microspheres consist of bovine serum albumin (BSA) and recombinant vitelline protein B (vpB) from the liver fluke Fasciola hepatica which is a known...from the liver fluke Fasciola hepatica ." Biochemistry 26, 7819-7825. 10. Waite, J.H., Rice-Ficht, A.C. (1992) "Eggshell precursor proteins of Fasciola ...precursor proteins of Fasciola hepatica : I. Structure and expression of vitelline protein B." Mol. Bioch. Parasitol. 54, 127-143. 12. Yapel, A.F. (1985

  16. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome

    DEFF Research Database (Denmark)

    Steg, Ph Gabriel; Mehta, Shamir R; Jukema, J Wouter

    2011-01-01

    To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS)....

  17. Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohn's Disease: A Randomized Placebo-controlled, Double-blind, Phase IIa Study

    National Research Council Canada - National Science Library

    Eser, Alexander; Colombel, Jean-Frederic; Rutgeerts, Paul; Vermeire, Severine; Vogelsang, Harald; Braddock, Martin; Persson, Tore; Reinisch, Walter

    2015-01-01

    AZD9056 is a selective orally active inhibitor of the purinergic receptor P2X7, which is a key player in the generation and secretion of several proinflammatory cytokines involved in the pathogenesis of Crohn's disease (CD...

  18. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor

    Science.gov (United States)

    Kavanaugh, Arthur; Mease, Philip J; Gomez-Reino, Juan J; Adebajo, Adewale O; Wollenhaupt, Jürgen; Gladman, Dafna D; Lespessailles, Eric; Hall, Stephen; Hochfeld, Marla; Hu, ChiaChi; Hough, Douglas; Stevens, Randall M; Schett, Georg

    2014-01-01

    Objectives Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. Methods In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. Results At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed. Conclusions Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. Clinical trial registration number NCT

  19. Explication of Definitional Description and Empirical Use of Fraction of Orally Administered Drugs Absorbed From the Intestine (Fa) and Intestinal Availability (Fg): Effect of P-glycoprotein and CYP3A on Fa and Fg.

    Science.gov (United States)

    Tanaka, Yuta; Kitamura, Yoshiaki; Maeda, Kazuya; Sugiyama, Yuichi

    2016-02-01

    Conventionally, it is believed that the fraction of orally administered drugs absorbed from the intestine (Fa) and intestinal availability (Fg) are independently determined by the apical membrane permeation and intestinal metabolism, respectively. However, the validity of this belief has not been well discussed, and Fa and Fg are often used without careful definition. In this review, Fa and Fg are mathematically described based on their definitions under the linear kinetics of metabolism and transport. Even considering with different models, intestinal metabolic enzymes such as cytochrome P450 3A affected both Fa and Fg, whereas apical efflux transporters including P-glycoprotein had no influence on Fg at least under the linear condition. To determine whether Fa and Fg calculated using different clinical methods are identical, empirical Fa and Fg were mathematically described based on "feces method" and "grapefruit juice method" and compared with their definitions. Fa and Fg obtained by the feces method corresponded with their definitions whereas the grapefruit juice method provided smaller Fa and larger Fg particularly for dual substrates of P-glycoprotein and cytochrome P450 3A with low membrane permeability. Our analyses suggest that the definitions and calculation methods of Fa and Fg should be considered when we intend to separately determine these values.

  20. [Treatment of endometriosis by aromatase inhibitors: efficacy and side effects].

    Science.gov (United States)

    Racine, A-C; Legrand, E; Lefebvre-Lacoeuille, C; Hoppe, E; Catala, L; Sentilhes, L; Descamps, P

    2010-05-01

    The recent demonstration that aromatase is expressed at higher levels in endometriosis implants than in normal endometrium has led to pilot studies using inhibitor aromatasis in patients with endometriosis. We conducted a systematic review of the literature and studied the efficacy of aromatase inhibitors on endometriosis. There were seventeen studies (case reports/series) evaluating outcomes of aromatase inhibitors. Studies suggest that aromatase inhibitors alone or co-administered with progestins, oral contraceptives or gonadotrophin releasing hormone (GnRH) agonist could reduce pain and endometriosis. There is only one randomized controlled trial comparing aromatase inhibitor+GnRH agonist and GnRH agonist and one study with eighty patients. Side-effects profiles of aromatase inhibitor regimens are favorable; it does not appear a significant bone loss. Aromatase inhibitors seem to have a promising effect on endometriosis but randomized controlled trials are needed to prove their effects and their safety.

  1. Therapeutic and hematological effects of native and low molecular weight condroitin sulphate administered orally in horses with experimental arthritis (Efectos terapéuticos y hemáticos de condroitin sulfato nativo y de bajo peso molecular administrado por vía oral en caballos con artritis experimental

    Directory of Open Access Journals (Sweden)

    Verde, C.R.

    2006-01-01

    Full Text Available The objective of the present study was to analyse the therapeutic and secondary effects of 2 types of condroitin sulphate (CS administered orally over three months in horses with arthritis. Ten horses with an arthoscopically created osteochondral defect of the carpal joint were divided into 3 groups. Group A consisted of 4 animals receiving a daily 2.5 g oral dose of low molecular weight condroitin sulphate (LMWCS. Group B comprised 4 animals receiving a daily 2.5 g oral dose of native condroitin sulphate (NCS. Group C (control comprised 2 animals receiving an oral placebo solution. Therapeutic and secondary effects were evaluated weekly, by changes in clinical parameters and through measurement of synovial mediators/substances related to inflammation. Significant beneficial changes were obtained on clinical signs of inflammation. There were also significant reductions in synovial fluid PGE2 and MMP-3 concentrations in the CS treated groups. These compounds also significantly affected temporal profile of total GAGs concentration. LMWCS and NCS, administered orally for 10 weeks to arthritic horses, alleviated clinical signs by reducing the synthesis and/or release of PGE2 and MMP-3. Its anti-inflammatory and chondroprotective effect is further indicated by an inhibition of GAGs degradation without any significant effect on blood parameters including those reflecting the normal functioning of the coagulation cascade. El objetivo del presente estudio es analizar los efectos terapéuticos y secundarios de 2 tipos de sulfato del condroitin (CS administrados vía oral durante tres meses en caballos con artritis. Diez caballos con un defecto osteochondral creado del empalme carpal fueron divididos en 3 grupos. El grupo A lo conforman 4 animales que reciben una dosis oral diaria de 2,5 g del sulfato bajo del condroitin del peso molecular (LMWCS. El grupo B abarcó 4 animales que recibieron una dosis oral diaria de 2,5 g del sulfato nativo del condroitin

  2. [Treatment with inhibitors of new oral direct anticoagulants in patients with severe bleedings or urgent surgical procedures. The new dabigatran antidote: the place of idarucizumab in clinical practice].

    Science.gov (United States)

    Boda, Zoltán

    2016-03-20

    Only vitamin K antagonists could be applied as oral anticoagulants over the past six decades. Coumarols have narrow therapeutic range, and unpredictable anticoagulant effects are resulted by multiple drug interactions. Therefore, regular routine monitoring of the international normalized ratio is necessary. There are two groups of factor-specific anticoagulants: molecules with anti-FIIa (dabigatran) and anti-FXa (rivaroxaban, apixaban and edoxaban) effect. Author summarizes the most important clinical features of the new oral anticoagulants, their indications and the possibilities of laboratory controls. Bleedings are the most important side effects of anticoagulants. This review summarizes the current published evidences for new oral anticoagulants reversal (non-specific and specific) agents, especially in cases with severe acute bleedings or urgent surgery procedures. It reports on how to use inhibitors, the recommended doses and the most important clinical results. The review focuses on idarucizumab - already approved by the U.S. Food and Drug Administration and the European Medicines Agency - which has a key role as the first specific inhibitor of dabigatran.

  3. MPT0B098, a Microtubule Inhibitor, Suppresses JAK2/STAT3 Signaling Pathway through Modulation of SOCS3 Stability in Oral Squamous Cell Carcinoma.

    Directory of Open Access Journals (Sweden)

    Hsuan-Yu Peng

    Full Text Available Microtubule inhibitors have been shown to inhibit Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3 signal transduction pathway in various cancer cells. However, little is known of the mechanism by which the microtubule inhibitors inhibit STAT3 activity. In the present study, we examined the effect of a novel small-molecule microtubule inhibitor, MPT0B098, on STAT3 signaling in oral squamous cell carcinoma (OSCC. Treatment of various OSCC cells with MPT0B098 induced growth inhibition, cell cycle arrest and apoptosis, as well as increased the protein level of SOCS3. The accumulation of SOCS3 protein enhanced its binding to JAK2 and TYK2 which facilitated the ubiquitination and degradation of JAK2 and TYK2, resulting in a loss of STAT3 activity. The inhibition of STAT3 activity led to sensitization of OSCC cells to MPT0B098 cytotoxicity, indicating that STAT3 is a key mediator of drug resistance in oral carcinogenesis. Moreover, the combination of MPT0B098 with the clinical drug cisplatin or 5-FU significantly augmented growth inhibition and apoptosis in OSCC cells. Taken together, our results provide a novel mechanism for the action of MPT0B098 in which the JAK2/STAT3 signaling pathway is suppressed through the modulation of SOCS3 protein level. The findings also provide a promising combinational therapy of MPT0B098 for OSCC.

  4. Efficacy of Albendazole Orally Administered at Different Dosages against Trichinella spiralis Encapsulated Larvae in Mice%口服阿苯达唑抗小鼠旋毛虫成囊期幼虫的效果观察

    Institute of Scientific and Technical Information of China (English)

    李润花; 裴彦江; 李起超; 霍将; 丁宇; 殷国荣

    2012-01-01

    Objective To evaluate the efficacy of albendazole (ABZ) orally administered at different dosages against Trichinella spirails encapsulated larvae in striated muscle in mice. Methods A total of 72 BALB/c mice were divided equally into 9 groups. Each mouse was infected orally with 50 T. Spiralis encapsulated larvae. At the 29th day after infection, albendazole was each orally administered to the mice of the 8 groups with doses of 50, 100, 150, 200, 250, 300, 350, and 400mg/(kg·d), respectively, once a day at fixed time for 6d. The control group was untreated. Mice were sacrificed at the 7lh day post administration. The encapsulated larvae in diaphragmatic muscle, jugomaxillary muscle and gastrocnemius muscle were examined with pellet method. The encapsulated larva that the capsule was complete and the larva inside curled naturally with clear structure was considered survived. The therapeutic effect was estimated on the average quantity of total, survival and dead encapsulated larvae per gram muscle, total worm reduction and survival worm reduction. Results The total worm burden and survival worms showed a decreasing trend and the numbers of dead worms increased in diaphragmatic muscle, jugomaxillary muscle and gastrocnemius muscle when the dosage of albendazole were 50-250 mg/(kg·d), but the number of larvae in the muscles remained similar when the dosage of albendazole was greater than 250mg/kg·d. Compared with the control group, the total and survival worms in the muscles in 200mg/(kg·d) and the greater dose groups decreased significantly (P<0.01). In 250 mg/(kg·d) group the total worm reduction in jugomaxillary muscle, diaphragmatic muscle and gastrocnemius muscle were 50.00%, 62.62% and 57.48%, and the survival worm reduction were 79.96%, 83.25% and 80.56%, respectively. Conclusion Orally administered to mice for 6d, albendazole at 250mg/(kg·d) is a suitable dose against encapsulated larva stage of T. Spiralis in muscle.%目的 观察口服不同剂量阿

  5. Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans.

    Science.gov (United States)

    Nakajima, Katsumasa; Chatelain, Ricardo; Clairmont, Kevin B; Commerford, Renee; Coppola, Gary M; Daniels, Thomas; Forster, Cornelia J; Gilmore, Thomas A; Gong, Yongjin; Jain, Monish; Kanter, Aaron; Kwak, Youngshin; Li, Jingzhou; Meyers, Charles D; Neubert, Alan D; Szklennik, Paul; Tedesco, Vivienne; Thompson, James; Truong, David; Yang, Qing; Hubbard, Brian K; Serrano-Wu, Michael H

    2017-06-08

    Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.

  6. P3 optimization of functional potency, in vivo efficacy and oral bioavailability in 3-aminopyrazinone thrombin inhibitors bearing non-charged groups at the P1 position.

    Science.gov (United States)

    Isaacs, Richard C A; Newton, Christina L; Cutrona, Kellie J; Mercer, Swati P; Dorsey, Bruce D; McDonough, Colleen M; Cook, Jacquelynn J; Krueger, Julie A; Lewis, S Dale; Lucas, Bobby J; Lyle, Elizabeth A; Lynch, Joseph J; Miller-Stein, Cynthia; Michener, Maria T; Wallace, Audrey A; White, Rebecca B; Wong, Bradley K

    2011-03-01

    Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position. Copyright © 2010 Elsevier Ltd. All rights reserved.

  7. Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors.

    Science.gov (United States)

    Kümmerle, Arthur E; Schmitt, Martine; Cardozo, Suzana V S; Lugnier, Claire; Villa, Pascal; Lopes, Alexandra B; Romeiro, Nelilma C; Justiniano, Hélène; Martins, Marco A; Fraga, Carlos A M; Bourguignon, Jean-Jacques; Barreiro, Eliezer J

    2012-09-13

    Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-α properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.

  8. Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension.

    Science.gov (United States)

    Zhu, Gui-Dong; Gandhi, Viraj B; Gong, Jianchun; Thomas, Sheela; Woods, Keith W; Song, Xiaohong; Li, Tongmei; Diebold, R Bruce; Luo, Yan; Liu, Xuesong; Guan, Ran; Klinghofer, Vered; Johnson, Eric F; Bouska, Jennifer; Olson, Amanda; Marsh, Kennan C; Stoll, Vincent S; Mamo, Mulugeta; Polakowski, James; Campbell, Thomas J; Martin, Ruth L; Gintant, Gary A; Penning, Thomas D; Li, Qun; Rosenberg, Saul H; Giranda, Vincent L

    2007-06-28

    Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

  9. Intestinal micropatches for oral insulin delivery.

    Science.gov (United States)

    Banerjee, Amrita; Wong, Jessica; Gogoi, Rohan; Brown, Tyler; Mitragotri, Samir

    2017-03-19

    Diabetes mellitus has become a major public health issue that has almost reached epidemic proportions worldwide. Injectable insulin has been typically utilized for the management of this chronic disease. However, lack of patient compliance with injectable formulations has spurred the development of oral insulin formulations, which although appealing, face several delivery challenges. We have developed novel mucoadhesive intestinal patches, several hundred micrometers in dimension (micropatches) that address the challenges of oral insulin delivery. The micropatches adhere to the intestinal mucosa, release their drug load rapidly within 30 min and are effective in lowering blood glucose levels in vivo. When insulin-loaded micropatches were administered with a permeation enhancer and protease inhibitor, a peak efficacy of 34% drop in blood glucose levels was observed within 3 h. Efficacy further improved to 41% when micropatches were administered in multiple doses. Here, we describe the design of micropatches as an oral insulin formulation and report their in vivo efficacy.

  10. Safety and tolerability of an intravenously administered alpha1-proteinase inhibitor at an increased infusion rate: a novel, randomized, placebo-masked, infusion rate-controlled, crossover study in healthy adults

    Directory of Open Access Journals (Sweden)

    Ngo LY

    2014-06-01

    Full Text Available Leock Y Ngo,1 Adam Haeberle,1 Jacqueline Dyck-Jones,1 David Gelmont,1 Leman Yel11Baxter Healthcare Corporation, Westlake Village, CA, USAPurpose: Alpha1-proteinase inhibitor (A1PI is indicated for chronic augmentation therapy in adults with emphysema due to congenital deficiency of A1PI. An intravenous infusion rate of 0.04 mL/kg/minute is currently recommended for the A1PI product, Glassia®. This randomized, placebo-masked, rate-controlled, crossover study was designed to evaluate the safety and tolerability of A1PI administration at an increased infusion rate.Patients and methods: A total of 30 healthy male and female subjects aged 19–61 years were enrolled. Each subject received simultaneous intravenous infusions of A1PI (Glassia® and placebo (human albumin 2.5% administered through a single infusion site on two separate treatment periods. Subjects were randomized in a 1:1 ratio to receive either test treatment (A1PI 0.2 mL/kg/minute + placebo 0.04 mL/kg/minute, or reference treatment (A1PI 0.04 mL/kg/minute + placebo 0.2 mL/kg/minute on Day 1. On Day 15, subjects received the other treatment regimen in a crossover sequence.Results: A total of 36 adverse events (AEs, regardless of causality, were reported; all were non-serious and of mild intensity, with headaches and dizziness occurring most frequently (12 [33.3%] and three [8.3%] of 36 AEs, respectively. Only seven AEs in six subjects were assessed as related to study treatment: with two AEs reported in two subjects treated with the 0.2 mL/kg/minute rate compared with five AEs in four subjects treated with the 0.04 mL/kg/minute rate.Conclusions: This study demonstrated the safety and tolerability of an A1PI product at an increased infusion rate (0.2 mL/kg/minute resulting in a shorter infusion duration in healthy subjects.Keywords: A1PI, Glassia, administration rate, Alpha-1 antitrypsin, ATT

  11. Changes in blood levels of proteinase inhibitors, pregnancy zone protein, steroid carriers and complement factors induced by oral contraceptives

    DEFF Research Database (Denmark)

    Nielsen, C H; Poulsen, H K; Teisner, B

    1993-01-01

    Three low-dose oral contraceptives Trinordiol, Gynatrol, and Marvelon, containing ethinylestradiol (EE) in combination with triphasic levonorgestrel (LNg), monophasic levonorgestrel, and monophasic desogestrel (DGS), respectively, were given to 65 healthy women, n = 21-22 in each group. Blood...

  12. Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl).

    Science.gov (United States)

    Podar, Klaus; Raab, Marc S; Zhang, Jing; McMillin, Douglas; Breitkreutz, Iris; Tai, Yu-Tzu; Lin, Boris K; Munshi, Nikhil; Hideshima, Teru; Chauhan, Dharminder; Anderson, Kenneth C

    2007-02-15

    In multiple myeloma (MM) protein kinase C (PKC) signaling pathways have been implicated in cell proliferation, survival, and migration. Here we investigated the novel, orally available PKC-inhibitor enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits phorbol ester-induced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCmu. Importantly, it also inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs), costimulation with fibronectin, vascular endothelial growth factor (VEGF), or interleukin-6 (IL-6), as well as MM patient serum. Consequently, enzastaurin inhibits proliferation, survival, and migration of MM cell lines and MM cells isolated from multidrug-resistant patients and overcomes MM-cell growth triggered by binding to BMSCs and endothelial cells. Importantly, strong synergistic cytotoxicity is observed when enzastaurin is combined with bortezomib and moderate synergistic or additive effects when combined with melphalan or lenalidomide. Finally, tumor growth, survival, and angiogenesis are abrogated by enzastaurin in an in vivo xenograft model of human MM. Our results therefore demonstrate in vitro and in vivo efficacy of the orally available PKC inhibitor enzastaurin in MM and strongly support its clinical evaluation, alone or in combination therapies, to improve outcome in patients with MM.

  13. Membrane-Permeable Calpain Inhibitors Promote Rat Oral Mucosal Epithelial Cell Proliferation by Inhibiting IL-1α Signaling.

    Directory of Open Access Journals (Sweden)

    Makoto Kondo

    Full Text Available To standardise regenerative medicine using cultured cells, the use of serum-free, chemically defined media will be necessary. We have reported that IL-1α inhibits the growth of epithelial cells in culture and that recombinant IL-1 receptor antagonist (IL-1RA significantly promotes epithelial cell growth in no feeder layer condition. In this study, we examined inhibitors of calpain, a cysteine proteinase that plays crucial roles in various cellular functions, including IL-1α maturation and secretion. The culturing of epithelial cells in serum-free media supplemented with a membrane-permeable calpain inhibitor significantly promoted growth while suppressing IL-1α maturation and secretion. By contrast, non-membrane-permeable calpain inhibitor treatment did not have these effects. Interestingly, immunoblotting analysis revealed that immature, untruncated, IL-1α expression was also downregulated by cell-permeable calpain inhibitor treatment, and the difference in IL-1α gene expression increased from day 2 to day 6. Although IL-1RA has been reported to promote epithelial cell growth, we detected no synergistic promotion of epithelial cell growth using a calpain inhibitor and IL-1RA. These findings indicate that calpain inhibitors promote epithelial cell proliferation by inhibiting IL-1α maturation at an early phase of epithelial cell culture and by suppressing the positive feedback-mediated amplification of IL-1α signalling.

  14. Township Administered Roads

    Data.gov (United States)

    Minnesota Department of Natural Resources — This data set contains roadway centerlines for township administered roads found on the USGS 1:24,000 mapping series. In some areas, these roadways are current...

  15. Speed of kill efficacy and efficacy of flavored spinosad tablets administered orally to cats in a simulated home environment for the treatment and prevention of cat flea (Ctenocephalides felis) infestations.

    Science.gov (United States)

    Snyder, Daniel E; Meyer, Katherine A; Wiseman, Scott; Trout, Candace M; Young, David R

    2013-09-23

    treatments were observed in either study. These studies demonstrated that spinosad administered orally to cats is safe and effective, providing >90% efficacy from 2h post-dosing and 100% knockdown at 24h, and preventing infestations over a 95 day study period from a flea-contaminated simulated home environment. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. In Vitro and In Vivo Activities of E5700 and ER-119884, Two Novel Orally Active Squalene Synthase Inhibitors, against Trypanosoma cruzi

    Science.gov (United States)

    Urbina, Julio A.; Concepcion, Juan Luis; Caldera, Aura; Payares, Gilberto; Sanoja, Cristina; Otomo, Takeshi; Hiyoshi, Hironobu

    2004-01-01

    Chagas' disease is a serious public health problem in Latin America, and no treatment is available for the prevalent chronic stage. Its causative agent, Trypanosoma cruzi, requires specific endogenous sterols for survival, and we have recently demonstrated that squalene synthase (SQS) is a promising target for antiparasitic chemotherapy. E5700 and ER-119884 are quinuclidine-based inhibitors of mammalian SQS that are currently in development as cholesterol- and triglyceride-lowering agents in humans. These compounds were found to be potent noncompetitive or mixed-type inhibitors of T. cruzi SQS with Ki values in the low nanomolar to subnanomolar range in the absence or presence of 20 μM inorganic pyrophosphate. The antiproliferative 50% inhibitory concentrations of the compounds against extracellular epimastigotes and intracellular amastigotes were ca. 10 nM and 0.4 to 1.6 nM, respectively, with no effects on host cells. When treated with these compounds at the MIC, all of the parasite's sterols disappeared from the parasite cells. In vivo studies indicated that E5700 was able to provide full protection against death and completely arrested the development of parasitemia when given at a concentration of 50 mg/kg of body weight/day for 30 days, while ER-119884 provided only partial protection. This is the first report of an orally active SQS inhibitor that is capable of providing complete protection against fulminant, acute Chagas' disease. PMID:15215084

  17. Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease.

    Science.gov (United States)

    Abe, Yasuyuki; Aoyagi, Atsushi; Hara, Takao; Abe, Kazumi; Yamazaki, Reina; Kumagae, Yoshihiro; Naruto, Shunji; Koyama, Kazuo; Marumoto, Shinji; Tago, Keiko; Toda, Narihiro; Takami, Kazuko; Yamada, Naho; Ori, Mayuko; Kogen, Hiroshi; Kaneko, Tsugio

    2003-09-01

    A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.

  18. Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) restrict oral availability and brain accumulation of the PARP inhibitor rucaparib (AG-014699).

    Science.gov (United States)

    Durmus, Selvi; Sparidans, Rolf W; van Esch, Anita; Wagenaar, Els; Beijnen, Jos H; Schinkel, Alfred H

    2015-01-01

    Rucaparib is a potent, orally available, small-molecule inhibitor of poly ADP-ribose polymerase (PARP) 1 and 2. Ongoing clinical trials are assessing the efficacy of rucaparib alone or in combination with other cytotoxic drugs, mainly in breast and ovarian cancer patients with mutations in the breast cancer associated (BRCA) genes. We aimed to establish whether the multidrug efflux transporters ABCG2 (BCRP) and ABCB1 (P-gp, MDR1) affect the oral availability and brain penetration of rucaparib in mice. In vitro, rucaparib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse Abcg2. Transport could be inhibited by the small-molecule ABCB1 and ABCG2 inhibitors zosuquidar and Ko143, respectively. In vivo, oral availability (plasma AUC0-1 and AUC0-24) and brain levels of rucaparib at 1 and 24 h were increased by the absence of both Abcg2 and Abcb1a/1b after oral administration of rucaparib at 10 mg/kg. Our data show to our knowledge for the first time that oral availability and brain accumulation of a PARP inhibitor are markedly and additively restricted by Abcg2 and Abcb1a/1b. This may have clinical relevance for improvement of rucaparib therapy in PARP inhibitor-resistant tumors with ABCB1 and/or ABCG2 expression and in patients with brain (micro)metastases positioned behind a functional blood-brain barrier.

  19. Spirocyclic ureas: orally bioavailable 11 beta-HSD1 inhibitors identified by computer-aided drug design.

    Science.gov (United States)

    Tice, Colin M; Zhao, Wei; Xu, Zhenrong; Cacatian, Salvacion T; Simpson, Robert D; Ye, Yuan-Jie; Singh, Suresh B; McKeever, Brian M; Lindblom, Peter; Guo, Joan; Krosky, Paula M; Kruk, Barbara A; Berbaum, Jennifer; Harrison, Richard K; Johnson, Judith J; Bukhtiyarov, Yuri; Panemangalore, Reshma; Scott, Boyd B; Zhao, Yi; Bruno, Joseph G; Zhuang, Linghang; McGeehan, Gerard M; He, Wei; Claremon, David A

    2010-02-01

    Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.

  20. Changes in blood levels of proteinase inhibitors, pregnancy zone protein, steroid carriers and complement factors induced by oral contraceptives

    DEFF Research Database (Denmark)

    Nielsen, Claus Henrik; Poulsen, Henning Kvist; Teisner, Børge

    1993-01-01

    Three low-dose oral contraceptives Trinordiol, Gynatrol, and Marvelon, containing ethinylestradiol (EE) in combination with triphasic levonorgestrel (LNg), monophasic levonorgestrel, and monophasic desogestrel (DGS), respectively, were given to 65 healthy women, n = 21-22 in each group. Blood...... presumably enhances fibrinolysis, and that LNg has higher anti-estrogenicity and androgenicity than DSG. Udgivelsesdato: 1993-Sep...

  1. Changes in blood levels of proteinase inhibitors, pregnancy zone protein, steroid carriers and complement factors induced by oral contraceptives

    DEFF Research Database (Denmark)

    Nielsen, C H; Poulsen, H K; Teisner, B

    1993-01-01

    Three low-dose oral contraceptives Trinordiol, Gynatrol, and Marvelon, containing ethinylestradiol (EE) in combination with triphasic levonorgestrel (LNg), monophasic levonorgestrel, and monophasic desogestrel (DGS), respectively, were given to 65 healthy women, n = 21-22 in each group. Blood...... presumably enhances fibrinolysis, and that LNg has higher anti-estrogenicity and androgenicity than DSG....

  2. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet ß cells in vivo and in vitro

    DEFF Research Database (Denmark)

    Lewis, Eli C; Blaabjerg, Lykke; Størling, Joachim;

    2011-01-01

    In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1ß (IL-1ß), IL-12, tumor necrosis factor-a (TNFa) and interferon-¿ (IFN¿); each contribute to ß-cell destruction, mediated in part by nitric oxide. Inhibitors...

  3. Oral administration of the NADPH-oxidase inhibitor apocynin partially restores diminished cartilage proteoglycan synthesis and reduces inflammation in mice.

    NARCIS (Netherlands)

    Hougee, S.; Hartog, A.; Sanders, A.; Graus, Y.M.; Hoijer, M.A.; Garssen, J.; Berg, W.B. van den; Beuningen, H.M. van; Smit, H.F.

    2006-01-01

    Apocynin, an inhibitor of NADPH-oxidase, is known to partially reverse the inflammation-mediated cartilage proteoglycan synthesis in chondrocytes. More recently, it was reported that apocynin prevents cyclooxygenase (COX)-2 expression in monocytes. The present study aimed to investigate whether thes

  4. Changes in glucose-induced plasma active glucagon-like peptide-1 levels by co-administration of sodium–glucose cotransporter inhibitors with dipeptidyl peptidase-4 inhibitors in rodents

    Directory of Open Access Journals (Sweden)

    Takahiro Oguma

    2016-12-01

    Full Text Available We investigated whether structurally different sodium–glucose cotransporter (SGLT 2 inhibitors, when co-administered with dipeptidyl peptidase-4 (DPP4 inhibitors, could enhance glucagon-like peptide-1 (GLP-1 secretion during oral glucose tolerance tests (OGTTs in rodents. Three different SGLT inhibitors—1-(β-d-Glucopyranosyl-4-chloro-3-[5-(6-fluoro-2-pyridyl-2-thienylmethyl]benzene (GTB, TA-1887, and canagliflozin—were examined to assess the effect of chemical structure. Oral treatment with GTB plus a DPP4 inhibitor enhanced glucose-induced plasma active GLP-1 (aGLP-1 elevation and suppressed glucose excursions in both normal and diabetic rodents. In DPP4-deficient rats, GTB enhanced glucose-induced aGLP-1 elevation without affecting the basal level, whereas metformin, previously reported to enhance GLP-1 secretion, increased both the basal level and glucose-induced elevation. Oral treatment with canagliflozin and TA-1887 also enhanced glucose-induced aGLP-1 elevation when co-administered with either teneligliptin or sitagliptin. These data suggest that structurally different SGLT2 inhibitors enhance plasma aGLP-1 elevation and suppress glucose excursions during OGTT when co-administered with DPP4 inhibitors, regardless of the difference in chemical structure. Combination treatment with DPP4 inhibitors and SGLT2 inhibitors having moderate SGLT1 inhibitory activity may be a promising therapeutic option for improving glycemic control in patients with type 2 diabetes mellitus.

  5. SKLB-287, a novel oral multikinase inhibitor of EGFR and VEGFR2, exhibits potent antitumor activity in LoVo colorectal tumor model.

    Science.gov (United States)

    Chen, X; Liu, Y; Yang, H-W; Zhou, S; Cheng, C; Zheng, M-W; Zhong, L; Fu, X-Y; Pan, Y-L; Ma, S; Tang, Y; Chen, Y-Z; Li, L-L; Yang, S-Y

    2014-01-01

    Colorectal cancer (CRC) is the third common cancer and most of the chemotherapies of CRC currently used often suffer limited efficacy and large side effects. Targeted small-molecule by anti-tumor drugs are thought a promising strategy for improving the efficacy and reducing the side effects. In this investigation, we report a novel multikinase inhibitor, termed SKLB-287, which was discovered by us recently. SKLB-287 could efficiently inhibit the activation of endothelial growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2). It displayed very good anti-proliferative activity against LoVo CRC cells and considerable antiangiogenic potency in transgenic zebrafish embryos. Oral administration of SKLB-287 resulted in dose-dependent suppression of tumor growth in LoVo xenograft mouse model. Immunohistochemistry was adopted to examine the in vivo anti-tumor mechanism of action of SKLB-287.

  6. A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies.

    Science.gov (United States)

    Graux, Carlos; Sonet, Anne; Maertens, Johan; Duyster, Justus; Greiner, Jochen; Chalandon, Yves; Martinelli, Giovanni; Hess, Dagmar; Heim, Dominik; Giles, Francis J; Kelly, Kevin R; Gianella-Borradori, Athos; Longerey, Blandine; Asatiani, Ekaterine; Rejeb, Narmyn; Ottmann, Oliver G

    2013-09-01

    A phase I dose-escalation study of MSC1992371A, an oral aurora kinase inhibitor, was carried out in patients with hematologic malignancies. Patients received escalating doses either on days 1-3 and 8-10 (n=36) or on days 1-6 (n=39) of a 21-day cycle. The maximum tolerated doses were 37 and 28 mg/m(2)/day, respectively. Dose-limiting toxicities included severe neutropenia with infection and sepsis, mucositis/stomatitis, and diarrhea. Complete responses occurred in 3 patients. Four disease-specific expansion cohorts then received the dose and schedule dictated by the escalation phase but the study was prematurely discontinued due to hematologic and gastrointestinal toxicity at clinically effective doses. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Discovery of Aryl Aminoquinazoline Pyridones as Potent, Selective, and Orally Efficacious Inhibitors of Receptor Tyrosine Kinase c-Kit

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Essa; Tasker, Andrew; White, Ryan D.; Kunz, Roxanne K.; Human, Jason; Chen, Ning; Bürli, Roland; Hungate, Randall; Novak, Perry; Itano, Andrea; Zhang, Xuxia; Yu, Violeta; Nguyen, Yen; Tudor, Yanyan; Plant, Matthew; Flynn, Shaun; Xu, Yang; Meagher, Kristin L.; Whittington, Douglas A.; Ng, Gordon Y. (Amgen)

    2008-12-09

    Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.

  8. Inhibition of osteosarcoma-induced thermal hyperalgesia in mice by the orally active dual enkephalinase inhibitor PL37. Potentiation by gabapentin.

    Science.gov (United States)

    Menéndez, Luis; Hidalgo, Agustín; Meana, Alvaro; Poras, Hervé; Fournié-Zaluski, Marie-Claude; Roques, Bernard P; Baamonde, Ana

    2008-10-31

    We have previously shown that stimulation of peripheral opioid receptors by exogenous opiates counteracts the thermal hyperalgesia elicited by a tibial osteosarcoma due to intraosteal inoculation of NCTC 2472 cells to mice. Aiming to study whether pheripheral endogenous enkephalins could also counteract this painful symptom, we assayed in this model the effects of PL37, an orally active dual inhibitor of enkephalin inactivating enzymes. Oral administration of PL37 (25 mg/kg) completely supressed osteosarcoma-induced thermal hyperalgesia through the activation of micro-opioid receptors, since the administration of cyprodime (1 mg/kg) inhibited its antihyperalgesic effect. Neither naltrindole (0.1 mg/kg) nor nor-binaltorphimine (10 mg/kg) modified this PL37-induced antihyperalgesic effect. Moreover, the inhibition of the antihyperalgesic effect induced by PL37 after the administration of naloxone-methiodide (2 mg/kg), a non selective opioid antagonist that does not cross the blood-brain barrier, demonstrates the involvement of peripheral opioid receptors. In contrast, centrally mediated effects may be detected when assaying a higher dose of PL37 (50 mg/kg). Besides, the administration of gabapentin (6.25-25 mg/kg, i.p.) dose-dependently inhibited osteosarcoma-induced thermal hyperalgesia. Interestingly, the combined administration of subeffective doses of PL37 and gabapentin completely prevented this type of thermal hyperalgesia. An isobolographic analysis of this interaction demonstrated a synergistic interaction between both drugs.

  9. Oral Cyclosporin A Inhibits CD4 T cell P-glycoprotein Activity in HIV-Infected Adults Initiating Treatment with Nucleoside Reverse Transcriptase Inhibitors

    Science.gov (United States)

    Hulgan, Todd; Donahue, John P.; Smeaton, Laura; Pu, Minya; Wang, Hongying; Lederman, Michael M.; Smith, Kimberly; Valdez, Hernan; Pilcher, Christopher; Haas, David W.

    2010-01-01

    Purpose P-glycoprotein limits tissue penetration of many antiretroviral drugs. We characterized effects of the P-glycoprotein substrate cyclosporin A on T cell P-glycoprotein activity in HIV-infected AIDS Clinical Trials Group study A5138 participants. Methods We studied P-glycoprotein activity on CD4 and CD8 T cells in 16 participants randomized to receive oral cyclosporin A (n=9) or not (n=7) during initiation antiretroviral therapy (ART) that did not include protease or non-nucleoside reverse transcriptase inhibitors. Results CD4 T cell P-glycoprotein activity decreased by a median of 8 percentage points with cyclosporin A/ART (difference between cyclosporin A/ART versus ART only P=0.001). Plasma trough cyclosporin A concentrations correlated with change in P-glycoprotein activity in several T cell subsets. Conclusions Oral cyclosporin A can inhibit peripheral blood CD4 T cell P-glycoprotein activity. Targeted P-glycoprotein inhibition might enhance delivery of ART to T cells. PMID:19779705

  10. 口服质子泵抑制剂合理使用辨析%Analysis on Reasonable Application of Oral Proton Pump Inhibitors

    Institute of Scientific and Technical Information of China (English)

    马宗强; 安洪亮

    2014-01-01

    口服质子泵抑制剂(proton pump inhibitors, PPIs)在治疗消化道疾病中的地位日益重要,然而使用过程中存在多种问题,尤其是在长程使用和联合用药过程中,据相关研究表明可能有增加骨折、心血管疾病及感染的风险。本文旨在提示临床应用PPIs应注意适应证及不同PPIs的特点,关注合并用药的相互作用及长期用药的不良反应,加强合理用药。%The status of oral proton pump inhibitors (PPIs) in the treatment of gastrointestinal diseases has become increasingly important, however, there are several problems during the use, especially in the long-term use and combination process, related studies indicated that the use of these drugs may increase fractures, cardiovascular diseases and risk of infection. Great caution should be attached to the indications and characteristics of different PPIs, as well as their interactions with other drugs if used in combination and the adverse effects in their long term use, to achieve rational use.

  11. NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies.

    Science.gov (United States)

    Valsasina, Barbara; Beria, Italo; Alli, Cristina; Alzani, Rachele; Avanzi, Nilla; Ballinari, Dario; Cappella, Paolo; Caruso, Michele; Casolaro, Alessia; Ciavolella, Antonella; Cucchi, Ulisse; De Ponti, Anna; Felder, Eduard; Fiorentini, Francesco; Galvani, Arturo; Gianellini, Laura M; Giorgini, Maria L; Isacchi, Antonella; Lansen, Jaqueline; Pesenti, Enrico; Rizzi, Simona; Rocchetti, Maurizio; Sola, Francesco; Moll, Jürgen

    2012-04-01

    Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Although five different PLKs are described in humans, depletion or inhibition of kinase activity of PLK1 is sufficient to induce cell-cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models. NMS-P937 is a novel, orally available PLK1-specific inhibitor. The compound shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid and hematologic tumors. NMS-P937 potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with clear PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. In addition, NMS-P937 shows potential for combination in clinical settings with approved cytotoxic drugs, causing tumor regression in HT29 human colon adenocarcinoma xenografts upon combination with irinotecan and prolonged survival of animals in a disseminated model of acute myelogenous leukemia in combination with cytarabine. NMS-P937, with its favorable pharmacologic parameters, good oral bioavailability in rodent and nonrodent species, and proven antitumor activity in different preclinical models using a variety of dosing regimens, potentially provides a high degree of flexibility in dosing schedules and warrants investigation in clinical settings.

  12. Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) Restrict Oral Availability and Brain Accumulation of the PARP Inhibitor Rucaparib (AG-014699)

    NARCIS (Netherlands)

    Durmus, Selvi; Sparidans, Rolf W|info:eu-repo/dai/nl/075047144; van Esch, Anita; Wagenaar, Els; Beijnen, Jos H|info:eu-repo/dai/nl/071919570; Schinkel, Alfred H

    2015-01-01

    BACKGROUND: Rucaparib is a potent, orally available, small-molecule inhibitor of poly ADP-ribose polymerase (PARP) 1 and 2. Ongoing clinical trials are assessing the efficacy of rucaparib alone or in combination with other cytotoxic drugs, mainly in breast and ovarian cancer patients with mutations

  13. Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo.

    Directory of Open Access Journals (Sweden)

    Maria Beconi

    Full Text Available Histone deacetylase (HDAC inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.

  14. Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief

    Science.gov (United States)

    Moriconi, Alessio; Cunha, Thiago M.; Souza, Guilherme R.; Lopes, Alexandre H.; Cunha, Fernando Q.; Carneiro, Victor L.; Pinto, Larissa G.; Brandolini, Laura; Aramini, Andrea; Bizzarri, Cinzia; Bianchini, Gianluca; Beccari, Andrea R.; Fanton, Marco; Bruno, Agostino; Costantino, Gabriele; Bertini, Riccardo; Galliera, Emanuela; Locati, Massimo; Ferreira, Sérgio H.; Teixeira, Mauro M.; Allegretti, Marcello

    2014-01-01

    Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent pronociceptive mediator in several models of inflammatory and neuropathic pain. Although there has long been interest in the identification of C5aR inhibitors, their development has been complicated, as for many peptidomimetic drugs, mostly by poor drug-like properties. Herein, we report the de novo design of a potent and selective C5aR noncompetitive allosteric inhibitor, DF2593A, guided by the hypothesis that an allosteric site, the “minor pocket,” previously characterized in CXC chemokine receptors-1 and -2, is functionally conserved in the GPCR class. In vitro, DF2593A potently inhibited C5a-induced migration of human and rodent neutrophils. In vivo, oral administration of DF2593A effectively reduced mechanical hyperalgesia in several models of acute and chronic inflammatory and neuropathic pain, without any apparent side effects. Mechanical hyperalgesia after spared nerve injury was also reduced in C5aR−/− mice compared with WT mice. Furthermore, treatment of C5aR−/− mice with DF2593A did not produce any further antinociceptive effect compared with C5aR−/− mice treated with vehicle. The successful medicinal chemistry strategy confirms that a conserved minor pocket is amenable for the rational design of selective inhibitors and the pharmacological results support that the allosteric blockade of the C5aR represents a highly promising therapeutic approach to control chronic inflammatory and neuropathic pain. PMID:25385614

  15. Reversal of High dietary fructose-induced PPARα suppression by oral administration of lipoxygenase/cyclooxygenase inhibitors

    Directory of Open Access Journals (Sweden)

    Azhar Salman

    2005-08-01

    Full Text Available Abstract High fructose feeding causes diet-induced alterations of lipid metabolism and decreased insulin sensitivity, hallmark of which is a rapid and profound hypertriglyceridemia. One of the mechanisms that contribute to serum hypertriglyceridemia in this model is suppression of hepatic PPARα. HMG-CoA inhibitors, which reduce serum triglycerides in these animals, also elevate/restore hepatic PPARα. Previously we demonstrated that two known lipoxygenase/cyclooxygenase inhibitors reversed diet-induced hypertriglyceridemia in this model and that reversal of certain inflammatory markers in the liver correlated with the metabolic benefit. In this paper we extended these studies by examining the impact of these compounds on expression of PPARα, both at the level of transcription and expression. Our data show that diet-induced suppression of hepaic PPARα is reversed upon treatment with lipoxygenase/cyclooxygenase compounds. We then tested one of these compounds, BW-755c, over a range of doses from 10 mg/kg to 100 mg/kg to establish a dose-response relationship with the reduction of serum hypertriglyceridemia in this model. These experiments support the concept of using anti-inflammatory medications as one method to correct metabolic dysfunction.

  16. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.

    Science.gov (United States)

    Huang, Wei-Sheng; Liu, Shuangying; Zou, Dong; Thomas, Mathew; Wang, Yihan; Zhou, Tianjun; Romero, Jan; Kohlmann, Anna; Li, Feng; Qi, Jiwei; Cai, Lisi; Dwight, Timothy A; Xu, Yongjin; Xu, Rongsong; Dodd, Rory; Toms, Angela; Parillon, Lois; Lu, Xiaohui; Anjum, Rana; Zhang, Sen; Wang, Frank; Keats, Jeffrey; Wardwell, Scott D; Ning, Yaoyu; Xu, Qihong; Moran, Lauren E; Mohemmad, Qurish K; Jang, Hyun Gyung; Clackson, Tim; Narasimhan, Narayana I; Rivera, Victor M; Zhu, Xiaotian; Dalgarno, David; Shakespeare, William C

    2016-05-26

    In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

  17. Oral leukoplakia

    DEFF Research Database (Denmark)

    Holmstrup, Palle; Dabelsteen, Erik

    2016-01-01

    The idea of identifying oral lesions with a precancerous nature, i.e. in the sense of pertaining to a pathologic process with an increased risk for future malignant development, of course is to prevent frank malignancy to occur in the affected area. The most common oral lesion with a precancerous...... nature is oral leukoplakia, and for decades it has been discussed how to treat these lesions. Various treatment modalities, such as systemic therapies and surgical removal, have been suggested. The systemic therapies tested so far include retinoids, extracts of green tea, inhibitors of cyclooxygenase-2...

  18. Pharmacokinetics of guaifenesin, pseudoephedrine and hydrocodone in a combination oral liquid formulation, administered as single and multiple doses in healthy Chinese volunteers, and comparison with data for individual compounds formulated as Antuss®.

    Science.gov (United States)

    Deng, Shuhua; Huang, Wencan; Ni, Xiaojia; Zhang, Ming; Lu, Haoyang; Wang, Zhanzhang; Hu, Jinqing; Zhu, Xiuqing; Qiu, Chang; Shang, Dewei; Zhang, Yuefeng; Xiong, Linghui; Wen, Yuguan

    2017-10-01

    1. A new oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone is effective in improving the symptoms of common cold. The pharmacokinetic properties of the individual components were evaluated in a randomized, open-label, four-period study in 12 healthy Chinese volunteers following single and multiple doses. The data were compared with data for the individual ingredients in Antuss®. 2. In the single-dose period, exposure levels (AUC and Cmax) for guaifenesin, pseudoephedrine and hydrocodone increased directly as the dose of the oral liquid formulation increased from 5 to 15 mL. Only minor amounts of guaifenesin and hydrocodone were excreted in urine (∼0.10% and 4.66%, respectively). Pseudoephedrine was mainly excreted unchanged, with 44.95% of the dose excreted in urine within 24 h. After multiple dosing, there was no obvious accumulation of any drug, as assessed by AUC. When considering Cmax, there was a trend toward accumulation of hydrocodone and pseudoephedrine. The pharmacokinetic profiles of guaifenesin and pseudoephedrine in the oral liquid formulation were similar to those in the branded preparation, Antuss®. 3. The newly developed oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone was safe and well tolerated and might provide a reliable alternative to the branded formulation for patients with common colds.

  19. Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE KPT-335 in spontaneous canine cancer: results of a phase I study.

    Directory of Open Access Journals (Sweden)

    Cheryl A London

    Full Text Available BACKGROUND: The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1 against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability. METHODS AND FINDINGS: Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL, mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed, mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday although biologic activity was observed at 1 mg/kg. Clinical benefit (CB including partial response to therapy (PR, n = 2 and stable disease (SD, n = 7 was observed in 9/14 dogs with NHL with a median time to progression (TTP for responders of 66 days (range 35-256 days. A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days. Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities. CONCLUSIONS: This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.

  20. Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580.

    Science.gov (United States)

    Conway, James G; McDonald, Brad; Parham, Janet; Keith, Barry; Rusnak, David W; Shaw, Eva; Jansen, Marilyn; Lin, Peiyuan; Payne, Alan; Crosby, Renae M; Johnson, Jennifer H; Frick, Lloyd; Lin, Min-Hwa Jasmine; Depee, Scott; Tadepalli, Sarva; Votta, Bart; James, Ian; Fuller, Karen; Chambers, Timothy J; Kull, Frederick C; Chamberlain, Stanley D; Hutchins, Jeff T

    2005-11-01

    Colony-stimulating-factor-1 (CSF-1) signaling through cFMS receptor kinase is increased in several diseases. To help investigate the role of cFMS kinase in disease, we identified GW2580, an orally bioavailable inhibitor of cFMS kinase. GW2580 completely inhibited human cFMS kinase in vitro at 0.06 microM and was inactive against 26 other kinases. GW2580 at 1 microM completely inhibited CSF-1-induced growth of mouse M-NFS-60 myeloid cells and human monocytes and completely inhibited bone degradation in cultures of human osteoclasts, rat calvaria, and rat fetal long bone. In contrast, GW2580 did not affect the growth of mouse NS0 lymphoblastoid cells, human endothelial cells, human fibroblasts, or five human tumor cell lines. GW2580 also did not affect lipopolysaccharide (LPS)-induced TNF, IL-6, and prostaglandin E2 production in freshly isolated human monocytes and mouse macrophages. After oral administration, GW2580 blocked the ability of exogenous CSF-1 to increase LPS-induced IL-6 production in mice, inhibited the growth of CSF-1-dependent M-NFS-60 tumor cells in the peritoneal cavity, and diminished the accumulation of macrophages in the peritoneal cavity after thioglycolate injection. Unexpectedly, GW2580 inhibited LPS-induced TNF production in mice, in contrast to effects on monocytes and macrophages in vitro. In conclusion, GW2580's selective inhibition of monocyte growth and bone degradation is consistent with cFMS kinase inhibition. The ability of GW2580 to chronically inhibit CSF-1 signaling through cFMS kinase in normal and tumor cells in vivo makes GW2580 a useful tool in assessing the role of cFMS kinase in normal and disease processes.

  1. ASB14780, an Orally Active Inhibitor of Group IVA Phospholipase A2, Is a Pharmacotherapeutic Candidate for Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Kanai, Shiho; Ishihara, Keiichi; Kawashita, Eri; Tomoo, Toshiyuki; Nagahira, Kazuhiro; Hayashi, Yasuhiro; Akiba, Satoshi

    2016-03-01

    We have previously shown that high-fat cholesterol diet (HFCD)-induced fatty liver and carbon tetrachloride (CCl4)-induced hepatic fibrosis are reduced in mice deficient in group IVA phospholipase A2 (IVA-PLA2), which plays a role in inflammation. We herein demonstrate the beneficial effects of ASB14780 (3-[1-(4-phenoxyphenyl)-3-(2-phenylethyl)-1H-indol-5-yl]propanoic acid 2-amino-2-(hydroxymethyl)propane-1,3-diol salt), an orally active IVA-PLA2 inhibitor, on the development of fatty liver and hepatic fibrosis in mice. The daily coadministration of ASB14780 markedly ameliorated liver injury and hepatic fibrosis following 6 weeks of treatment with CCl4. ASB14780 markedly attenuated the CCl4-induced expression of smooth muscle α-actin (α-SMA) protein and the mRNA expression of collagen 1a2, α-SMA, and transforming growth factor-β1 in the liver, and inhibited the expression of monocyte/macrophage markers, CD11b and monocyte chemotactic protein-1, while preventing the recruitment of monocytes/macrophages to the liver. Importantly, ASB14780 also reduced the development of fibrosis even in matured hepatic fibrosis. Additionally, ASB14780 also reduced HFCD-induced lipid deposition not only in the liver, but also in already established fatty liver. Furthermore, treatment with ASB14780 suppressed the HFCD-induced expression of lipogenic mRNAs. The present findings suggest that an IVA-PLA2 inhibitor, such as ASB14780, could be useful for the treatment of nonalcoholic fatty liver diseases, including fatty liver and hepatic fibrosis. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  2. Computer-Aided Design of Orally Bioavailable Pyrrolidine Carboxamide Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Pharmacokinetic Profiles

    Science.gov (United States)

    Kouassi, Affiba Florance; Kone, Mawa; Keita, Melalie; Esmel, Akori; Megnassan, Eugene; N’Guessan, Yao Thomas; Frecer, Vladimir; Miertus, Stanislav

    2015-01-01

    We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs) inhibitors of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (MTb). Three-dimensional (3D) models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB) entry code: 4U0J), the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC50exp). First, we built a gas phase quantitative structure-activity relationships (QSAR) model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC50exp. Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔGcom) of InhA-PCAM complex formation and IC50exp (pIC50exp = −0.1552·ΔΔGcom + 5.0448, R2 = 0.94), which was further validated with a 3D-QSAR pharmacophore model generation (PH4). Structural information from the models guided us in designing of a virtual combinatorial library (VL) of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME) focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC50pre reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles. PMID:26703572

  3. Computer-Aided Design of Orally Bioavailable Pyrrolidine Carboxamide Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Pharmacokinetic Profiles

    Directory of Open Access Journals (Sweden)

    Affiba Florance Kouassi

    2015-12-01

    Full Text Available We have carried out a computational structure-based design of new potent pyrrolidine carboxamide (PCAMs inhibitors of enoyl-acyl carrier protein reductase (InhA of Mycobacterium tuberculosis (MTb. Three-dimensional (3D models of InhA-PCAMx complexes were prepared by in situ modification of the crystal structure of InhA-PCAM1 (Protein Data Bank (PDB entry code: 4U0J, the reference compound of a training set of 20 PCAMs with known experimental inhibitory potencies (IC50exp. First, we built a gas phase quantitative structure-activity relationships (QSAR model, linearly correlating the computed enthalpy of the InhA-PCAM complex formation and the IC50exp. Further, taking into account the solvent effect and loss of inhibitor entropy upon enzyme binding led to a QSAR model with a superior linear correlation between computed Gibbs free energies (ΔΔGcom of InhA-PCAM complex formation and IC50exp (pIC50exp = −0.1552·ΔΔGcom + 5.0448, R2 = 0.94, which was further validated with a 3D-QSAR pharmacophore model generation (PH4. Structural information from the models guided us in designing of a virtual combinatorial library (VL of more than 17 million PCAMs. The VL was adsorption, distribution, metabolism and excretion (ADME focused and reduced down to 1.6 million drug like orally bioavailable analogues and PH4 in silico screened to identify new potent PCAMs with predicted IC50pre reaching up to 5 nM. Combining molecular modeling and PH4 in silico screening of the VL resulted in the proposed novel potent antituberculotic agent candidates with favorable pharmacokinetic profiles.

  4. AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM-deficiency in gastric cancer cells.

    Science.gov (United States)

    Min, Ahrum; Im, Seock-Ah; Jang, Hyemin; Kim, Seongyeong; Lee, Miso; Kim, Debora Keunyoung; Yang, Yaewon; Kim, Hee-Jun; Lee, Kyung-Hun; Kim, Jin Won; Kim, Tae-Yong; Oh, Do-Youn; Brown, Jeff; Lau, Alan; O Connor, Mark J; Bang, Yung-Jue

    2017-01-30

    Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect (HRD). The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer. In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in an in vivo tumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis. These findings suggest synthetic lethality between ATR inhibition and ATM-deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM-deficiency are warranted to develop novel treatment strategies for gastric cancer.

  5. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.

    Science.gov (United States)

    Audeh, M William; Carmichael, James; Penson, Richard T; Friedlander, Michael; Powell, Bethan; Bell-McGuinn, Katherine M; Scott, Clare; Weitzel, Jeffrey N; Oaknin, Ana; Loman, Niklas; Lu, Karen; Schmutzler, Rita K; Matulonis, Ursula; Wickens, Mark; Tutt, Andrew

    2010-07-24

    Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations. In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged >or=18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442. Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%]; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4). Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer. AstraZeneca. Copyright 2010 Elsevier Ltd. All rights reserved.

  6. Pharmacokinetics, pharmacodynamics and safety of single, oral doses of GSK1278863, a novel HIF-prolyl hydroxylase inhibitor, in healthy Japanese and Caucasian subjects.

    Science.gov (United States)

    Hara, Katsutoshi; Takahashi, Naoki; Wakamatsu, Akira; Caltabiano, Stephen

    2015-12-01

    This study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of GSK1278863, a novel prolyl hydroxylase inhibitor, following a single oral administration of GSK1278863 from 10 to 100 mg or placebo in Japanese (n = 19), and 10, 25 and 100 mg in Caucasians (n = 14). Dose-proportional increases were observed in AUCinf of GSK1278863 in both ethnic groups, with a 1.3-1.5-fold higher exposure seen in Japanese relative to Caucasians for all doses. This difference in exposure can be mainly explained by the observed differences in body weights between the two groups. Statistically significant increases in erythropoietin (EPO), vascular endothelial growth factor (VEGF) and reticulocyte counts were observed in Japanese subjects after the 50 and 100 mg dose as compared to placebo. In Caucasians, similar to Japanese, EPO and VEGF levels were observed to be increased in response to the 100 mg dose. Drug-related adverse events, including headache and abdominal pain were reported in 3 Japanese subjects, while headache was reported in 3 Caucasians. In conclusion, GSK1278863 was well tolerated, with dose-proportional increases in exposure observed in both groups. There was no evidence of ethnic differences between Japanese and Caucasian with regard to PK or PD.

  7. Subacute toxicity evaluation of KR-33493, FAF1 inhibitor for a new anti-parkinson's disease agent, after oral administration in rats and dogs.

    Science.gov (United States)

    Jeong, Jong-Woo; Yu, Changsun; Lee, Jong-Hwa; Moon, Kyoung-Sik; Kim, Eunhee; Yoo, Sung-Eun; Koo, Tae-Sung

    2016-11-01

    KR33493, a newly developed FAS-associated factor 1 (FAF1) inhibitor for Parkinson's disease, is being evaluated in a Phase I clinical trial. In the present study, the subchronic toxicity of KR33493 in Sprague-Dawley (SD) rats and beagle dogs was investigated at various oral doses for 28 and 14 days, respectively. During the study, food consumption, body weights, organ weights, gross findings, and mortality were examined; and ophthalmoscopy, electrocardiography, hematology, serum biochemistry, urinalysis, histopathology, and toxicokinetics were performed. In rats, weight gain decreased in both sexes at 500 mg/kg/day, with no significant differences. In dogs, some significant differences compared with the control were found during the trial; however, at the end of recovery periods, these were no longer observed and there was no dose correlation. Some histopathological findings were observed, but these were considered as incidental changes. Since no other significant changes were observed, doses above 500 and 1000 mg/kg KR33493 in rat and dogs, respectively, caused no observed adverse effects. Therefore, based on these results, the Phase 1 clinical trial for KR33493 was approved by the Korean Food & Drug Administration.

  8. The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects

    Science.gov (United States)

    Hurchla, MA; Garcia-Gomez, A; Hornick, MC; Ocio, EM; Li, A; Blanco, JF; Collins, L; Kirk, CJ; Piwnica-Worms, D; Vij, R; Tomasson, MH; Pandiella, A; Miguel, JF San; Garayoa, M; Weilbaecher, KN

    2013-01-01

    Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical trials, carfilzomib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the number and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM. PMID:22763387

  9. A phase II trial of R115777, an oral farnesyl transferase inhibitor, in      patients with advanced urothelial tract transitional cell carcinoma

    DEFF Research Database (Denmark)

    Rosenberg, Jonathan E.; Maase, Hans von der; Seigne, John D.;

    2005-01-01

    BACKGROUND: R115777 is a potent farnesyl transferase inhibitor and has       significant antitumor effects in vitro and in vivo. METHODS: The objective       of the current study was to determine the objective response proportion in       patients with metastatic transitional cell carcinoma (TCC......) of the       urothelial tract who received treatment with R115777 at a dose of 300 mg       orally given twice daily for 21 days followed by 7 days of rest for every       4-week cycle. Thirty-four patients with TCC were enrolled in this Phase II       study. Patients were allowed to have received a maximum of one prior......       observed. CONCLUSIONS: The objective response rate of R115777 was not       sufficient to warrant future investigation in TCC as a single agent.       Preliminary evidence of the activity of R115777 in 2 chemotherapy-naive       patients may warrant further investigation in combination with first...

  10. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism.

    Science.gov (United States)

    Zanin-Zhorov, Alexandra; Weiss, Jonathan M; Nyuydzefe, Melanie S; Chen, Wei; Scher, Jose U; Mo, Rigen; Depoil, David; Rao, Nishta; Liu, Ben; Wei, Jianlu; Lucas, Sarah; Koslow, Matthew; Roche, Maria; Schueller, Olivier; Weiss, Sara; Poyurovsky, Masha V; Tonra, James; Hippen, Keli L; Dustin, Michael L; Blazar, Bruce R; Liu, Chuan-ju; Waksal, Samuel D

    2014-11-25

    Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and the development of autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects down-regulates the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively, but not IFN-γ in response to T-cell receptor stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, significantly diminished STAT3 phosphorylation and binding to IL-17 and IL-21 promoters and reduced IFN regulatory factor 4 and nuclear hormone RAR-related orphan receptor γt protein levels in T cells derived from healthy subjects or rheumatoid arthritis patients. Simultaneously, treatment with KD025 also promotes the suppressive function of regulatory T cells through up-regulation of STAT5 phosphorylation and positive regulation of forkhead box p3 expression. The administration of KD025 in vivo down-regulates the progression of collagen-induced arthritis in mice via targeting of the Th17-mediated pathway. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between proinflammatory and regulatory T-cell subsets. Targeting of ROCK2 in man may therefore restore disrupted immune homeostasis and have a role in the treatment of autoimmunity.

  11. Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban – an oral, direct Factor Xa inhibitor

    Directory of Open Access Journals (Sweden)

    Rolf eBurghaus

    2014-11-01

    Full Text Available The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2–3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban.

  12. Combination of the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus as a new option for epi-virotherapeutic treatment of hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Benjamin Ruf

    2015-01-01

    Full Text Available Epigenetic therapies such as histone deacetylase inhibitors (HDACi not only have the capability to decrease tumor cell proliferation and to induce tumor cell death but also to silence antiviral response genes. Here, we investigated whether the combination of an oncolytic measles vaccine virus (MeV with the novel oral HDACi resminostat (Res, being in clinical testing in patients with hepatocellular carcinoma (HCC, results in an enhanced efficacy of this epi-virotherapeutic approach compared to any of the two corresponding monotherapies. When testing a panel of human hepatoma cell lines, we found (i a significantly improved rate of primary infections when using oncolytic MeV under concurrent treatment with resminostat, (ii a boosted cytotoxic effect of the epi-virotherapeutic combination (Res + MeV with enhanced induction of apoptosis, and, quite importantly, (iii an absence of any resminostat-induced impairment of MeV replication and spread. Beyond that, we could also show that (iv resminostat, after hepatoma cell stimulation with exogenous human interferon (IFN-β, is able to prevent the induction of IFN-stimulated genes, such as IFIT-1. This finding outlines the possible impact of resminostat on cellular innate immunity, being instrumental in overcoming resistances to MeV-mediated viral oncolysis. Thus, our results support the onset of epi-virotherapeutic clinical trials in patients exhibiting advanced stages of HCC.

  13. Exposure-safety-efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study.

    Science.gov (United States)

    Gupta, Neeraj; Labotka, Richard; Liu, Guohui; Hui, Ai-Min; Venkatakrishnan, Karthik

    2016-06-01

    Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy outcomes (hematologic [grade ≥ 3 vs ≤ 2] or non-hematologic [grade ≥ 2 vs ≤ 1] adverse events [AEs], and clinical benefit [≥stable disease vs progressive disease]) using phase 1 data in relapsed/refractory MM (NCT00963820; N = 44). Results Significant relationships to ixazomib exposure were observed for five AEs (neutropenia, thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (p phase 3 maintenance trial will initiate ixazomib at a once-weekly dose of 3 mg, increasing to 4 mg if acceptable tolerability after 4 cycles, to provide maximum clinical benefit balanced with adequate tolerability.

  14. A phase II trial of R115777, an oral farnesyl transferase inhibitor, in      patients with advanced urothelial tract transitional cell carcinoma

    DEFF Research Database (Denmark)

    Rosenberg, Jonathan E.; Maase, Hans von der; Seigne, John D.

    2005-01-01

    BACKGROUND: R115777 is a potent farnesyl transferase inhibitor and has       significant antitumor effects in vitro and in vivo. METHODS: The objective       of the current study was to determine the objective response proportion in       patients with metastatic transitional cell carcinoma (TCC......) of the       urothelial tract who received treatment with R115777 at a dose of 300 mg       orally given twice daily for 21 days followed by 7 days of rest for every       4-week cycle. Thirty-four patients with TCC were enrolled in this Phase II       study. Patients were allowed to have received a maximum of one prior......       observed. CONCLUSIONS: The objective response rate of R115777 was not       sufficient to warrant future investigation in TCC as a single agent.       Preliminary evidence of the activity of R115777 in 2 chemotherapy-naive       patients may warrant further investigation in combination with first...

  15. Inhibition of AKT with the orally active allosteric AKT inhibitor, MK-2206, sensitizes endometrial cancer cells to progestin.

    Directory of Open Access Journals (Sweden)

    Alok Pant

    Full Text Available Progestin resistance is a major obstacle to treating early stage, well-differentiated endometrial cancer as well as recurrent endometrial cancer. The mechanism behind the suboptimal response to progestin is not well understood. The PTEN tumor suppressor gene is frequently mutated in type I endometrial cancers and this mutation results in hyperactivation of the PI3K/AKT pathway. We hypothesized that increased activation of AKT promotes an inadequate response to progestins in endometrial cancer cells. Ishikawa cells stably transfected with progesterone receptor B (PRB23 cells were treated with the AKT inhibitor, MK-2206, which effectively decreased levels of p(Ser473-AKT in a dose-dependent (10 nM to 1 uM and time-dependent manner (0.5 h to 24 h. MK-2206 inhibited levels of p(Thr308-AKT and a downstream target, p(Thr246-PRAS40, but did not change levels of p(Thr202/Tyr204ERK or p(Thr13/Tyr185SAPK/JNK, demonstrating specificity of MK-2206 for AKT. Additionally, MK-2206 treatment of PRB23 cells resulted in a significant increase in levels of progesterone receptor B (PRB protein. Microarray analysis of PRB23 cells identified PDK4 as the most highly upregulated gene among 70 upregulated genes in response to R5020. Inhibition of AKT further upregulated progestin-mediated expression of PDK4 but did not affect another progestin-responsive gene, SGK1. Treatment of PRB23 cells with R5020 and MK-2206 independently decreased viability of cells while the combination of R5020 and MK-2206 caused the greatest decrease in cell viability. Furthermore, mice with xenografted tumors treated with MK-2206 alone or with progesterone alone exhibited modest reductions in their tumor volume. The largest decrease in tumor size was observed in the mice treated with both MK-2206 and progesterone; these tumors exhibited the least proliferation (Ki67 and the most apoptosis (cleaved caspase-3 of all the treatment groups. In summary, inhibition of AKT stabilizes the Progesterone

  16. Behavioral effects of α,α,β,β-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor

    Science.gov (United States)

    Halberstadt, Adam L.; Nichols, David E.; Geyer, Mark A.

    2012-01-01

    RATIONALE Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral Pattern Monitor (BPM) experiments demonstrated that the combination of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAOA inhibitor such as harmaline or clorgyline induces biphasic effects on locomotor activity in rats, initially reducing locomotion and then increasing activity as time progresses. OBJECTIVES The present study investigated whether the biphasic locomotor profile induced by the combination of 5-MeO-DMT and an MAOI is a consequence of a reduction in the rate of 5-MeO-DMT metabolism. This hypothesis was tested using a deuterated derivative of 5-MeO-DMT (α,α,β,β-tetradeutero-5-MeO-DMT) that is resistant to metabolism by MAO. RESULTS Confirming our previous findings, 1.0 mg/kg 5-MeO-DMT (s.c.) had biphasic effects on locomotor activity in rats pretreated with a behaviorally inactive dose of the nonselective MAOI pargyline (10 mg/kg). Administration of 5-MeO-DMT alone, even at doses greater than 1.0 mg/kg, produced only reductions in locomotor activity. Although low doses of α,α,β,β-tetradeutero-5-MeO-DMT (0.3 and 1.0 mg/kg, s.c.) produced only hypoactivity in the BPM, a dose of 3.0 mg/kg induced a biphasic locomotor profile similar to that produced by the combination of 5-MeO-DMT and an MAOI. Receptor binding studies demonstrated that deuterium substitution had little effect on the affinity of 5-MeO-DMT for a wide variety of neurotransmitter binding sites. CONCLUSIONS The finding with α,α,β,β-tetradeutero-5-MeO-DMT indicates that the hyperactivity induced by 5-MeO-DMT after MAO inhibition is a consequence of reduced metabolism of 5-MeO-DMT, leading to prolonged occupation of central serotonin receptors. These results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of

  17. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of Latin American patients with rheumatoid arthritis: Pooled efficacy and safety analyses of Phase 3 and long-term extension studies.

    Science.gov (United States)

    Radominski, Sebastião Cezar; Cardiel, Mario Humberto; Citera, Gustavo; Goecke, Annelise; Jaller, Juan Jose; Lomonte, Andrea Barranjard Vannucci; Miranda, Pedro; Velez, Patricia; Xibillé, Daniel; Kwok, Kenneth; Rojo, Ricardo; García, Erika Gabriela

    Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We assessed tofacitinib efficacy and safety in the Latin American (LA) subpopulation of global Phase 3 and long-term extension (LTE) studies. Data from LA patients with RA and inadequate response to disease-modifying antirheumatic drugs (DMARDs) were pooled across five Phase 3 studies. Phase 3 patients received tofacitinib 5 or 10mg twice daily (BID), adalimumab or placebo; patients in the single LTE study received tofacitinib 5 or 10mg BID; treatments were administered alone or with conventional synthetic DMARDs. Efficacy was reported up to 12 months (Phase 3) and 36 months (LTE) by American College of Rheumatology (ACR) 20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate [ESR]) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Incidence rates (IRs; patients with event/100 patient-years) of adverse events (AEs) of special interest were reported. The Phase 3 studies randomized 496 LA patients; the LTE study enrolled 756 LA patients from Phase 2 and Phase 3. In the Phase 3 studies, patients who received tofacitinib 5 and 10mg BID showed improvements vs placebo at Month 3 in ACR20 (68.9% and 75.7% vs 35.6%), ACR50 (45.8% and 49.7% vs 20.7%) and ACR70 (17.5% and 23.1% vs 6.9%) responses, mean change from baseline in HAQ-DI (-0.6 and -0.8 vs -0.3) and DAS28-4(ESR) score (-2.3 and -2.4 vs -1.4). The improvements were sustained up to Month 36 in the LTE study. In the Phase 3 studies, IRs with tofacitinib 5 and 10mg BID and placebo were 7.99, 6.57 and 9.84, respectively, for SAEs, and 3.87, 5.28 and 3.26 for discontinuation due to AEs. IRs of AEs of special interest in tofacitinib-treated LA patients were similar to the global population. In Phase 3 and LTE studies in LA patients with RA, tofacitinib demonstrated efficacy up to 36 months with a manageable safety profile up to 60 months, consistent with the overall tofacitinib

  18. First-in-Human study of CH5132799, an Oral Class I PI3K Inhibitor, Studying Toxicity, Pharmacokinetics and Pharmacodynamics, in Patients with Metastatic Cancer

    Science.gov (United States)

    Blagden, Sarah; Olmin, Aurelius; Josephs, Debra; Stavraka, Chara; Zivi, Andrea; Pinato, David J.; Anthoney, Alan; Decordova, Shaun; Swales, Karen; Riisnaes, Ruth; Pope, Lorna; Noguchi, Kohei; Shiokawa, Rie; Inatani, Michiyasu; Prince, Jenny; Jones, Keith; Twelves, Chris; Spicer, James; Banerji, Udai

    2014-01-01

    Purpose This Phase I dose-escalation study investigated the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary clinical activity of CH5132799. Patients and Methods Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily (QD) or twice daily (BID) in 28-day cycles. Results Thirty-eight patients with solid tumors received CH5132799 at 2-96 mg QD or 48-72 mg BID. The MTD was 48 mg on the BID schedule but was not reached on the QD schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/ml and 1,550 ng·hr/ml respectively, consistent with efficacious exposure based on preclinical modelling. Reduction in SUVmax with [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in five of seven patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pre-treated patient with triple negative breast cancer had marked improvement in her cutaneous skin lesions lasting 6 cycles. Conclusion CH5132799 is well tolerated at the MTD dose 48 mg BID. At this dose the drug had a favorable PK and PD profile and preliminary evidence of clinical activity. PMID:25231405

  19. No clinically meaningful pharmacokinetic interaction between the hepatitis C virus inhibitors elbasvir and grazoprevir and the oral contraceptives ethinyl estradiol and levonorgestrel.

    Science.gov (United States)

    Marshall, William L; Feng, Hwa-Ping; Caro, Luzelena; Talaty, Jennifer; Guo, Zifang; Huang, Xiaobi; Panebianco, Deborah; Ma, Joanne; Mangin, Eric; O'Reilly, Terry E; Butterton, Joan R; Yeh, Wendy W

    2017-05-01

    Oral contraceptive pills (OCPs) are an important element of hepatitis C virus (HCV) treatment in women of childbearing potential. These studies evaluated the safety and pharmacokinetic interactions between elbasvir (EBR) and grazoprevir (GZR) and ethinyl estradiol/levonorgestrel (EE/LNG). Both studies were open-label, single-site, two-period, fixed-sequence, one-way interaction studies. In period 1, subjects received one tablet of EE/LNG (0.03 mg/0.15 mg). In period 2, subjects received EBR (50 mg once daily) for 13 days or GZR (200 mg once daily) for 10 days, with one tablet of EE/LNG on day 7 (GZR group) or 10 (EBR group). Each study enrolled 20 healthy, nonsmoking adult females. There was no clinically meaningful effect of multiple doses of EBR or GZR on the pharmacokinetics of EE or LNG. Geometric mean ratios (GMRs) for AUC0-∞ and Cmax in the presence and absence of EBR were 1.01 and 1.10 for EE and 1.14 and 1.02 for LNG, with 90% confidence intervals (CIs) that were contained in the interval [0.80, 1.25]. Similarly, the AUC0-∞ and Cmax GMRs in the presence and absence of GZR were 1.10 and 1.05 for EE and 1.23 and 0.93 for LNG, respectively. The 90% CIs for EE AUC0-∞ and for EE and LNG Cmax were contained in the interval [0.80, 1.25]; however, the 90% CI for the LNG AUC0-∞ [1.15, 1.32] slightly exceeded the upper bound. These results suggest that EBR/GZR can be co-administered to female patients with HCV of childbearing potential who are on OCPs to prevent pregnancy.

  20. Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R).

    Science.gov (United States)

    Degorce, Sébastien L; Boyd, Scott; Curwen, Jon O; Ducray, Richard; Halsall, Christopher T; Jones, Clifford D; Lach, Franck; Lenz, Eva M; Pass, Martin; Pass, Sarah; Trigwell, Catherine

    2016-05-26

    Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.

  1. Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants.

    Science.gov (United States)

    Devineni, Damayanthi; Manitpisitkul, Prasarn; Vaccaro, Nicole; Bernard, Apexa; Skee, Donna; Mamidi, Rao N V S; Tian, Hong; Weiner, Sveta; Stieltjes, Hans; Sha, Sue; Rothenberg, Paul

    2015-01-01

    Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor approved for the management of type-2 diabetes mellitus, and an oral contraceptive (OC), warfarin, and digoxin were evaluated in three phase 1 studies in healthy participants. All studies were open-label; study 1 included a fixed-sequence design, and studies 2 and 3 used a crossover design. Regimens were: study 1: OC (levonorgestrel (150 μg) + ethinyl estradiol (30 μg))/day (day 1), canagliflozin 200 mg/day (days 4 - 8), and canagliflozin with OC (day 9); study 2: canagliflozin 300 mg/day (days 1 - 12) with warfarin 30 mg/day (day 6) in period 1, and only warfarin 30 mg/day (day 1) in period 2, or vice versa; study 3: digoxin alone (0.5 mg/day (day 1) + 0.25 mg/day (days 2 - 7)) in period 1, and with canagliflozin 300 mg/day (days 1 - 7) in period 2, or vice versa. Pharmacokinetics (PK) were assessed at prespecified intervals; OC: days 1 and 9, canagliflozin: days 8 - 9 (study 1); warfarin: days 6 (period 1) and 1 (period 2) (study 2); and digoxin: days 5 - 7 (periods 1 and 2) (study 3). Warfarin's pharmacodynamics (PD; International Normalized Ratio (INR)) was assessed on days 6 (period 1) and 1 (period 2). Canagliflozin increased the plasma exposure of OC (maximum plasma concentration (Cmax): 22%, area under the curve (AUC): 6%) and digoxin (Cmax: 36%, AUC: 20%); but did not alter warfarin'€™s PK and PD. No clinically relevant safety findings (including hypoglycemia) were noted. Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were well-tolerated.

  2. A Phase 1 Study of Oral ARRY-614, a p38 MAPK/Tie2 Dual Inhibitor, in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes

    Science.gov (United States)

    Garcia-Manero, Guillermo; Khoury, Hanna J.; Jabbour, Elias; Lancet, Jeffrey; Winski, Shannon L.; Cable, LouAnn; Rush, Selena; Maloney, Lara; Hogeland, Grant; Ptaszynski, Mieke; Calvo, Monica Cabrero; Bohanan, Zach; List, Alan; Kantarjian, Hagop; Komrokji, Rami

    2015-01-01

    Purpose Data suggest that activity of p38 MAPK and Tie2 kinase are dysregulated in MDS and may be targets for novel therapies. A Phase 1 study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by IWG 2006 criteria. Experimental Design Forty-five patients received ARRY-614 either QD or BID in dose escalation (400, 600, 900 or 1200 mg QD; 200 or 300 mg BID) or expansion cohorts. Results The 300 mg BID schedule was not tolerated, and a maximum tolerated dose was not reached for QD dosing. Treatment-related adverse events were primarily grade 1–2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Inter-patient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 RBC transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI. Conclusions ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1200 mg QD as the optimal dose for further study. PMID:25480830

  3. Home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban. Rationale and design of the HoT-PE Trial.

    Science.gov (United States)

    Barco, Stefano; Lankeit, Mareike; Binder, Harald; Schellong, Sebastian; Christ, Michael; Beyer-Westendorf, Jan; Duerschmied, Daniel; Bauersachs, Rupert; Empen, Klaus; Held, Matthias; Schwaiblmair, Martin; Fonseca, Cândida; Jiménez, David; Becattini, Cecilia; Quitzau, Kurt; Konstantinides, Stavros

    2016-07-01

    Pulmonary embolism (PE) is a potentially life-threatening acute cardiovascular syndrome. However, more than 95 % of patients are haemodynamically stable at presentation, and among them are patients at truly low risk who may qualify for immediate or early discharge. The Home Treatment of Pulmonary Embolism (HoT-PE) study is a prospective international multicentre single-arm phase 4 management (cohort) trial aiming to determine whether home treatment of acute low-risk PE with the oral factor Xa inhibitor rivaroxaban is feasible, effective, and safe. Patients with confirmed PE, who have no right ventricular dysfunction or free floating thrombi in the right atrium or ventricle, are eligible if they meet none of the exclusion criteria indicating haemodynamic instability, serious comorbidity or any condition mandating hospitalisation, or a familial/social environment unable to support home treatment. The first dose of rivaroxaban is given in hospital, and patients are discharged within 48 hours of presentation. Rivaroxaban is taken for at least three months. The primary outcome is symptomatic recurrent venous thromboembolism or PE-related death within three months of enrolment. Secondary outcomes include quality of life and patient satisfaction, and health care resource utilisation compared to existing data on standard-duration hospital treatment. HoT-PE is planned to analyse 1,050 enrolled patients, providing 80 % power to reject the null hypothesis that the recurrence rate of venous thromboembolism is >3 % with α≤0.05. If the hypothesis of HoT-PE is confirmed, early discharge and out-of-hospital treatment may become an attractive, potentially cost-saving option for a significant proportion of patients with acute PE.

  4. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089, cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer.

    Directory of Open Access Journals (Sweden)

    Manish A Shah

    Full Text Available PURPOSE: The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma. PATIENTS AND METHODS: Foretinib safety and tolerability, and objective response rate (ORR were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks or daily (80 mg/day dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of ≥ 25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity. RESULTS: From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25-88; 93% had received prior therapy. Best response was stable disease (SD in 10 (23% patients receiving intermittent dosing and five (20% receiving daily dosing; SD duration was 1.9-7.2 months (median 3.2 months. Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15% and elevated aspartate aminotransferase (23% vs. 8% were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET, the pMET:total MET protein ratio decreased with foretinib treatment. CONCLUSION: These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in

  5. Tofacitinib, an oral Janus kinase inhibitor, in patients from Mexico with rheumatoid arthritis: Pooled efficacy and safety analyses from Phase 3 and LTE studies.

    Science.gov (United States)

    Burgos-Vargas, Ruben; Cardiel, Mario; Xibillé, Daniel; Pacheco-Tena, César; Pascual-Ramos, Virginia; Abud-Mendoza, Carlos; Mahgoub, Ehab; Rahman, Mahboob; Fan, Haiyun; Rojo, Ricardo; García, Erika; Santana, Karina

    2017-05-25

    Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We characterized efficacy and safety of tofacitinib in Mexican patients from RA Phase 3 and long-term extension (LTE) studies. Data from Mexican patients with RA and an inadequate response to disease-modifying antirheumatic drugs (DMARDs) were taken from four Phase 3 studies (pooled across studies) and one open-label LTE study of tofacitinib. Patients received tofacitinib 5 or 10mg twice daily, adalimumab (one Phase 3 study) or placebo (four Phase 3 studies) as monotherapy or in combination with conventional synthetic DMARDs. Efficacy up to Month 12 (Phase 3) and Month 36 (LTE) was assessed by American College of Rheumatology 20/50/70 response rates, Disease Activity Score (erythrocyte sedimentation rate), and Health Assessment Questionnaire-Disability Index. Safety, including incidence rates (IRs; patients with events/100 patient-years) for adverse events (AEs) of special interest, was assessed throughout the studies. 119 and 212 Mexican patients were included in the Phase 3 and LTE analyses, respectively. Tofacitinib-treated patients in Phase 3 had numerically greater improvements in efficacy responses versus placebo at Month 3. Efficacy was sustained in Phase 3 and LTE studies. IRs for AEs of special interest were similar to those with tofacitinib in the global and Latin American RA populations. In Mexican patients from the tofacitinib global RA program, tofacitinib efficacy was demonstrated up to Month 12 in Phase 3 studies and Month 36 in the LTE study, with a safety profile consistent with tofacitinib global population. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  6. Pharmacokinetic profile of rizatriptan 10-mg tablet and 10-mg orally disintegrating tablet administered with or without water in healthy subjects: an open-label, randomized, single-dose, 3-period crossover study.

    Science.gov (United States)

    Swan, Suzanne K; Alcorn, Harry; Rodgers, Anthony; Hustad, Carolyn M; Ramsey, Karen E; Woll, Susan; Skobieranda, Franck

    2006-02-01

    This open-label, 3-period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10-mg rizatriptan tablet, 10-mg rizatriptan ODTs, or 10-mg rizatriptan ODTc. The authors hypothesized that ODTc has a greater geometric mean AUC(0-2h) than ODTs and that ODTc has a greater geometric mean AUC(0-1h) than tablet. A secondary end point was to compare the time of occurrence of the maximum rizatriptan plasma concentration (t(max)) of each dosing method. ODTc had a statistically significantly greater geometric mean AUC(0-2h) compared with ODTs (33.84 h x ng/mL vs 18.83 h x ng/mL; P rizatriptan tablet (17.07 h x ng/mL vs 13.32 h x ng/mL). The median t(max) was 0.67 hours for ODTc and tablet and 1.33 hours for ODTs. ODTc showed a slightly, but not significantly, faster rate of absorption compared with tablet. ODTs with water had a faster rate of absorption than ODTc. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting.

  7. Evaluation of the potential inhibitor of Ix (Pp-Ix) protoporphyrin of the genetic damage induced by gamma rays administered to different dose reasons in Drosophila melanogaster; Evaluacion del potencial inhibidor de la protoporfirina IX (PP-IX) del dano genetico inducido por rayos gama administrados a diferentes razones de dosis en Drosophila melanogaster

    Energy Technology Data Exchange (ETDEWEB)

    Flores A, J. A.

    2016-10-01

    Ionizing radiation can damage in DNA directly or indirectly by free radicals (Rl), characterized by unstable and highly reactive. To avoid damage by Rl the cell has endogenous antioxidants such as Sod, Cat, GSH or exogenous as some vitamins, but if with these mechanisms does not reach the cell homeostasis, the consequence may be the generation of chronic-disease degenerative such as cancer. This study was conducted in order to test the inhibitory role of Rl protoporphyrin Ix (Pp-Ix), induced by 20 Gy of gamma rays administered at different dose ratios using the assay of somatic mutation and recombination in the Drosophila wing. The results indicated that 20 Gy delivered at a rate of low dose (6.659 Gy/h), caused elevated frequencies of genetic damage (p <0.001), compared with those that induced a high dose reason (1111.42 Gy/h) in larvae of 48 h old. The difference is probably due to an indirect damage by Rl; when this hypothesis was approved with the possible inhibitor role of Pp-Ix (0.69 m M), damage was increased with the two reasons of tested doses. This result may be due to: 1) the Pp-Ix is not a good inhibitor of Rl, 2) the difference in the frequency of mutation found with both dose reasons, not due to Rl so that this compound did not reduce the genetic damage, and 3) that Pp-Ix acts as pro oxidant. (Author)

  8. Changes in glucose-induced plasma active glucagon-like peptide-1 levels by co-administration of sodium-glucose cotransporter inhibitors with dipeptidyl peptidase-4 inhibitors in rodents.

    Science.gov (United States)

    Oguma, Takahiro; Kuriyama, Chiaki; Nakayama, Keiko; Matsushita, Yasuaki; Hikida, Kumiko; Tsuda-Tsukimoto, Minoru; Saito, Akira; Arakawa, Kenji; Ueta, Kiichiro; Minami, Masabumi; Shiotani, Masaharu

    2016-12-01

    We investigated whether structurally different sodium-glucose cotransporter (SGLT) 2 inhibitors, when co-administered with dipeptidyl peptidase-4 (DPP4) inhibitors, could enhance glucagon-like peptide-1 (GLP-1) secretion during oral glucose tolerance tests (OGTTs) in rodents. Three different SGLT inhibitors-1-(β-d-Glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene (GTB), TA-1887, and canagliflozin-were examined to assess the effect of chemical structure. Oral treatment with GTB plus a DPP4 inhibitor enhanced glucose-induced plasma active GLP-1 (aGLP-1) elevation and suppressed glucose excursions in both normal and diabetic rodents. In DPP4-deficient rats, GTB enhanced glucose-induced aGLP-1 elevation without affecting the basal level, whereas metformin, previously reported to enhance GLP-1 secretion, increased both the basal level and glucose-induced elevation. Oral treatment with canagliflozin and TA-1887 also enhanced glucose-induced aGLP-1 elevation when co-administered with either teneligliptin or sitagliptin. These data suggest that structurally different SGLT2 inhibitors enhance plasma aGLP-1 elevation and suppress glucose excursions during OGTT when co-administered with DPP4 inhibitors, regardless of the difference in chemical structure. Combination treatment with DPP4 inhibitors and SGLT2 inhibitors having moderate SGLT1 inhibitory activity may be a promising therapeutic option for improving glycemic control in patients with type 2 diabetes mellitus. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  9. Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 6. Structure-activity studies of orally bioavailable, 2-pyridone-containing peptidomimetics.

    Science.gov (United States)

    Dragovich, Peter S; Prins, Thomas J; Zhou, Ru; Brown, Edward L; Maldonado, Fausto C; Fuhrman, Shella A; Zalman, Leora S; Tuntland, Tove; Lee, Caroline A; Patick, Amy K; Matthews, David A; Hendrickson, Thomas F; Kosa, Maha B; Liu, Bo; Batugo, Minerva R; Gleeson, Jean-Paul R; Sakata, Sylvie K; Chen, Lijian; Guzman, Mark C; Meador, James W; Ferre, Rose Ann; Worland, Stephen T

    2002-04-11

    The structure-based design, chemical synthesis, and biological evaluation of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and a Michael acceptor moiety, which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The 2-pyridone-containing inhibitors typically display improved 3CP inhibition properties relative to related peptide-derived molecules along with more favorable antiviral properties. The cocrystal structure of one pyridone-derived 3CP inhibitor complexed with HRV-2 3CP is also described along with certain ab initio conformation analyses. Optimization of the 2-pyridone-containing compounds is shown to provide several highly active 3CP inhibitors (k(obs)/[I] > 500,00 M(-1) s(-1)) that function as potent antirhinoviral agents (EC(50) = <0.05 microM) against multiple virus serotypes in cell culture. One 2-pyridone-containing 3CP inhibitor is shown to be bioavailable in the dog after oral dosing (F = 48%).

  10. Treatment of relapse in herpes simplex on labial and facial areas and of primary herpes simplex on genital areas and "area pudenda" with low-power He-Ne laser or Acyclovir administered orally

    Science.gov (United States)

    Velez-Gonzalez, Mariano; Urrea-Arbelaez, Alejandro; Nicolas, M.; Serra-Baldrich, E.; Perez, J. L.; Pavesi, M.; Camarasa, J. M.; Trelles, Mario A.

    1996-01-01

    Sixty patients (greater than 16 yrs old) suffering primary or relapse genital herpes simplex viruses (HSV) and relapse labial HSV were appointed for this study. Three or more relapses were experienced per year. Patients (under treatment) were divided into two groups (distribution areas), corresponding to either labial herpes or genital herpes. These groups were sub-divided into 3 groups. The total number of labial or facial HSV patients was 36 (10 in group 1, 12 in group 2, 14 in group 3) and 24 for genital, buttocks, or 'area pudenda' HSV patients (6 in group 1, 8 in group 2, 10 in group 3). The design was a randomized, double- blind study. The setting was hospital and outpatient. The patients diagnosed as having the HVS disease were sent to the dermatology department and were assigned to a group at random. Treatment was begun as follows: During the treatment signs and symptoms were assessed and after the treatment, the relapses were also assessed (biochemical and hematological tests before and after the treatment) and the diagnosis of the HSV type I and II. The statistical evaluation of the results was performed and carried out with the SPSS and BMDP program. The relapses of the herpes infection in the lips and the face were significantly reduced (p less than 0.026) in patients treated with laser He-Ne and laser He-Ne plus Acyclovir. The interim between the relapses also increased significantly (p less than 0.005) in relation with the group treated with Acyclovir. The duration of the herpetic eruptions was clearly reduced in all locations in patients treated with laser He-Ne plus Acyclovir. No differences were noted between patients treated with laser He-Ne only or Acyclovir only. Therefore it is probable that therapeutic synergism took place. In relation with this, laser He-Ne shows the same therapeutic efficacy as Acyclovir taken orally. The association of Acyclovir and laser Ne-Ne could be an alternative method for the treatment of HSV in the face. The number

  11. Effect of nimesulide-a preferential COX-2 inhibitor on arterial blood pressure, compared to ketoprofen.

    Science.gov (United States)

    Saran, Tomasz; Sodolski, Wojciech; Sodolska, Katarzyna; Danilkiewicz, Wit Cezary; Schabowski, Janusz

    2004-01-01

    Clinical and experimental studies have shown that renal and cardiovascular effects of most selective COX-2 inhibitors (rofecoxib, celecoxib) are similar to other traditional NSAIDs (dual COX inhibitors). In these study the effect of nimesulide--preferential COX-2 inhibitor, administration on 24-hour blood pressure profile was investigated in 40 adult individuals on antihypertensive therapy with pain states caused by osteoartritis. Nimesulide was administered orally, twice a day at the conventional dose of 0.1 g for five days. In the next (or previous) 5 days the same patients were administered with ketoprofen at the dose of 0.05 g three times a day. On the last day of the NSAID administration period, 24-hour blood pressure monitoring was performed. Our results indicate no difference between nimesulide and ketoprofen effects on mean blood pressure values during antihypertensive therapy.

  12. Oral targeted therapies: managing drug interactions, enhancing adherence and optimizing medication safety in lymphoma patients.

    Science.gov (United States)

    Liewer, Susanne; Huddleston, Ashley N

    2015-04-01

    The advent of newer, targeted oral chemotherapy medications such as small molecule kinase inhibitors, ibrutinib and idelalisib, has created additional options for the treatment of lymphoma. The targeted nature of these agents offers many patient-identified advantages over older, intravenously administered chemotherapy regimens such as ease of self-administration and an increased sense of independence. However, newer oral agents also present unique challenges not previously experienced with older therapies that may affect safety, efficacy and patient adherence. In this article, we review oral agents for the treatment of lymphoma, how to evaluate and manage drug-drug and drug-food interactions with concomitant oral medications, and issues with patient adherence as well as methods to determine adherence for oral chemotherapy.

  13. Inhibition of in vivo histamine metabolism in rats by foodborne and pharmacologic inhibitors of diamine oxidase, histamine N-methyltransferase, and monoamine oxidase

    Energy Technology Data Exchange (ETDEWEB)

    Hui, J.Y.; Taylor, S.L.

    1985-11-01

    When (/sup 14/C)histamine was administered orally to rats, an average of 80% of the administered radioactivity was recovered in the urine at the end of 24 hr. About 10% of the total dose was excreted via the feces. Analysis of 4-hr urine samples found imidazoleacetic acid to be the predominant metabolite (60.6%), with N tau-methylimidazoleacetic acid (8.6%), N tau-methylhistamine (7.3%), and N-acetylhistamine (4.5%) to be the minor metabolites. Histamine metabolism was inhibited by simultaneous oral administration of aminoguanidine, isoniazid, quinacrine, cadaverine, putrescine, tyramine, and beta-phenylethylamine. The administration of inhibitors resulted in an increased amount of unmetabolized histamine and a decreased amount of metabolites reaching the urine. Pharmacologic inhibitors were found to be more potent and have a longer duration of action than foodborne ones. The inhibitors could potentiate food poisoning caused by histamine by inhibiting its metabolism.

  14. Highly Eribulin-resistant KBV20C Oral Cancer Cells Can Be Sensitized by Co-treatment with the Third-generation P-Glycoprotein Inhibitor, Elacridar, at a Low Dose.

    Science.gov (United States)

    Park, Yujin; Son, Ji-Yeon; Lee, Byung-Mu; Kim, Hyung Sik; Yoon, Sungpil

    2017-08-01

    Eribulin mesylate, also called Halaven® (HAL), was recently developed as a microtubule-targeting drug and is used in the clinic for resistant or metastatic cancer. Previously, we showed that P-glycoprotein (P-gp)-overexpressing KBV20C oral cancer cells are highly resistant to HAL compared to sensitive KB cells. This qualitative study was designed to identify specific P-gp inhibitors that increase the sensitivity of highly resistant cancer cells to HAL. In order to identify functional P-gp inhibitors, HAL-treated KBV20C cells were co-treated with P-gp inhibitors, verapamil, elacridar, cyclosporine A, mitotane, piperine, fumagillin, curcumin, indomethacin, probenecid, sulindac, tesmilifene, and C-4. We then evaluated which P-gp inhibitors required a low dose to sensitize KBV20C cells to HAL. We also determined whether a low dose of a P-gp inhibitor could inhibit P-gp efflux pumping. We found that cyclosporine A sensitized HAL-treated KBV20C cells at a low dose, whereas verapamil, another first-generation P-gp inhibitor, required a dose that was nearly 10-fold higher. We also found that the natural products, piperine and mitotane, sensitized KBV20C cells to HAL co-treatment. Interestingly, we found that elacridar, a third-generation P-gp inhibitor, sensitized HAL-treated cells at a low dose. Elacridar required approximately a 500-fold lower dose than that of verapamil to exert a similar effect. All inhibitors showed P-gp inhibitory activity that correlated with sensitivity to HAL. These results suggest that highly HAL-resistant cancer cells can be sensitized with cyclosporine A or elacridar, specific P-gp inhibitors that exert their effects at a low dose. These findings provide important information regarding the sensitization of highly HAL-resistant cells with selective P-gp inhibitors and indicate that elacridar may be used to treat such highly HAL-resistant cancer cells. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios

  15. The effects of ketoconazole and cimetidine on the pharmacokinetics of oral tramadol in greyhound dogs.

    Science.gov (United States)

    KuKanich, B; KuKanich, K; Black, J

    2017-06-11

    Tramadol is administered to dogs for analgesia but has variability in its extent of absorption, which may hinder its efficacy. Additionally, the active opioid metabolite (M1) occurs in low concentrations. The purpose of this study was to determine if administration of oral tramadol with suspected metabolism inhibitors (ketoconazole, cimetidine) would lead to improved bioavailability of tramadol and M1. Six healthy Greyhounds were included. They were administered tramadol orally and intravenously, M1 intravenously, oral tramadol with oral ketoconazole and oral tramadol with oral cimetidine. Oral tramadol bioavailability was low (2.6%). Ketoconazole and cimetidine significantly increased tramadol bioavailability to 18.2% and 20.3%, respectively. The mean maximum plasma concentration of tramadol alone was 22.9 ng/ml, and increased to 109.9 and 143.2 μg/ml with ketoconazole and cimetidine, respectively. However, measured tramadol plasma concentrations were below the minimum concentration considered effective in humans (228 μg/ml). In all treatment groups, measured M1 concentrations (tramadol and M1 concentrations were low and variable in dogs after oral dosing of tramadol, even in combination with cimetidine or ketoconazole, but effective concentrations in dogs have not been defined. © 2017 John Wiley & Sons Ltd.

  16. PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES ON VAGINALLY ADMINISTERED LEVONORGESTREL

    Institute of Scientific and Technical Information of China (English)

    HEChang-Hai; XUJian-Qiu; ZHUYue-Hua; SHIYong-En

    1989-01-01

    Comparative studies on pharmacokinetics of vaginally and orally administered levonorgestrel (LNG) tablet (Postinor) in one single dose containing 0,75mg LNG were performed. The pharmacokinetics of LNG and its effects on ovarian functions werealso studied after repeated vaginal administration.

  17. Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily

    Energy Technology Data Exchange (ETDEWEB)

    Schroeder, Gretchen M.; An, Yongmi; Cai, Zhen-Wei; Chen, Xiao-Tao; Clark, Cheryl; Cornelius, Lyndon A.M.; Dai, Jun; Gullo-Brown, Johnni; Gupta, Ashok; Henley, Benjamin; Hunt, John T.; Jeyaseelan, Robert; Kamath, Amrita; Kim, Kyoung; Lippy, Jonathan; Lombardo, Louis J.; Manne, Veeraswamy; Oppenheimer, Simone; Sack, John S.; Schmidt, Robert J.; Shen, Guoxiang; Stefanski, Kevin; Tokarski, John S.; Trainor, George L.; Wautlet, Barri S.; Wei, Donna; Williams, David K.; Zhang, Yingru; Zhang, Yueping; Fargnoli, Joseph; Borzilleri, Robert M.; (BMS)

    2009-12-01

    Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.

  18. Iron-deficiency anemia caused by a proton pump inhibitor.

    Science.gov (United States)

    Hashimoto, Rintaro; Matsuda, Tomoki; Chonan, Akimichi

    2014-01-01

    A 59-year-old man was orally administered rabeprazole, a proton pump inhibitor (PPI), for gastroesophageal reflux disease, after which he gradually developed iron-deficiency anemia. The anemia did not improve following the administration of ferrous fumarate, and endoscopic screening of the entire gastrointestinal tract, including the small intestine, did not reveal any findings indicating the cause of the anemia. The patient was then switched from rabeprazole to famotidine and the anemia was cured within three months. There is much debate as to whether the long-term use of PPIs causes iron-deficiency. However, this case strongly suggests that PPIs can induce iron-deficiency anemia.

  19. Oral calcitonin

    Directory of Open Access Journals (Sweden)

    Hamdy RC

    2012-09-01

    Full Text Available Ronald C Hamdy,1,2 Dane N Daley11Osteoporosis Center, College of Medicine, East Tennessee State University, 2Veterans Affairs Medical Center, Johnson City, TN, USAAbstract: Calcitonin is a hormone secreted by the C-cells of the thyroid gland in response to elevations of the plasma calcium level. It reduces bone resorption by inhibiting mature active osteoclasts and increases renal calcium excretion. It is used in the management of postmenopausal osteoporosis, Paget's disease of bone, and malignancy-associated hypercalcemia. Synthetic and recombinant calcitonin preparations are available; both have similar pharmacokinetic and pharmacodynamic profiles. As calcitonin is a peptide, the traditional method of administration has been parenteral or intranasal. This hinders its clinical use: adherence with therapy is notoriously low, and withdrawal from clinical trials has been problematic. An oral formulation would be more attractive, practical, and convenient to patients. In addition to its effect on active osteoclasts and renal tubules, calcitonin has an analgesic action, possibly mediated through β-endorphins and the central modulation of pain perception. It also exerts a protective action on cartilage and may be useful in the management of osteoarthritis and possibly rheumatoid arthritis. Oral formulations of calcitonin have been developed using different techniques. The most studied involves drug-delivery carriers such as Eligen® 8-(N-2hydroxy-5-chloro-benzoyl-amino-caprylic acid (5-CNAC (Emisphere Technologies, Cedar Knolls, NJ. Several factors affect the bioavailability and efficacy of orally administered calcitonin, including amount of water used to take the tablet, time of day the tablet is taken, and proximity to intake of a meal. Preliminary results looked promising. Unfortunately, in two Phase III studies, oral calcitonin (0.8 mg with 200 mg 5-CNAC, once a day for postmenopausal osteoporosis and twice a day for osteoarthritis failed to

  20. JAK inhibitors in dermatology: The promise of a new drug class.

    Science.gov (United States)

    Damsky, William; King, Brett A

    2017-01-28

    New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase-signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. The use of JAK inhibitors in dermatology is reviewed here.

  1. A comparison of orally administered misoprostol and membrane ...

    African Journals Online (AJOL)

    Post-term pregnancy is fairly common in obstetric practice and is the most ... MS involves digital separation of the fetal membranes from the lower ... term.10,11 This method causes an increase in local PG production,12,13 which results in ...

  2. Biodegradable Bioadherent Microcapsules for Orally Administered Sustained Release Vaccines

    Science.gov (United States)

    1997-05-01

    Fasciola hepatica which is a known bioadhesive’’. The encapsulation method is the classical, well described water in oil technique for the preparation of...immunization, Vaccine 12 (1994) 387-340. 6. Waite, J.H., Rice-Ficht, A.C., Presclerotized eggshell protein from the liver fluke Fasciola hepatica ...Biochemistry 26 (1987) 7819-7825. 7. Waite, J.H., Rice-Ficht, A.C., Eggshell precursor proteins of Fasciola hepatica : II. Microheterogeneity in vitelline

  3. Antinociceptive effects of Cremophor EL orally administered to mice

    Directory of Open Access Journals (Sweden)

    Z. Tabarelli

    2003-01-01

    Full Text Available Surfactants are frequently used to improve solubilization of lipophilic drugs. Cremophor EL (CrEL is a polyoxyethylated castor oil surfactant used to solubilize water-insoluble drugs such as anesthetic, antineoplastic, immunosuppressive and analgesic drugs, vitamins and new synthetic compounds, including potential analgesics. The antinociceptive effect of CrEL (3.2, 6.4 and 10.6 g/kg, in 10 ml/kg body weight, by gavage on the abdominal writhing response induced by intraperitoneal administration of acetic acid (0.8%, 10 ml/kg body weight and on the tail immersion test was investigated in mice. Control animals received castor oil (10 ml/kg body weight or saline (0.9% NaCl, 10 ml/kg body weight. CrEL reduced nociception in a dose-dependent manner in both tests. At 10.6 g/kg, CrEL caused antinociception similar to that induced by dipyrone (300 mg/kg, by gavage in the abdominal writhing test, and antinociception similar to that induced by morphine (20 mg/kg, by gavage in the tail immersion test. The effect of castor oil was similar to that of saline in both assays. These data indicate that the appropriate controls should be used when evaluating the effects of potential antinociceptive agents dissolved in CrEL.

  4. Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant.

    Science.gov (United States)

    Holmgren, J; Bourgeois, L; Carlin, N; Clements, J; Gustafsson, B; Lundgren, A; Nygren, E; Tobias, J; Walker, R; Svennerholm, A-M

    2013-05-07

    A first-generation oral inactivated whole-cell enterotoxigenic Escherichia coli (ETEC) vaccine, comprising formalin-killed ETEC bacteria expressing different colonization factor (CF) antigens combined with cholera toxin B subunit (CTB), when tested in phase III studies did not significantly reduce overall (generally mild) ETEC diarrhea in travelers or children although it reduced more severe ETEC diarrhea in travelers by almost 80%. We have now developed a novel more immunogenic ETEC vaccine based on recombinant non-toxigenic E. coli strains engineered to express increased amounts of CF antigens, including CS6 as well as an ETEC-based B subunit protein (LCTBA), and the optional combination with a nontoxic double-mutant heat-labile toxin (LT) molecule (dmLT) as an adjuvant. Two test vaccines were prepared under GMP: (1) A prototype E. coli CFA/I-only formalin-killed whole-cell+LCTBA vaccine, and (2) A "complete" inactivated multivalent ETEC-CF (CFA/I, CS3, CS5 and CS6 antigens) whole-cell+LCTBA vaccine. These vaccines, when given intragastrically alone or together with dmLT in mice, were well tolerated and induced strong intestinal-mucosal IgA antibody responses as well as serum IgG and IgA responses to each of the vaccine CF antigens as well as to LT B subunit (LTB). Both mucosal and serum responses were further enhanced (adjuvanted) when the vaccines were co-administered with dmLT. We conclude that the new multivalent oral ETEC vaccine, both alone and especially in combination with the dmLT adjuvant, shows great promise for further testing in humans. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Palkanlaskennan perehdytysopas Case: Administer Oy

    OpenAIRE

    Vänttinen, Sakari

    2016-01-01

    Opinnäytetyössä tehtiin palkanlaskennan perehdytysopas sähköisen taloushallinnon palveluntarjoajalle Administer Oy:lle. Työn päätavoitteena oli luoda palkanlaskennan perehdytysopas Administer Oy:n sisäiseen käyttöön. Perehdytysoppaan on tarkoitus tukea ja selkeyttää uusien palkanlaskijoiden työn aloittamista ja työtehtävien omaksumista. Perehdytysoppaan tavoitteena on lisäksi nopeuttaa ja helpottaa perehdyttäjien työtä perehdytysprosessin aikana. Työ keskittyy vain palkanlaskentapalveluun...

  6. Drug-drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus.

    Science.gov (United States)

    Scheen, André J

    2014-04-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. They are proposed as a novel approach for the management of type 2 diabetes mellitus. They have proven their efficacy in reducing glycated haemoglobin, without inducing hypoglycaemia, as monotherapy or in combination with various other glucose-lowering agents, with the add-on value of promoting some weight loss and lowering arterial blood pressure. As they may be used concomitantly with many other drugs, we review the potential drug-drug interactions (DDIs) regarding the three leaders in the class (dapagliglozin, canagliflozin and empagliflozin). Most of the available studies were performed in healthy volunteers and have assessed the pharmacokinetic interferences with a single administration of the SGLT2 inhibitor. The exposure [assessed by peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC)] to each SGLT2 inhibitor tested was not significantly influenced by the concomitant administration of other glucose-lowering agents or cardiovascular agents commonly used in patients with type 2 diabetes. Reciprocally, these medications did not influence the pharmacokinetic parameters of dapagliflozin, canagliflozin or empagliflozin. Some modest changes were not considered as clinically relevant. However, drugs that could specifically interfere with the metabolic pathways of SGLT2 inhibitors [rifampicin, inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)] may result in significant changes in the exposure of SGLT2 inhibitors, as shown for dapagliflozin and canagliflozin. Potential DDIs in patients with type 2 diabetes receiving chronic treatment with an SGLT2 inhibitor deserve further attention, especially in individuals treated with several medications or in more fragile patients with hepatic and/or renal impairment.

  7. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo.

    Science.gov (United States)

    Vendetti, Frank P; Lau, Alan; Schamus, Sandra; Conrads, Thomas P; O'Connor, Mark J; Bakkenist, Christopher J

    2015-12-29

    ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.

  8. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases.

    Science.gov (United States)

    Abbott-Banner, Katharine H; Page, Clive P

    2014-05-01

    Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bronchodilator/anti-inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose-limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast-n-oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non-selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti-inflammatory and bronchodilator effects that have been observed pre-clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis.

  9. Inherent formulation issues of kinase inhibitors.

    Science.gov (United States)

    Herbrink, M; Schellens, J H M; Beijnen, J H; Nuijen, B

    2016-10-10

    The small molecular Kinase Inhibitor (smKI) drug class is very promising and rapidly expanding. All of these drugs are administered orally. The clear relationship between structure and function has led to drugs with a general low intrinsic solubility. The majority of the commercial pharmaceutical formulations of the smKIs are physical mixtures that are limited by the low drug solubility of a salt form. This class of drugs is therefore characterized by an impaired and variable bioavailability rendering them costly and their therapies suboptimal. New formulations are sparingly being reported in literature and patents. The presented data suggests that continued research into formulation design can help to develop more efficient and cost-effective smKI formulation. Moreover, it may also be of help in the future design of the formulations of new smKIs.

  10. EBI-907, a novel BRAF(V600E) inhibitor, has potent oral anti-tumor activity and a broad kinase selectivity profile.

    Science.gov (United States)

    Zhang, Jiayin; Lu, Biao; Liu, Dong; Shen, Ru; Yan, Yinfa; Yang, Liuqing; Zhang, Minsheng; Zhang, Lei; Cao, Guoqing; Cao, Hu; Fu, Beibei; Gong, Aishen; Sun, Qiming; Wan, Hong; Zhang, Lianshan; Tao, Weikang; Cao, Jingsong

    2016-01-01

    The oncogenic mutation of BRAF(V600E) has been found in approximately 8% of all human cancers, including more than 60% of melanoma and 10% of colorectal cancers. The clinical proof of concept in treating BRAF(V600E)-driving melanoma patients with the BRAF inhibitors has been well established. We have sought to identify and develop novel BRAF(V600E) inhibitors with more favorable profiles. Our chemistry effort has led to the discovery of EBI-907 as a novel BRAF(V600E) inhibitor with potent anti-tumor activity in vitro and in vivo. In a LanthaScreen BRAF(V600E) kinase assay, EBI-907 showed an IC50 of 4.8 nM, which is >10 -fold more potent than Vemurafenib (IC50 = 58.5 nM). In addition, EBI-907 showed a broader kinase selectivity profile, with potent activity against a number of important oncogenic kinases including FGFR1-3, RET, c-Kit, and PDGFRb. Concomitant with such properties, EBI-907 exhibits potent and selective cytotoxicity against a broader range of BRAF(V600E)-dependent cell lines including certain colorectal cancer cell lines with innate resistance to Vemurafenib. In BRAF(V600E)-dependent human Colo-205 and A375 tumor xenograft mouse models, EBI-907 caused a marked tumor regression in a dose-dependent manner, with superior efficacy to Vemurafenib. Our results also showed that combination with EGFR or MEK inhibitor enhanced the potency of EBI-907 in cell lines with innate or acquired resistance to BRAF inhibition alone. Our findings present EBI-907 as a potent and promising BRAF inhibitor, which might be useful in broader indications.

  11. Absorption, distribution, metabolism and excretion of novel phosphodiesterase type 4 inhibitor ASP3258 in rats.

    Science.gov (United States)

    Ohtsu, Yoshiaki; Sonoda, Takuya; Susaki, Yoko; Tohda, Toshifumi; Fukunaga, Yasuhisa; Iwatsubo, Takafumi; Noguchi, Kiyoshi

    2015-01-01

    The potent and selective phosphodiesterase 4 inhibitor ASP3258 is a novel therapeutic agent for asthma and chronic obstructive pulmonary disease (COPD). After a single oral administration to rats, ASP3258 is rapidly absorbed with a bioavailability of 106%. In situ absorption data indicated that ASP3258 is mainly absorbed in the small intestine. Tissue distribution data after oral administration of (14)C-ASP3258 showed rapid and extensive distribution to various tissues. Excluding the gastrointestinal tract, the tissues with the highest concentrations were liver, heart and plasma. Liquid chromatography-nuclear magnetic resonance spectroscopy data revealed that O-glucuronidation of the carboxylic acid moiety of ASP3258 (formation of an acyl glucuronide) plays a key role in metabolism. No indication was found that the acyl glucuronide reacted with proteins in plasma or tissues. When (14)C-ASP3258 was orally administered to intact rats, urinary and fecal excretion accounted for 1.3% and 100.6% of the administered radioactivity, respectively. After a single oral administration of (14)C-ASP3258 to bile-cannulated rats, urinary and biliary excretion accounted for 0.7% and 93.8% of the administered radioactivity, respectively. These findings suggest that fecal excretion via bile plays an important role in the elimination of ASP3258-derived radioactivity. In vitro metabolic profiles were relatively similar among the species examined, suggesting that our findings in rats may help us to understand pharmacokinetics, efficacy and safety profiles in humans and other species.

  12. Synthesis and SAR of novel, potent and orally bioavailable benzimidazole inhibitors of poly(ADP-ribose) polymerase (PARP) with a quaternary methylene-amino substituent.

    Science.gov (United States)

    Zhu, Gui-Dong; Gandhi, Viraj B; Gong, Jianchun; Thomas, Sheela; Luo, Yan; Liu, Xuesong; Shi, Yan; Klinghofer, Vered; Johnson, Eric F; Frost, David; Donawho, Cherrie; Jarvis, Ken; Bouska, Jennifer; Marsh, Kennan C; Rosenberg, Saul H; Giranda, Vincent L; Penning, Thomas D

    2008-07-15

    Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. Utilizing a benzimidazole carboxamide scaffold in which the amide forms a key intramolecular hydrogen bond for optimal interaction with the enzyme, we have identified a novel series of PARP inhibitors containing a quaternary methylene-amino substituent at the C-2 position of the benzimidazole. Geminal dimethyl analogs at the methylene-amino substituent were typically more potent than mono-methyl derivatives in both intrinsic and cellular assays. Smaller cycloalkanes such as cyclopropyl or cyclobutyl were tolerated at the quaternary carbon while larger rings were detrimental to potency. In vivo efficacy data in a B16F10 murine flank melanoma model in combination with temozolomide (TMZ) are described for two optimized analogs.

  13. Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

    Energy Technology Data Exchange (ETDEWEB)

    Scola, Paul M.; Wang, Alan Xiangdong; Good, Andrew C.; Sun, Li-Qiang; Combrink, Keith D.; Campbell, Jeffrey A.; Chen, Jie; Tu, Yong; Sin, Ny; Venables, Brian L.; Sit, Sing-Yuen; Chen, Yan; Cocuzza, Anthony; Bilder, Donna M.; D’Andrea, Stanley; Zheng, Barbara; Hewawasam, Piyasena; Ding, Min; Thuring, Jan; Li, Jianqing; Hernandez, Dennis; Yu, Fei; Falk, Paul; Zhai, Guangzhi; Sheaffer, Amy K.; Chen, Chaoqun; Lee, Min S.; Barry, Diana; Knipe, Jay O.; Li, Wenying; Han, Yong-Hae; Jenkins, Susan; Gesenberg, Christoph; Gao, Qi; Sinz, Michael W.; Santone, Kenneth S.; Zvyaga, Tatyana; Rajamani, Ramkumar; Klei, Herbert E.; Colonno, Richard J.; Grasela, Dennis M.; Hughes, Eric; Chien, Caly; Adams, Stephen; Levesque, Paul C.; Li, Danshi; Zhu, Jialong; Meanwell, Nicholas A.; McPhee, Fiona

    2014-03-13

    The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.

  14. Design of Randomized, double-blind, Evaluation in secondary Stroke Prevention comparing the EfficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS).

    Science.gov (United States)

    Diener, Hans-Christoph; Easton, J Donald; Granger, Christopher B; Cronin, Lisa; Duffy, Christine; Cotton, Daniel; Brueckmann, Martina; Sacco, Ralph L

    2015-12-01

    Cryptogenic ischemic strokes constitute 20-30% of ischemic strokes, the majority of which are embolic strokes of undetermined source. The standard preventive treatment in these patients is usually acetylsalicylic acid. The Randomized, double-blind, Evaluation in secondary Stroke Prevention comparing the EfficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS) is designed to determine whether the oral thrombin inhibitor dabigatran, taken within three-months after embolic stroke of undetermined source, is superior to acetylsalicylic acid for prevention of recurrent stroke and to characterize the safety of dabigatran in this setting. Prospective, randomized, double-blind, multicenter trial in approximately 6000 patients and 550 centers with embolic stroke of undetermined source. Subjects are randomized to dabigatran or acetylsalicylic acid and treated for an expected minimum of six-months and up to approximately three-years. It is an event-driven trial aiming for 353 adjudicated primary outcome events. The primary efficacy outcome is time to first recurrent stroke (ischemic, hemorrhagic, or unspecified). Key secondary outcomes are time to first ischemic stroke and time to first occurrence in the composite outcome of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death. The primary safety outcome is major hemorrhage, including symptomatic intracranial hemorrhage. Acetylsalicylic acid is the most common antithrombotic given to patients with embolic strokes of undetermined source to reduce recurrence risk. This trial will determine whether anticoagulation with dabigatran is more effective than acetylsalicylic acid, and acceptably safe. © 2015 World Stroke Organization.

  15. 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....... Thus, orally administered DDC enhanced cadmium-induced duodenal and ileal tissue damage and inhibition of peristalsis, as indicated by an increased intestinal transit time. At low cadmium doses, the whole-body retention of cadmium was increased by oral DDC administration. Intraperitoneally administered...

  16. Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor.

    Science.gov (United States)

    Stepan, Antonia F; Subramanyam, Chakrapani; Efremov, Ivan V; Dutra, Jason K; O'Sullivan, Theresa J; DiRico, Kenneth J; McDonald, W Scott; Won, Annie; Dorff, Peter H; Nolan, Charles E; Becker, Stacey L; Pustilnik, Leslie R; Riddell, David R; Kauffman, Gregory W; Kormos, Bethany L; Zhang, Liming; Lu, Yasong; Capetta, Steven H; Green, Michael E; Karki, Kapil; Sibley, Evelyn; Atchison, Kevin P; Hallgren, Andrew J; Oborski, Christine E; Robshaw, Ashley E; Sneed, Blossom; O'Donnell, Christopher J

    2012-04-12

    Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) with the bicyclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (~4-fold ↑ C(max) and AUC values relative to 1) in a mouse model of γ-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., γ-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere "spacer" unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness. © 2012 American Chemical Society

  17. Orally active 7-substituted (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitriles as active-site inhibitors of sphingosine 1-phosphate lyase for the treatment of multiple sclerosis.

    Science.gov (United States)

    Weiler, Sven; Braendlin, Nadine; Beerli, Christian; Bergsdorf, Christian; Schubart, Anna; Srinivas, Honnappa; Oberhauser, Berndt; Billich, Andreas

    2014-06-26

    Sphingosine 1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitrile 5 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the cocrystal structure of derivative 31 with the homodimeric human S1P lyase. 31 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis. In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell-targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases.

  18. A novel orally available inhibitor of focal adhesion signaling increases survival in a xenograft model of diffuse large B-cell lymphoma with central nervous system involvement.

    Science.gov (United States)

    Bosch, Rosa; Moreno, María José; Dieguez-Gonzalez, Rebeca; Céspedes, María Virtudes; Gallardo, Alberto; Trias, Manuel; Grañena, Albert; Sierra, Jorge; Casanova, Isolda; Mangues, Ramon

    2013-08-01

    Central nervous system dissemination is a relatively uncommon but almost always fatal complication in diffuse large B-cell lymphoma patients. Optimal therapy for central nervous involvement in this malignancy has not been established. In this paper, we aimed to evaluate the therapeutic effect of E7123, a celecoxib derivative that inhibits focal adhesion signaling, in a novel xenograft model of diffuse large B-cell lymphoma with central nervous system involvement. Cells obtained after disaggregation of HT subcutaneous tumors (HT-SC cells) were intravenously injected in NOD/SCID mice. These mice received oral vehicle or 75 mg/kg of E7123 daily until they were euthanized for weight loss or signs of sickness. The antitumor effect of E7123 was validated in an independent experiment using a bioluminescent mouse model. Intravenously injected HT-SC cells showed higher take rate and higher central nervous system tropism (associated with increased expression of β1-integrin and p130Cas proteins) than HT cells. The oral administration of E7123 significantly increased survival time in 2 independent experiments using mice injected with unmodified or bioluminescent HT-SC cells. We have developed a new xenograft model of diffuse large B-cell lymphoma with central nervous system involvement that can be used in the pre-clinical evaluation of new drugs for this malignancy. E7123 is a new, well-tolerated and orally available therapeutic agent that merits further investigation since it may improve current management of diffuse large B-cell lymphoma patients with central nervous system involvement.

  19. Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.

    Science.gov (United States)

    Byrn, Randal A; Jones, Steven M; Bennett, Hamilton B; Bral, Chris; Clark, Michael P; Jacobs, Marc D; Kwong, Ann D; Ledeboer, Mark W; Leeman, Joshua R; McNeil, Colleen F; Murcko, Mark A; Nezami, Azin; Perola, Emanuele; Rijnbrand, Rene; Saxena, Kumkum; Tsai, Alice W; Zhou, Yi; Charifson, Paul S

    2015-03-01

    VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m(7)GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection.

  20. Pharmacology of new oral anticoagulants: mechanism of action, pharmacokinetics, pharmacodynamics

    Directory of Open Access Journals (Sweden)

    Luca Masotti

    2013-12-01

    Full Text Available Due to their mechanism of action, the new oral anticoagulants are named direct oral anticoagulants (DOACs. Dabigatran is a selective, competitive, direct inhibitor of thrombin (Factor IIa while rivaroxaban, apixaban and edoxaban act by directly inhibiting the activated Factor X (FXa in a selective and competitive manner. DOACs have a relatively short half-life and almost immediate anticoagulant activity, and rapidly reach the plasma peak concentration. Therefore, they do not need a phase of overlapping with parenteral anticoagulants. After their withdrawal, their removal is sufficiently rapid, although influenced by renal function. Dabigatran is the only DOACs to be administered as a pro-drug and becomes active after drug metabolization. The route of elimination of dabigatran is primarily renal, whereas FXa inhibitors are mainly eliminated by the biliary-fecal route. The drug interactions of DOACs are mainly limited to drugs that act on P-glycoprotein for dabigatran and on P-glycoprotein and/or cytochrome P3A4 for anti-Xa. DOACs have no interactions with food. Given their linear pharmacodynamics, with a predictable dose/response relationship and anticoagulant effect, DOACs are administered at a fixed dose and do not require routine laboratory monitoring.

  1. Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty. A dose finding study (ONYX-2)

    DEFF Research Database (Denmark)

    Eriksson, B I; Turpie, A G G; Lassen, M R

    2010-01-01

    BACKGROUND: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic......, 60 or 120 mg) (double-blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary...

  2. Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens

    Science.gov (United States)

    Cento, Valeria; Nguyen, Thi Huyen Tram; Di Carlo, Domenico; Biliotti, Elisa; Gianserra, Laura; Lenci, Ilaria; Di Paolo, Daniele; Calvaruso, Vincenza; Teti, Elisabetta; Cerrone, Maddalena; Romagnoli, Dante; Melis, Michela; Danieli, Elena; Menzaghi, Barbara; Polilli, Ennio; Siciliano, Massimo; Nicolini, Laura Ambra; Di Biagio, Antonio; Magni, Carlo Federico; Bolis, Matteo; Antonucci, Francesco Paolo; Di Maio, Velia Chiara; Alfieri, Roberta; Sarmati, Loredana; Casalino, Paolo; Bernardini, Sergio; Micheli, Valeria; Rizzardini, Giuliano; Parruti, Giustino; Quirino, Tiziana; Puoti, Massimo; Babudieri, Sergio; D’Arminio Monforte, Antonella; Andreoni, Massimo; Craxì, Antonio; Angelico, Mario; Pasquazzi, Caterina; Taliani, Gloria; Guedj, Jeremie; Ceccherini-Silberstein, Francesca

    2017-01-01

    Background Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Study design Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. Results HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted δ and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted λ, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Conclusions Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of “cell-cure” by DAAs, leading to a fast improvement of liver homeostasis. PMID:28545127

  3. Preclinical Activity of VX-787, a First-in-Class, Orally Bioavailable Inhibitor of the Influenza Virus Polymerase PB2 Subunit

    OpenAIRE

    2014-01-01

    VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m7GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compou...

  4. Analysis of the influence of dabigatran on coagulation factors and inhibitors.

    Science.gov (United States)

    Tsutsumi, Y; Shimono, J; Ohhigashi, H; Ito, S; Shiratori, S; Teshima, T

    2015-04-01

    Dabigatran is an oral intake thrombin inhibitor for preventive administration against stroke accompanied by atrial fibrillation. Although dabigatran causes prolonged activated partial thromboplastin time (APTT), the effect of dabigatran on each coagulation factor and coagulation factor inhibitor remains to be investigated. Our aim was to analyze the influence of dabigatran on coagulation factors and coagulation factor inhibitors. We administered dabigatran to 40 patients. In 26 of these 40, we analyzed the activity of several coagulation factors and their inhibitors. We used Fisher's exact test to determine statistical significance. The activities of many coagulation factors changed during the dabigatran therapy. Factor II levels decreased in all patients showing prolongation of partial thromboplastin (PT) and APTT. The antifactor VIII inhibitor was positive in the majority of patients with prolonged PT and APTT, while activities of protein C, protein S, and antifactor IX inhibitor were not associated with PT and APTT prolongation. Dabigatran affects the activities of many coagulation factors, including factors II, V, VIII, and IX, as well as the antifactor VIII inhibitor. © 2014 John Wiley & Sons Ltd.

  5. Thrombin inhibitor design.

    Science.gov (United States)

    Sanderson, P E; Naylor-Olsen, A M

    1998-08-01

    Recently, iv formulated direct thrombin inhibitors have been shown to be safe and efficacious alternatives to heparin. These results have fueled the hopes for an orally active compound. Such a compound could be a significant advance over warfarin if it had predictable pharmacokinetics and a duration of action sufficient for once or twice a day dosing. In order to develop an orally active compound which meets these criteria, the deficiencies of the prototype inhibitor efegatran have had to be addressed. First, using a combination of structure based design and empirical structure optimization, more selective compounds have been identified by modifying the P1 group or by incorporating different peptidomimetic P2/P3 scaffolds. Secondly, this optimization has resulted in the development of potent and selective non-covalent inhibitors, thus bypassing the liabilities of the serine trap. Thirdly, oral bioavailability has been achieved while maintaining selectivity and efficacy through the incorporation of progressively less basic P1 groups. The duration of action of these compounds remains to be optimized. Other advances in thrombin inhibitor design have included the development of uncharged P1 groups and the discovery of two non-peptide templates.

  6. Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class.

    Science.gov (United States)

    Turner, S R; Strohbach, J W; Tommasi, R A; Aristoff, P A; Johnson, P D; Skulnick, H I; Dolak, L A; Seest, E P; Tomich, P K; Bohanon, M J; Horng, M M; Lynn, J C; Chong, K T; Hinshaw, R R; Watenpaugh, K D; Janakiraman, M N; Thaisrivongs, S

    1998-08-27

    A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based substitution (III). Incorporation of sulfonamide substitution within the dihydropyrone template provided a series of highly potent HIV protease inhibitors, with structure-activity relationships described in this paper. Crystallographic studies provided further information on important binding interactions responsible for high enzymatic binding. These studies culminated in compound VI, which inhibits HIV protease with a Ki value of 8 pM and shows an IC90 value of 100 nM in antiviral cell culture. Clinical trials of this compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently underway.

  7. Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthroplasty. A dose finding study (ONYX-2)

    DEFF Research Database (Denmark)

    Eriksson, B I; Turpie, A G G; Lassen, M R

    2010-01-01

    safety outcome was major bleeding up to 9 days after surgery. RESULTS: Primary efficacy endpoint: of 1017 patients randomized, 960 patients were evaluable for safety and 729 patients for efficacy. A dose-related decrease in VTE incidence from YM150 5 to 60 mg (P = 0.0005) and from 5 to 120 mg (P = 0......BACKGROUND: Anticoagulant prophylaxis substantially reduces the risk of venous thromboembolism (VTE) after major orthopedic surgery. The direct factor Xa inhibitor YM150 is currently under investigation for the prevention of VTE, stroke and ischemic vascular events in patients after orthopedic......, 60 or 120 mg) (double-blind) or preoperative subcutaneous (open label) enoxaparin (40 mg) for 5 weeks. The primary efficacy endpoint comprised VTE diagnosed by mandatory bilateral venography or verified symptomatic deep vein thrombosis (DVT) plus all deaths up to 9 days after surgery. The primary...

  8. Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).

    Science.gov (United States)

    Woolford, Alison J-A; Day, Philip J; Bénéton, Véronique; Berdini, Valerio; Coyle, Joseph E; Dudit, Yann; Grondin, Pascal; Huet, Pascal; Lee, Lydia Y W; Manas, Eric S; McMenamin, Rachel L; Murray, Christopher W; Page, Lee W; Patel, Vipulkumar K; Potvain, Florent; Rich, Sharna J; Sang, Yingxia; Somers, Don O; Trottet, Lionel; Wan, Zehong; Zhang, Xiaomin

    2016-12-08

    Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.

  9. Involvement of intestinal permeability in the oral absorption of clarithromycin and telithromycin.

    Science.gov (United States)

    Togami, Kohei; Hayashi, Yoshiaki; Chono, Sumio; Morimoto, Kazuhiro

    2014-09-01

    The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, an in vitro transport experiment was performed using Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, the results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells.

  10. Synthesis and characterization of related substances and metabolite of tadalafil, a PDE-5 inhibitor

    Directory of Open Access Journals (Sweden)

    Goverdhan Gilla

    2013-03-01

    Full Text Available Tadalafil (Cialis is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP-specific phosphodiesterase type-5 (PDE-5 and it is administered orally for the treatment of erectile dysfunction (ED. Two synthetic schemes were evaluated to study the impurity profile of tadalafil. Six impurities were detected in the bulk substance (prepared by two methods at a level of 0.1-0.15%. Identification, synthesis, characterization of impurities (related substances and metabolite and origin of their formation is described .

  11. Role of angiotensin-converting enzyme inhibitor, lisinopril, on spermatozoal functions in rats.

    Science.gov (United States)

    Saha, L; Garg, S K; Bhargava, V K; Mazumdar, S

    2000-04-01

    Angiotensin-converting enzyme is present in the male reproductive system but its role in the physiology of reproduction is not known. To see the effect of angiotensin-converting enzyme on spermatozoal functions, lisinopril, an angiotensin-converting enzyme inhibitor, was administered orally using two different doses (10 and 20 mg/kg/day) to rats. Both short-term (2 weeks) and long-term (6 weeks) effects of the drug were observed. Lisinopril treatment resulted in a marked decrease in sperm density, sperm motility and zona pellucida penetration. Acrosome reaction by spermatozoa obtained from drug-treated animals was significantly lower when compared with spermatozoa from normal animals.

  12. Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate

    Directory of Open Access Journals (Sweden)

    Michael Eder de Oliveira

    2013-12-01

    Full Text Available Herein, we report the antimalarial activity of nine 4-methoxychalcone derivatives 1a–i and an initial analysis of their ADMET properties. All compounds showed potent activity against the P. falciparum chloroquine-resistant clone W2, with IC50 values ranging from 1.96 µM to 10.99 µM, with moderate or low cytotoxicity against the HeLa cell line. The compound 1a (IC50 = 2.06 µM had the best selectivity index (9.0. All the sulfonamide 4-metychalcone derivatives synthesized had cLogP values between 2 and 5 (mean value 3.79 and molecular weights (MWs below 500. The substitution of the pyrrolidine group in 1i by a morpholine group in 1a reduced the cLogP value from 3.05 in compound 1i to 2.34 in compound 1a. Indeed, compound 1a had the highest LipE value. The binding free energy of compound 1a showed it to be the most optimal chalcone derivative for plasmepsin-2 (−7.3 Kcal/mol. The physicochemical properties and LipE analysis of the dataset allowed us to establish that compound 1a is the highest quality compound of the series and a potential oral lead candidate.

  13. Discovery of 3H-Benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (PIM) Kinases

    Energy Technology Data Exchange (ETDEWEB)

    Tao, Zhi-Fu; Hasvold, Lisa A.; Leverson, Joel D.; Han, Edward K.; Guan, Ran; Johnson, Eric F.; Stoll, Vincent S.; Stewart, Kent D.; Stamper, Geoff; Soni, Nirupama; Bouska, Jennifer J.; Luo, Yan; Sowin, Thomas J.; Lin, Nan-Horng; Giranda, Vincent S.; Rosenberg, Saul H.; Penning, Thomas D.; (Abbott)

    2010-02-19

    Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been found to be overexpressed in a variety of hematopoietic malignancies and solid tumors. Benzothienopyrimidinones were discovered as a novel class of Pim inhibitors that potently inhibit all three Pim kinases with subnanomolar to low single-digit nanomolar K{sub i} values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones 3b (PDB code 3JYA), 6e (PDB code 3JYO), and 12b (PDB code 3JXW) were determined and used to guide SAR studies. Multiple compounds exhibited potent antiproliferative activity in K562 and MV4-11 cells with submicromolar EC{sub 50} values. For example, compound 14j inhibited the growth of K562 cells with an EC{sub 50} value of 1.7 {micro}M and showed K{sub i} values of 2, 3, and 0.5 nM against Pim-1, Pim-2, and Pim-3, respectively. These novel Pim kinase inhibitors efficiently interrupted the phosphorylation of Bad in both K562 and LnCaP-Bad cell lines, indicating that their potent biological activities are mechanism-based. The pharmacokinetics of 14j was studied in CD-1 mice and shown to exhibit bioavailability of 76% after oral dosing. ADME profiling of 14j suggested a long half-life in both human and mouse liver microsomes, good permeability, modest protein binding, and no CYP inhibition below 20 {micro}M concentration.

  14. In vitro activity of a new oral glucan synthase inhibitor (MK-3118) tested against Aspergillus spp. by CLSI and EUCAST broth microdilution methods.

    Science.gov (United States)

    Pfaller, Michael A; Messer, Shawn A; Motyl, Mary R; Jones, Ronald N; Castanheira, Mariana

    2013-02-01

    MK-3118, a glucan synthase inhibitor derived from enfumafungin, and comparator agents were tested against 71 Aspergillus spp., including itraconazole-resistant strains (MIC, ≥ 4 μg/ml), using CLSI and EUCAST reference broth microdilution methods. The CLSI 90% minimum effective concentration (MEC(90))/MIC(90) values (μg/ml) for MK-3118, amphotericin B, and caspofungin, respectively, were as follows: 0.12, 2, and 0.03 for Aspergillus flavus species complex (SC); 0.25, 2, and 0.06 for Aspergillus fumigatus SC; 0.12, 2, and 0.06 for Aspergillus terreus SC; and 0.06, 1, and 0.03 for Aspergillus niger SC. Essential agreement between the values found by CLSI and EUCAST (± 2 log(2) dilution steps) was 94.3%. MK-3118 was determined to be a potent agent regardless of the in vitro method applied, with excellent activity against contemporary wild-type and itraconazole-resistant strains of Aspergillus spp.

  15. National Maternal and Child Oral Health Resource Center

    Science.gov (United States)

    ... a central convener, coordinator, and promoter of new oral health knowledge and skills. OHRC Announces MCHB Award OHRC has been awarded a cooperative agreement to administer the Center for Oral Health Systems Integration and Improvement . Healthy Futures Proceedings ...

  16. All-oral therapy with nucleotide inhibitors sofosbuvir and GS-0938 for 14 days in treatment-naive genotype 1 hepatitis C (nuclear).

    Science.gov (United States)

    Lawitz, E J; Rodriguez-Torres, M; Denning, J; Mathias, A; Mo, H; Gao, B; Cornpropst, M T; Berrey, M M; Symonds, W T

    2013-10-01

    Sofosbuvir and GS-0938 are distinct nucleotide analogues with activity against hepatitis C virus (HCV) in vitro. We evaluated the antiviral activity and safety of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 patients. In this double-blind study, 40 treatment-naïve patients were randomly assigned to 4 treatment cohorts: (i) GS-0938 for 14 days, (ii) GS-0938 for 7 days followed by GS-0938 plus sofosbuvir for 7 days, (iii) sofosbuvir for 7 days followed by GS-0938 plus sofosbuvir for 7 days and (iv) GS-0938 plus sofosbuvir for 14 days. In each arm, 8 patients received active drug and 2 placebo. After 7 days of dosing, patients in all 4 dose groups experienced substantial reductions in HCV RNA, with median declines (Q1, Q3) of -4.50 (-4.66, -4.24) in Cohort 1, -4.55 (-4.97, -4.13) in Cohort 2, -4.65 (-4.78, -4.17) in Cohort 3 and -4.43 (-4.81, -4.13) in Cohort 4; patients receiving placebo had essentially no change in HCV RNA (+0.07 log(10) IU/mL). Seven days after the end of treatment, the proportions of patients with HCV RNA Sofosbuvir and GS-0938-alone and in combination--were well tolerated and led to substantial reductions in viral load. Sofosbuvir is undergoing further investigation as a possible backbone of an all-oral regimen for chronic HCV.

  17. Activity of MK-3118, a new oral glucan synthase inhibitor, tested against Candida spp. by two international methods (CLSI and EUCAST).

    Science.gov (United States)

    Pfaller, Michael A; Messer, Shawn A; Motyl, Mary R; Jones, Ronald N; Castanheira, Mariana

    2013-04-01

    To evaluate the activity of the orally bioavailable enfumafungin derivative MK-3118 and comparator antifungal agents tested against a collection of 113 clinical isolates of Candida spp. using CLSI and EUCAST broth microdilution (BMD) methods. Candida spp. isolates (n=113) were tested by CLSI and EUCAST methods. The collection contained 29 Candida albicans, 29 Candida glabrata, 21 Candida tropicalis, 15 Candida parapsilosis and 19 Candida krusei, including azole- and echinocandin-resistant isolates. CLSI and EUCAST MIC endpoints of 50% and 100% inhibition were determined using visual reading at 24 and 48 h of incubation and spectrophotometric reading at 24 h of incubation, respectively. MK-3118 CLSI MIC results ranged from 0.06 to 16 mg/L depending on species, duration of incubation and endpoint criteria (EC) used. Comparison of CLSI and EUCAST following 24 h of incubation and either 50% or 100% inhibition revealed an essential agreement (EA; ± 2 doubling dilutions) of 99.1% using the 50% inhibition EC and 93.2% using the 100% inhibition EC. MK-3118 (24 h of incubation and 50% EC) was active against all the species tested and displayed similar potency to caspofungin (using CLSI BMD) against C. albicans (MIC90, 1 and 2 mg/L, respectively), C. tropicalis (1 and 1 mg/L, respectively), C. parapsilosis (0.5 and 0.5 mg/L, respectively) and C. krusei (2 and 1 mg/L, respectively), but was 8-fold more potent than caspofungin against C. glabrata strains (MIC90, 2 and 16 mg/L, respectively). MK-3118 was active against fluconazole-resistant strains as well as caspofungin-resistant strains with documented fks mutations. MK-3118 was documented to have potent in vitro activity against Candida spp. when tested by both CLSI and EUCAST BMD methods, with the highest overall EA (99.1%) obtained when MK-3118 MIC results were read after 24 h of incubation using a partial inhibition EC (50%).

  18. Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06-02)

    Science.gov (United States)

    Iwamoto, Fabio M.; Lamborn, Kathleen R.; Robins, H. Ian; Mehta, Minesh P.; Chang, Susan M.; Butowski, Nicholas A.; DeAngelis, Lisa M.; Abrey, Lauren E.; Zhang, Wei-Ting; Prados, Michael D.; Fine, Howard A.

    2010-01-01

    The objective of this phase II single-arm study was to evaluate the efficacy and safety of pazopanib, a multi-targeted tyrosine kinase inhibitor, against vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor-α and -β, and c-Kit, in recurrent glioblastoma. Patients with ≤2 relapses and no prior anti-VEGF/VEGFR therapy were treated with pazopanib 800 mg daily on 4-week cycles without planned interruptions. Brain magnetic resonance imaging and clinical reassessment were made every 8 weeks. The primary endpoint was efficacy as measured by 6-month progression-free survival (PFS6). Thirty-five GBM patients with a median age of 53 years and median Karnofsky performance scale of 90 were accrued. Grade 3/4 toxicities included leukopenia (n = 1), lymphopenia (n = 2), thrombocytopenia (n = 1), ALT elevation (n = 3), AST elevation (n = 1), CNS hemorrhage (n = 1), fatigue (n = 1), and thrombotic/embolic events (n = 3); 8 patients required dose reduction. Two patients had a partial radiographic response by standard bidimensional measurements, whereas 9 patients (6 at the 8-week point and 3 only within the first month of treatment) had decreased contrast enhancement, vasogenic edema, and mass effect but <50% reduction in tumor. The median PFS was 12 weeks (95% confidence interval [CI]: 8–14 weeks) and only 1 patient had a PFS time ≥6 months (PFS6 = 3%). Thirty patients (86%) had died and median survival was 35 weeks (95% CI: 24–47 weeks). Pazopanib was reasonably well tolerated with a spectrum of toxicities similar to other anti-VEGF/VEGFR agents. Single-agent pazopanib did not prolong PFS in this patient population but showed in situ biological activity as demonstrated by radiographic responses. ClinicalTrials.gov identifier: NCT00459381. PMID:20200024

  19. A meta-regression evaluating the effectiveness and prognostic factors of oral phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction

    Directory of Open Access Journals (Sweden)

    Jin-Qiu Yuan

    2016-01-01

    Full Text Available The effectiveness of phosphodiesterase type 5 inhibitors (PDE5-Is for erectile dysfunction (ED varies considerably among trials, but available studies investigating the factors that affect the effectiveness are few and findings are not consistent. A systematic search was performed in PubMed, Cochrane Library, and EMBASE to identify randomized controlled trials comparing PDE5-Is with placebo for the treatment of ED. The methodological quality of included studies was assessed by the Cochrane Collaboration′s tool for assessing risk of bias. The associations between prespecified study-level factors and effectiveness were tested by a random effects meta-regression model. This study included 93 trials with 26 139 patients. When all PDE5-Is were grouped together, Caucasian ethnicity was associated with 15.636% (95% confidence interval [CI]: 0.858% to 32.579% increase in risk ratio (RR for Global Assessment Questionnaire question-1 (GAQ-1, and 1.473 (95% CI: 0.406 to 2.338 score increase in mean difference (MD for posttreatment International Index of Erectile Function-Erectile Function domain score (IIEF-EF, compared to Asian ethnicity. A one-score increase in baseline IIEF-EF was associated with −5.635% (95% CI: −9.120% to −2.017% reduction in RR for GAQ-1, and −0.229 (95% CI: −0.425 to −0.042 score decrease in MD for posttreatment IIEF-EF. In conclusion, PDE5-Is are more effective in Caucasians than Asians, and in patients with more severe ED.

  20. Comparative study of proton pump inhibitors on dexamethasone plus pylorus ligation induced ulcer model in rats

    Directory of Open Access Journals (Sweden)

    Thippeswamy A. H. M.

    2010-01-01

    Full Text Available The present study was designed to compare ulcer protective effect of proton pump inhibitors viz. omeprazole, rabeprazole and lansoprazole against dexamethasone plus pylorus ligation induced ulcer model. Dexamethasone (5 mg/kg was used as an ulcerogen. Dexamethasone suspended in 1% CMC in water was given orally to all the rats 15 min after the pylorus ligation. Omeprazole (20 mg/kg, rabeprazole (20 mg/kg, and lansoprazole (20 mg/kg were administered by oral route 30 min prior to ligation was used for ulcer protective studies, gastric secretion and mucosal studies. Effects of proton pump inhibitors were determined by the evaluation of various biochemical parameters such as ulcer index, free and total acidity, gastric pH, mucin, pepsin and total proteins. Oral administration of proton pump inhibitors showed significant reduction in gastric acid secretion and ulcer protective activity against dexamethasone plus pylorus ligation induced ulcer model. The % protection of omeprazole, rabeprazole and lansoprazole was 84.04, 89.36 and 79.78, respectively. Rabeprazole significantly inhibited the acid-pepsin secretion and increased the gastric mucin secretion. The observations made in the present study suggest that rabeprazole is the most effective gastric antisecretory and ulcer healing agent as compared to omeprazole and lansoprazole.

  1. Research progress on quorum sensing inhibitors in oral microbiol area%密度感应抑制剂及其在口腔微生物领域中的研究进展

    Institute of Scientific and Technical Information of China (English)

    王爽; 张利平

    2012-01-01

    Quorum sensing systems are bacterial cell-to-cell communication systems. Some natural substances and chemical compounds found recently interfere with quorum sensing systems. In this review we highlight inhibitors of acylhomoserine lactone and LuxS/AI-2 mediated quorum sensing in gram-negative bacteria and the corresponding research outcomes in the oral microbiol area.%密度感应即密度感知或群体感应,是细菌彼此间信号传递的一种机制.诸多的天然植物提取物和化合物皆具有抑制密度感应的作用.本文就革兰阴性菌的密度感应系统中N-酰基高丝氨酸内酯抑制剂和LuxS/AI-2信号系统拮抗剂及其在口腔领域中的应用作一综述.

  2. The Pharmacodynamic Impact of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, on Circulating Levels of Inflammatory Biomarkers in Patients with Psoriatic Arthritis: Substudy Results from a Phase III, Randomized, Placebo-Controlled Trial (PALACE 1

    Directory of Open Access Journals (Sweden)

    Peter H. Schafer

    2015-01-01

    Full Text Available Apremilast, an oral phosphodiesterase 4 inhibitor, demonstrated effectiveness (versus placebo for treatment of active psoriatic arthritis in the psoriatic arthritis long-term assessment of clinical efficacy (PALACE phase III clinical trial program. Pharmacodynamic effects of apremilast on plasma biomarkers associated with inflammation were evaluated in a PALACE 1 substudy. Of 504 patients randomized in PALACE 1, 150 (placebo: n=51; apremilast 20 mg BID: n=51; apremilast 30 mg BID: n=48 provided peripheral blood plasma samples for analysis in a multiplexed cytometric bead array assay measuring 47 proteins associated with systemic inflammatory immune responses. Association between biomarker levels and achievement of 20% improvement from baseline in modified American College of Rheumatology (ACR20 response criteria was assessed by logistic regression. At Week 24, IL-8, TNF-α, IL-6, MIP-1β, MCP-1, and ferritin were significantly reduced from baseline with apremilast 20 mg BID or 30 mg BID versus placebo. ACR20 response correlated with change in TNF-α level with both apremilast doses. At Week 40, IL-17, IL-23, IL-6, and ferritin were significantly decreased and IL-10 and IL-1 receptor antagonists significantly increased with apremilast 30 mg BID versus placebo. In patients with active psoriatic arthritis, apremilast reduced circulating levels of Th1 and Th17 proinflammatory mediators and increased anti-inflammatory mediators.

  3. Fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis: a meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Kunwar, Sumit; Devkota, Ashok Raj; Ghimire, Dipesh K C

    2016-08-01

    Fostamatinib is a selective inhibitor of spleen tyrosine kinase which has a role in the pathogenesis of RA. Multiple RCTs have been performed to study the effects of fostamatinib. The objective of this study was to perform a meta-analysis to analyze the efficacy and safety of fostamatinib in the management of RA. We searched PubMed, EMBASE and Cochrane CENTRAL through 11/9/15. Random effect model was used to estimate odds ratio (OR) and 95 % confidence interval. We measured outcomes with efficacy analysis using ACR20/50/70 response criteria and safety with adverse events. Five studies were included in the meta-analysis with total of 2105 patients including 1419 in fostamatinib group and 686 in placebo. Fostamatinib was effective in achieving ACR20, ACR50 and ACR70 responses compared to placebo (48 vs. 32.8 %, OR 1.86, 95 % CI 1.32-2.62, P = 0.0004, I (2) 63 %; 26.4 vs. 12.5 %, OR 2.50, 95 % CI 1.93-3.23, P < 0.00001, I (2) 0 % and 12.7 vs. 4.4 %, OR 3.00, 95 % CI 1.99-4.51, P < 0.00001, I (2) 0 %, respectively). Response to fostamatinib was rapid and significant effect on ACR20 response was seen by week 1 (OR 3.70, 95 % CI 2.33-5.87, P < 0.00001, I (2) 42 %). Safety analysis showed an increased risk of infection (OR 1.59, 95 % CI 1.2-2.11; P = 0.001; I (2) 0 %), diarrhea (OR 3.54; 95 % CI 2.43-5.16; P < 0.00001; I (2) 2 %), hypertension (OR 2.55, 95 % CI 1.54-4.22, P = 0.0003; I (2) 42 %) and neutropenia (OR 5.68, 95 % CI 1.97-16.42, P = 0.001, I (2) 35 %) and showed a trend toward the increase in ALT ≥3 times ULN (OR 1.76, 95 % CI 0.99-3.13; P = 0.05; I (2) 0 %). This meta-analysis concludes that fostamatinib has moderate effect in the treatment of RA with mostly mild-to-moderate adverse events and dose-dependent, transient neutropenia and hypertransaminasemia.

  4. An oral cathepsin K inhibitor ONO-5334 inhibits N-terminal and C-terminal collagen crosslinks in serum and urine at similar plasma concentrations in postmenopausal women.

    Science.gov (United States)

    Tanaka, Makoto; Hashimoto, Yoshitaka; Hasegawa, Chihiro

    2015-12-01

    Relationships between the plasma concentration of a cathepsin K inhibitor (ONO-5334) and inhibition of bone resorption markers N-telopeptide of type I collagen (NTX) and C-telopeptide of type I collagen (CTX) in serum and urinary NTX/creatinine and CTX/creatinine were examined in 10 postmenopausal women. The subjects received slow-release tablets of 100mg ONO-5534 under fasted or fed conditions in a study with a crossover design. Inhibition of serum NTX and CTX levels and plasma concentrations of ONO-5334 were monitored at 0, 24, 48 and 168 h after dosing. Changes in urinary NTX/creatinine and CTX/creatinine levels in second morning urine were evaluated on 0, 1, 2 and 7 days after dosing. Data were analyzed using sigmoid maximal drug effect (Emax) models. The maximal inhibition, estimated Emax values, were -31.8% for serum NTX, -53.1% for serum CTX, -67.2% for urinary NTX/creatinine, and -95.2% for urinary CTX/creatinine. The estimated half maximal effective plasma concentrations (EC50) of ONO-5334 and confidence intervals were 1.79 (1.01 to 3.16) ng/mL for serum NTX, 2.07 (1.63 to 2.62) ng/mL for serum CTX, 1.85 (1.30 to 2.61) ng/mL for urinary NTX/creatinine, and 1.98 (0.94 to 3.76) ng/mL for urinary CTX/creatinine. EC50 values for the four crosslinks did not significantly differ, as indicated by the overlapping 95% confidence intervals. The highest signal-to-noise ratio was achieved with serum CTX, and was 2-fold higher than that on serum NTX. Inhibition for serum NTX and CTX, and urinary NTX/creatinine and CTX/creatinine by ONO-5334 were all correlated with correlation coefficients ranging from 0.55 to 0.80. In conclusion, data of ONO-5334 slow-releasing tablets in postmenopausal women were well fitted in Emax model. In all measured telopeptides, the maximal inhibition was obtained at urinary CTX/creatinine level, but serum CTX had the highest signal-to-noise ratio. Inhibition for all measured telopeptides by ONO-5334 were all correlated. The estimated half

  5. Oral Medication

    Science.gov (United States)

    ... Size: A A A Listen En Español Oral Medication The first treatment for type 2 diabetes blood ... new — even over-the-counter items. Explore: Oral Medication How Much Do Oral Medications Cost? Save money ...

  6. Oral myiasis

    OpenAIRE

    Thalaimalai Saravanan; Mathan A Mohan; Meera Thinakaran; Saneem Ahammed

    2015-01-01

    Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability ...

  7. Primed Activation of Macrophages by Oral Administration of Lipopolysaccharide Derived from Pantoea agglomerans.

    Science.gov (United States)

    Inagawa, Hiroyuki; Kobayashi, Yutaro; Kohchi, Chie; Zhang, Ran; Shibasaki, Yasuhiro; Soma, Gen-Ichiro

    2016-01-01

    Bacterial lipopolysaccharide (LPS) is involved in the activation of the innate immune responses on monocytes/macrophages in vitro, and by intravenous injection. Although small quantities of LPS are usually found in traditional Chinese medicines, vegetables and fruits, the mode of action of orally administered LPS is still unclear. LPS derived from Pantoea agglomerans (LPSp) was orally administered to C3H/HeN or C3H/HeJ mice ad libitum. The LPSp treatment enhanced phagocytosis by resident peritoneal macrophages of C3H/HeN mice but not of C3H/HeJ mice. This activation can be defined as primed activation because no augmentation of inflammatory cytokines production was detected. LPSp in peritoneal fluid was detected and successfully quantified. Moreover, the LPSp reduced the expression of avian reticuloendotheliosis viral oncogene-related B (RelB) in the macrophages without degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor, alpha (IκBα). Orally administered LPSp can reach the peritoneum, and enhance phagocytosis via Toll-like receptor 4 signaling pathway in resident peritoneal macrophages. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  8. (2R)-4-Oxo-4[3-(Trifluoromethyl)-5,6-diihydro:1,2,4}triazolo[4,3-a}pyrazin-7(8H)-y1]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, D.; Wang, L.; Beconi, M.; Eiermann, G.; Fisher, M.; He, H.; Hickey, G.; Kowalchick, Jennifer; Leiting, Barbara; Lyons, K.; Marsilio, F.; McCann, F.; Patel, R.; Petrov, A.; Scapin, G.; Patel, S.; Roy, R.; Wu, J.; Wyvratt, M.; Zhang, B.; Zhu, L.; Thornberry, N.; Weber, A. (Merck)

    2010-11-10

    A novel series of {beta}-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC{sub 50} = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.

  9. Design and synthesis of a novel family of triazine-based inhibitors of sorbitol dehydrogenase with oral activity: 1-[4-[3R,5S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-[1,3,5]triazin-2-yl]-(R) ethanol.

    Science.gov (United States)

    Mylari, Banavara L; Withbroe, Gregory J; Beebe, David A; Brackett, Nathaniel S; Conn, Edward L; Coutcher, James B; Oates, Peter J; Zembrowski, William J

    2003-09-15

    Two new templates, (R) 2-hydroxyethyl-pyridine and (R) 2-hydroxyethyl-triazine, were used to design novel sorbitol dehydrogenase inhibitors (SDIs). The design concept included spawning of these templates to function as effective ligands to the catalytic zinc within the enzyme through incorporation of optimally substituted piperazino-triazine side chains so as to accommodate the active site in the enzyme for efficient binding. This strategy resulted in orally active SDIs, which penetrate key tissues, for example, sciatic nerve of chronically diabetic rats. The latter template led to the design of the title inhibitor, 33, which normalized the elevated sciatic nerve fructose by 96% at an oral dose of 10mg/kg.

  10. Analysis and Evaluation of Clinical Application and Safety of Oral Proton Pump Inhibitor Preparations%口服质子泵抑制剂临床应用及安全性评价分析

    Institute of Scientific and Technical Information of China (English)

    司继刚; 孙敏

    2015-01-01

    质子泵抑制剂(PPI)能够特异性地作用于胃黏膜壁细胞,抑制壁细胞中H+-K+-ATP酶的活性,对各种原因引起的胃酸分泌具有强而持久的抑制作用。PPI广泛应用于消化性溃疡、胃食管反流病、幽门螺杆菌感染、消化道出血等疾病的治疗,以及用于预防应激性急性胃黏膜损伤。但是,近年来PPI口服制剂的过度使用、不正确的使用方法、不合理的联合用药及药物相互作用导致的安全性及不规范使用问题较为突出。本文回顾了PPI口服制剂临床应用的相关文献,对口服制剂的的分类、作用特点、临床使用方法、药物相互作用及药品不良反应等进行了综述分析,以促进PPI口服制剂的安全合理使用。%Proton pump inhibitors (PPI) can inhibit H+-K+-ATP enzyme activity in the cell wall through specifically acting on parietal cells of the gastric mucosa, and have strong and long-lasting inhibition on secretion of gastric acid due to various causes. PPI are widely used in peptic ulcers, gastroesophageal re-flux disease, Helicobacter pylori infection, gastrointestinal bleeding and prevention of stress of acute gastric mucosal injury. However, in recent years, excessive use of oral PPI, improper method of use, irrational combined use of drugs and drug interactions lead to prominent problems of safety and rationality. This pa-per reviews the literatures related to PPI oral preparations on their classification, characteristics, clinical applications, drug interactions and adverse drug reactions, in order to promote safe and rational use of PPI.

  11. Nurse-administered propofol sedation for endoscopy

    DEFF Research Database (Denmark)

    Jensen, J T; Vilmann, P; Horsted, T

    2011-01-01

    The aim of the present study was to perform a risk analysis during the implementation phase of nurse-administered propofol sedation (NAPS) and to validate our structured training program.......The aim of the present study was to perform a risk analysis during the implementation phase of nurse-administered propofol sedation (NAPS) and to validate our structured training program....

  12. 22 CFR 196.4 - Administering office.

    Science.gov (United States)

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Administering office. 196.4 Section 196.4 Foreign Relations DEPARTMENT OF STATE INTERNATIONAL COMMERCIAL ARBITRATION THOMAS R. PICKERING FOREIGN AFFAIRS/GRADUATE FOREIGN AFFAIRS FELLOWSHIP PROGRAM § 196.4 Administering office. The Department of State...

  13. Oral pre-exposure prophylaxis by anti-retrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model.

    Directory of Open Access Journals (Sweden)

    C Preston Neff

    Full Text Available Sexual HIV-1 transmission by vaginal route is the most predominant mode of viral transmission, resulting in millions of new infections every year. In the absence of an effective vaccine, there is an urgent need to develop other alternative methods of pre-exposure prophylaxis (PrEP. Many novel drugs that are currently approved for clinical use also show great potential to prevent viral sexual transmission when administered systemically. A small animal model that permits rapid preclinical evaluation of potential candidates for their systemic PrEP efficacy will greatly enhance progress in this area of investigation. We have previously shown that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and displays CD4 T cell loss typical to that seen in the human. Thus far systemic PrEP studies have been primarily limited to RT inhibitors exemplified by tenofovir and emtricitabine. In these proof-of-concept studies we evaluated two new classes of clinically approved drugs with different modes of action namely, an integrase inhibitor raltegravir and a CCR5 inhibitor maraviroc as potential systemically administered chemo-prophylactics. Our results showed that oral administration of either of these drugs fully protects against vaginal HIV-1 challenge in the RAG-hu mouse model. Based on these results both these drugs show great promise for further development as orally administered PrEPs.

  14. MucoRice-cholera toxin B-subunit, a rice-based oral cholera vaccine, down-regulates the expression of α-amylase/trypsin inhibitor-like protein family as major rice allergens.

    Science.gov (United States)

    Kurokawa, Shiho; Nakamura, Rika; Mejima, Mio; Kozuka-Hata, Hiroko; Kuroda, Masaharu; Takeyama, Natsumi; Oyama, Masaaki; Satoh, Shigeru; Kiyono, Hiroshi; Masumura, Takehiro; Teshima, Reiko; Yuki, Yoshikazu

    2013-07-05

    To develop a cold chain- and needle/syringe-free rice-based cholera vaccine (MucoRice-CTB) for human use, we previously advanced the MucoRice system by introducing antisense genes specific for endogenous rice storage proteins and produced a molecularly uniform, human-applicable, high-yield MucoRice-CTB devoid of plant-associated sugar. To maintain the cold chain-free property of this vaccine for clinical application, we wanted to use a polished rice powder preparation of MucoRice-CTB without further purification but wondered whether this might cause an unexpected increase in rice allergen protein expression levels in MucoRice-CTB and prompt safety concerns. Therefore, we used two-dimensional fluorescence difference gel electrophoresis and shotgun MS/MS proteomics to compare rice allergen protein expression levels in MucoRice-CTB and wild-type (WT) rice. Both proteomics analyses showed that the only notable change in the expression levels of rice allergen protein in MucoRice-CTB, compared with those in WT rice, was a decrease in the expression levels of α-amylase/trypsin inhibitor-like protein family such as the seed allergen protein RAG2. Real-time PCR analysis showed mRNA of RAG2 reduced in MucoRice-CTB seed. These results demonstrate that no known rice allergens appear to be up-reregulated by genetic modification of MucoRice-CTB, suggesting that MucoRice-CTB has potential as a safe oral cholera vaccine for clinical application.

  15. Oral heparin: status review

    Directory of Open Access Journals (Sweden)

    Gomez-Orellana Isabel

    2006-05-01

    Full Text Available Abstract Unfractionated heparin and low molecular weight heparin are the most commonly used antithrombotic and thromboprophylactic agents in hospital practice. Extended out-of-hospital treatment is inconvenient in that these agents must be administered parenterally. Current research is directed at development of a safe and effective oral antithrombotic agent as an alternative for the effective, yet difficult to use vitamin K antagonists. A novel drug delivery technology that facilitates transport of drugs across the gastrointestinal epithelium has been harnessed to develop an oral dosage form of unfractionated heparin. Combining unfractionated heparin with the carrier molecule, sodium N-(8 [2-hydroxybenzoyl]amino caprylate, or SNAC has markedly increased the gastrointestinal absorption of this drug. Preclinical and clinical studies to-date suggests that oral heparin-SNAC can confer a clinical efficacious effect; further confirmation is sought in planned clinical trials.

  16. Review article: immediate-release proton-pump inhibitor therapy--potential advantages.

    Science.gov (United States)

    Howden, C W

    2005-12-01

    The absorption of most oral proton-pump inhibitors is delayed by the enteric coating required to protect the acid-labile proton-pump inhibitor from degradation in the stomach and, as a result, antisecretory effect is also delayed. This article provides an overview of the pharmacokinetics and pharmacodynamics of a new immediate-release omeprazole [(IR-OME) Zegerid power for oral suspension; Santarus Inc., San Diego, CA, USA] and its potential advantages over delayed-release proton-pump inhibitors. Immediate-release omeprazole has a higher mean peak plasma omeprazole concentration (C(max)) and a significantly shorter mean time to reach C(max) (t(max)) than delayed-release omeprazole. Immediate-release omeprazole 40 mg has a prolonged antisecretory effect with median intragastric pH above 4.0 for 18.6 h/day at steady-state, after 7 days of once daily dosing. The sodium bicarbonate in immediate-release omeprazole protects the uncoated omeprazole from degradation by gastric acid. The accelerated antisecretory action of immediate-release omeprazole compared with delayed-release omeprazole may be due to the activation of proton pumps by the rapid neutralization of intragastric acid by the sodium bicarbonate. The faster onset of action seen with immediate-release omeprazole is not achieved by using an antacid with a delayed-release proton-pump inhibitor, because administering antacids with conventional delayed-release proton-pump inhibitors does not significantly enhance absorption of the proton-pump inhibitor. In conclusion, immediate-release omeprazole is associated with rapid absorption of omeprazole and rapid onset of antisecretory effect, without compromising the duration of acid suppression.

  17. Drug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir.

    Science.gov (United States)

    Ouwerkerk-Mahadevan, Sivi; Snoeys, Jan; Peeters, Monika; Beumont-Mauviel, Maria; Simion, Alexandru

    2016-02-01

    Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug-drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.

  18. Pharmacokinetics of Three Benzimidazoles Suspended in Oleic Acid,Soybean Oil or 1% Tragacanth,and Administered Orally to Mice at A Single Dose%小鼠口服3种苯并咪唑类药物的油酸、大豆油和1%西黄耆胶混悬剂的药动学

    Institute of Scientific and Technical Information of China (English)

    姜斌; 张皓冰; 刘丛珊; 陶奕

    2012-01-01

    OBJECTIVE To determine the pharmacokinetics of three benzimidazoles ( albendazole, fenbendazole and fluben-dazole) suspended in three different media [oleic acid, soybean oil or 1% tragacanth (served as control) ] in mice, and observe the correlation of those pharmacokinetic parameters with the solubilities of the three benzimidazoles in corresponding medium. METHODS Albendazole, fenbendazole and flubendazole suspened in oleic acid, soybean oil or 1% tragacanth were prepared by ball grinding mill. Groups of 45 - 54 mice were administered orally with one of aforementioned benzimidazole suspensions at a single dose of 100 mg·kg-1 ( albendazole) or 50 mg·kg-1 (fenbendazole and flubendazole). Subgroups with 5-6 mice in each group were bled at varying intervals within 24 h. Plasma was then separated from heparin-anticoagulated blood, and evaluated for the presence of the drug by high performance liquid chromatography ( HPLC ). Pharmacokinetic parameters of each drug were calculated using DAS ( Drug AnaLyze System). RESULTS After oral administration of three benzimidazoles suspended in oleic acid, soybean oil or 1% tragacanth, the pharmacokinetic parameters of each drug were described as follows; albendazole, the MRT (average retention time) were (3. 91 ± 0.29), (3.70±0.09) and (1. 59 ± 0. 14) h, ρmax (maximum concentration) were (0.66±0.08), (0.29±0.05) and (0. 34±0. 09) mg·L-1 , AUC (area under the concentration-time curve) were (3. 19 ±0.40) , (1. 25 ±0.09) and (0. 50 ±0. 05) mg·L·h-1, F (relative bioavailability, the AUC compared with that of 1% tragacanth group) were 6. 38 and 2. 50; fenbendazole, the MRT were (5. 72 ±0. 14) , (4. 83 ±0.38) and (3. 85 ±0.25) h, ρmax were( 0. 70 ± 0. 11) , (0.20 ±0.05) and (0. 12 ±0.03) mg·L-1 , AUC were (5. 02 ±0.73) , (1.08 ±0.21) and (0.52 ±0.07) mg·h·L-1 , F were 9.65 and 2.08; flubendazole, the MRT were (5.71 ±0.37), (4.59±0.39) and (3. 34 ±0.20) h, pmax were (0.93 ±0. 14), (0.58 ±0.09) and (0

  19. Oral myiasis

    Directory of Open Access Journals (Sweden)

    Thalaimalai Saravanan

    2015-01-01

    Full Text Available Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability and history of epilepsy.

  20. Single-dose and steady-state pharmacokinetics of diltiazem administered in two different tablet formulations

    DEFF Research Database (Denmark)

    Christrup, Lona Louring; Bonde, J; Rasmussen, S N

    1992-01-01

    Single-dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assessed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in tmax was observed (2.9 +/- 1.9 and 6.8 +/- 2.6 hr r...

  1. nduced hyperlipidemic rats. Methods: Column chromatographic fractionation of butanol fraction of total methanol extract of leaves of Bauhinia variegata (Linn. yields four sub-fractions (sub-fraction A-D. All sub-fractions tested for their anti-hyperlipidemic activity. Sub-fractions administered at a dose of 65 mg/kg (oral to the Triton WR-1339 induced hyperlipidemic rats and total cholesterol, triglycerides, HDL, LDL and VLDL

    Directory of Open Access Journals (Sweden)

    Deepak Kumar

    2012-10-01

    Full Text Available Objective: To investigate the effect and evaluation of Anti-hyperlipidemic activity guided subfraction isolated from total methanolic extract of Bauhinia variegata (Linn. leaves on Triton WR-1339 induced hyperlipidemic rats. Methods: Column chromatographic fractionation of butanol fraction of total methanol extract of leaves of Bauhinia variegata (Linn. yields four subfractions (sub-fraction A-D. All sub-fractions tested for their anti-hyperlipidemic activity. Subfractions administered at a dose of 65 mg/kg (oral to the Triton WR-1339 induced hyperlipidemic rats and total cholesterol, triglycerides, HDL, LDL and VLDL level in the blood were checked. Results: Sub-fraction D showed significant reduction (P<0.05 among four sub-fraction in comparison with standard drug fenofibrate. Conclusions: From the above study it could be concluded that butanol sub-fraction D of Bauhinia variegata (Linn. not only have resulted in significant reduction in cholesterol, triglyceride, LDL, VLDL level but also increases the HDL level at a reduced dose level.

  2. Renal-selective delivery and angiotensin-converting enzyme inhibition by subcutaneously administered captopril-lysozyme

    NARCIS (Netherlands)

    Prakash, Jai; van Loenen - Weemaes, Anne-miek; Haas, M; Proost, Hans; Meijer, D.K F; Moolenaar, Frits; Poelstra, Klaas; Kok, R.J

    In previous studies, we have demonstrated that the low molecular weight protein lysozyme can be used as a renal-selective drug carrier for delivery of the angiotensin-converting enzyme ( ACE) inhibitor captopril. Typically, such macromolecular drug-targeting preparations are administered

  3. Renal and hepatic histopathology of intraperitoneally administered ...

    African Journals Online (AJOL)

    user

    2016-10-12

    Oct 12, 2016 ... The biochemistry and histopathology of intraperitoneally administered potassium ... and necrosis of crops in birds. ..... The stressful behavior of respiratory impairment .... specific bile acid transport system) which is responsible.

  4. Antidotes for novel oral anticoagulants: current status and future potential.

    Science.gov (United States)

    Crowther, Mark; Crowther, Mark A

    2015-08-01

    The direct thrombin inhibitor dabigatran and the anti-Xa agents rivaroxaban, edoxaban, and apixaban are a new generation of oral anticoagulants. Their advantage over the vitamin K antagonists is the lack of the need for monitoring and dose adjustment. Their main disadvantage is currently the absence of a specific reversal agent. Dabigatran's, unlike the anti-Xa agents, absorption can be reduced by activated charcoal if administered shortly after ingestion and it can be removed from the blood with hemodialysis. Prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa all show some activity in reversing the anticoagulant effect of these drugs but this is based on ex vivo, animal, and volunteer studies. It is unclear, which, if any, of these drugs is the most suitable for emergency reversal. Three novel molecules (idarucizumab, andexanet, and PER977) may provide the most effective and safest way of reversal. These agents are currently in premarketing studies.

  5. Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor.

    Science.gov (United States)

    Deecher, Darlene C; Beyer, Chad E; Johnston, Grace; Bray, Jenifer; Shah, S; Abou-Gharbia, M; Andree, Terrance H

    2006-08-01

    The purpose of this study was to characterize a new chemical entity, desvenlafaxine succinate (DVS). DVS is a novel salt form of the isolated major active metabolite of venlafaxine. Competitive radioligand binding assays were performed using cells expressing either the human serotonin (5-HT) transporter (hSERT) or norepinephrine (NE) transporter (hNET) with K(i) values for DVS of 40.2 +/- 1.6 and 558.4 +/- 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 microM) at the human dopamine (DA) transporter. Inhibition of [3H]5-HT or [3H]NE uptake by DVS for the hSERT or hNET produced IC50 values of 47.3 +/- 19.4 and 531.3 +/- 113.0 nM, respectively. DVS (10 microM), examined at a large number of nontransporter targets, showed no significant activity. DVS (30 mg/kg orally) rapidly penetrated the male rat brain and hypothalamus. DVS (30 mg/kg orally) significantly increased extracellular NE levels compared with baseline in the male rat hypothalamus but had no effect on DA levels using microdialysis. To mimic chronic selective serotonin reuptake inhibitor treatment and to block the inhibitory 5-HT(1A) autoreceptors, a 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo hexanecarboxamide maleate salt (WAY-100635) (0.3 mg/kg s.c.), was administered with DVS (30 mg/kg orally). 5-HT increased 78% compared with baseline with no additional increase in NE or DA levels. In conclusion, DVS is a new 5-HT and NE reuptake inhibitor in vitro and in vivo that demonstrates good brain-to-plasma ratios, suggesting utility in a variety of central nervous system-related disorders.

  6. Oral vs. salivary diagnostics

    Science.gov (United States)

    Marques, Joana; Corby, Patricia M.; Barber, Cheryl A.; Abrams, William R.; Malamud, Daniel

    2015-05-01

    The field of "salivary diagnostics" includes studies utilizing samples obtained from a variety of sources within the oral cavity. These samples include; whole unstimulated saliva, stimulated whole saliva, duct saliva collected directly from the parotid, submandibular/sublingual glands or minor salivary glands, swabs of the buccal mucosa, tongue or tonsils, and gingival crevicular fluid. Many publications state "we collected saliva from subjects" without fully describing the process or source of the oral fluid. Factors that need to be documented in any study include the time of day of the collection, the method used to stimulate and collect the fluid, and how much fluid is being collected and for how long. The handling of the oral fluid during and post-collection is also critical and may include addition of protease or nuclease inhibitors, centrifugation, and cold or frozen storage prior to assay. In an effort to create a standard protocol for determining a biomarker's origin we carried out a pilot study collecting oral fluid from 5 different sites in the mouth and monitoring the concentrations of pro- and anti-inflammatory cytokines detected using MesoScaleDiscovery (MSD) electrochemiluminesence assays. Our data suggested that 3 of the cytokines are primarily derived from the submandibular gland, while 7 of the cytokines come from a source other than the major salivary glands such as the minor salivary glands or cells in the oral mucosae. Here we review the literature on monitoring biomarkers in oral samples and stress the need for determining the blood/saliva ratio when a quantitative determination is needed and suggest that the term oral diagnostic be used if the source of an analyte in the oral cavity is unknown.

  7. Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Kishimoto M

    2013-05-01

    Full Text Available Miyako KishimotoDepartment of Diabetes and Metabolic Medicine, Center Hospital, Tokyo, Japan; Diabetes and Metabolism Information Center, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, JapanAbstract: Dipeptidyl peptidase-4 (DPP-4 inhibitors have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin, a novel DPP-4 inhibitor, exhibits a unique structure characterized by five consecutive rings, which produce a potent and long-lasting effect. Teneligliptin is currently used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea- or thiazolidine-class drugs. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day. Because the metabolites of this drug are eliminated via renal and hepatic excretion, no dose adjustment is necessary in patients with renal impairment. The safety profile of teneligliptin is similar to those of other available DPP-4 inhibitors. However, caution needs to be exercised when administering teneligliptin to patients who are prone to QT prolongation. One study has reported that the postprandial blood glucose-lowering effects of teneligliptin administered prior to breakfast were sustained throughout the day, and the effects observed after dinner were similar to those observed after breakfast or lunch. Thus, although clinical data for this new drug are limited, this drug shows promise in stabilizing glycemic fluctuations throughout the day and consequently suppressing the progression of diabetic complications. However, continued evaluation in long-term studies and clinical trials is required to evaluate the efficacy and safety of the drug as well as to identify additional indications for its clinical use

  8. Oral Thrush

    Science.gov (United States)

    ... feeding mothers In addition to the distinctive white mouth lesions, infants may have trouble feeding or be fussy ... candidiasis (yeast infection) patient information. American Academy of Oral & Maxillofacial Pathology. http://www.aaomp.org/public/oral-candidiasis.php. ...

  9. Oral Dysfunction

    OpenAIRE

    鈴木, 規子; スズキ, ノリコ; Noriko, SUZUKI

    2004-01-01

    The major oral functions can be categorized as mastication, swallowing, speech and respiratory functions. Dysfunction of these results in dysphagia, speech disorders and abnormal respiration (such as Sleep Apnea). These functions relate to dentistry in the occurrence of : (1) oral preparatory and oral phases, (2) articulation disorders and velopharyngeal incompetence (VPI), and (3) mouth breathing, respiratory and blowing disorders. These disorders are related to oral and maxillofacial diseas...

  10. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.

    Science.gov (United States)

    Alexander, John H; Becker, Richard C; Bhatt, Deepak L; Cools, Frank; Crea, Filippo; Dellborg, Mikael; Fox, Keith A A; Goodman, Shaun G; Harrington, Robert A; Huber, Kurt; Husted, Steen; Lewis, Basil S; Lopez-Sendon, Jose; Mohan, Puneet; Montalescot, Gilles; Ruda, Mikhail; Ruzyllo, Witold; Verheugt, Freek; Wallentin, Lars

    2009-06-09

    After an acute coronary syndrome, patients remain at risk of recurrent events. Apixaban, an oral direct factor Xa inhibitor, is a novel anticoagulant that may reduce these events but also poses a risk of bleeding. Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) was a phase 2, double-blind, placebo-controlled, dose-ranging study. Patients (n=1715) with recent ST-elevation or non-ST-elevation acute coronary syndrome were randomized to 6 months of placebo (n=611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n=317), 10 mg once daily (n=318), 10 mg twice daily (n=248), or 20 mg once daily (n=221). Nearly all patients received aspirin; 76% received clopidogrel. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. At the recommendation of the Data Monitoring Committee, the 2 higher-dose apixaban arms were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (hazard ratio, 1.78; 95% confidence interval, 0.91 to 3.48; P=0.09) and 10 mg once daily (hazard ratio, 2.45; 95% confidence interval, 1.31 to 4.61; P=0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding. Apixaban 2.5 mg twice daily (hazard ratio, 0.73; 95% confidence interval, 0.44 to 1.19; P=0.21) and 10 mg once daily (hazard ratio, 0.61; 95% confidence interval, 0.35 to 1.04; P=0.07) resulted in lower rates of ischemic events compared with placebo. The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone. We observed a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet therapy in patients with recent acute coronary syndrome

  11. Amphotericin B cochleates: a vehicle for oral delivery.

    Science.gov (United States)

    Perlin, David S

    2004-02-01

    Cochleates are a novel lipid-based delivery vehicle consisting of crystalline phospholipid-cation structures that form spiral lipid sheets. They represent a new technology platform for oral delivery of clinically important drugs that possess poor oral bioavailability. Orally administered cochleates containing amphotericin B (CAMB) showed broad-spectrum activity in murine infection models of candidiasis, aspergillosis and cryptococcosis. Initial biodistribution studies of CAMB administered orally in mice demonstrated that cochleates delivered significant levels of AMB to target organs. The lipid particulate nature of cochleates also imparted reduced toxicity that mimics other lipid-amphotericin B complexes. Cochleates are a promising new vehicle for oral delivery of amphotericin B at therapeutic levels.

  12. Review: Ontogeny of oral drug absorption processes in children

    NARCIS (Netherlands)

    M.G. Mooij (Miriam); B.A.E. Koning, de (Barbara); M.L. Huijsman (Mark); S.N. de Wildt (Saskia)

    2012-01-01

    textabstractA large proportion of prescribed drugs to children are administered orally. Age-related change in factors affecting oral absorption can have consequences for drug dosing. Areas covered: For each process affecting oral drug absorption, a systematic search has been performed using Medline

  13. Best Practices for Administering Concept Inventories

    CERN Document Server

    Madsen, Adrian; Sayre, Eleanor C

    2014-01-01

    There are a plethora of concept inventories in physics available for faculty to use, but it is not always clear exactly why you would use these tests, or how you should administer them and interpret the results. These multiple-choice research-based tests about physics concepts are valuable because they allow for standardized comparisons among institutions, instructors, or over time. In order for these comparisons to be meaningful, you should use best practices for administering the tests. Here we discuss best practices for administering concept inventories including background on these types of tests and specifics of how to give them online or in-class. We also discuss advantages and disadvantages of different incentives you could give your students, interpretation of scores and common concerns you may have about using concept inventories.

  14. Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group.

    Science.gov (United States)

    Chonan, Tomomichi; Wakasugi, Daisuke; Yamamoto, Daisuke; Yashiro, Miyoko; Oi, Takahiro; Tanaka, Hiroaki; Ohoka-Sugita, Ayumi; Io, Fusayo; Koretsune, Hiroko; Hiratate, Akira

    2011-03-01

    Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration.

  15. Chemoprevention of oral cancer

    Directory of Open Access Journals (Sweden)

    Yogesh Chhaparwal

    2012-01-01

    Full Text Available Oral cancer is one among the ten most common cancers in the world and shows a marked geographic variation in occurrence. It causes considerable morbidity and is associated with a 5-year survival rate of less than 50%. Current treatment primarily consists of surgery and radiotherapy and improvement in long-term cure rates with these modalities has reached a plateau. As, curative therapy available for oral cancer often results in debilitating changes in appearance, speech, swallowing and breathing, preventive strategies are desirable. Cancer chemoprevention is the use of natural, synthetic or biologic chemical agents to reverse, suppress, or prevent carcinogenic progression. Chemoprevention has been an extensively-studied strategy and continues to hold promise in the management of oral cancer. Many agents have been evaluated as possible chemopreventive agents including vitamin A and retinoids, betacarotene, vitamin E and dietary agents. Recently, molecularly targeted approach has generated interest among researchers worldwide which includes cyclooxygenase-2 (COX-2 inhibitors, EGFR inhibitors and adenovirus vectors. This article reviews the various aspects of chemoprevention and describes important chemopreventive agents and design of chemopreventive trials.

  16. Use of aminoguanidine, a selective inducible nitric oxide synthase inhibitor, to evaluate the role of nitric oxide in periapical inflammation.

    Science.gov (United States)

    Farhad, Ali R; Razavi, Seyedmohammad; Jahadi, Sanaz; Saatchi, Masoud

    2011-06-01

    The purpose of this study was to evaluate the effects of aminoguanidine (AG) as a selective inhibitor of inducible nitric oxide synthase (iNOS) on the degree of inflammatory response in periapical lesions in the canine teeth of cats. Root canals from 52 cat canine teeth were exposed to the oral cavity and sealed after 7 days. One day before pulp exposure, cats were administered either AG (experimental group) or normal saline (control group), which was continued on a daily basis until the day of sacrifice. Animals were sacrificed at 28 days after pulp exposure. Inflammatory response in the periapical zones was analyzed histologically. The degree of periapical inflammation in the AG group was significantly lower than that in the control group (P < 0.05). Selective iNOS inhibitors such as AG thus reduce the intensity of inflammatory responses in periapical lesions.

  17. Oral histoplasmosis

    Directory of Open Access Journals (Sweden)

    Patil Karthikeya

    2009-01-01

    Full Text Available Histoplasmosis is a systemic fungal disease that takes various clinical forms, among which oral lesions are rare. The disseminated form of the disease that usually occurs in association with Human Immunodeficiency Virus (HIV is one of the AIDS-defining diseases. Isolated oral histoplasmosis, without systemic involvement, with underlying immunosuppression due to AIDS is very rare. We report one such case of isolated oral histoplasmosis in a HIV-infected patient.

  18. On the Interchangeability of Individually Administered and Group Administered Ability Tests

    Science.gov (United States)

    Nevo, Baruch; Sela, Roni

    2003-01-01

    This research studied the interchangeability of individually administered and group administered cognitive tests. Seventy undergraduate students took the Hebrew version of the WAIS-R (Wechsler Adult Intelligence Scale-Revised), and their IQs were measured. They also took the IPET (Israeli Psychometric Entrance Test) and their IPET scores were…

  19. [Oral rehydration immediately after appendectomy].

    Science.gov (United States)

    Azabache, W; Johanson, L

    1989-01-01

    An experimental study of 20 patients with appendicitis was carried out in order to know if after the appendectomy they tolerate the hidratation with rehidratant salts by mouth in place of endovenous hydratation. The oral hydratation was indicated in all the cases immediately after the operation and only was one failure (5%). In the 95% the oral hydratation was tolerated, 45% without gastric symptoms, 35% with mild gastric symptoms and in 15% with moderate gastric symptoms. The association of gentamycin-metronidazol administered by intramuscular and oral way respectively was used in 100% of the patients. In 80% as profilaxis and in 20% as treatment. Two cases had complication as sepsis of the wound one of the profilactic group (5.9%) and another of the treatment group. In conclusion the oral hydratation with rehydrating salts were tolerated for the patients immediately after the appendectomy.

  20. Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice

    OpenAIRE

    Chung, Sanny S. W.; Wang, Xiangyuan; Roberts, Shelby S.; Stephen M Griffey; Reczek, Peter R.; Wolgemuth, Debra J.

    2011-01-01

    Meeting men's contraceptive needs, orally administered retinoic acid receptor antagonists represent new lead molecules in developing non-hormonal, reversible male contraceptives without adverse side effects.

  1. Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension.

    Science.gov (United States)

    Sun, Xiao-Yu; Duan, Zhi-Jun; Liu, Zhen; Tang, Shun-Xiong; Li, Yang; He, Shou-Cheng; Wang, Qiu-Ming; Chang, Qing-Yong

    2016-12-01

    The aim of the present study was to increase the intestinal transport of octreotide (OCT) by targeting the first-pass impact to identify a potential method for decreasing portal vein pressure (PVP) using oral OCT. Thus, the bioavailability of intestinally absorbed OCT was evaluated in normal rats and rats with portal hypertension (PH) that had been administered P-glycoprotein/multidrug resistance-associated protein 2/cytochrome P450 3A4 (P-gp/MRP2/CYP3A4) inhibitors. The mRNA and protein expression levels of P-gp, MRP2 and CYP3A4 were evaluated in normal and PH rats with or without OCT and the inhibitors using RT-PCR, western blot and immunohistochemical analyses. The potential effects of the inhibitor administration on PVP were also examined. The results suggest that P-gp, MRP2 and CYP3A4 play important roles in prohibiting the enteral absorption of OCT, particularly under a PH environment. Moreover, inhibitors of P-gp, MRP2 and CYP3A4 decrease the first-pass effects of OCT and effectively reduce PVP under PH conditions. Therefore, the present results suggest P-gp, MRP2 and CYP3A4 are key factors in the intestinal absorption of OCT. The inhibition of P-gp, MRP2 and CYP3A4 can markedly decrease the first-pass effects of OCT, and their use may facilitate the use of orally administered OCT.

  2. Characterization and comparison of sodium-glucose cotransporter 2 inhibitors: Part 2. Antidiabetic effects in type 2 diabetic mice

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    Atsuo Tahara

    2016-07-01

    Full Text Available Previously we investigated the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six sodium-glucose cotransporter (SGLT 2 inhibitors commercially available in Japan using normal and diabetic mice. We classified the SGLT2 inhibitors with respect to duration of action as either long-acting (ipragliflozin and dapagliflozin or intermediate-acting (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. In the present study, antidiabetic effects of repeated administration of these SGLT2 inhibitors in type 2 diabetic mice were investigated. When repeatedly administered for 4 weeks, all SGLT2 inhibitors significantly exhibited antihyperglycemic, antihyperinsulinemic, and pancreas-protective effects, as well as insulin resistance-improving effects. When compared at doses producing comparable reduction in hyperglycemia across all drugs, the antidiabetic effects of ipragliflozin and dapagliflozin were more potent than those of the other four drugs, but these differences among the six drugs were not statistically significant. Further, an oral glucose tolerance test performed after repeated administration demonstrated significant improvement in glucose tolerance only with ipragliflozin and dapagliflozin, implying improved insulin resistance and secretion. Taken together, these findings demonstrate that, although all SGLT2 inhibitors exert antidiabetic effects in type 2 diabetic mice, these pharmacologic effects might be slightly superior with the long-acting drugs, which are able to provide favorable blood glucose control throughout the day.

  3. DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice {beta} cells

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    Nagamatsu, Shinya, E-mail: shinya@ks.kyorin-u.ac.jp [Department of Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611 (Japan); Ohara-Imaizumi, Mica; Nakamichi, Yoko; Aoyagi, Kyota; Nishiwaki, Chiyono [Department of Biochemistry, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611 (Japan)

    2011-09-09

    Highlights: {yields} Anti-diabetic new drug, DPP-4 inhibitor, can affect the insulin exocytosis. {yields} DPP-4 inhibitor treatment altered syntaxin 1 expression. {yields} Treatment of db/db mice with DPP-4 inhibitor increased insulin release. -- Abstract: Incretin promotes insulin secretion acutely. Recently, orally-administered DPP-4 inhibitors represent a new class of anti-hyperglycemic agents. Indeed, inhibitors of dipeptidyl peptidase-IV (DPP-4), sitagliptin, has just begun to be widely used as therapeutics for type 2 diabetes. However, the effects of sitagliptin-treatment on insulin exocytosis from single {beta}-cells are yet unknown. We therefore investigated how sitagliptin-treatment in db/db mice affects insulin exocytosis by treating db/db mice with des-F-sitagliptin for 2 weeks. Perfusion studies showed that 2 weeks-sitagliptin treatment potentiated insulin secretion. We then analyzed insulin granule motion and SNARE protein, syntaxin 1, by TIRF imaging system. TIRF imaging of insulin exocytosis showed the increased number of docked insulin granules and increased fusion events from them during first-phase release. In accord with insulin exocytosis data, des-F-sitagliptin-treatment increased the number of syntaxin 1 clusters on the plasma membrane. Thus, our data demonstrated that 2-weeks des-F-sitagliptin-treatment increased the fusion events of insulin granules, probably via increased number of docked insulin granules and that of syntaxin 1 clusters.

  4. Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes

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    Kodera, Ryo, E-mail: kodera@cc.okayama-u.ac.jp [Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Shikata, Kenichi [Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Takatsuka, Tetsuharu; Oda, Kaori; Miyamoto, Satoshi; Kajitani, Nobuo; Hirota, Daisho; Ono, Tetsuichiro [Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Usui, Hitomi Kataoka [Department of Primary Care and Medical Education, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan); Makino, Hirofumi [Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 (Japan)

    2014-01-17

    Highlights: •DPP-4 inhibitor decreased urinary albumin excretion in a rat of type 1 diabetes. •DPP-4 inhibitor ameliorated histlogical changes of diabetic nephropathy. •DPP-4 inhibitor has reno-protective effects through anti-inflammatory action. •DPP-4 inhibitor is beneficial on diabetic nephropathy besides lowering blood glucose. -- Abstract: Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The me