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Sample records for multiple intravenous doses

  1. Pharmacokinetics of cefpimizole in normal humans after single- and multiple-dose intravenous infusions.

    PubMed Central

    Lakings, D B; Friis, J M; Brown, R J; Allen, H R

    1984-01-01

    The pharmacokinetics of cefpimizole (free acid equivalents of cefpimizole sodium), a broad-spectrum cephalosporin antibiotic, were determined after single- and multiple-dose 20-min intravenous infusions of 1, 2, and 4 g. The kinetics of single-dose administration of cefpimizole correspond to a two-compartment model with an average apparent volume of distribution of 20.0 +/- 3.5 liters, a distribution rate constant of 2.24 +/- 1.00 h-1, and a terminal rate constant of 0.358 +/- 0.036 h-1 (half-life, 1.9 h). The total body clearance was 118.6 +/- 20.2 ml/min. The primary route of elimination for cefpimizole was the renal route, with approximately 80% of the administered dose excreted as the parent compound. The elimination rate constant, as calculated from urinary excretion data, was 0.339 +/- 0.043 h-1, which is in close agreement with the terminal rate constant for plasma. Renal clearance of cefpimizole was 96.2 +/- 17.3 ml/min. Dose proportionality over the three dose levels was obtained from area under the plasma curve and cumulative urinary excretion data. The results of the multiple-dose study indicated that no apparent change in the distribution or elimination kinetics of cefpimizole occurred after the administration of 1-, 2-, and 4-g doses for 7 days, three times a day. The kinetics from the multiple-dose study were in close agreement with those from the single-dose study. No accumulation of cefpimizole occurred, and nondetectable levels was observed 24 h after administration of the last dose. Peaks that could be attributed to metabolites of cefpimizole were not observed during high-pressure liquid chromatographic analysis of either plasma or urine specimens. PMID:6524897

  2. Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers.

    PubMed

    Chow, A T; Fowler, C; Williams, R R; Morgan, N; Kaminski, S; Natarajan, J

    2001-07-01

    The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation.

  3. Pharmacokinetics and pharmacodynamics of multiple-dose intravenous nemonoxacin in healthy Chinese volunteers.

    PubMed

    Wu, Xiao-jie; Zhang, Jing; Guo, Bei-ning; Zhang, Ying-yuan; Yu, Ji-cheng; Cao, Guo-ying; Chen, Yuan-cheng; Zhu, De-mei; Ye, Xin-yu; Wu, Ju-fang; Shi, Yao-guo; Chang, Li-wen; Chang, Yu-ting; Tsai, Cheng-yuan

    2015-03-01

    This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (Cmax_ss) were 9.60 ± 1.84 and 11.04 ± 2.18 μg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0-24_ss) were 44.03 ± 8.62 and 65.82 ± 10.78 μg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin Cmax_ss values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 μg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0-24_ss values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 μg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

  4. Similar biological effect of high-dose oral versus intravenous methylprednisolone in multiple sclerosis relapses.

    PubMed

    Grau-López, L; Teniente-Serra, A; Tintoré, M; Rovira, A; Ramió-Torrenta, L; Brieva, L; Saiz, A; Cano, A; Carmona, O; Hervás, J V; Martínez-Cáceres, E M; Ramo-Tello, C

    2015-04-01

    Our aim was to investigate differences in immune mechanisms in multiple sclerosis (MS) relapse, after high-dose oral methylprednisolone (oMP) or intravenous methylprednisolone (ivMP). We measured serum cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFN-γ) in 39 of 49 MS patients with moderate-severe relapse, whom were treated with ivMP or oMP in a placebo-controlled, non-inferiority clinical trial. We assessed these cytokine levels at baseline and at 1 and 4 weeks post-treatment. The cytokine levels between oMP and ivMP were similar at any time. Proinflammatory cytokines (IL-6 and IFN-γ) were significantly decreased in both groups at week 1 (p = 0.05 / p = 0.03) and at week 4 (p = 0.04 / p = 0.05). This study provides further confirmatory evidence that oMP is not inferior to ivMP. clinicaltrials.gov identifier: NCT00753792. © The Author(s), 2014.

  5. The pharmacokinetics of methocarbamol and guaifenesin after single intravenous and multiple-dose oral administration of methocarbamol in the horse.

    PubMed

    Rumpler, M J; Colahan, P; Sams, R A

    2014-02-01

    A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration. © 2013 John Wiley & Sons Ltd.

  6. Detection and identification of flunixin after multiple intravenous and intramuscular doses to horses.

    PubMed

    Sams, R A; Gerken, D F; Ashcraft, S M

    1999-09-01

    The objectives of the study were to compare various methods to determine flunixin in test samples collected periodically from horses after intramuscular (IM) and intravenous (IV) dosing at the maximum recommended dosage and to document detection times for this drug in test samples. Flunixin, a nonsteroidal anti-inflammatory drug approved for use in horses, was administered to eight mares in five consecutive daily doses of 1.1 mg per kilogram of body weight by the IM or IV route. Flunixin was detected in urine samples collected at various times after drug administration by flunixin enzyme-linked immunosorbent assay (ELISA), thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and gas chromatographic-mass spectrometric (GC-MS) methods. Detection time was defined as the time period over which flunixin was detected and was dependent on the method used. The shortest detection times were 24 to 48 h and were observed when the TLC method was used. On the other hand, detection times were as long as 15 days when HPLC, GC-MS, and flunixin ELISA methods were used. The use of these more sensitive tests to monitor official samples collected from racehorses could result in positive tests for flunixin when it is exerting no detectable clinical effects because it produces clinical effects lasting only 24-36 h in horses.

  7. Radiation dose and cancer risk in patients undergoing multiple radiographs in intravenous urography X-ray examinations

    NASA Astrophysics Data System (ADS)

    Suliman, I. I.; Al-Jabri, Amna J.; Badawi, A. A.; Halato, M. A.; Alzimami, K.; Sulieman, A.

    2014-11-01

    The purpose of the this study was to measure the entrance surface air kerma (ESAK) and body organs, and the effective doses in intravenous urography (IVU) X-ray examinations in Sudanese hospitals. Seventy-two patients who underwent IVU multiple radiographs from five hospitals (six rooms) were examined. ESAK was calculated from incident air kerma (Ki) using patient exposure parameters and tube output Y(d). Dose calculations were performed using CALDOSE X 5.1 Monte Carlo-based software. Risk of cancer induction (4-8) and mortality per million (2-4) varied. The gallbladder, colon, stomach, gonads and uterus received organ doses of 5.3, 3.6, 3.2, 0.61, and 0.8 mGy, respectively. ESAK values ranged from 6.6 to 15.3 mGy (effective doses: 0.70-1.6 mSv). Mean ESAK fall slightly above the diagnostic reference level. Several optimization strategies to improve dose performance were discussed. Reducing the number of radiographs and the use of technique charts according to patient sizes and anatomic areas are among the most important dose optimization tools in IVU.

  8. IN VIVO EVALUATION OF SAFETY OF NANOPOROUS SILICON CARRIERS FOLLOWING SINGLE AND MULTIPLE DOSE INTRAVENOUS ADMINISTRATIONS IN MICE

    PubMed Central

    Tanaka, T.; Godin, B.; Bhavane, R.; Nieves-Alicea, R.; Gu, J.; Liu, X.; Chiappini, C.; Fakhoury, J. R.; Amra, S.; Ewing, A.; Li, Q.; Fidler, I.J.; Ferrari, M.

    2010-01-01

    Porous silicon (pSi) is being extensively studied as an emerging material for use in biomedical applications, including drug delivery, based on the biodegradability and versatile chemical and biophysical properties. We have recently introduced multistage nanoporous silicon microparticles (S1MP) designed as a cargo for nanocarrier drug delivery to enable the loaded therapeutics and diagnostics to sequential overcoming of the biological barriers to reach their target. In this first report on biocompatibility of intravenously administered pSi structures, we examined biocompatibility of negatively (−32.5±3.1mV) and positively (8.7±2.5mV) charged S1MP in acute single dose (107, 108, 5×108 S1MP/animal) and subchronic multiple dose (108 S1MP/animal/week for 4 weeks) administration schedules. Our data demonstrate that S1MP did not change plasma levels of renal (BUN and creatinine) and hepatic (LDH) biomarkers as well as23 plasma cytokines. LDH plasma levels of 145.2±23.6, 115.4±29.1 vs. 127.0±10.4; and 155.8±38.4, 135.5±52.3 vs. 178.4±74.6 were detected in mice treated with 108 negatively charged S1MP, 108 positively charged S1MP vs. saline control in single and multiple dose schedules, respectively. The S1MPs did not alter LDH levels in liver and spleen, nor lead to infiltration of leukocytes into the liver, spleen, kidney, lung, brain, heart, and thyroid. Collectively, these data provide evidence of a safe intravenous administration of S1MPs as a drug delivery carrier. PMID:20883755

  9. Single-dose and multiple-dose pharmacokinetics and dose proportionality of intravenous and intramuscular HPβCD-diclofenac (Dyloject) compared with other diclofenac formulations.

    PubMed

    Mermelstein, Fred; Hamilton, Douglas A; Wright, Curtis; Lacouture, Peter G; Ramaiya, Atulkumar; Carr, Daniel B

    2013-10-01

    To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. Clinical research center. Healthy adult volunteers. Study 1: Subjects received HPβCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPβCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. Study 1: IV HPβCD-diclofenac had a higher peak plasma concentration (Cmax ) and earlier time to reach maximum plasma concentration (Tmax ), but equivalent plasma exposure (area under the curve from time zero to t [AUC0-t ]) to IV Voltarol. The geometric mean ratio of HPβCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPβCD-diclofenac (IV) to HPβCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IV) for AUC0-t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPβCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng·hour/ml) and 37.5 mg (1843 ng·hour/ml) IV HPβCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml). Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPβCD-diclofenac compared with Voltarol and after IM administration of HPβCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPβCD-diclofenac was equivalent to IV administration of HP

  10. Effect of multiple intravenous doses of lanicemine (AZD6765) on the pharmacokinetics of midazolam in healthy subjects.

    PubMed

    Bui, Khanh H; Zhou, Diansong; Agbo, Felix; Guo, Jian

    2015-09-01

    The objectives of the present study were to evaluate safety and tolerability as well as the effects of multiple doses of lanicemine on the pharmacokinetics of a CYP3A substrate, midazolam. A total of 46 healthy volunteers were enrolled in the open-label, fixed-sequence, nonrandomized study. All volunteers received an oral dose of 5 mg of midazolam alone or after 6 days of 150 mg daily intravenous infusion of lanicemine. Lanicemine reached a plasma Cmax of 1.51 μg/mL after 150 mg daily dosing to steady state. The geometric mean CL, Vss, and t1/2 of lanicemine were 8.1 L/h, 122.0 L, and 10.4 hours, respectively. The geometric least-squares mean ratios and 90% confidence intervals for midazolam AUC0- ∞ , and Cmax were within the 80% to 125% limits when lanicemine plus midazolam treatment was compared with midazolam alone, demonstrating that daily dosing with 150 mg of lanicemine for 6 days had no effect on CYP3A activity. Comprehensive physiologically based pharmacokinetic modeling using in vitro and in silico findings also indicated lanicemine would have little impact on the pharmacokinetics of CYP3A substrate, such as midazolam. In addition, lanicemine and midazolam administered alone or in combination were generally safe and well tolerated. © 2015, The American College of Clinical Pharmacology.

  11. Intravenous theophylline poisoning and multiple-dose charcoal in an animal model.

    PubMed

    Kulig, K W; Bar-Or, D; Rumack, B H

    1987-08-01

    Large overdoses of IV theophylline (50 to 100 mg/kg) were administered to five canines on two separate occasions. On day one, with no charcoal administered, theophylline levels were serially obtained between ten minutes and 12 hours after infusion and the animals were recovered from anesthesia. Three days later the same dose of theophylline was administered, but then 50 g activated charcoal was placed through a nasogastric tube into the duodenum every hour for eight doses. In all five animals tested, activated charcoal significantly decreased the area under the serum concentration-time curve, decreased the half-life of elimination, and increased the clearance of theophylline. This effect on pharmacokinetics was not seen when the nasogastric tube was put into the stomach instead of the small bowel because the charcoal administered did not pass beyond the pylorus. In a separate experiment in which bile theophylline concentrations were measured, it was demonstrated that enhanced elimination was not from interruption of enterohepatic circulation of theophylline. This suggests that the demonstrated physiologic mechanism is that of gastrointestinal dialysis.

  12. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial.

    PubMed

    Le Page, Emmanuelle; Veillard, David; Laplaud, David A; Hamonic, Stéphanie; Wardi, Rasha; Lebrun, Christine; Zagnoli, Fabien; Wiertlewski, Sandrine; Deburghgraeve, Véronique; Coustans, Marc; Edan, Gilles

    2015-09-05

    High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis, but can be inconvenient and expensive. We aimed to assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration. We did this multicentre, double-blind, randomised, controlled, non-inferiority trial at 13 centres for multiple sclerosis in France. We enrolled patients aged 18-55 years with relapsing-remitting multiple sclerosis who reported a relapse within the previous 15 days that caused an increase of at least one point in one or more scores on the Kurtzke Functional System Scale. With use of a computer-generated randomisation list and in blocks of four, we randomly assigned (1:1) patients to either oral or intravenous methylprednisolone, 1000 mg, once a day for 3 days. Patients, treating physicians and nurses, and data and outcome assessors were all masked to treatment allocation, which was achieved with the use of saline solution and placebo capsules. The primary endpoint was the proportion of patients who had improved by day 28 (decrease of at least one point in most affected score on Kurtzke Functional System Scale), without need for retreatment with corticosteroids, in the per-protocol population. The trial was powered to assess non-inferiority of oral compared with intravenous methylprednisolone with a predetermined non-inferiority margin of 15%. This trial is registered with ClinicalTrials.gov, number NCT00984984. Between Jan 29, 2008, and June 14, 2013, we screened 200 patients and enrolled 199. We randomly assigned 100 patients to oral methylprednisolone and 99 patients to intravenous methylprednisolone with a mean time from relapse onset to treatment of 7·0 days (SD 3·6) and 7·4 days (3·9), respectively. In the per-protocol population, 66 (81%) of 82 patients in the oral group and 72 (80%) of 90 patients in the intravenous group achieved the primary endpoint (absolute treatment

  13. Pharmacokinetics and tolerability of intravenous ibuprofen injection in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose study
.

    PubMed

    Zhou, Huili; Xu, Wei; Wu, Guolan; Wu, Lihua; Shentu, Jianzhong; Pan, Zhengfei; Hu, Shuai; Liu, Yang

    2016-11-01

    Recently a formulation of intravenous (IV) ibuprofen was developed in China for management of mild to moderate pain in patients who could not take oral medications or where intravenous administration was preferable. The aim of this study was to evaluate the pharmacokinetic properties and tolerability of single and multiple doses of ibuprofen injection in healthy Chinese volunteers. This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. In the single-dose phase, subjects were randomized to receive a single dose of ibuprofen injection 0.2, 0.4, or 0.8 g administered as a 30-minute IV infusion with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 12.5 hours after drug administration and were analyzed using a validated LC-MS/MS method. In the multiple-dose phase, subjects received 0.4 g ibuprofen every 6 hours for 9 doses. Blood samples were obtained before the 7th, 8th, and 9th administration to determine the Cmin at steady state; on the 9th intravenous administration, blood samples were also collected for 12.5 hours after drug administration. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). A total of 12 healthy male (n = 6) and female (n = 6) Chinese volunteers were enrolled and completed the trial. After IV administration of single dose, the mean (SD) Cmax value increased from 35.77 (6.98) to 117.12 (19.78) µg/mL, and the mean (SD) AUC0-t value increased from 67.63 (10.30) to 230.50 (33.55) µg×h/mL in the range of 0.2-g to 0.8-g dose. The terminal half-life in plasma was ~ 2.0 hours. After IV administration of 9 doses of ibuprofen 400 mg every 6 hours, the mean (SD) Cmax was 66.49 (8.49) µg/mL, the AUC0-t was 135.65 (26.91) µg×h/mL, the t1

  14. Patient-reported adverse effects of high-dose intravenous methylprednisolone treatment: a prospective web-based multi-center study in multiple sclerosis patients with a relapse.

    PubMed

    Jongen, Peter Joseph; Stavrakaki, Ioanna; Voet, Bernard; Hoogervorst, Erwin; van Munster, Erik; Linssen, Wim H; Sinnige, Ludovicus G; Verhagen, Wim I; Visser, Leo H; van der Kruijk, Ruud; Verheul, Freek; Boringa, Jan; Heerings, Marco; Gladdines, Werner; Lönnqvist, Fredrik; Gaillard, Pieter

    2016-08-01

    In a prospective multi-center observational study, we evaluated the frequency, severity, and impact on activities of daily living (ADL) of adverse effects (AEs) of high-dose intravenous methylprednisolone (IVMP) in relapsing remitting multiple sclerosis (MS) patients with a relapse. Online self-report questionnaires stating IVMP's most common AEs were completed at baseline, the 2nd day of treatment, and 1 day and 1 week after treatment. Eighty-five patients were included, 66 completed the baseline questionnaire, and 59 completed at least one post-baseline questionnaire. Patients reported on average 4 (median) AEs; two (3.4 %) reported no AE. Most frequent was change in taste (61 %), facial flushing (61 %), sick/stomach pain (53 %), sleep disturbance (44 %), appetite change (37 %), agitation (36 %), and behavioral changes (36 %). Of all AEs, 34.3 % were severe and 37.9 % impacted on ADL. A 3-day course resulted in 4 (median) AEs and a 5-day course in 7. All patients with high disease impact had two or more AEs, compared with 79 % of those with low impact (p < 0.01). Of patients with high disability, 45 % had severe AEs, compared with 16 % of those with low disability. Severe central nervous system (CNS)-related AEs occurred two times more frequently in patients with high disease impact, and two-and-a-half times more frequently in patients with high disability. Therefore, in virtually all patients, high-dose IVMP leads to AEs, with about one of three AEs being severe with impact on ADL. Patients with high disease impact or high disability may experience more (severe) AEs, due to a higher occurrence of severe CNS-related AEs.

  15. Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects.

    PubMed

    Munjal, Sagar; Gautam, Anirudh; Okumu, Franklin; McDowell, James; Allenby, Kent

    2016-01-01

    In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0-inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product. © 2015, The American College of Clinical Pharmacology.

  16. Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain.

    PubMed

    Tzortzopoulou, Aikaterini; McNicol, Ewan D; Cepeda, M Soledad; Francia, Marie Belle D; Farhat, Tamman; Schumann, Roman

    2011-10-05

    Paracetamol (acetaminophen) is the most commonly prescribed analgesic for the treatment of acute pain. It may be administered orally or intravenously. The efficacy and safety of intravenous (IV) formulations of paracetamol, IV paracetamol and IV propacetamol, compared with placebo and other analgesics, is unclear. To assess the efficacy and safety of IV formulations of paracetamol for treatment of postoperative pain in both adults and children. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), MEDLINE (1950 to May 2010), EMBASE (1980 to 2010, Week 18), LILACS (1992 to May 2010) and reference lists of retrieved articles. Randomized, double-blind, placebo- or active-controlled single dose clinical trials of IV propacetamol or IV paracetamol for acute postoperative pain in adults or children. Two review authors independently assessed the risk of bias and extracted data. We contacted study authors for additional information. We collected adverse event information from the studies. Thirty-six studies (3896 participants) were included. Thirty-seven percent of participants receiving IV propacetamol/paracetamol experienced at least 50% pain relief over four hours compared with 16% of those receiving placebo (number needed to treat to benefit (NNT = 4.0; 95% confidence interval 3.5 to 4.8). The proportion of participants in IV propacetamol/paracetamol groups experiencing at least 50% pain relief diminished over six hours, as reflected in a higher NNT of 5.3 (4.2 to 6.7). Participants receiving IV propacetamol/paracetamol required 30% less opioid over four hours than those receiving placebo. However, this did not translate to a reduction in opioid-induced adverse events.Meta-analysis of efficacy comparisons between IV propacetamol/paracetamol and active comparators (opioids or nonsteroidal anti-inflammatories (NSAIDs)) were either not statistically significant, not clinically significant, or both.Adverse events

  17. Single dose intravenous paracetamol or intravenous propacetamol for postoperative pain.

    PubMed

    McNicol, Ewan D; Ferguson, McKenzie C; Haroutounian, Simon; Carr, Daniel B; Schumann, Roman

    2016-05-23

    This is an updated version of the original Cochrane review published in Issue 10, 2011. Paracetamol (acetaminophen) is the most commonly prescribed analgesic for the treatment of acute pain. It may be administered orally, rectally, or intravenously. The efficacy and safety of intravenous (IV) formulations of paracetamol, IV paracetamol, and IV propacetamol (a prodrug that is metabolized to paracetamol), compared with placebo and other analgesics, is unclear. To assess the efficacy and safety of IV formulations of paracetamol for the treatment of postoperative pain in both adults and children. We ran the search for the previous review in May 2010. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE (May 2010 to 16 February 2016), EMBASE (May 2010 to 16 February 2016), LILACS (2010 to 2016), a clinical trials registry, and reference lists of reviews for randomized controlled trials (RCTs) in any language and we retrieved articles. Randomized, double-blind, placebo- or active-controlled single dose clinical trials of IV paracetamol or IV propacetamol for acute postoperative pain in adults or children. Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We contacted study authors for additional information. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. We included 75 studies (36 from the original review and 39 from our updated review) enrolling a total of 7200 participants.Among primary outcomes, 36% of participants receiving IV paracetamol/propacetamol experienced at least 50% pain relief over four hours compared with 16% of those receiving placebo (number needed to treat to benefit (NNT) = 5; 95% confidence interval (CI) 3.7 to 5.6, high quality evidence). The proportion of participants in IV

  18. Decreased vitamin B12 and folate levels in cerebrospinal fluid and serum of multiple sclerosis patients after high-dose intravenous methylprednisolone.

    PubMed

    Frequin, S T; Wevers, R A; Braam, M; Barkhof, F; Hommes, O R

    1993-05-01

    Twenty-one patients (15 women, 6 men) with definite multiple sclerosis (MS) were treated with 1000 mg intravenous methylprednisolone-succinate (MP) daily for 10 days. Before MP treatment there was a negative correlation (r = 0.59, P = 0.0084) between serum vitamin B12 and progression rate, defined as the ratio of the score on Kurtzke's Expanded Disability Status Scale and disease duration. A significant decrease was demonstrated in the cerebrospinal fluid (CSF) and serum levels of folate and in the CSF level of vitamin B12 after MP treatment. The decrease in serum B12 was not statistically significant. After MP treatment all median levels of vitamin B12 and folate were below the reference medians. We hypothesize that low or reduced vitamin B12/folate levels found in MS patients may be related to previous corticosteroid treatments. Otherwise a more causal relationship between low vitamin B12/folate and MS cannot be excluded. Further studies may be required to clarify the vitamin B12 and folate metabolism in patients with MS.

  19. Water Intoxication Following Low-Dose Intravenous Cyclophosphamide

    PubMed Central

    Koo, Tai Yeon; Bae, Sang-Cheol; Park, Joon Sung; Lee, Chang Hwa; Park, Moon Hyang; Kang, Chong Myung

    2007-01-01

    Cyclophosphamide is frequently used for the treatment of severe lupus nephritis, but is very rarely associated with dilutional hyponatremia. Recently we experienced a case of water intoxication following low-dose intravenous cyclophosphamide. Five hours after one dose of intravenous pulse cyclophosphamide 750 mg, the patient developed nausea, vomiting, and general weakness. Serum sodium concentration revealed 114 mEq/L and her hyponatremia was initially treated with hypertonic saline infusion. Then her serum sodium concentration rapidly recovered to normal with water restriction alone. During the course of intravenous pulse cyclophosphamide therapy, one must be aware of the possibility of significant water retention. PMID:24459501

  20. Water intoxication following low-dose intravenous cyclophosphamide.

    PubMed

    Koo, Tai Yeon; Bae, Sang-Cheol; Park, Joon Sung; Lee, Chang Hwa; Park, Moon Hyang; Kang, Chong Myung; Kim, Gheun-Ho

    2007-06-01

    Cyclophosphamide is frequently used for the treatment of severe lupus nephritis, but is very rarely associated with dilutional hyponatremia. Recently we experienced a case of water intoxication following low-dose intravenous cyclophosphamide. Five hours after one dose of intravenous pulse cyclophosphamide 750 mg, the patient developed nausea, vomiting, and general weakness. Serum sodium concentration revealed 114 mEq/L and her hyponatremia was initially treated with hypertonic saline infusion. Then her serum sodium concentration rapidly recovered to normal with water restriction alone. During the course of intravenous pulse cyclophosphamide therapy, one must be aware of the possibility of significant water retention.

  1. Multiple Intravenous Infusions Phase 1b

    PubMed Central

    Cassano-Piché, A; Fan, M; Sabovitch, S; Masino, C; Easty, AC

    2012-01-01

    Background Minimal research has been conducted into the potential patient safety issues related to administering multiple intravenous (IV) infusions to a single patient. Previous research has highlighted that there are a number of related safety risks. In Phase 1a of this study, an analysis of 2 national incident-reporting databases (Institute for Safe Medical Practices Canada and United States Food and Drug Administration MAUDE) found that a high percentage of incidents associated with the administration of multiple IV infusions resulted in patient harm. Objectives The primary objectives of Phase 1b of this study were to identify safety issues with the potential to cause patient harm stemming from the administration of multiple IV infusions; and to identify how nurses are being educated on key principles required to safely administer multiple IV infusions. Data Sources and Review Methods A field study was conducted at 12 hospital clinical units (sites) across Ontario, and telephone interviews were conducted with program coordinators or instructors from both the Ontario baccalaureate nursing degree programs and the Ontario postgraduate Critical Care Nursing Certificate programs. Data were analyzed using Rasmussen’s 1997 Risk Management Framework and a Health Care Failure Modes and Effects Analysis. Results Twenty-two primary patient safety issues were identified with the potential to directly cause patient harm. Seventeen of these (critical issues) were categorized into 6 themes. A cause-consequence tree was established to outline all possible contributing factors for each critical issue. Clinical recommendations were identified for immediate distribution to, and implementation by, Ontario hospitals. Future investigation efforts were planned for Phase 2 of the study. Limitations This exploratory field study identifies the potential for errors, but does not describe the direct observation of such errors, except in a few cases where errors were observed. Not all

  2. Pharmacokinetic properties of S-adenosylmethionine after oral and intravenous administration of its tosylate disulfate salt: a multiple-dose, open-label, parallel-group study in healthy Chinese volunteers.

    PubMed

    Yang, Jin; He, Ying; Du, Ying-Xiang; Tang, Li-Ling; Wang, Guang-Ji; Fawcett, J Paul

    2009-02-01

    S-adenosylmethionine (SAMe) is an endogenous molecule that plays an important role in cellular metabolism. Despite being widely used as a dietary supplement with claimed benefits for numerous conditions, there is little information about the pharmacokinetic properties of exogenous SAMe. One aim of this study was to characterize the pharmacokinetic properties of SAMe after administration of single and multiple doses of orally and intravenously administered SAMe tosylate disulfate (STD) in healthy male and female Chinese volunteers. Because men have higher erythrocyte levels of endogenous SAMe than do women, we also assessed the effects of sex on the disposition of SAMe. A simple and sensitive assay for SAMe based on liquid chromatography-mass spectrometry using selected-ion monitoring of analyte and acyclovir as internal standard was developed and validated. The assay was used to study the pharmacokinetic properties of SAMe. STD was administered as single and multiple doses of enteric-coated tablets and IV infusion of STD to groups of healthy native Chinese volunteers. After an overnight fast, male and female Chinese volunteers were assigned to receive STD 1000 mg for 5 days, either in enteric-coated tablet formulation or as a 250-mL IV infusion. Blood samples were collected 24 hours after the first and last dose and used for determining plasma SAMe concentrations and pharmacokinetic parameters. For the oral formulation, SAMe concentrations were corrected for concentrations of endogenous SAMe. Pharmacokinetic parameters were calculated for men and women separately and for the total group of volunteers. Adverse events were monitored using a physician during blood collection and by spontaneous reporting. Twenty healthy volunteers were enrolled (oral formulation: 5 men, 5 women; mean [SD] age, 24.1 [4.7] years [range, 21-37 years]; mean [SD] weight, 59.9 [4.8] kg [range, 54-70 kg]; IV formulation: 5 men, 5 women; mean [SD] age, 22.6 [1.8] years [range, 21-27 years

  3. Disposition of 2-mercaptobenzimidazole in rats dosed orally or intravenously

    SciTech Connect

    El Dareer, S.M.; Kalin, J.R.; Tillery, K.F.; Hill, D.L.

    1984-01-01

    The disposition of (/sup 14/C)-labeled 2-mercaptobenzimidazole (MBI) in male Fischer-344 rats dosed orally (49 or 0.5 mg/kg) or intravenously (0.5 mg/kg) was determined. Absorption of the oral dose was evident, since, in 72 h, most of the radioactivity administered by either route appeared in the urine. Smaller amounts appeared in the feces. In 4 h, 12% of the radioactivity from an intravenous dose of 0.5 mg/kg was excreted in the bile of rats with biliary cannulas. For rats dosed intravenously, the half-life for disappearance of unchanged MBI from plasma was 125 min. In contrast, the terminal half-life for loss of radioactivity from blood was 83 h. The concentration of total radioactivity was higher in liver and kidney tissue than in blood. One of the major urinary metabolites was identified as benzimidazole, and a minor component was tentatively identified as unchanged MBI. Neither of these could be detected in bile. 8 references, 6 figures, 1 table.

  4. Single-dose pharmacokinetics of intravenous sulbactam in pediatric patients.

    PubMed

    Schaad, U B; Guenin, K; Straehl, P

    1986-01-01

    The pharmacokinetics of intravenously administered sulbactam were studied in 17 pediatric patients two to 14 years of age. Single doses of 12.5 or 25 mg/kg were infused over 3 min, and in previously healthy children, mean peak plasma concentrations 5 min after dosing were 71 and 163 micrograms/ml, respectively. Noncompartmental and compartmental calculations resulted in similar pharmacokinetic parameters. Linear pharmacokinetics were found in the concentration range studied. The mean terminal-phase half-life was 1.75 hr, the mean total plasma clearance was 180 ml/min per 1.73 m2, and the mean apparent volume of distribution was 340 ml/kg. Approximately 70%-80% of an intravenous dose was excreted unchanged in the urine. In children with cystic fibrosis, both total plasma clearance and apparent volume of distribution were significantly increased. The data support the intravenous administration of 12.5-25 mg of sulbactam/kg every 6 to 8 hr for assessing the adequacy of this drug as an adjunct to beta-lactam therapy for various bacterial infections in children.

  5. Rhabdomyolysis associated with single-dose intravenous esomeprazole administration

    PubMed Central

    Jeon, Dae-Hong; Kim, Yire; Kim, Min Jeong; Cho, Hyun Seop; Bae, Eun Jin; Chang, Se-Ho; Park, Dong Jun

    2016-01-01

    Abstract Background: Proton pump inhibitors are usually safe, although serious adverse effects can occur. We report the first case of rhabdomyolysis associated with single-dose intravenous esomeprozole administration. Methods: A 45-year-old Korean male visited our emergency room because of persistent lower chest discomfort that started 10 hours before. He had been diagnosed with diabetes and coronary heart disease, but discontinued oral hypoglycemic agents 1 month earlier. He continued to take medications for coronary heart disease. There was no abnormality on an electrocardiogram or in cardiac enzymes. Initial laboratory findings did not show abnormalities for muscle enzymes. Esomeprozole 40 mg was administrated intravenously for the control of his ambiguous chest discomfort. Then, 12 hours later, he complained of abrupt severe right buttock pain. An area of tender muscle swelling 8 cm in diameter was seen on his right buttock area. Creatine kinase and lactate dehydrogenase were elevated to 40,538 and 1326 U/L, respectively. A bone scan using 20 mCi of 99mTc-hydroxymethylene diphosphonate was compatible with rhabdomyolysis. Results: His muscular symptoms, signs, and laboratory findings improved markedly with conservative management, including hydration and urine alkalinization. He is being followed in the outpatient department with no evidence of recurrence. Conclusion: We should keep in mind that single-dose intravenous administration of esomeprazole can induce rhabdomyolysis. PMID:27442680

  6. Multiple Intravenous Infusions Phase 2b: Laboratory Study

    PubMed Central

    Pinkney, Sonia; Fan, Mark; Chan, Katherine; Koczmara, Christine; Colvin, Christopher; Sasangohar, Farzan; Masino, Caterina; Easty, Anthony; Trbovich, Patricia

    2014-01-01

    Background Administering multiple intravenous (IV) infusions to a single patient via infusion pump occurs routinely in health care, but there has been little empirical research examining the risks associated with this practice or ways to mitigate those risks. Objectives To identify the risks associated with multiple IV infusions and assess the impact of interventions on nurses’ ability to safely administer them. Data Sources and Review Methods Forty nurses completed infusion-related tasks in a simulated adult intensive care unit, with and without interventions (i.e., repeated-measures design). Results Errors were observed in completing common tasks associated with the administration of multiple IV infusions, including the following (all values from baseline, which was current practice): setting up and programming multiple primary continuous IV infusions (e.g., 11.7% programming errors) identifying IV infusions (e.g., 7.7% line-tracing errors) managing dead volume (e.g., 96.0% flush rate errors following IV syringe dose administration) setting up a secondary intermittent IV infusion (e.g., 11.3% secondary clamp errors) administering an IV pump bolus (e.g., 11.5% programming errors) Of 10 interventions tested, 6 (1 practice, 3 technology, and 2 educational) significantly decreased or even eliminated errors compared to baseline. Limitations The simulation of an adult intensive care unit at 1 hospital limited the ability to generalize results. The study results were representative of nurses who received training in the interventions but had little experience using them. The longitudinal effects of the interventions were not studied. Conclusions Administering and managing multiple IV infusions is a complex and risk-prone activity. However, when a patient requires multiple IV infusions, targeted interventions can reduce identified risks. A combination of standardized practice, technology improvements, and targeted education is required. PMID:26316919

  7. Pharmacokinetics of high-dose intravenous melatonin in humans.

    PubMed

    Andersen, Lars P H; Werner, Mads U; Rosenkilde, Mette M; Fenger, Andreas Q; Petersen, Marian C; Rosenberg, Jacob; Gögenur, Ismail

    2016-03-01

    This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221,500.0 (185,637.5-326,175.0) pg/mL and 1,251,500.0 (864,375.0-1,770,500.0) pg/mL, respectively; mean (SD) t1/2 was 42.3 (5.6) minutes and 46.2 (6.2) minutes; mean (SD) Vd was 1.6 (0.9) L/kg and 2.0 (0.8) L/kg; mean (SD) CL was 0.0253 (0.0096) L/min · kg and 0.0300 (0.0120) L/min · kg; and median (IQR) AUC0- ∞ , 8,997,633.0 (6,071,696.2-11,602,811.9) pg · min/mL and 54,685,979.4 (36,028,638.6-105,779,612.0) pg · min/mL. High-dose intravenous melatonin did not induce sedation, evaluated as simple reaction times. No adverse effects were reported in the study.

  8. Pharmacokinetics of florfenicol after intravenous and intramuscular dosing in llamas.

    PubMed

    Pentecost, Rebecca L; Niehaus, Andrew J; Werle, Nick A; Lakritz, Jeffrey

    2013-10-01

    Florfenicol, is a broad spectrum antimicrobial agent with wide tissue distribution commonly used to treat camelids. To address the lack of drug disposition data for florfenicol in llamas, we evaluated the pharmacokinetics after 20mg/kg intravenous (i.v.) and intramuscular (i.m.) dosing. Serum concentrations were determined using a HPLC-UV assay and pharmacokinetic analysis was conducted using non-compartmental analysis. Following i.v. injection, systemic clearance and Vdss in llamas were 4.6 mL/min/kg and 737 mL/kg, respectively. Mean residence time after i.v. dosing was 3h. After i.m. injection, florfenicol was rapidly absorbed, with Cmax concentrations being 3.2 μg/mL at 0.5h, mean residence time was 15 h, mean absorption time was 12h and absolute bioavailability of florfenicol after i.m. injection was 63%. The prolonged absorption of florfenicol after i.m. administration suggests the apparent HL_λz reflects the absorption process rather than elimination of the drug. Florfenicol administration was not associated with adverse reactions after dosing by either route. Serum florfenicol concentrations remained >1.0 μg/mL for 12h after i.m. administration. For susceptible pathogens, once daily dosing of 20mg/kg body weight appears appropriate.

  9. Intravenous heparin dosing strategy in hospitalized patients with atrial dysrhythmias.

    PubMed

    Roswell, Robert O; Greet, Brian; Shah, Sunny; Bernard, Samuel; Milin, Alexandra; Lobach, Iryna; Guo, Yu; Radford, Martha J; Berger, Jeffrey S

    2016-08-01

    Patients with non-valvular atrial fibrillation (AF) have an elevated stroke risk that is 2-7 times greater than in those without AF. Intravenous unfractionated heparin (UFH) is commonly used for hospitalized patients with atrial fibrillation and atrial flutter (AFL) to prevent stroke. Dosing strategies exist for intravenous anticoagulation in patients with acute coronary syndromes and venous thromboembolic diseases, but there are no data to guide providers on a dosing strategy for intravenous anticoagulation in patients with AF/AFL. 996 hospitalized patients with AF/AFL on UFH were evaluated. Bolus dosing and initial infusion rates of UFH were recorded along with rates of stroke, thromboemobolic events, and bleeding events as defined by the International Society on Thrombosis and Haemostasis criteria. Among 226 patients included in the analysis, 76 bleeding events occurred. Using linear regression analysis, initial rates of heparin infusion ranging from 9.7 to 11.8 units/kilogram/hour (U/kg/h) resulted in activated partial thromboplastin times that were within therapeutic range. The median initial infusion rate in patients with bleeding was 13.3 U/kg/h, while in those without bleeding it was 11.4 U/kg/h; p = 0.012. An initial infusion rate >11.0 U/kg/h yielded an OR 1.95 (1.06-3.59); p = 0.03 for any bleeding event. Using IV heparin boluses neither increased the probability of attaining a therapeutic aPTT (56.1 vs 56.3 %; p = 0.99) nor did it significantly increase bleeding events in the study (35.7 vs 31.3 %; p = 0.48). The results suggest that higher initial rates of heparin are associated with increased bleeding risk. From this dataset, initial heparin infusion rates of 9.7-11.0 U/kg/h without a bolus can result in therapeutic levels of anticoagulation in hospitalized patients with AF/AFL without increasing the risk of bleeding.

  10. Analgesic efficacy and safety of a novel injectable formulation of diclofenac compared with intravenous ketorolac and placebo after orthopedic surgery: a multicenter, randomized, double-blinded, multiple-dose trial.

    PubMed

    Daniels, Stephen; Melson, Timothy; Hamilton, Douglas A; Lang, Eric; Carr, Daniel B

    2013-08-01

    A novel injectable formulation of diclofenac, Dyloject, utilizes hydroxypropyl-β-cyclodextrin (HPβCD) as a solubilizing agent, allowing dosing as a small-volume intravenous bolus for postoperative pain. In this test of the efficacy and safety of HPβCD diclofenac, we hypothesized that HPβCD diclofenac would relieve moderate and severe pain after orthopedic surgery. Adults 18 to 85 years old with moderate and severe pain within 6 hours after surgery were randomized to HPβCD diclofenac, ketorolac tromethamine, or placebo, and stratified by risk cohort. The HPβCD diclofenac non-high-risk cohort dose was 37.5 mg, the high-risk cohort received 18.75 mg, and patients ≥95 kg received 50 mg. The ketorolac dose was 30 mg in the non-high-risk and high-weight cohorts and 15 mg in the high-risk cohort. Rescue intravenous morphine was given for pain as needed. Efficacy was measured by the sum of pain intensity differences (SPID). Mean SPID scores of 277 patients were significantly better with HPβCD diclofenac and ketorolac than with placebo (P<0.0001), across all risk cohorts (P<0.05). HPβCD diclofenac was associated with better SPID scores, faster onset of analgesia, and significantly lower opioid requirement (P<0.008) than ketorolac. In patients more than or equal to 65 years, HPβCD diclofenac was associated with significantly better analgesic efficacy (P=0.05), and lower opioid requirement versus ketorolac. The incidence of treatment-related adverse events was similar across groups. HPβCD diclofenac is safe and efficacious for acute moderate and severe pain after orthopedic surgery and significantly spares morphine use.

  11. Pharmacokinetics of flunixin in mature heifers following multiple intravenous administration.

    PubMed

    Jaroszewski, J; Jedziniak, P; Markiewicz, W; Grabowski, T; Chrostowska, M; Szprengier-Juszkiewicz, T

    2008-01-01

    The pharmacokinetics of flunixin meglumine was determined after its multiple (altogether 4 doses at 24-hours intervals) intravenous administration at a dose of 2.2 mg/kg body weight in six mature clinically healthy heifers. Plasma flunixin and its metabolite 5-hydroxyflunixin concentrations were analyzed with high-pressure liquid chromatography using an assay with a lower limit detection of 0.03 microg/ml for both substances. Plasma concentrations versus time curves were described by a two compartment open model. Mean plasma flunixin concentrations were similar on day 1 and 4, and than rapidly decreased (within 2 hours) from initial concentrations higher than 10 microg/ml to the concentrations lower than 1 microg/ml. The distribution phase of flunixin was short (t0.5 alpha = 0.29 +/- 0.16 and 0.18 +/- 0.04 on day 1 and 4, respectively) and the elimination phase was more prolonged (t0.5 beta = 3.30 +/- 0.60 and 3.26 +/- 0.22 on day 1 and 4, respectively). The mean residence time of flunixin was similar on day 1 (1.83 +/- 0.83) and 4 (1.88 +/- 0.46), and for 5-hydroxyflunixin this parameter was insignificantly (P > 0.05) higher on day 1 (5.49 +/- 2.22) as compared to that found on day 4 (3.99 +/- 2.17). The clearance of flunixin was similar on both examined days (0.23 +/- 0.12 on day 1 and 0.31 +/- 0.15 on day 4), and for 5-hydroxyflunixin was insignificantly (P > 0.05) lower on day 1 (2.37 +/- 1.21) as compared to that determined on day 4 (3.23 +/- 1.06). Our data indicate that multiple administration of flunixin did not alter significantly the parent drug and its metabolite concentrations in plasma, however may cause some small changes in pharmacokinetic parameters.

  12. Treatment of multiple system atrophy using intravenous immunoglobulin.

    PubMed

    Novak, Peter; Williams, Arlene; Ravin, Paula; Zurkiya, Omar; Abduljalil, Amir; Novak, Vera

    2012-11-01

    Multiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA. This was a single-arm interventional, single-center, open-label pilot study. Interventions included monthly infusions of the IVIG preparation Privigen®, dose 0.4 gram/kg, for 6 months. Primary outcome measures evaluated safety and secondary outcome measures evaluated preliminary efficacy of IVIG. Unified MSA Rating Scale (UMSARS) was measured monthly. Quantitative brain imaging using 3T MRI was performed before and after treatment. Nine subjects were enrolled, and seven (2 women and 5 men, age range 55-64 years) completed the protocol. There were no serious adverse events. Systolic blood pressure increased during IVIG infusions (p<0.05). Two participants dropped out from the study because of a non-threatening skin rash. The UMSARS-I (activities of daily living) and USMARS-II (motor functions) improved significantly post-treatment. UMSARS-I improved in all subjects (pre-treatment 23.9 ± 6.0 vs. post-treatment 19.0±5.9 (p=0.01). UMSARS-II improved in 5 subjects, was unchanged in 1 and worsened in 1 (pre-treatment 26.1±7.5 vs. post-treatment 23.3±7.3 (p=0.025). The MR imaging results were not different comparing pre- to post-treatment. Treatment with IVIG appears to be safe, feasible and well tolerated and may improve functionality in MSA. A larger, placebo-controlled study is needed.

  13. Treatment of multiple system atrophy using intravenous immunoglobulin

    PubMed Central

    2012-01-01

    Background Multiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA. Methods This was a single-arm interventional, single-center, open-label pilot study. Interventions included monthly infusions of the IVIG preparation Privigen®, dose 0.4 gram/kg, for 6 months. Primary outcome measures evaluated safety and secondary outcome measures evaluated preliminary efficacy of IVIG. Unified MSA Rating Scale (UMSARS) was measured monthly. Quantitative brain imaging using 3T MRI was performed before and after treatment. Results Nine subjects were enrolled, and seven (2 women and 5 men, age range 55–64 years) completed the protocol. There were no serious adverse events. Systolic blood pressure increased during IVIG infusions (p<0.05). Two participants dropped out from the study because of a non-threatening skin rash. The UMSARS-I (activities of daily living) and USMARS-II (motor functions) improved significantly post-treatment. UMSARS-I improved in all subjects (pre-treatment 23.9 ± 6.0 vs. post-treatment 19.0±5.9 (p=0.01). UMSARS-II improved in 5 subjects, was unchanged in 1 and worsened in 1 (pre-treatment 26.1±7.5 vs. post-treatment 23.3±7.3 (p=0.025). The MR imaging results were not different comparing pre- to post-treatment. Conclusions Treatment with IVIG appears to be safe, feasible and well tolerated and may improve functionality in MSA. A larger, placebo-controlled study is needed. PMID:23116538

  14. Postmarketing review of intravenous acetaminophen dosing based on Food and Drug Administration prescribing guidelines.

    PubMed

    dela Cruz Ubaldo, Catherine; Hall, Natalie Semaan; Le, Brenden

    2014-12-01

    To evaluate the appropriateness of intravenous acetaminophen dosing-prescribed dose, frequency, duration, and indication-based on United States Food and Drug Administration (FDA)-approved prescribing guidelines and to evaluate the adverse effect profile of intravenous acetaminophen. Retrospective chart review. United States Navy medical center. Three hundred patients who received intravenous acetaminophen from August 1, 2011, to August 1, 2012. The indications, dose, frequency, and duration of intravenous acetaminophen were recorded for each patient. Adverse effects of intravenous acetaminophen were analyzed by thoroughly reviewing any adverse effects documented, including nausea, vomiting, headache, or any symptom specifically attributed to the drug. Baseline liver function tests, including aspartate aminotransferase and alanine aminotransferase levels, and elevations 3 times the upper limit of normal during intravenous acetaminophen therapy were recorded. The average patient weight was 78±21 kg, with 12 patients (4%) weighing less than 50 kg and 288 (96%) patients weighing 50 kg or greater. Two hundred forty-one patients (80%) were appropriately dosed, whereas 59 (20%) patients were not appropriately dosed based on the FDA-approved dosing. No patients exceeded the FDA-approved maximum daily dosing recommendations for intravenous acetaminophen (4 g). Sixty-five patients (22%) received intravenous acetaminophen for longer than 24 hours. Intravenous acetaminophen was well tolerated, without any reported adverse effects, including the commonly reported adverse effects of nausea, vomiting, headache, and insomnia. Ten patients (3%) had a documented history of liver disease and did not experience any adverse effects or increases in liver function tests after the administration of intravenous acetaminophen. Intravenous acetaminophen appeared to be a safe and effective analgesic and antipyretic agent. Dosing for patients weighing less than 50 kg needs to be appropriately

  15. A novel injectable formulation of diclofenac compared with intravenous ketorolac or placebo for acute moderate-to-severe pain after abdominal or pelvic surgery: a multicenter, double-blind, randomized, multiple-dose study.

    PubMed

    Gan, Tong J; Daniels, Stephen E; Singla, Neil; Hamilton, Douglas A; Carr, Daniel B

    2012-11-01

    Injectable formulations of diclofenac have long been available in Europe and other countries. These formulations use a default dose of 75 mg of diclofenac delivered IV over 30 to 120 minutes or as an IM injection. A novel formulation of injectable diclofenac sodium, Dyloject®, is solubilized with hydroxypropyl β-cyclodextrin (HPβCD) so that it can be given IV or IM in a small volume bolus. In this multicenter, multiple-dose, multiple-day, randomized, double-blind, parallel-group phase 3 study, we investigated whether lower doses of HPβCD diclofenac delivered as a small volume bolus would be effective for the management of acute pain after abdominal or pelvic surgery. Adults with moderate and severe pain, defined as ≥50 mm on a 0 to 100 mm visual analog scale, within 6 hours after surgery were randomly assigned (1:1:1:1 ratio) to receive HPβCD diclofenac, 18.75 mg or 37.5 mg; ketorolac tromethamine 30 mg; or placebo. Patients in all treatment arms received a bolus IV injection every 6 hours until discharged. They were observed for at least 48 h, and for up to 5 days. Rescue IV morphine was available any time, up to a total of 7.5 mg over a 3-hour period. The primary efficacy measure was the sum of pain intensity differences from 0 to 48 hours after study drug initiation. Three hundred thirty-one patients received ≥1 dose of study drug. Over the first 48 hours, both IV HPβCD diclofenac doses, as well as ketorolac, produced significant reductions in pain intensity over placebo (all P < 0.05), as well as significant reductions in the need for rescue morphine administration. Both doses of HPβCD diclofenac, as well as ketorolac, significantly reduced rescue morphine dosages, as compared to placebo (P < 0.0001), and time to rescue morphine administration was significantly increased by treatment with 18.75 mg diclofenac and ketorolac. The overall incidence of treatment-related adverse events was 20.2%. No treatment-related serious adverse events were reported in

  16. Intravenous busulfan dose individualization - impact of modeling approach on dose recommendation.

    PubMed

    Abdel-Rahman, Susan M; Casey, K Leigh; Garg, Uttam; Dalal, Jignesh

    2016-05-01

    TDM is intended to limit unintended consequences of drugs with narrow therapeutic indices. However, the application of different sampling strategies and pharmacokinetic approaches results in different dosing recommendations and ostensibly different outcomes. TDM approaches for intravenous busulfan dose individualization employ compartmental or non-compartmental modeling with anywhere from three to seven drug levels. This investigation was designed to examine the differences in dosing recommendations that arise in children (n = 30) when five different TDM approaches were employed. Significant differences in recommended doses between modeling strategies were observed. More importantly, the recommendations were discordant in 13 cases with at least one model recommending a dose adjustment in the opposite direction relative to the remaining models. The mathematical differences introduced by the application of different TDM approaches are not purely academic. Unification of busulfan TDM approaches should be considered to mitigate inconsistently applied dose adjustment, and facilitate comparisons of outcome, between clinical centers. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Does Intravenous Midazolam Dose Influence the Duration of Recovery Room Stay Following Outpatient Third Molar Surgery?

    PubMed

    Ettinger, Kyle S; Jacob, Adam K; Viozzi, Christopher F; Van Ess, James M; Fillmore, W Jonathan; Arce, Kevin

    2015-12-01

    To evaluate the impact of intravenous midazolam dose on the duration of recovery room stay for patients undergoing outpatient third molar surgery. Using a retrospective cohort study design, a sample of patients undergoing outpatient third molar surgery under intravenous sedation at Mayo Clinic from 2010 to 2014 was identified. All patients underwent extraction of all 4 third molars during a single operative procedure and the age range was limited to 14 to 29 years. The primary predictor variable was the total dose of intravenous midazolam administered during sedation. The primary outcome variable was recovery room length of stay (LOS) after completion of surgery. Multiple covariates also abstracted included patient age, gender, American Society of Anesthesiologists (ASA) score, duration of surgical procedure, complexity of surgical procedure, types and dosages of all intravenous medications administered during sedation, and volume of crystalloid fluid administered perioperatively. Univariable and multivariable models were developed to evaluate associations between the primary predictor variable and covariates relative to the primary outcome variable. The study sample was composed of 2,610 patients. Mean age was 18.3 years (SD, 3.0 yr; range, 14 to 29 yr) and gender distribution was 52% female. Mean dosage of midazolam administered was 4.1 mg (SD, 1.1 mg; range, 0.5 to 10.0 mg). Variables predicting shorter LOS at multivariable analysis included older age (P < .001), male gender (P = .004), and administration of larger crystalloid fluid volumes (P < .001). Variables predicting longer LOS included higher ASA score (P < .001), administration of ketamine (P < .001), and administration of ketorolac (P < .001). The dose of midazolam administered during sedation was not found to be significantly associated with prolonged recovery room LOS in univariable or multivariable settings. Dosage of intravenous midazolam does not appear to significantly impact the

  18. High Dose versus Low Dose Intravenous Pantoprazole in Bleeding Peptic Ulcer: A Randomized Clinical Trial

    PubMed Central

    Masjedizadeh, Abdol Rahim; Hajiani, Eskandar; Alavinejad, Pezhman; Hashemi, Seyed Jalal; Shayesteh, Ali Akbar; Jamshidian, Noordin

    2014-01-01

    BACKGROUND The appropriate dose of proton pump inhibitors for treatment of patients with upper (GI) bleeding remains controversial. This study compares high-dose versus low-dose intravenous proton pump inhibitor (PPI) infusion for prevention of GI bleeding complications. METHODS A total of 166 patients with bleeding peptic ulcers underwent therapeutic endoscopy using concomitant therapy by argon plasma coagulation (APC) and diluted epinephrine injection. Patients were randomly divided into two groups: high-dose pantoprazole (80 mg bolus, 8 mg per hour) and low-dose pantoprazole (40 mg bolus, 4 mg per hour) infused for three days. Initial outcomes were rebleeding, need for surgery, hemoglobin drop more than two units, and hospitalization for more than five days. Secondary outcome included mortality rate. RESULTS Overall, 166 patients (83 patients per group) enrolled in the study. The average age of patients in the high-dose group was 59.5±15.6 years and 52.3±13.3 years in the low-dose group (p=0.58). Males comprised 69.7% of patients. In the high-dose group, the mean number of units of transfused blood was 3.3±1.71 and in the low-dose group, it was 2.82±1.73 (p=0.50). There were 36 (43.37%) patients in the high-dose group and 40 (48.19%) in the low-dose group who were hospitalized for more than 5 days (p=0.53). Rebleeding was observed in 27 (32.53%) patients in the high-dose group and in 21 (25.30%) in the low-dose group (p=0.30). There were no significant differences observed in drop in hemoglobin of more than two units (p=0.15), mortality (p=0.99) and surgery (p=0.75) between the two groups. CONCLUSION For controlling peptic ulcer bleeding, there is no difference between high dose and low dose pantoprazole infusion. PMID:25093061

  19. Acute hepatotoxicity associated with therapeutic doses of intravenous acetaminophen.

    PubMed

    Seifert, Steven A; Kovnat, Daniel; Anderson, Victoria E; Green, Jody L; Dart, Richard C; Heard, Kennon J

    2016-03-01

    likely catabolic state and multiple acetaminophen doses over several days. These uncommon circumstances limit the generalizability of risk. We believe the findings are most consistent with acetaminophen-induced liver injury. This case illustrates a potential hazard of IV acetaminophen and demonstrates the potential utility of APAP-CYS adducts in evaluating causality in acute liver injury.

  20. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke.

    PubMed

    Anderson, Craig S; Robinson, Thompson; Lindley, Richard I; Arima, Hisatomi; Lavados, Pablo M; Lee, Tsong-Hai; Broderick, Joseph P; Chen, Xiaoying; Chen, Guofang; Sharma, Vijay K; Kim, Jong S; Thang, Nguyen H; Cao, Yongjun; Parsons, Mark W; Levi, Christopher; Huang, Yining; Olavarría, Verónica V; Demchuk, Andrew M; Bath, Philip M; Donnan, Geoffrey A; Martins, Sheila; Pontes-Neto, Octavio M; Silva, Federico; Ricci, Stefano; Roffe, Christine; Pandian, Jeyaraj; Billot, Laurent; Woodward, Mark; Li, Qiang; Wang, Xia; Wang, Jiguang; Chalmers, John

    2016-06-16

    Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively

  1. Bioequivalence of Two Intravenous Artesunate Products with Its Active Metabolite Following Single and Multiple Injections

    PubMed Central

    Li, Qigui; Xie, Lisa; Melendez, Victor; Weina, Peter

    2011-01-01

    In animal species and humans, artesunate (AS) undergoes extensive and complex biotransformation to an active metabolite, dihydroartemisinin (DHA). The bioequivalence of two intravenous AS pharmaceutical products with 5% NaHCO3 (China Formulation) or 0.3 M PBS (WRAIR Formulation) was determined in rats in a two-formulation, two-period, and two-sequence crossover experimental design. Following single and multiple intravenous administrations, a series of blood samples was collected by using an automated blood sampler and drug concentrations were analyzed by LC-MS/MS. The 90% CI of the difference between the two intravenous formulations was contained within 80–125% of the geometric mean of pharmacokinetic parameters for AS and DHA in all animals dosed. Hematological effects were studied on days 1 and 3 after the final dosing, and a rapidly reversible hematological toxicity (significant reductions in reticulocyte levels) was seen in the peripheral blood of the rats treated with each formulation. The results showed that bioequivalence with the parent compound and active metabolite was fulfilled in the 82.3–117.7% ranges of all parameters (AUC0−t, Cmax, concentration average and degree of fluctuation) in the two-period and two-sequence crossover studies following single and repeated intravenous injections. For the metabolite, the equivalence was satisfied in most pharmacokinetic parameters tested due to the variability in the hydrolysis rate of AS to DHA. The WRAIR formulation of AS was considered to be bioequivalent to the Chinese formulation at steady-state according to the total drug exposure, in terms of both parent drug and active metabolite, rapidly reversal in reticulocyte decline, and extension of single and multiple administrations. Therefore, the parent drug and active metabolites should play similar important roles in the determination of efficacy and safety of the drug.

  2. Backscattering measuring system for optimization of intravenous laser irradiation dose

    NASA Astrophysics Data System (ADS)

    Rusina, Tatyana V.; Popov, V. D.; Melnik, Ivan S.; Dets, Sergiy M.

    1996-11-01

    Intravenous laser blood irradiation as an effective method of biostimulation and physiotherapy becomes a more popular procedure. Optimal irradiation conditions for each patient are needed to be established individually. A fiber optics feedback system combined with conventional intravenous laser irradiation system was developed to control of irradiation process. The system consists of He-Ne laser, fiber optics probe and signal analyzer. Intravenous blood irradiation was performed in 7 healthy volunteers and 19 patients with different diseases. Measurements in vivo were related to in vitro blood irradiation which was performed in the same conditions with force-circulated venous blood. Comparison of temporal variations of backscattered light during all irradiation procedures has shown a strong discrepancy on optical properties of blood in patients with various health disorders since second procedure. The best cure effect was achieved when intensity of backscattered light was constant during at least five minutes. As a result, the optical irradiation does was considered to be equal 20 minutes' exposure of 3 mW He-Ne laser light at the end of fourth procedure.

  3. Inversion-based propofol dosing for intravenous induction of hypnosis

    NASA Astrophysics Data System (ADS)

    Padula, F.; Ionescu, C.; Latronico, N.; Paltenghi, M.; Visioli, A.; Vivacqua, G.

    2016-10-01

    In this paper we propose an inversion-based methodology for the computation of a feedforward action for the propofol intravenous administration during the induction of hypnosis in general anesthesia. In particular, the typical initial bolus is substituted with a command signal that is obtained by predefining a desired output and by applying an input-output inversion procedure. The robustness of the method has been tested by considering a set of patients with different model parameters, which is representative of a large population.

  4. Postoperative high-dose intravenous iron sucrose with low dose erythropoietin therapy after total hip replacement.

    PubMed

    Yoon, Jiyeol; Kim, Sungmin; Lee, Soo Chan; Lim, Hongsub

    2010-12-01

    Erythropoietin combined with parenteral iron sucrose therapy is an alternative to blood transfusion in anemic patients. It was shown to be effective in surgical patients in several previous studies when used in conjunction with other methods. However, there are no guidelines about safety limits in dosage amounts or intervals. In this study, we report a case of significant postoperative hemorrhage managed with high dose parenteral iron sucrose, low dose erythropoietin, vitamin B(12), vitamin C, and folic acid. An 80-year-old female patient presented for severe anemia after a total hip arthroplasty and refused an allogenic blood transfusion as treatment. The preoperative hemoglobin of 12.2 g/dL decreased to 5.3 g/dL postoperatively. She received the aforementioned combination of iron sucrose, erythropoietin, and vitamins. A total of 1,500 mg of intravenous iron sucrose was given postoperatively for 6 consecutive days. Erythropoietin was also administered at 2,000 IU every other day for a total of 12,000 IU. The patient was discharged in good condition on the twelfth postoperative day with a hemoglobin of 8.5 g/dL. Her hemoglobin was at 11.2 g/dL on the twentieth postoperative day.

  5. Comparative dose response using the intravenous versus enteral route of administration for potassium replenishment.

    PubMed

    DeCarolis, Douglas D; Kim, Grace Miran; Rector, Thomas S; Ishani, Areef

    2016-10-01

    To compare the change in potassium concentration (dose-response) using the intravenous versus enteral route for potassium replenishment. Cross-sectional analysis of individual potassium chloride doses with resulting changes in plasma potassium concentrations in intensive care patients. Potassium chloride was administered according to potassium replenishment protocols. For inclusion, doses were required to have pre- and post-dose plasma potassium concentrations obtained within 8hours of administration. Medical and surgical intensive care units of a United States Veterans Affairs Medical Center. The primary outcome was the dose-response slope for intravenous versus enteral potassium administration as estimated by linear regression analysis. Multivariable linear regression was employed to adjust for potential confounders. The sample had 278 potassium chloride doses administered to 142 patients. The potassium concentration change per 20mmol of potassium chloride was similar for intravenous and enteral routes, 0.25mmol/L (95% confidence interval 0.16-0.33) versus 0.27mmol/L (0.15-0.39) respectively (p=0.73). Multivariable linear regression did not alter results. The success of achieving a minimum potassium concentration defined by the specific protocol was similar for intravenous (61%) and enteral (59%) administration. Overall, 77% of potassium chloride doses were administered at a time when patients were eligible to receive an enteral dosage form. The enteral route was as effective as the intravenous route in increasing the plasma potassium concentration. The enteral route was widely available for potassium replenishment. Despite enteral route availability and the well-known reliability of potassium chloride absorption, the majority of doses were administered intravenously. Published by Elsevier Ltd.

  6. Multiple intravenous infusions phase 1b: practice and training scan.

    PubMed

    Cassano-Piché, A; Fan, M; Sabovitch, S; Masino, C; Easty, A C

    2012-01-01

    Minimal research has been conducted into the potential patient safety issues related to administering multiple intravenous (IV) infusions to a single patient. Previous research has highlighted that there are a number of related safety risks. In Phase 1a of this study, an analysis of 2 national incident-reporting databases (Institute for Safe Medical Practices Canada and United States Food and Drug Administration MAUDE) found that a high percentage of incidents associated with the administration of multiple IV infusions resulted in patient harm. The primary objectives of Phase 1b of this study were to identify safety issues with the potential to cause patient harm stemming from the administration of multiple IV infusions; and to identify how nurses are being educated on key principles required to safely administer multiple IV infusions. A field study was conducted at 12 hospital clinical units (sites) across Ontario, and telephone interviews were conducted with program coordinators or instructors from both the Ontario baccalaureate nursing degree programs and the Ontario postgraduate Critical Care Nursing Certificate programs. Data were analyzed using Rasmussen's 1997 Risk Management Framework and a Health Care Failure Modes and Effects Analysis. Twenty-two primary patient safety issues were identified with the potential to directly cause patient harm. Seventeen of these (critical issues) were categorized into 6 themes. A cause-consequence tree was established to outline all possible contributing factors for each critical issue. Clinical recommendations were identified for immediate distribution to, and implementation by, Ontario hospitals. Future investigation efforts were planned for Phase 2 of the study. This exploratory field study identifies the potential for errors, but does not describe the direct observation of such errors, except in a few cases where errors were observed. Not all issues are known in advance, and the frequency of errors is too low to be

  7. Multiple Intravenous Administrations of Human Umbilical Cord Blood Cells Benefit in a Mouse Model of ALS

    PubMed Central

    Garbuzova-Davis, Svitlana; Rodrigues, Maria C. O.; Mirtyl, Santhia; Turner, Shanna; Mitha, Shazia; Sodhi, Jasmine; Suthakaran, Subatha; Eve, David J.; Sanberg, Cyndy D.; Kuzmin-Nichols, Nicole; Sanberg, Paul R.

    2012-01-01

    Background A promising therapeutic strategy for amyotrophic lateral sclerosis (ALS) is the use of cell-based therapies that can protect motor neurons and thereby retard disease progression. We recently showed that a single large dose (25×106 cells) of mononuclear cells from human umbilical cord blood (MNC hUCB) administered intravenously to pre-symptomatic G93A SOD1 mice is optimal in delaying disease progression and increasing lifespan. However, this single high cell dose is impractical for clinical use. The aim of the present pre-clinical translation study was therefore to evaluate the effects of multiple low dose systemic injections of MNC hUCB cell into G93A SOD1 mice at different disease stages. Methodology/Principal Findings Mice received weekly intravenous injections of MNC hUCB or media. Symptomatic mice received 106 or 2.5×106 cells from 13 weeks of age. A third, pre-symptomatic, group received 106 cells from 9 weeks of age. Control groups were media-injected G93A and mice carrying the normal hSOD1 gene. Motor function tests and various assays determined cell effects. Administered cell distribution, motor neuron counts, and glial cell densities were analyzed in mouse spinal cords. Results showed that mice receiving 106 cells pre-symptomatically or 2.5×106 cells symptomatically significantly delayed functional deterioration, increased lifespan and had higher motor neuron counts than media mice. Astrocytes and microglia were significantly reduced in all cell-treated groups. Conclusions/Significance These results demonstrate that multiple injections of MNC hUCB cells, even beginning at the symptomatic disease stage, could benefit disease outcomes by protecting motor neurons from inflammatory effectors. This multiple cell infusion approach may promote future clinical studies. PMID:22319620

  8. Multiple Intravenous Infusions Phase 2a: Ontario Survey

    PubMed Central

    Fan, Mark; Koczmara, Christine; Masino, Caterina; Cassano-Piché, Andrea; Trbovich, Patricia; Easty, Anthony

    2014-01-01

    Background Research conducted in earlier phases of this study prospectively identified a number of concerns related to the safe administration of multiple intravenous (IV) infusions in Ontario hospitals. Objective To investigate the potential prevalence of practices or policies that may contribute to the patient safety risks identified in Phase 1b of this study. Data Sources and Review Methods Sixty-four survey responses were analyzed from clinical units where multiple IV infusions may occur (e.g., adult intensive care units). Survey questions were organized according to the topics identified in Phase 1b as potential contributors to patient harm (e.g., labelling practices, patient transfer practices, secondary infusion policies). Results Survey results indicated suboptimal practices and policies in some clinical units, and variability in a number of infusion practices. Key areas of concern included the following: use of primary IV tubing without back check valves when administering secondary infusions administration of secondary infusions with/as high-alert continuous IV medications potential confusion about how IV tubing should be labelled to reflect replacement date and time interruptions to IV therapy due to IV pump and/or tubing changes when patients are transferred between clinical units coadministration of continuous or intermittent infusions on central venous pressure monitoring ports variability in respondents’ awareness of the infusion pump's bolus capabilities Limitations Due to the limited sample size, survey responses may not be representative of infusion practices across Ontario. Answers to some questions indicated that the intent of the questions might have been misunderstood. Due to a design error, 1 question about bolus administration methods was not shown to as many respondents as appropriate. Conclusions The Ontario survey revealed variability in IV infusion practice across the province and potential opportunities to improve safety. PMID

  9. Multiple-dose amikacin kinetics in pediatric oncology patients.

    PubMed

    Kramer, W G; Cleary, T; Frankel, L S; Kohl, S; Pickering, L K

    1979-11-01

    Amikacin kinetics was studied in 8 pediatric oncology patients who received the drug by intravenous infusion over 30 or 60 min at a dose of 5 mg/kg every 6 or 8 hr. This regimen is recommended but, due to patient variability, patients should be monitored. Dosing intervals during 1 or 2 and 3 or 4 days of therapy were studied with serum samples collected before and at the end of the infusion and serially to the end of the dosing interval. The data appeared consistent with and were analyzed according to 1-compartment model. An equation describing serum concentration with time for the multiple-dose case was fit to each patient's multiple-interval data with nonlinear regression. Half-life averaged 1.2 hr. volume of distribution 0.24 l/kg, and total body clearance 109 ml/min/1.73 m2 or 2.51 ml/min/kg. The volume of distribution and the clearance are greater than reported for adults and probably account for the larger dose needed to achieve and maintain therapeutic levels. Although the total daily dose was greater than previously reported, there were no signs of toxicity, although therapuetic concentrations were maintained.

  10. Pharmacokinetics of azapropazone following single oral and intravenous doses.

    PubMed

    Breuing, K H; Gilfrich, H J; Meinertz, T; Jähnchen, E

    1979-01-01

    The pharmacokinetics of azapropazone (Prolixan) was studied in 7 healthy volunters following single oral and i.v. doses of 600 mg. After i.v. injection plasma concentration declined biexponentially with time. The half-life of the beta-phase was 13.6 +/- 2.6 h (mean +/- SD), the apparent volume of distribution 11.9 +/- 3.5 l, and the total clearance 10.1 +/- 2.1 ml . min-1. Following oral administration peak plasma concentrations occurred between 3 and 6 h and declined with a beta-phase half-life of 14.3 +/- 2.8 h. The binding of azapropazone to plasma proteins was high (ranging from 99.52 to 99.67% at a total plasma concentration of 75 micrograms/ml). The bioavailability of azapropazone when administered as capsules was 83 +/- 19%.

  11. Single intravenous and oral dose pharmacokinetics of florfenicol in the channel catfish Ictalurus punctatus

    USDA-ARS?s Scientific Manuscript database

    Plasma distribution and elimination of florfenicol in channel catfish were investigated after a single dose (10mg/kg) of intravenous i.v.) or oral administration in freshwater at a mean water temperature of 25.4°C. Florfenicol concentrations in plasma were analyzed by means of liquid chromatography...

  12. Comparative serum bactericidal activities of three doses of ciprofloxacin administered intravenously.

    PubMed Central

    Dan, M; Poch, F; Quassem, C; Kitzes, R

    1994-01-01

    The pharmacokinetics and serum bactericidal activities of three intravenous doses of ciprofloxacin were studied comparatively in 30 patients. Single 200-, 300-, and 400-mg intravenous doses of ciprofloxacin were given over 30 min to 10 patients each, and serum samples were obtained at 0.5, 1, 2, 3, 4, 8, and 12 h after the start of the infusion. Serum drug concentrations were determined by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by using noncompartmental analysis methods. Serum bactericidal activity against clinical isolates of Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Acinetobacter calcoaceticus, and Staphylococcus aureus was determined for samples obtained at 0.5, 4, 8, and 12 h. Excellent activity was demonstrated up to 12 h by all doses against E. coli and E. cloacae. Much poorer titers were observed for the remaining organisms, although the 400-mg dose prompted improved results against P. aeruginosa with a mean bactericidal titer of 1:2.9 at 8 h. In conclusion, while the 200-mg dose appears to be largely adequate for infections caused by members of the family Enterobacteriaceae, it seems that when P. aeruginosa is involved, 400 mg twice a day or even three times a day is more appropriate. Intravenous ciprofloxacin performs poorly against A. calcoaceticus and S. aureus, even at a higher dose. PMID:8031055

  13. Timing of maintenance phenytoin therapy after intravenous loading dose.

    PubMed

    Riviello, J J; Roe, E J; Sapin, J I; Grover, W D

    1991-01-01

    The specific timing of maintenance phenytoin therapy in children has not been addressed. Prevention of a subtherapeutic phenytoin level is important for seizure control. We devised a protocol using an 18 mg/kg loading dose of phenytoin with serial levels (obtained after 2,6,12 hours) and analyzed the results in 20 consecutive patients. A therapeutic level (greater than 10 micrograms/ml) was present in all patients at 2 hours, in 16 of 20 at 6 hours, and in 10 of 20 at 12 hours. The patients were divided into 2 groups by the 12-hour levels: group I: therapeutic level; and group II: subtherapeutic level. The mean 2-hour level in group I was 22.7 micrograms/ml versus 15.6 micrograms/ml in group II (P less than 0.001). The mean decline in plasma concentration in individual patients was 0.7 micrograms/ml/hr in group I versus 1.02 micrograms/ml/hr in group II (P less than 0.05). We now use the 2-hour level to decide the timing of maintenance phenytoin therapy and have devised an equation to estimate the duration of the therapeutic range. Phenytoin can be administered at 12 hours when the 2-hour level is satisfactory or earlier when the 2-hour level indicates that a subtherapeutic level will occur.

  14. Multiple anatomy optimization of accumulated dose

    SciTech Connect

    Watkins, W. Tyler Siebers, Jeffrey V.; Moore, Joseph A.; Gordon, James; Hugo, Geoffrey D.

    2014-11-01

    Purpose: To investigate the potential advantages of multiple anatomy optimization (MAO) for lung cancer radiation therapy compared to the internal target volume (ITV) approach. Methods: MAO aims to optimize a single fluence to be delivered under free-breathing conditions such that the accumulated dose meets the plan objectives, where accumulated dose is defined as the sum of deformably mapped doses computed on each phase of a single four dimensional computed tomography (4DCT) dataset. Phantom and patient simulation studies were carried out to investigate potential advantages of MAO compared to ITV planning. Through simulated delivery of the ITV- and MAO-plans, target dose variations were also investigated. Results: By optimizing the accumulated dose, MAO shows the potential to ensure dose to the moving target meets plan objectives while simultaneously reducing dose to organs at risk (OARs) compared with ITV planning. While consistently superior to the ITV approach, MAO resulted in equivalent OAR dosimetry at planning objective dose levels to within 2% volume in 14/30 plans and to within 3% volume in 19/30 plans for each lung V20, esophagus V25, and heart V30. Despite large variations in per-fraction respiratory phase weights in simulated deliveries at high dose rates (e.g., treating 4/10 phases during single fraction beams) the cumulative clinical target volume (CTV) dose after 30 fractions and per-fraction dose were constant independent of planning technique. In one case considered, however, per-phase CTV dose varied from 74% to 117% of prescription implying the level of ITV-dose heterogeneity may not be appropriate with conventional, free-breathing delivery. Conclusions: MAO incorporates 4DCT information in an optimized dose distribution and can achieve a superior plan in terms of accumulated dose to the moving target and OAR sparing compared to ITV-plans. An appropriate level of dose heterogeneity in MAO plans must be further investigated.

  15. "Half-half" blisters in bullous pemphigoid successfully treated with adjuvant high-dose intravenous immunoglobulin.

    PubMed

    Pacheco, David; Lopes, Leonor; Soares-Almeida, Luis; Marques, Manuel Sacramento; Filipe, Paulo

    2012-09-01

    Bullous pemphigoid is a rare, autoimmune blistering disease. Its clinical presentation is tense blisters that may arise on normal-appearing or erythematous skin. Bullous pemphigoid refractory to systemic corticosteroids in combination with immunosuppressants such as azathioprine and mycophenolate mofetil may benefit from adjuvant high-dose intravenous immunoglobulin (IVIg). We describe a particular case with an unusual clinical presentation unresponsive to systemic corticosteroids plus azathioprine, in which the addition of high-dose IVIg was successful. The combined therapy of systemic corticosteroids and azathioprine plus high-dose IVIg can be an option in refractory cases due to its efficiency and tolerability.

  16. Effect of high-dose intravenous eletriptan on coronary artery diameter.

    PubMed

    Goldstein, J A; Massey, K D; Kirby, S; Gibson, M; Hettiarachchi, J; Rankin, A J; Jackson, N C

    2004-07-01

    The goal of this study was to evaluate the coronary vasoconstrictive effects of high doses of eletriptan compared with a standard dose of sumatriptan. Patients with no clinically significant coronary artery disease were randomized to receive high-dose intravenous eletriptan (n = 24) vs a standard dose of sumatriptan (n = 18; 6 mg subcutaneously) vs placebo (n = 18). Serial angiograms were obtained. The primary non-inferiority analysis found equivalence between the mean maximum change in left anterior descending coronary artery diameter for eletriptan, -22%[95% confidence interval (CI) -26, -19], and sumatriptan, -19% (95% CI -22, -16). The change due to placebo was -16% (95% CI -20, -12). No individual cases of clinically significant vasoconstriction were observed. The results confirm that eletriptan has a broad cardiovascular safety margin, with plasma concentrations comparable to three to five times the Cmax of an oral 80-mg dose associated with modest vasoconstriction equivalent to standard therapeutic doses of sumatriptan.

  17. Facilitating Early-In-Day Discharge for Multiple Sclerosis Patients Treated With Intravenous Methylprednisolone

    PubMed Central

    Hawley, Gina; Burnett, Margie; Gibson, Lorrie; Carter, Kathryn; Harlow, Elizabeth; Russell, Holly; Huffman, Linda; Adams, Jane; Ziegler, Terry; Sporney, Hilary; Levy, Michael; Puttgen, Hans A.

    2015-01-01

    Background and Purpose: Delays in patient hospital discharge affect care value through costs of prolonged length of stay and barriers to patient flow within the hospital. We sought to facilitate early-in-day discharges (EIDDs) without extending length of stay for inpatients with multiple sclerosis admitted for acute exacerbations and treated with intravenous (IV) methylprednisolone. Methods: We developed a standardized admission order set, a provider checklist, and a patient checklist to better coordinate in-hospital care and discharge planning for patients with multiple sclerosis admitted for IV methylprednisolone treatment. The order set allowed providers to enter an accelerated dosing schedule of methylprednisolone, as appropriate, to ensure administration of the final dose of methylprednisolone in the morning on the anticipated day of discharge. We compared a prospective intervention cohort to a retrospective, preintervention baseline cohort. Results: At baseline (N = 25), 12.0% of patients were EIDD compared to 40.7% of intervention patients (N = 27; P = .03). In all, 85.2% of intervention patients compared to 64.0% of baseline patients were discharged on the same day as last methylprednisolone treatment (P = .11). No difference was observed in median length of stay and 30-day readmission rate between groups. Conclusions: Use of a standard admission order set as well as provider and patient checklists can facilitate EIDD and hospital bed availability without compromising care quality for a select group of neurology inpatients. PMID:26425247

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

    PubMed

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

    2002-09-01

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

  19. Pharmacokinetics of difloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications.

    PubMed

    Ding, H Z; Yang, G X; Huang, X H; Chen, Z L; Zeng, Z L

    2008-06-01

    Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t(1/2beta)) were 17.14 +/- 4.14, 25.79 +/- 8.10, 16.67 +/- 4.04 (pigs) and 6.11 +/- 1.50, 5.64 +/- 0.74, 8.20 +/- 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (C(max)) of 1.77 +/- 0.66, 2.29 +/- 0.85 (pigs) and 2.51 +/- 0.36, 1.00 +/- 0.21 microg/mL (broilers) attained at t(max) of 1.29 +/- 0.26, 1.41 +/- 0.88 (pigs) and 0.86 +/- 0.4, 4.34 +/- 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 +/- 28.9)% and (105.7 +/- 37.1)% (pigs) and (77.0 +/- 11.8)% and (54.2 +/- 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(V(d(area))) of 4.91 +/- 1.88 and 3.10 +/- 0.67 L/kg and total body clearances(Cl(B)) of 0.20 +/- 0.06 and 0.37 +/- 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t(1/2ka), t(1/2alpha)) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC(90) are <0.25 microg/mL and <0.1 microg/mL respectively.

  20. Visual Outcome after Treatment with High Dose Intravenous Methylprednisolone in Indirect Traumatic Optic Neuropathy.

    PubMed

    Pokharel, S; Sherpa, D; Shrestha, R; Shakya, K; Shrestha, R; Malla, O K; Pradhananga, C L; Pokhrel, R P; Shrestha, P

    2016-01-01

    Traumatic optic neuropathy is an acute injury of the optic nerve due to trauma. It is an ocular emergency, requiring early treatment though there is no proven standard treatment protocol for the condition. Various studies have shown improvement in vision after intravenous steroids, but not statistically significant. Studies have revealed even optical decompression surgery is not the ultimate treatment because of no significant improvement of vision. Our study aims to assess visual outcome after high dose (1 gram) of intravenous methylprednisolone in cases with indirect optic neuropathy. This was a non-randomized interventional study carried out in Kathmandu Medical College Teaching Hospital from May 1st 2013- June 1st 2014. There were 10 cases with indirect traumatic optic neuropathy included in the study. Four cases received IV methylprednisolone and six cases were observed without steroid treatment. Traumatic optic neuropathy was observed more in males[8 (80%)]with higher number in age group 21-30 years old. The visual recovery after intravenous steroid treatment was rapid and beneficial in cases with vision better than Non Perception of Light (NPL), even in cases presented 4 days after the trauma. There was rapid and beneficial improvement in visual acuity after high dose of intravenous steroid treatment in cases with indirect traumatic optic neuropathy with vision better than Non Perception of Light (NPL).

  1. The effect of intravenous low dose ketamine for reducing postoperative sore throat.

    PubMed

    Park, Sun Young; Kim, Sang Hyun; Noh, Jung Il; Lee, Su Myoung; Kim, Mun Gyu; Kim, Sang Ho; Ok, Si Young; Kim, Soon Im

    2010-07-01

    This study was performed to evaluate the effectiveness of intravenous low dose ketamine for reducing the incidence and severity of postoperative sore throat (POST). This was a prospective, randomized, double-blind clinical trial. The study population consisted of 70 patients between 20 and 70 years old who were classified as American Society of Anesthesiologists I-II and were scheduled for elective laparoscopic cholecystectomy. The patients were divided randomly into two groups. Patients in the ketamine group received an intravenous injection of 0.5 mg/kg of ketamine just before induction, followed by 10 microg/kg/min throughout the operation. Patients in the control group received intravenous saline instead of ketamine. The patients were interviewed 1, 6, and 24 h after the operation. The incidence and severity of POST were recorded. No significant differences in the incidence and severity of POST during the 24 h after the operation were found between the two groups (21/31 in the ketamine group vs. 26/34 in the control group, P = 0.398). Intravenous injection of low dose ketamine was not effective for reducing POST.

  2. The effect of intravenous low dose ketamine for reducing postoperative sore throat

    PubMed Central

    Kim, Sang Hyun; Noh, Jung Il; Lee, Su Myoung; Kim, Mun Gyu; Kim, Sang Ho; Ok, Si Young; Kim, Soon Im

    2010-01-01

    Background This study was performed to evaluate the effectiveness of intravenous low dose ketamine for reducing the incidence and severity of postoperative sore throat (POST). Methods This was a prospective, randomized, double-blind clinical trial. The study population consisted of 70 patients between 20 and 70 years old who were classified as American Society of Anesthesiologists I-II and were scheduled for elective laparoscopic cholecystectomy. The patients were divided randomly into two groups. Patients in the ketamine group received an intravenous injection of 0.5 mg/kg of ketamine just before induction, followed by 10 µg/kg/min throughout the operation. Patients in the control group received intravenous saline instead of ketamine. The patients were interviewed 1, 6, and 24 h after the operation. The incidence and severity of POST were recorded. Results No significant differences in the incidence and severity of POST during the 24 h after the operation were found between the two groups (21/31 in the ketamine group vs. 26/34 in the control group, P = 0.398). Conclusions Intravenous injection of low dose ketamine was not effective for reducing POST. PMID:20651994

  3. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial.

    PubMed

    Merz, Maximilian; Salwender, Hans; Haenel, Mathias; Mai, Elias K; Bertsch, Uta; Kunz, Christina; Hielscher, Thomas; Blau, Igor W; Scheid, Christof; Hose, Dirk; Seckinger, Anja; Jauch, Anna; Hillengass, Jens; Raab, Marc S; Schurich, Baerbel; Munder, Markus; Schmidt-Wolf, Ingo G H; Gerecke, Christian; Lindemann, Hans-Walter; Zeis, Matthias; Weisel, Katja; Duerig, Jan; Goldschmidt, Hartmut

    2015-07-01

    We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16.

  4. [Prevention of psychedelic side effects associated with low dose continuous intravenous ketamine infusion].

    PubMed

    Remerand, Francis; Couvret, Claude; Pourrat, Xavier; Le Tendre, Charlotte; Baud, Annick; Fusciardi, Jacques

    2007-01-01

    Continuous low dose infusion of intravenous ketamine for postoperative analgesia was often associated with frightening acute psychodysleptic experiences in our patients. We hypothesized they were due to boluses of ketamine accumulated in the infusion line. We evaluated on two successive groups the impact of perfusion line modifications on psychodysleptic side effects occurrence. We compared a reference historic group (in which ketamine line was connected to perfusion line) to a second prospective group (in which ketamine line was connected to the venous catheter via an unidirectional valve). Psychodysleptic experiences occurrence decreased from 4 patients of 26 (15%) to 2 of 116 (2%, p = 0.01). Moreover, these experiences were no longer associated with severe anxious symptoms like near death experiences. An unidirectional valve must be considered to limit the occurrence of low dose intravenous ketamine infusion associated psychedelic side effects, during postoperative analgesia.

  5. [A case of primary erythromelalgia successfully treated with high-dose intravenous immunoglobulin therapy].

    PubMed

    Kuroda, Takeshi; Sugimoto, Azusa; Ishigaki, Seiichirou; Murakami, Hidetomo; Kawamura, Mitsuru

    2014-02-01

    Erythromelalgia is a rare condition characterized by constant or paroxysmal burning pain, erythema, and the elevation of skin temperature in the extremities. Recently, the impairment of C-fiber function due to autoimmune system involvement is considered as the primary cause of erythromelalgia. However, a successful treatment has yet not been established. We report a case of a 39-year-old woman with primary erythromelalgia accompanied by high cerebrospinal fluid protein concentration and axonal neuropathy. She received various antiepileptic and anti-inflammatory drugs, but failed to improve. She finally underwent high-dose intravenous immunoglobulin therapy, which dramatically improved her symptoms and normalized cerebrospinal fluid protein concentration. This result demonstrates the effectiveness of high-dose intravenous immunoglobulin therapy for the treatment of primary erythromelalgia and the possibility of autoimmune system involvement.

  6. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression.

    PubMed

    Loo, C K; Gálvez, V; O'Keefe, E; Mitchell, P B; Hadzi-Pavlovic, D; Leyden, J; Harper, S; Somogyi, A A; Lai, R; Weickert, C S; Glue, P

    2016-07-01

    This pilot study assessed the feasibility, efficacy and safety of an individual dose-titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. Fifteen treatment-refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double-blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose-related. Antidepressant response occurred at a range of doses and at <0.5 mg/kg. The dose-titration approach is a practical method for optimizing the efficacy - side-effects trade-off on an individual patient basis. This pilot study provides preliminary evidence for SC injection as a practical, feasible and efficacious treatment approach. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. When is high-dose intravenous iron repletion needed? Assessing new treatment options

    PubMed Central

    Gozzard, David

    2011-01-01

    High doses of intravenous iron have a role in the treatment of a number of clinical situations associated with iron deficiency, iron deficiency anemia, and blood loss. In the presence of functioning erythropoiesis, iron supplementation alone may be adequate to replenish iron stores and restore blood loss. Where hormone replacement with an erythropoiesis-stimulating agent is required, iron adequacy will optimize treatment. Intravenous iron offers a rapid means of iron repletion and is superior to oral iron in many circumstances, especially in the presence of anemia of chronic disease, where it appears to overcome the block to absorption of iron from the gastrointestinal tract and immobilization of stored iron. The clinical situations where high doses of iron are commonly required are reviewed. These include nondialysis-dependent chronic kidney disease, inflammatory bowel disease, obstetrics, menorrhagia, and anemia associated with cancer and its treatment. The literature indicates that high doses of iron are required, with levels of 1500 mg in nondialysis-dependent chronic kidney disease and up to 3600 mg in inflammatory bowel disease. New formulations of intravenous iron have recently been introduced that allow clinicians to administer high doses of iron in a single administration. Ferumoxytol is available in the US, has a maximum dose of 510 mg iron in a single administration, but is limited to use in chronic kidney disease. Ferric carboxymaltose can be rapidly administered in doses of 15 mg/kg body weight, up to a ceiling dose of 1000 mg. A test dose is not required, and it can be used more widely across a spectrum of iron deficiency and iron deficiency anemia indications. The latest introduction is iron isomaltoside 1000. Again, a test dose is not required, and it can be delivered rapidly as an infusion (in an hour), allowing even higher doses of iron to be administered in a single infusion, ie, 20 mg/kg body weight with no ceiling. This will allow clinicians to

  8. Single-dose Intravenous Toxicology Testing of Daebohwalryeok Pharmcopuncture in Sprague-Dawley Rats

    PubMed Central

    Sun, Seung-Ho; Park, Sunju; Jeong, Jong-Jin; Lee, Kwang-Ho; Yu, Jun-Sang; Seo, Hyung-Sik; Kwon, Ki-Rok

    2015-01-01

    Objectives: The aims of the study were to test the single-dose intravenous toxicity of Daebohwalryeok pharmacopuncture (DHRP) in Sprague-Dawley (SD) rats and to estimate the crude lethal dose. Methods: The experiments were conducted at Biotoxtech Co., a Good Laboratory Practice (GLP) laboratory, according to the GLP regulation and were approved by the Institutional Animal Care and Use Committee of Biotoxtech Co. (Approval no: 110156). The rats were divided into three groups: DHRP was injected into the rats in the two test groups at doses of 10 mL/kg and 20 mL/kg, respectively, and normal saline solution was injected into the rats in the control group. Single doses of DHRP were injected intravenously into 6 week old SD rats (5 male and 5 female rats per group). General symptoms were observed and weights were measured during the 14 day observation period after the injection. After the observation period, necropsies were done. Then, histopathological tests were performed. Weight data were analyzed with a one-way analysis of variance (ANOVA) by using statistical analysis system (SAS, version 9.2). Results: No deaths and no statistical significant weight changes were observed for either male or female SD rats in either the control or the test groups during the observation period. In addition, no treatment related general symptoms or necropsy abnormalities were observed. Histopathological results showed no DHRP related effects in the 20 mL/kg DHRP group for either male or female rats. Conclusion: Under the conditions of this study, the results from single-dose intravenous injections of DHRP showed that estimated lethal doses for both male and female rats were above 20 mL/kg. PMID:26120487

  9. High-dose intravenous IgG treatment and renal function.

    PubMed

    Schifferli, J; Leski, M; Favre, H; Imbach, P; Nydegger, U; Davies, K

    1991-02-23

    In an open trial of high dose intravenous IgG (IVIG) treatment in nephrotic patients with glomerulonephritis, the first six patients so far studied showed a transient rise in plasma creatinine. This increase was not associated with any symptoms and the urinary deposit remained unchanged. Two other patients with pre-existing renal impairment but without nephrotic syndrome had a transient and reversible rise in plasma creatinine immediately after IVIG. These observations suggest that high-dose IVIG infusion can produce short-lived disturbances in renal function in patients with kidney diseases.

  10. Single Intravenous-dose Toxicity of Water-soluble Carthami-flos Pharmacopuncture (WCF) in Rats

    PubMed Central

    Jung, Da-jung; Choi, Yoo-min; Kim, Seok-hee; Kim, Jong-uk; Yook, Tae-han

    2014-01-01

    Objectives: This study was performed to analyze the toxicity and to find the lethal dose of the test substance Water-soluble Carthami-flos pharmacopuncture (WCF) when used as a single intravenous-dose in 6-week-old, male and female Sprague-Dawley rats. Methods: The experiment was conducted at Biotoxtech according to Good Laboratory Practices. 20 female and 20 male Spague-Dawley rats were divided into 4 groups of 5 female and 5 male animals per group. The rats in the three experimental groups received single intravenous injections with 0.125-mL, 0.25-mL and 0.5-mL/animal doses of WCF, Groups 2, 3, and 4, respectively, and the control group, Group 1, received a single intravenous injection with a 0.5-mL dose of normal saline. Clinical signs were observed and body weight measurements were carried out for 14 days following the injections. At the end of the observation period, hematology, clinical chemistry, histopathological tests and necropsy were performed on the injected parts. Results: No deaths occurred in any of the groups. Also, no significant changes in body weight, hematological parameters or clinical chemistry test results between the control group and the experimental groups were observed. Visual inspection after necropsy showed no abnormalities. Histopathological tests on the injected parts showed no significant differences, except for Group 1 females; however, the result was spontaneous generation and had no toxicological meaning because it was not dose-dependent. Therefore, this study showed that WCF had no effect on the injected parts in terms of clinical signs, body weight, hematology, clinical chemistry, and necropsy. Conclusion: As a result of single intravenous-dose tests of the test substance WCF in 4 groups of rats, the lethal dose for both males and females exceeded 0.5 mL/animal. Therefore, WCF is a relatively safe pharmacopuncture that can be used for treatment, but further studies should be performed. PMID:25780707

  11. Human pharmacokinetics and toxicity of high-dose metronidazole administered orally and intravenously

    SciTech Connect

    Urtasun, R.C.; Rabin, H.R.; Partington, J.

    1983-01-01

    This study is part of a clinical program to assess the use of nitroimidazoles as radiosensitizers of hypoxic tumor cells. A total of 37 patients with malignant tumors have been entered into the study to receive oral high-dose metronidazole in conjunction with radiation. Twenty-eight patients with malignant brain tumors received 6 gm/m2 three times a week for 3 weeks (a mean total dose of 5.3 gm/m2). Maximum mean plasma drug concentration of 1 mM was obtained at 4 hours after drug ingestion with a mean half-life of 13 hours. Tissue and cerebrospinal fluid levels of 80% to 90% of the plasma levels were obtained at 4 to 6 hours. A linear relationship between increased drug dose and increased plasma concentration was observed at doses of 2.5 gm/m2 up to 6 gm/m2. Acute gastrointestinal and central nervous system toxicity was the dose-limiting factor (50% and 25%, respectively, at total doses of 5.3 gm/m2). Pharmacokinetic studies of intravenous metronidazole were performed in eight consenting patients. Single doses of 0.5, 1, 1.5, and 2 gm were administered intravenously by zero-order infusion pump. Seven of the eight patients received a second identical dose orally 1 week later and the results were compared. Open two-compartment kinetic characteristics of metronidazole were computed from simultaneous plasma infusion and urine excretion rate equations, by use of a nonlinear least-squares regression analysis program (NONLIN). The mean (+/- SD) for alpha half-life was 1.2 +/- 1.3 hours, and that for the beta half-life was 9.8 +/- 5.9 hours. The absolute oral bioavailability was estimated to approximate 100%.

  12. Low-dose intravenous lipid emulsion for the treatment of severe quetiapine and citalopram poisoning.

    PubMed

    Purg, Darinka; Markota, Andrej; Grenc, Damjan; Sinkovič, Andreja

    2016-06-01

    The treatment of quetiapine and/or citalopram poisoning is mainly supportive and involves gastric lavage, activated charcoal, intubation, and mechanical ventilation. Recently, however, there were reports of successful treatment with intravenous lipid emulsion. Here we report a case of a 19-year-old Caucasian girl who ingested approximately 6000 mg of quetiapine, 400 mg of citalopram, and 45 mg of bromazepam in a suicide attempt. The patient developed ventricular tachycardia and epileptic seizures 12 h after admission to the hospital. As the patient's condition deteriorated, we combined standard therapy (intubation, mechanical ventilation, and vasopressors) with low-dose intravenous lipid emulsion (ILE) (a total of 300 mL of 20 % lipid emulsion) and normalised her heart rhythm and stopped the seizures. She was discharged to the psychiatric ward after 48 h and home after a prolonged (2-month) psychiatric rehabilitation. Intravenous lipid emulsion turned out to be effective even in the lower dose range than previously reported for quetiapine poisoning in patients presenting with seizure and ventricular arrhythmia. To our knowledge, there are no case reports describing the use of ILE in treating citalopram poisoning.

  13. Safety and Efficacy of Intermittent Intravenous Administration of High-Dose Micafungin

    PubMed Central

    Neofytos, Dionysis; Huang, Yao-Ting; Cheng, Kimberly; Cohen, Nina; Perales, Miguel-Angel; Barker, Juliet; Giralt, Sergio; Jakubowski, Ann; Papanicolaou, Genovefa

    2015-01-01

    Background. The use of mold-active azoles for antifungal prophylaxis after allogeneic stem cell transplantation (SCT) is hindered by adverse events and drug–drug interactions. Higher doses of echinocandins administered intermittently may be an alternative in this setting. Methods. This was a single-center, observational 5-year study to characterize the safety and efficacy of intermittent administration of high-dose intravenous micafungin (≥5 doses of ≥300 mg micafungin 2–3 times weekly) in patients with acute leukemia and allogeneic SCT recipients. Results. A total of 104 patients (84 allogeneic SCT recipients and 20 patients with leukemia) received intermittent high-dose intravenous micafungin, 83 (79.8%) as prophylaxis. Large variability in the micafungin dosing regimen was observed; 78 (75%) patients received >75% of their course as 300 mg micafungin 3 times weekly. Liver function tests decreased from baseline to end of treatment (EOT; P < .001). Patients with normal baseline liver function (n = 55 [52%]) maintained similar enzyme levels throughout the study. For patients with abnormal baseline liver function (n = 49 [47%]), liver function tests significantly improved from baseline to EOT (P ≤ .005). Duration and/or micafungin dosing algorithms were not associated with liver toxicity at EOT. There were no significant changes in renal function, and infusion-related reactions or deaths were not observed. Five of 83 (6.0%) patients in the prophylaxis group developed a breakthrough fungal infection. Conclusions. In this largest cohort of patients to date, intermittent administration of high-dose micafungin was well tolerated, without any associated liver or renal function abnormalities, and may be considered an alternative antifungal prophylactic strategy. Prospective studies are needed to further validate these findings. PMID:26567284

  14. Effects of intravenous Escherichia coli (E. coli) dose on the pathophysiological response of colostrum-fed Jersey calves

    USDA-ARS?s Scientific Manuscript database

    The objective was to determine the effects of E. coli dose on the pathophysiological response of dairy calves following an intravenous challenge. Eighteen 3-week old colostrum-fed Jersey calves were completely randomized to 1 of 6 doses of E. coli. The challenge doses included 0, 105, 106, 107, 108,...

  15. Effects of perioperative intravenous low dose of ketamine on postoperative analgesia in children.

    PubMed

    Bazin, Véronique; Bollot, Julie; Asehnoune, Karim; Roquilly, Antoine; Guillaud, Christian; De Windt, Ariane; Nguyen, Jean-Michel; Lejus, Corinne

    2010-01-01

    Low dose of ketamine reduces postoperative pain and opioid consumption in adult studies. However, there are only a few data with controversial results in the paediatric population. The aim of this randomized controlled trial was to evaluate the use of low doses of intravenous ketamine on postoperative pain in children after surgery on the lower part of the body. Thirty-seven children with ASA 1 or 2 from 6 to 60 months of age, undergoing scheduled surgery, were prospectively enrolled in a double blind sequential trial using a triangular test, with analysis every 10 patients treated. The children were randomly assigned to intravenously receive saline or 0.15 mg kg(-1) ketamine before surgery, followed by a continuous infusion of 1.4 microg kg(-1) min(-1) over 24 h. After sevoflurane induction and tracheal intubation, a caudal anaesthesia was performed in all children (1 ml kg(-1) of bupivacaine 0.25% with epinephrine). The postoperative analgesic technique was standardized with intravenous paracetamol 15 mg kg(-1) 6 h(-1), rectal morniflumate (20 mg kg(-1) 12 h(-1)) and intravenous nalbuphine infusion 1.2 mg kg(-1) 24 h(-1) for 24 h. The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) scores, additional bolus of nalbuphine (if CHEOPS >7) and side effects were recorded from eye opening every 2 h over 24 h. The primary endpoint was the CHEOPS area under the curve. There was no difference in terms of additional bolus of nalbuphine as well as CHEOPS score area under the curve between groups, that is, 76 +/- 10 in the ketamine group versus 74 +/- 7 in the control group. No psychomimetic side effects were noted. The study failed to show any evidence of benefit of ketamine to improve analgesia in children when given in addition to a multimodal analgesic therapy with paracetamol, a NSAID and an opiate.

  16. Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses.

    PubMed Central

    Barbhaiya, R H; Forgue, S T; Gleason, C R; Knupp, C A; Pittman, K A; Weidler, D J; Martin, R R

    1990-01-01

    In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min intravenous infusion) received each antibiotic, according to a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 ml/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime. PMID:2203303

  17. Hemoglobin maintenance and dosing strategies using intravenous continuous erythropoietin receptor activator in Japanese hemodialysis patients.

    PubMed

    Hirai, Takayuki; Nishizawa, Yoshiko; Nakazono, Hiroshi; Asai, Mariko; Yamashita, Hideki; Sasaki, Ayako; Yamashita, Tetsumasa; Yamashita, Kazuomi; Shigemoto, Kenichiro; Harada, Satoru; Mizuiri, Sonoo

    2013-10-01

    Methoxy polyethylene glycol-epoetin beta, a continuous erythropoietin receptor activator (CERA), is reported to be effective in managing renal anemia but there is little data about CERA in Japan. This study aimed to ascertain the effects of CERA in Japanese hemodialysis patients and the appropriate starting dose of CERA when switching from other erythropoiesis-stimulating agents. We switched 61 stable hemodialysis patients to 4-weekly intravenous CERA, from either epoetin beta (rHuEPO) or darbepoetin alpha (DA). When determining the initial dose of CERA, we used guidelines recommended by the Japanese supplier for switching from rHuEPO, but for DA we based the CERA dose on European reports, because no Japanese guidelines exist. Fifty-two patients completed the 28-week study. Hemoglobin was maintained within the target range (10.0-12.0 g/dL). The required CERA dose decreased over the 28 weeks. The hemoglobin level and CERA dose stabilized faster when switching from DA. CERA showed similar efficacy in diabetic and non-diabetic patients. The effect of CERA is similar regardless of whether patients switch from low- or high-dose erythropoiesis-stimulating agents. In conclusion, CERA is effective for Japanese hemodialysis patients at a lower dose than expected. © 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.

  18. Evaluation of patient effective doses in CT urography, intravenous urography and renal scintigraphy.

    PubMed

    Hamza, Y; Sulieman, A; Abuderman, A; Alzimami, K; Omer, H

    2015-07-01

    Imaging of the renal system is performed with different techniques depending mainly on clinical symptoms and signs. This study intended to evaluate patient effective doses undergoing renal scintigraphy (technetium-99m-diethylene-triamine-pentaacetic acid), computed tomography urography (CTU) and intravenous urography (IVU). A total of 60 patients were evaluated using Orbiter 37 Gamma camera single head, dual-slice CT scanner and conventional X-ray machine with computed radiography (CR) processing unit. Patients effective dose were estimated using the administered activity, DosCal software and dose length product value for renal scan, IVU and CTU procedures, respectively. Patients' effective doses during renal scan, CTU and IVU procedures were 0.78 ± 0.18, 2.53 ± 0.94 and 1.81 ± 0.20 mSv, in that order. Patients were exposed to a higher effective dose during CTU compared with other two procedures. Patient doses depend on the size of patient, the type of scanner and the imaging protocol used. Effective doses considered low compared with previous studies.

  19. Disposition of styrene-acrylonitrile (SAN) trimer in female rats: single dose intravenous and gavage studies.

    PubMed

    Gargas, Michael L; Collins, Brad; Fennell, Timothy R; Gaudette, Norman F; Sweeney, Lisa M

    2008-04-21

    Styrene-acrylonitrile trimer (SAN Trimer), a mixture of six isomers (four isomers of 4-cyano-1,2,3,4-tetrahydro-alpha-methyl-1-naphthaleneacetonitrile [THAN] and two isomers of 4-cyano-1,2,3,4-tetrahydro-1-naphthaleneproprionitrile [THNP]), is a by-product of a specific production process of styrene-acrylonitrile polymer. Disposition studies in female rats were conducted to evaluate the pharmacokinetic behavior of [3H]SAN Trimer following a single intravenous administration (26 mg/kg) to nonpregnant rats; a single gavage administration (nominal doses of 25 mg/kg, 75 mg/kg, or 200 mg/kg in corn oil) to nonpregnant rats; and a single gavage administration (nominal dose of 200 mg/kg in corn oil) to pregnant and lactating rats. SAN Trimer was rapidly eliminated from blood (T1/2 approximately 1h) following a single intravenous dose and following single oral doses (T1/2 approximately 3-4h). SAN Trimer was also rapidly excreted in the urine and feces following single oral doses, while total radioactivity was cleared more slowly. In pregnant rats, the concentrations of both radioactivity and SAN Trimer 2h after dosing were highest in the blood, followed by the placenta, with the lowest levels in the fetus. In lactating rats, the concentrations of both radioactivity and SAN Trimer were higher in milk than in maternal blood. Total radioactivity and SAN Trimer blood concentrations in nonpregnant, pregnant, and lactating rats were both higher in lactating rats compared to nonpregnant and pregnant rats.

  20. Pharmacokinetics of Colistin Following a Single Dose of Intravenous Colistimethate Sodium in Critically Ill Neonates.

    PubMed

    Nakwan, Narongsak; Usaha, Siripa; Chokephaibulkit, Kulkanya; Villani, Paola; Regazzi, Mario; Imberti, Roberto

    2016-11-01

    In this study, we sought to evaluate the pharmacokinetics of colistin after intravenous administration of colistimethate sodium (CMS) in the critically ill neonates with Gram-negative bacterial infections. A single intravenous dose of CMS [approximately 150,000 IU/kg, equivalent to 5 mg/kg colistin base activity (CBA)] was administered to 7 critically ill neonates. Mean (±SD) maximum plasma colistin concentration and area under the time-concentration curve from 0 to infinity were 3.0 ± 0.7 µg/mL and 25.3 ± 10.4 µg·h/mL, respectively. Time to maximum concentration, half-life, apparent volume of distribution and clearance were 1.3 ± 0.9 hours, 9.0 ± 6.5 hours, 7.7 ± 9.3 L/kg and 0.6 ± 0.3 L/h/kg, respectively. After a dose regimen of 5 mg/kg CBA every 24 hours, the average concentration expected at steady state is 1.1 ± 0.4 µg/mL. In critically ill neonates, a single intravenous dose of 5 mg CBA/kg (approximately 150,000 IU/kg of CMS) resulted in suboptimal plasma concentrations of colistin. According to our pharmacokinetics data, the dosage of CMS currently used in critically ill neonates is insufficient.

  1. Low-dose intravenous heparin infusion in patients with aneurysmal subarachnoid hemorrhage: a preliminary assessment

    PubMed Central

    Simard, J. Marc; Aldrich, E. Francois; Schreibman, David; James, Robert F.; Polifka, Adam; Beaty, Narlin

    2015-01-01

    Object Aneurysmal subarachnoid hemorrhage (aSAH) predisposes to delayed neurological deficits, including stroke and cognitive and neuropsychological abnormalities. Heparin is a pleiotropic drug that antagonizes many of the pathophysiological mechanisms implicated in secondary brain injury after aSAH. Methods The authors performed a retrospective analysis in 86 consecutive patients with Fisher Grade 3 aSAH due to rupture of a supratentorial aneurysm who presented within 36 hours and were treated by surgical clipping within 48 hours of their ictus. Forty-three patients were managed postoperatively with a low-dose intravenous heparin infusion (Maryland low-dose intravenous heparin infusion protocol: 8 U/kg/hr progressing over 36 hours to 10 U/kg/hr) beginning 12 hours after surgery and continuing until Day 14 after the ictus. Forty-three control patients received conventional subcutaneous heparin twice daily as deep vein thrombosis prophylaxis. Results Patients in the 2 groups were balanced in terms of baseline characteristics. In the heparin group, activated partial thromboplastin times were normal to mildly elevated; no clinically significant hemorrhages or instances of heparin-induced thrombocytopenia or deep vein thrombosis were encountered. In the control group, the incidence of clinical vasospasm requiring rescue therapy (induced hypertension, selective intraarterial verapamil, and angioplasty) was 20 (47%) of 43 patients, and 9 (21%) of 43 patients experienced a delayed infarct on CT scanning. In the heparin group, the incidence of clinical vasospasm requiring rescue therapy was 9% (4 of 43, p = 0.0002), and no patient suffered a delayed infarct (p = 0.003). Conclusions In patients with Fisher Grade 3 aSAH whose aneurysm is secured, postprocedure use of a low-dose intravenous heparin infusion may be safe and beneficial. PMID:24032706

  2. Topical and low-dose intravenous tranexamic acid in cyanotic cardiac surgery.

    PubMed

    Patel, Jigar; Prajapati, Mrugesh; Patel, Hardik; Gandhi, Hemang; Deodhar, Shilpa; Pandya, Himani

    2017-02-01

    Background Coagulopathy is a major problem in surgery for cyanotic congenital heart disease. Tranexamic acid has been used both topically and systemically and plays a vital role in pediatric cardiac surgery by reducing blood loss and blood product requirement. We aimed to determine the anti-fibrinolytic effectiveness of low-dose systemic or topical tranexamic acid or a combination of both. Methods Seventy-five patients were divided in 3 groups of 25. Group A patients were given tranexamic acid 20 mg kg(-1) intravenously after sternotomy and 20 mg kg(-1) after heparin reversal. Group B patients were given tranexamic acid 50 mg kg(-1) in 20 mL of saline intrapericardially before sternal closure, with the drain clamped for 20 min. Group C patients were given tranexamic acid 20 mg kg(-1) intravenously after sternotomy and 50 mg kg(-1) intrapericardially before sternal closure. A number of clinical variables were recorded in the first 3 postoperative days. Ventilator time, intensive care unit stay, and outcome were also recorded. Results Chest tube drainage and blood product requirements were lowest in group C. Blood urea and serum creatinine levels were higher in groups A and C ( p < 0.05). Intensive care unit stay and ventilator time were similar in all 3 groups. No patient died and none had a seizure or other neurological event or thromboembolic complication postoperatively. Conclusion The combination of low-dose intravenous and topical tranexamic acid reduces postoperative blood loss and blood product requirement without incurring neurological, renal or thromboembolic complications. We recommend the routine use of topical and low-dose systemic tranexamic acid in cyanotic pediatric cardiac surgery.

  3. Optimal dose of intravenous oxycodone for attenuating hemodynamic changes after endotracheal intubation in healthy patients

    PubMed Central

    Park, Yong-Hee; Lee, Seung-Hyuk; Lee, Oh Haeng; Kang, Hyun; Shin, Hwa-Yong; Baek, Chong-Wha; Jung, Yong Hun; Woo, Young Cheol

    2017-01-01

    Abstract Background: Intravenous oxycodone has been used as an adjunct to anesthetic agents. This study aimed to assess the optimal dose of intravenous oxycodone for the attenuation of the hemodynamic responses to laryngoscopy and endotracheal intubation. Methods: A prospective, randomized, double-blind study was conducted. Ninety-five patients were randomly divided into 5 groups based on the oxycodone dose: 0, 0.05, 0.1, 0.15, 0.2 mg/kg. After administering the assigned dose of intravenous oxycodone, anesthesia was induced with thiopental. Heart rate (HR) and blood pressure (BP) were measured at baseline, before intubation, and 1, 2, and 3 minutes after intubation. The percentage increase of BP was calculated as (highest BP after intubation − baseline BP)/baseline BP × 100 (%). The percentage increase of HR was calculated in same formula as above. Hypertension was defined as a 15% increase of systolic BP from baseline, and probit analysis was conducted. Results: Hemodynamic data from 86 patients were analyzed. The percentage increase of mean arterial pressure after intubation in groups 0.05, 0.1, 0.15, and 0.2 was significantly different from that in the control (P < 0.001). For HR, the percentage increase was lower than control group when oxycodone was same or more than 0.1 mg/kg (P < 0.05). Using probit analysis, the 95% effective dose (ED95) for preventing hypertension was 0.159 mg/kg (95% confidence interval [CI], 0.122–0.243). In addition, ED50 was 0.020 mg/kg (95% CI, −0.037 to 0.049). However, oxycodone was not effective for maintaining the HR in our study dosage. There were no significant differences in the incidence of hypotension during induction between groups. Conclusions: Using 0.1 mg/kg of intravenous oxycodone is sufficient to attenuate the increase of BP and HR during induction period in healthy patients. The ED95, which was 0.159 mg/kg, can be useful to adjust the dosage of IV oxycodone for maintain stable BP

  4. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens.

    PubMed

    Conte, PierFranco; Guarneri, Valentina

    2004-01-01

    Patients with advanced cancers--particularly breast and prostate cancers--are at high risk for bone metastasis, leading to accelerated bone resorption and clinically significant skeletal morbidity. Bisphosphonates are effective inhibitors of bone resorption and reduce the risk of skeletal complications in patients with bone metastases. The standard routes of administration for bisphosphonates used in clinical practice are either oral or i.v. infusion. Oral administration of bisphosphonates is complicated by poor bioavailability (generally <5%) and poor gastrointestinal tolerability. First-generation bisphosphonates, such as clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), must be administered at high oral doses (1,600-3,200 mg/day) to achieve therapeutic effects, which leads to poor tolerability and compliance with oral dosing regimens. Infusion of bisphosphonates is associated with dose- and infusion-rate-dependent effects on renal function. In particular, high bisphosphonate doses (e.g., 1,500 mg clodronate) can cause severe renal toxicity unless infused slowly over many hours. In contrast, the newer, more potent bisphosphonates effectively inhibit bone resorption at micromolar concentrations, and the small doses required can be administered via relatively short i.v. infusions without adversely affecting renal function. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ) is a new generation bisphosphonate, and the recommended dose of 4 mg can be safely infused over 15 minutes. The 90-mg dose of pamidronate (Aredia; Novartis Pharmaceuticals Corp.) and the 6-mg dose of ibandronate (Bondronat; Hoffmann-La Roche Inc.; Nutley, NJ) require 1- to 4-hour infusions. Intravenous bisphosphonates require less frequent dosing (once a month) and are generally well tolerated with long-term use in patients with bone metastases. Zoledronic acid has demonstrated the broadest clinical activity in patients with bone metastases.

  5. Multiplication of Nosocomial Pathogens in Intravenous Feeding Solutions

    PubMed Central

    Gelbart, S. M.; Reinhardt, G. F.; Greenlee, H. B.

    1973-01-01

    A major problem in total parenteral nutrition is sepsis, particularly that caused by Candida. Studies of four solutions, a casein hydrolysate, a fibrin hydrolysate, and two crystalline amino acid solutions, show that the protein hydrolysate solutions appear to be highly selective for Candida over bacteria, whereas the crystalline amino acid solutions are not. These findings suggest that the crystalline amino acid preparations may offer a partial solution to the infection problem by minimizing the contribution of the solution as a reservoir for organism multiplication, because they retard the growth of both bacteria and Candida. PMID:4203333

  6. Antibiotic dosing in multiple organ dysfunction syndrome.

    PubMed

    Ulldemolins, Marta; Roberts, Jason A; Lipman, Jeffrey; Rello, Jordi

    2011-05-01

    Although early and appropriate antibiotic therapy remains the cornerstone of success for the treatment of septic shock, few data exist to guide antibiotic dose optimization in critically ill patients, particularly those with multiple organ dysfunction syndrome (MODS). It is well known that MODS significantly alters the patient's physiology, but the effects of these variations on pharmacokinetics have not been reviewed concisely. Therefore, the aims of this article are to summarize the disease-driven variations in pharmacokinetics and pharmacodynamics and to provide antibiotic dosing recommendations for critically ill patients with MODS. The main findings of this review are that the two parameters that vary with greatest significance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the first day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary, "front-loaded" doses of antibiotic during the first 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, maintenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction.

  7. Response of osteosarcoma to preoperative intravenous high-dose methotrexate chemotherapy: CT evaluation

    SciTech Connect

    Mail, J.T.; Cohen, M.D.; Mirkin, L.D.; Provisor, A.J.

    1985-01-01

    The histologic response of an osteosarcoma to preamputation high-dose methotrexate therapy can be used to determine the optimum maintenance chemotherapy regimen to be administered after amputation. This study evaluates computed tomography (CT) as a method of assessing the response of the tumor to the methotrexate therapy. Nine patients with nonmetastatic osteosarcoma of an extremity had a CT scan of the tumor at initial presentation. This was compared with a second CT scan after four courses of high-dose intravenous methotrexate. Each set of scans was evaluated for changes in bony destruction, soft-tissue mass, pattern of calcification, and extent of tumor involvement of the marrow cavity. These findings were correlated with the histologic response of the tumor as measured by the degree of tumor necrosis. The changes seen on CT correlated well with the degree of the histologic response in seven of the nine patients.

  8. High-dose intravenous therapy with immune globulin before delivery for idiopathic thrombocytopenic purpura.

    PubMed Central

    Adderley, R. J.; Rogers, P. C.; Shaw, D.; Wadsworth, L. D.

    1984-01-01

    A 15-year-old girl with a 9-year history of idiopathic thrombocytopenic purpura resistant to high-dose steroid therapy and to splenectomy was admitted to hospital at 35 weeks' gestation with a platelet count of 10 X 10(9)/L. The bleeding time was normal, and measures of platelet aggregation were nearly so. Treatment with high intravenous doses of polyvalent immune globulin led to a rise in the platelet count to more than 110 X 10(9)/L within 5 days. An elective cesarean section was performed through the lower uterine segment with good hemostasis. After delivery the platelet count fell to its former level, but no postpartum bleeding occurred. There was a brief episode of thrombocytopenia in the infant, with some petechiae but no other hemorrhagic manifestations. No untoward effects of the immune globulin infusion were observed in either mother or daughter. PMID:6423252

  9. Low dose naltrexone therapy in multiple sclerosis.

    PubMed

    Agrawal, Y P

    2005-01-01

    The use of low doses of naltrexone for the treatment of multiple sclerosis (MS) enjoys a worldwide following amongst MS patients. There is overwhelming anecdotal evidence, that in low doses naltrexone not only prevents relapses in MS but also reduces the progression of the disease. It is proposed that naltrexone acts by reducing apoptosis of oligodendrocytes. It does this by reducing inducible nitric oxide synthase activity. This results in a decrease in the formation of peroxynitrites, which in turn prevent the inhibition of the glutamate transporters. Thus, the excitatory neurotoxicity of glutamate on neuronal cells and oligodendrocytes via activation of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid class of glutamate receptor is prevented. It is crucial that the medical community respond to patient needs and investigate this drug in a clinical trial.

  10. Intravenous Iron Therapy in Patients with Iron Deficiency Anemia: Dosing Considerations

    PubMed Central

    Koch, Todd A.; Myers, Jennifer; Goodnough, Lawrence Tim

    2015-01-01

    Objective. To provide clinicians with evidence-based guidance for iron therapy dosing in patients with iron deficiency anemia (IDA), we conducted a study examining the benefits of a higher cumulative dose of intravenous (IV) iron than what is typically administered. Methods. We first individually analyzed 5 clinical studies, averaging the total iron deficit across all patients utilizing a modified Ganzoni formula; we then similarly analyzed 2 larger clinical studies. For the second of the larger studies (Study 7), we also compared the efficacy and retreatment requirements of a cumulative dose of 1500 mg ferric carboxymaltose (FCM) to 1000 mg iron sucrose (IS). Results. The average iron deficit was calculated to be 1531 mg for patients in Studies 1–5 and 1392 mg for patients in Studies 6-7. The percentage of patients who were retreated with IV iron between Days 56 and 90 was significantly (p < 0.001) lower (5.6%) in the 1500 mg group, compared to the 1000 mg group (11.1%). Conclusions. Our data suggests that a total cumulative dose of 1000 mg of IV iron may be insufficient for iron repletion in a majority of patients with IDA and a dose of 1500 mg is closer to the actual iron deficit in these patients. PMID:26257955

  11. Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents.

    PubMed

    Rocha, Luis B; Schaberle, Fábio; Dąbrowski, Janusz M; Simões, Sérgio; Arnaut, Luis G

    2015-12-08

    We assessed the tolerability and safety in rodents of a single intravenous (i.v.) dose of redaporfin, a novel photosensitizer for Photodynamic Therapy (PDT) of cancer. Two approaches were used to evaluate acute toxicity: (i) a dose escalation study in BALB/c mice to evaluate the maximum tolerated dose of redaporfin; and (ii) a safety toxicology study in Wistar rats, of a single dose of redaporfin, with or without illumination, to evaluate possible signs of systemic toxicity. Redaporfin formulation was well tolerated by mice, with no signs of adverse reactions up to 75 mg/kg. In rats, there were no relevant changes, except for a significant, but transient, increase in the blood serum markers for hepatic function and muscle integrity, and also on neutrophil counts, observed after the application of light. The overall results showed that redaporfin-PDT is very well tolerated. No abnormalities were observed, including reactions at the injection site or skin phototoxicity, although the animals were maintained in normal indoor lighting. Redaporfin also showed a high efficacy in the treatment of male BALB/c mice with subcutaneously implanted colon (CT26) tumours. Vascular-PDT with 1.5 mg/kg redaporfin and a light dose of 74 J/cm² led to the complete tumour regression in 83% of the mice.

  12. Low dose intravenous immunoglobulin in systemic lupus erythematosus: analysis of 62 cases.

    PubMed

    Sherer, Yaniv; Kuechler, Sabine; Jose Scali, Juan; Rovensky, Josef; Levy, Yair; Zandman-Goddard, Gisele; Shoenfeld, Yehuda

    2008-01-01

    Systemic lupus erythematosus is an autoimmune disease with diverse clinical manifestations that cannot always be regulated by steroids and immunosuppressive therapy. Intravenous immunoglobulin is an optional immunomodulatory agent for the treatment of SLE, but the appropriate indications for its use, duration of therapy and recommended dosage are yet to be established. In SLE patients, most publications report the utilization of a high dose (2 g/kg body weight) protocol. To investigate whether lower doses of IVIg are beneficial for SLE patients. We retrospectively analyzed the medical records of 62 patients who received low dose IVIg (approximately 0.5 g/kg body weight). The treatment was associated with clinical improvement in many specific disease manifestations, along with a continuous decrease in SLEDAI scores (SLE Disease Activity Index). However, thrombocytopenia, alopecia and vasculitis did not improve following IVIg therapy. Low dose IVIg is a possible therapeutic option in SLE and is associated with lower cost than the high dose regimen and possibly fewer adverse effects.

  13. Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents

    PubMed Central

    Rocha, Luis B.; Schaberle, Fábio; Dąbrowski, Janusz M.; Simões, Sérgio; Arnaut, Luis G.

    2015-01-01

    We assessed the tolerability and safety in rodents of a single intravenous (i.v.) dose of redaporfin, a novel photosensitizer for Photodynamic Therapy (PDT) of cancer. Two approaches were used to evaluate acute toxicity: (i) a dose escalation study in BALB/c mice to evaluate the maximum tolerated dose of redaporfin; and (ii) a safety toxicology study in Wistar rats, of a single dose of redaporfin, with or without illumination, to evaluate possible signs of systemic toxicity. Redaporfin formulation was well tolerated by mice, with no signs of adverse reactions up to 75 mg/kg. In rats, there were no relevant changes, except for a significant, but transient, increase in the blood serum markers for hepatic function and muscle integrity, and also on neutrophil counts, observed after the application of light. The overall results showed that redaporfin-PDT is very well tolerated. No abnormalities were observed, including reactions at the injection site or skin phototoxicity, although the animals were maintained in normal indoor lighting. Redaporfin also showed a high efficacy in the treatment of male BALB/c mice with subcutaneously implanted colon (CT26) tumours. Vascular-PDT with 1.5 mg/kg redaporfin and a light dose of 74 J/cm2 led to the complete tumour regression in 83% of the mice. PMID:26670231

  14. Single dose intravenous methyl prednisolone versus oral prednisolone in Bell's palsy: A randomized controlled trial

    PubMed Central

    Giri, Prithvi; Garg, Ravindra Kumar; Singh, Maneesh Kumar; Verma, Rajesh; Malhotra, Hardeep Singh; Sharma, Praveen Kumar

    2015-01-01

    Objectives: Corticosteroids have been used in the treatment of Bell's palsy and several other postinfectious neurological conditions. We hypothesized that administration of a single dose of intravenous (IV) methylprednisolone might be an effective alternative to oral prednisolone. Materials and Methods: In this open label, randomized trial, patients with acute Bell's palsy were randomized into two groups. One group received single dose (500 mg) of IV methylprednisolone while the other group received 10 days of oral prednisone. Outcome was assessed at 1 and 3 months with House–Brackmann scale. Results: At 3 months, 93 (79.48%) patients had completely recovered. IV methylprednisolone and oral prednisolone groups had similar recovery rates (80% vs. 78.33%, P > 0.05). Patients with Grade 2 and 3 recovered completely. In patients with Grade 6, the recovery rate was 20%. A better outcome was observed if corticosteroids were administered within 3 days of onset of palsy. Conclusion: Intravenous methylprednisolone and oral prednisolone showed equivalent benefit in patients with acute Bell's palsy. PMID:25878371

  15. Pharmacokinetics of a single bolus intravenous, intramuscular and subcutaneous dose of disodium fosfomycin in horses.

    PubMed

    Zozaya, D H; Gutiérrez, O L; Ocampo, C L; Sumano, L H

    2008-08-01

    Pharmacokinetic parameters of fosfomycin were determined in horses after the administration of disodium fosfomycin at 10 mg/kg and 20 mg/kg intravenously (IV), intramuscularly (IM) and subcutaneously (SC) each. Serum concentration at time zero (C(S0)) was 112.21 +/- 1.27 microg/mL and 201.43 +/- 1.56 microg/mL for each dose level. Bioavailability after the SC administration was 84 and 86% for the 10 mg/kg and the 20 mg/kg dose respectively. Considering the documented minimum inhibitory concentration (MIC(90)) range of sensitive bacteria to fosfomycin, the maximum serum concentration (Cmax) obtained (56.14 +/- 2.26 microg/mL with 10 mg/kg SC and 72.14 +/- 3.04 microg/mL with 20 mg/kg SC) and that fosfomycin is considered a time-dependant antimicrobial, it can be concluded that clinically effective plasma concentrations might be obtained for up to 10 h administering 20 mg/kg SC. An additional predictor of efficacy for this latter dose and route, and considering a 12 h dosing interval, could be area under the curve AUC(0-12)/MIC(90) ratio which in this case was calculated as 996 for the 10 mg/kg dose and 1260 for the 20 mg/kg dose if dealing with sensitive bacteria. If a more resistant strain is considered, the AUC(0-12)/MIC(90) ratio was calculated as 15 for the 10 mg/kg dose and 19 for the 20 mg/kg dose.

  16. [Low-dose ketamine combined with fentanyl for intravenous postoperative analgesia in elderly patients].

    PubMed

    Liang, Shi-wei; Chen, Ye-ming; Lin, Chun-shui

    2006-11-01

    To investigate the clinical efficacy of and complications arising from low-dose ketamine combined with fentanyl for intravenous postoperative analgesia in comparison with the exclusive use of fentanyl in elderly patients. Eighty elderly patients were randomized into two equal groups following thoracoabdominal surgery, and received intravenous analgesia with the combination of 0.5 mg/ml ketamine, 5.0 microg/ml fentanyl and 50 microg/ml midazolam (KF group) and with 7.5 microg/ml fentanyl plus 50 microg/ml midazolam (FT group), respectively. The drugs used were diluted in 200 ml normal saline. For analgesic administration, a loading dose (2-4 ml) was given followed by a background infusion (2.5-3.5 ml), with patient-controlled bolus doses of 2.0-3.0 ml with lock-out time of 20 min via PCA pump (Automedical, Korea). The static pain score (VAS), sedation score, and incidences of nausea, vomiting, pruritus and hallucinations were recorded during the initial 48 h after the surgery. The total analgesic dosage and PCA dosage in the two groups were similar (P>0.05). With similar VAS in the two groups (P>0.05), the sedative effect in KF group was much better than that in FT group (P<0.05) during the initial 48 h postoperatively. The incidences of nausea, vomiting and itching were lower in KF group than in FT group (P<0.05), and no illusion was reported in two groups during the initial 48 h. For producing comparable postoperative analgesic effect, low-dose ketamine combined with fentanyl can markedly reduce fentanyl requirement in the elderly patients and lowers the incidences of nausea, vomiting and itching in comparison with the exclusive use of fentanyl.

  17. Survey of pain specialists regarding conversion of high-dose intravenous to neuraxial opioids

    PubMed Central

    Gorlin, Andrew W; Rosenfeld, David M; Maloney, Jillian; Wie, Christopher S; McGarvey, Johnathan; Trentman, Terrence L

    2016-01-01

    The conversion of high-dose intravenous (IV) opioids to an equianalgesic epidural (EP) or intrathecal (IT) dose is a common clinical dilemma for which there is little evidence to guide practice. Expert opinion varies, though a 100 IV:10:EP:1 IT conversion ratio is commonly cited in the literature, especially for morphine. In this study, the authors surveyed 724 pain specialists to elucidate the ratios that respondents apply to convert high-dose IV morphine, hydromorphone, and fentanyl to both EP and IT routes. Eighty-three respondents completed the survey. Conversion ratios were calculated and entered into graphical scatter plots. The data suggest that there is wide variation in how pain specialists convert high-dose IV opioids to EP and IT routes. The 100 IV:10 EP:1 IT ratio was the most common answer of survey respondent, especially for morphine, though also for hydromorphone and fentanyl. Furthermore, more respondents applied a more aggressive conversion strategy for hydromorphone and fentanyl, likely reflecting less spinal selectivity of those opioids compared with morphine. The authors conclude that there is little consensus on this issue and suggest that in the absence of better data, a conservative approach to opioid conversion between IV and neuraxial routes is warranted. PMID:27703394

  18. Survey of pain specialists regarding conversion of high-dose intravenous to neuraxial opioids.

    PubMed

    Gorlin, Andrew W; Rosenfeld, David M; Maloney, Jillian; Wie, Christopher S; McGarvey, Johnathan; Trentman, Terrence L

    2016-01-01

    The conversion of high-dose intravenous (IV) opioids to an equianalgesic epidural (EP) or intrathecal (IT) dose is a common clinical dilemma for which there is little evidence to guide practice. Expert opinion varies, though a 100 IV:10:EP:1 IT conversion ratio is commonly cited in the literature, especially for morphine. In this study, the authors surveyed 724 pain specialists to elucidate the ratios that respondents apply to convert high-dose IV morphine, hydromorphone, and fentanyl to both EP and IT routes. Eighty-three respondents completed the survey. Conversion ratios were calculated and entered into graphical scatter plots. The data suggest that there is wide variation in how pain specialists convert high-dose IV opioids to EP and IT routes. The 100 IV:10 EP:1 IT ratio was the most common answer of survey respondent, especially for morphine, though also for hydromorphone and fentanyl. Furthermore, more respondents applied a more aggressive conversion strategy for hydromorphone and fentanyl, likely reflecting less spinal selectivity of those opioids compared with morphine. The authors conclude that there is little consensus on this issue and suggest that in the absence of better data, a conservative approach to opioid conversion between IV and neuraxial routes is warranted.

  19. A simple dosing scheme for intravenous busulfan based on retrospective population pharmacokinetic analysis in korean patients.

    PubMed

    Choe, Sangmin; Kim, Gayeong; Lim, Hyeong-Seok; Cho, Sang-Heon; Ghim, Jong-Lyul; Jung, Jin Ah; Kim, Un-Jib; Noh, Gyujeong; Bae, Kyun-Seop; Lee, Dongho

    2012-08-01

    Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (V(d)) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and V(d) were 16% and 9%. Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target AUC(0-inf) (defined as median AUC(0-inf) with a once-daily dosage) of 26.18 mg/l·hr, was proposed: 24.79·ABW(0.5) mg q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. We propose a new simple dosing scheme for iBu based only on ABW.

  20. A Simple Dosing Scheme for Intravenous Busulfan Based on Retrospective Population Pharmacokinetic Analysis in Korean Patients

    PubMed Central

    Choe, Sangmin; Kim, Gayeong; Lim, Hyeong-Seok; Cho, Sang-Heon; Ghim, Jong-Lyul; Jung, Jin Ah; Kim, Un-Jib; Noh, Gyujeong; Lee, Dongho

    2012-01-01

    Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (Vd) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and Vd were 16% and 9%. Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target AUC0-inf (defined as median AUC0-inf with a once-daily dosage) of 26.18 mg/l·hr, was proposed: 24.79·ABW0.5 mg q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. We propose a new simple dosing scheme for iBu based only on ABW. PMID:22915993

  1. Intravenous paracetamol (acetaminophen).

    PubMed

    Duggan, Sean T; Scott, Lesley J

    2009-01-01

    Intravenous paracetamol (rINN)/intravenous acetaminophen (USAN) is an analgesic and antipyretic agent, recommended worldwide as a first-line agent for the treatment of pain and fever in adults and children. In double-blind clinical trials, single or multiple doses of intravenous paracetamol 1 g generally provided significantly better analgesic efficacy than placebo treatment (as determined by primary efficacy endpoints) in adult patients who had undergone dental, orthopaedic or gynaecological surgery. Furthermore, where evaluated, intravenous paracetamol 1 g generally showed similar analgesic efficacy to a bioequivalent dose of propacetamol, and a reduced need for opioid rescue medication. In paediatric surgical patients, recommended doses of intravenous paracetamol 15 mg/kg were not significantly different from propacetamol 30 mg/kg for the treatment of pain, and showed equivocal analgesic efficacy compared with intramuscular pethidine 1 mg/kg in several randomized, active comparator-controlled studies. In a randomized, noninferiority study in paediatric patients with an infection-induced fever, intravenous paracetamol 15 mg/kg treatment was shown to be no less effective than propacetamol 30 mg/kg in terms of antipyretic efficacy. Intravenous paracetamol was well tolerated in clinical trials, having a tolerability profile similar to placebo. Additionally, adverse reactions emerging from the use of the intravenous formulation of paracetamol are extremely rare (<1/10 000). [table: see text].

  2. [Single intravenous tranexamic acid dose to reduce blood loss in primary total knee replacement].

    PubMed

    Sanz-Reig, J; Parra Ruiz, B; Ferrández Martínez, J; Martínez López, J F

    2016-01-01

    To evaluate the effectiveness and safety of a single intravenous dose of tranexamic acid in order to reduce blood loss in total knee replacement. Prospective observational study of the administration of tranexamic acid in patients undergoing primary total knee arthroplasty from November 2013 to February 2015, in which an autologous blood recovery system was used. The study included 98 patients, distributed into two groups of 49 patients according to whether or not they received intravenous tranexamic acid. The primary endpoint was the number of patients requiring autologous transfusion from the recovery system autologous blood recovery system. No drop-outs were recorded during follow-up. There were no significant differences between groups as regards the preoperative and hospital variables. The mean preoperative haemoglobin and haematocrit at 24 and 48 hours postoperatively were similar in both groups. The average volume of bleeding in the autologous blood recovery system and estimated average blood loss was lower in patients who had been administered tranexamic acid, with significant differences. No patients in the group that was administered tranexamic acid required blood autotransfusion. The transfusion rate was zero in the two groups. No adverse events related to the administration of tranexamic acid were recorded. Intravenous administration of tranexamic acid, according to the described protocol, has presented a non-autotransfusion or allo-transfusion rate of 100%, with no increased incidence of thrombotic events. Thus, its use in this group of patients is recommended. The indication should be individualized, its use justified in the patient medical records, and informed consent is mandatory. Copyright © 2015 SECOT. Published by Elsevier Espana. All rights reserved.

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

    PubMed

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

    2015-02-20

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

  4. High-dose intravenous desferrioxamine (DFO) delivery in four thalassemic patients allergic to subcutaneous DFO administration.

    PubMed

    Lombardo, T; Ferro, G; Frontini, V; Percolla, S

    1996-01-01

    To test the hypothesis that allergy to desferrioxamine is not an immunologic mechanism, but arises from a local effect on the dermal mast cell, we have treated four patients who were not receiving chelation therapy because of hypersensitivity to standard subcutaneous (SC) therapy, with high-dose desferrioxamine (DFO) by the intravenous (IV) route. Three patients had central venous access ports implanted on the anterior chest wall. The fourth patient had the therapy delivered by the peripheral vein route. All patients had the drug delivered via an elastomeric infusor. Intravenous therapy was successful for all patients. During one year of therapy no local or systemic allergic manifestations were noted. In addition, no impairment of hearing or vision or any catheter complications were reported. A very high level of patient compliance to the therapy resulted in dramatically decreased iron stores and ferritin levels (2,759 ng/ml to 717.5 ng/ml) and a significant improvement in the clinical status of all patients. The absence of allergic episodes in this patient group after 1 year of i.v. therapy would strongly support the hypothesis that SC DFO allergy is related to a direct effect on dermal mast cells and is not an immunological reaction. This study suggests that patients with severe allergy to SC DFO can therefore safely receive their chelation therapy via the i.v. route.

  5. Biotin kinetics in serum of cattle after intravenous and oral dosing.

    PubMed

    Frigg, M; Hartmann, D; Straub, O C

    1994-01-01

    Single oral (p.o.) or intravenous (i.v.) doses of biotin were given to four cattle (400-450 kg body weight) in two consecutive tests two weeks apart. Dosages were p.o. 20, 40, 80 or 160 and i.v. 5, 10, 20, 40 mg biotin per 300 kg body weight. A three-compartment model was used to describe the course of serum concentrations with time. After i.v. administration, terminal half-lives of about 8 h were found. Areas under the curves were linearly related to both the p.o. and the i.v. doses. The systemically available fraction of the p.o. dose was 50 to 60%. On the basis of kinetic parameters, the biotin uptake via the feed was estimated to be 2.5 mg/day, which was about half of that estimated to be in the hay consumed. The data suggest that there was no relevant ruminal synthesis of biotin.

  6. Review of high-dose intravenous vitamin C as an anticancer agent.

    PubMed

    Wilson, Michelle K; Baguley, Bruce C; Wall, Clare; Jameson, Michael B; Findlay, Michael P

    2014-03-01

    In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid). These studies were criticized for their retrospective nature and lack of standardization of key prognostic factors including performance status. Subsequently, several well-designed randomized controlled trials failed to demonstrate a significant survival benefit, although these trials used high-dose oral vitamin C. Marked differences are now recognized in the pharmacokinetics of vitamin C with oral and IV administration, opening the issue of therapeutic efficacy to question. In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant but may have pro-oxidant activity at high concentrations. The mechanism of its pro-oxidant action is not fully understood, and both intra- and extracellular mechanisms that generate hydrogen peroxide have been proposed. It remains to be proven whether vitamin C-induced reactive oxygen species occur in vivo and, if so, whether this will translate to a clinical benefit. Current clinical evidence for a therapeutic effect of high-dose IV vitamin C is ambiguous, being based on case series. The interpretation and validation of these studies is hindered by limited correlation of plasma vitamin C concentrations with response. The methodology exists to determine if there is a role for high-dose IV vitamin C in the treatment of cancer, but the limited understanding of its pharmacodynamic properties makes this challenging. Currently, the use of high-dose IV vitamin C cannot be recommended outside of a clinical trial. © 2014 Wiley Publishing Asia Pty Ltd.

  7. Low-dose intravenous nitrite improves hemodynamics in a canine model of acute pulmonary thromboembolism.

    PubMed

    Dias-Junior, Carlos A C; Gladwin, Mark T; Tanus-Santos, Jose E

    2006-12-15

    Acute pulmonary thomboembolism (APT)-induced pulmonary hypertension can be counteracted by activating the nitric oxide (NO)-cGMP pathway. Recent studies have demonstrated that the naturally occurring anion nitrite (NO(2)(-)) is a bioactive storage reservoir for NO, and is reduced to NO under conditions of hypoxia and acidosis. We hypothesized that nitrite infused intravenously could attenuate the hemodynamic changes associated with APT. APT was induced with autologous blood clots injected into the right atrium in mongrel dogs. After APT (or saline), the dogs received an intravenous nitrite (or saline) infusion (6.75 micromol/kg over 15 min and then 0.28 micromol/kg/min) and hemodynamic evaluations were carried out for 2 h. Plasma nitrite concentrations were measured using ozone-based reductive chemiluminescence methodologies. APT decreased cardiac index (CI) and increased pulmonary vascular resistance index (PVRI); these effects were improved during infusions of sodium nitrite. Accordingly, nitrite infusion increased cardiac index by 28%, reduced the PVRI by 48%, and the systemic vascular resistance index (SVRI) by 21% in embolized dogs, suggesting a greater effect on the ischemic embolized vascular system than the systemic circulation following embolization. Interestingly, in nonembolized control dogs the same nitrite infusion decreased MAP and CI (all P<0.05). The nitrite infusion increased plasma nitrite concentrations by approximately 2 microM, and produced dose-dependent effects on PVRI, MAP, and SVRI. Remarkably, blood levels of nitrite as low as 500 nM decreased PVRI and SVRI in this model, suggesting a potential role of nitrite in physiological blood flow regulation. These results suggest that a low-dose nitrite infusion produces beneficial hemodynamic effects in a dog model of APT. These findings suggest a new therapeutic application for nitrite and support emerging evidence for a surprisingly potent and potentially physiological vasoactivity of nitrite.

  8. Pharmacokinetics of iron(III)-hydroxide sucrose complex after a single intravenous dose in healthy volunteers.

    PubMed

    Danielson, B G; Salmonson, T; Derendorf, H; Geisser, P

    1996-06-01

    The pharmacokinetics of iron were investigated after intravenous administration to 12 healthy volunteers of iron(III)-hydroxide sucrose complex (Venofer) as a single i.v. dose containing 100 mg Fe. The average predose concentration was 35.7 +/- 12.5 mumol/l. There was no statistically significant difference between the serum iron level before injection (0 h) and the level at 24 h after the injection. The compartment model used includes a Michaelis-Menten term and is in excellent agreement with the observed exchange of iron to transferrin and with the daily iron turnover by transferrin. The intravenously injected iron(III)-hydroxide sucrose complex led rapidly to high serum iron levels. Maximum measured levels averaged 538 mumol/l (30.0 mg/l) at 10 min after the injection. The terminal half-life of the injected iron was calculated to be 5.3 h. Mean total area under the curve (AUC) was 1491 mumol/l h, the mean residence time (MRT) was 5.5 h. The total body clearance was 20.5 ml/min. The volume of distribution of the central compartment (Vc) was 3.21, hence close to the volume of the serum; the volume of distribution at steady state (Vdss) was 7.31; and the volume of distribution during elimination (Vdarea) was 9.21. The calculated amount of iron transported by transferrin was 31.0 +/- 6.6 mg Fe/ 24h. In summary, the data show that the injected iron(III)-hydroxide sucrose complex is quickly cleared from the serum with a terminal half-life of approximately 5-6 h. Renal elimination of iron contributed very little to the overall elimination (in average < 5%). Renal elimination of sucrose averaged about 68 +/- 10% and 75 +/- 11% of the administered dose after 4 h and 24 h, respectively.

  9. Updated US and European Dose Recommendations for Intravenous Colistin: How Do They Perform?

    PubMed

    Nation, Roger L; Garonzik, Samira M; Li, Jian; Thamlikitkul, Visanu; Giamarellos-Bourboulis, Evangelos J; Paterson, David L; Turnidge, John D; Forrest, Alan; Silveira, Fernanda P

    2016-03-01

    The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved updated dose recommendations for intravenous colistin in patients with various degrees of renal function. We assessed the recommendations in relation to their ability to achieve clinically relevant plasma colistin concentrations. Pharmacokinetic data from 162 adult critically ill patients (creatinine clearance range, 5.4-211 mL/min) were used to determine the average steady-state plasma colistin concentration (Css,avg) that would be achieved if each patient received the FDA or EMA dose. Target attainment rates for FDA- and EMA-approved daily doses to achieve colistin Css,avg of ≥0.5, ≥1, ≥2, and ≥4 mg/L were determined for each creatinine clearance category (≥80 mL/min, 50 to <80 mL/min, 30 to <50 mL/min, and <30 mL/min). For creatinine clearance <30 mL/min, 100% of patients receiving the EMA dose achieved a colistin Css,avg ≥1 mg/L, but the attainment rate was as low as 53.1% for patients receiving the FDA-approved dose. For colistin Css,avg ≥2 mg/L, the attainment rates were 87.5% with the EMA dose but only 6.3%-34.4% in patients receiving the FDA dose. Differences in attainment rates for a colistin Css,avg of ≥2 mg/L and ≥4 mg/L extended to patients with creatinine clearance 30 to <50 mL/min. For patients with creatinine clearance ≥80 mL/min, only approximately 65%-75% of patients achieved a colistin Css,avg of ≥1 mg/L with either set of recommendations. The study highlights important differences between the FDA- and EMA-approved dose recommendations and informs the setting of clinical breakpoints. NCT00235690. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  10. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

    PubMed

    Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

    2015-02-01

    Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

  11. Effect of high-dose intravenous vitamin C on inflammation in cancer patients

    PubMed Central

    2012-01-01

    Background An inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP) are associated with poor prognosis and decreased survival in many types of cancer. Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels. Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients. Methods 45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g) after standard treatments by conventional methods. CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests. Results According to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment. There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3) and changes in the levels of C-reactive protein. Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments. Conclusions The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels. In

  12. Serum toxicokinetics after intravenous and oral dosing of larkspur toxins in goats

    USDA-ARS?s Scientific Manuscript database

    Poisoning of cattle by larkspur plants (Delphinium spp.) is a concern for cattle ranchers in western North America. Previous research studies have evaluated the toxicokinetic profile of multiple larkspur toxins in several livestock species. However, those studies were all performed by orally dosing ...

  13. Encephalopathy is the dose-limiting toxicity of intravenous hepsulfam: results of a phase I trial in patients with advanced hematological malignancies.

    PubMed

    Larson, R A; Geller, R B; Janisch, L; Milton, J; Grochow, L B; Ratain, M J

    1995-01-01

    Hepsulfam is a bisulfamic ester which is similar in structure to busulfan and is believed to act as a bifunctional alkylator inducing both DNA-DNA and DNA-protein crosslinks. Prior studies in patients with refractory solid tumors have identified the dose-limiting toxicity of hepsulfam to be cumulative myelosuppression resulting in prolonged leukopenia and thrombocytopenia. This phase I trial was designed to determine the maximally tolerated dose of hepsulfam administered intravenously in patients with refractory leukemias and other advanced hematologic malignancies. Hepsulfam was administered as a 30-min or 2-h intravenous infusion to 21 patients with advanced leukemia or multiple myeloma. All patients had been extensively treated and had progressive disease. Cycles were repeated every 5 weeks. Cohorts of patients were treated at 360, 480, 640, and 800 mg/m2. The dose-limiting toxicity of intravenous hepsulfam was severe encephalopathy. The single patient treated at 800 mg/m2 became comatose within 48 h and required 3 weeks for his mental status to return to baseline. There were, however, no irreversible neurological sequelae. Several patients treated at 640 mg/m2 had clinical evidence of toxic deliriums and slowing of alpha rhythm waves on electroencephalograms indicative of a gray-matter encephalopathy. When hepsulfam was infused over 30 min, patients complained of uncomfortable parasthesias, but when the drug was administered over 2 h, these acute symptoms were less common. Myelosuppression was observed in most patients. Among those patients who had some suppression of their leukemia, peripheral blood counts recovered to pretreatment levels after 3-5 weeks. Apart from CNS toxicity, non-hematologic toxicity was minimal. Pharmacokinetic studies demonstrated rapid clearance of hepsulfam so that the drug was not reliably detected in the plasma after 24 h. The recommended phase II dose of hepsulfam as a single 2-h intravenous infusion is 480 mg/m2, but this dose

  14. Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to sheep.

    PubMed

    Craigmill, A L; Brown, S A; Wetzlich, S E; Gustafson, C R; Arndt, T S

    1997-04-01

    Twenty-four sheep (38.0-54.1 kg body wt) were allocated into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two-route (intravenous, i.v.: intramuscular, i.m.), two-period crossover design, with a two-week washout between injections. After another two-week washout period, 12 sheep were selected and dosed with ceftiofur sodium i.m. for five consecutive days at either 1.1 or 2.2 mg CFAE/kg. After all injections, blood samples were obtained serially for determination of serum concentrations of ceftiofur and metabolites. The terminal phase half-lives derived from the last 3-5 concentration-time points were 350 and 292 min (harmonic means) after i.v. doses of 1.1 and 2.2 mg/kg, respectively, and 389 and 459 min after i.m. doses of 1.1 and 2.2 mg/kg, respectively. The i.m. bioavailability of ceftiofur sodium in sheep was 100%, and the area under the curve from time 0 to the limit of quantitation (AUC0 LOQ) was dose-proportional from 1.1-2.2 mg CFAE/kg body wt in sheep. After 5 daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE/kg there was minimal accumulation of drug in serum as assessed by the observed maximum serum concentration (Cmax), and serum concentrations were dose-proportional after the multiple dosing regimen.

  15. Influence of the intravenous contrast media on treatment planning dose calculations of lower esophageal and rectal cancers.

    PubMed

    Nasrollah, Jabbari; Mikaeil, Molazadeh; Omid, Esnaashari; Mojtaba, Seyed Siahi; Ahad, Zeinali

    2014-01-01

    The impact of intravenous (IV) contrast media (CM) on radiation dose calculations must be taken into account in treatment planning. The aim of this study is to evaluate the effect of an intravenous contrast media on dose calculations in three-dimensional conformal radiation therapy (3D-CRT) for lower esophageal and rectal cancers. Seventeen patients with lower esophageal tumors and 12 patients with rectal cancers were analyzed. At the outset, all patients were planned for 3D-CRT based on the computed tomography (CT) scans with IV contrast media. Subsequently, all the plans were copied and replaced on the scans without intravenous CM. The radiation doses calculated from the two sets of CTs were compared. The dose differences between the planning image set using intravenous contrast and the image set without contrast showed an average increase in Monitor Units (MUs) in the lower esophageal region that was 1.28 and 0.75% for 6 and 15 MV photon beams, respectively. There was no statistical significant difference in the rectal region between the two sets of scans in the 3D-CRT plans. The results showed that the dose differences between the plans for the CT scans with and without CM were small and clinically tolerable. However, the differences in the lower esophageal region were significant in the statistical analysis.

  16. Brain temperature effects of intravenous heroin: State dependency, environmental modulation, and the effects of dose.

    PubMed

    Bola, R Aaron; Kiyatkin, Eugene A

    2017-11-01

    Here we examined how intravenous heroin at a dose that maintains self-administration (0.1 mg/kg) affects brain temperature homeostasis in freely moving rats under conditions that seek to mimic some aspects of human drug use. When administered under standard laboratory conditions (quiet rest at 22 °C ambient temperature), heroin induced moderate temperature increases (1.0-1.5 °C) in the nucleus accumbens (NAc), a critical structure of the brain motivation-reinforcement circuit. By simultaneously recording temperatures in the temporal muscle and skin, we demonstrate that the hyperthermic effects of heroin results primarily from inhibition of heat loss due to strong and prolonged skin vasoconstriction. Heroin-induced brain temperature increases were enhanced during behavioral activation (i.e., social interaction) and in a moderately warm environment (29 °C). By calculating the "net" effects of the drug in these two conditions, we found that this enhancement results from the summation of the hyperthermic effects of heroin with similar effects induced by either social interaction or a warmer environment. When the dose of heroin was increased (to 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 mg/kg), brain temperature showed a biphasic down-up response. The initial temperature decrease was dose-dependent and resulted from a transient inhibition of intra-brain heat production coupled with increased heat loss via skin surfaces-the effects typically induced by general anesthetics. These initial inhibitory effects induced by large-dose heroin injections could be related to profound CNS depression-the most serious health complications typical of heroin overdose in humans. Published by Elsevier Ltd.

  17. Pharmacokinetics of loxiglumide after single intravenous or oral doses in man.

    PubMed

    Setnikar, I; Chisté, R; Makovec, F; Rovati, L C; Warrington, S J

    1988-05-01

    Loxiglumide (D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5-oxo-pentanoic acid, CR 1505) was given intravenously to 8 male healthy volunteers in a single dose of 2 mg/kg body weight (b.w.) or orally in a single dose of 5 mg/kg b.w. Loxiglumide was measured in plasma and in urine by HPLC during 48 h following the administration. After i.v. infusion the plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = 43.791 x e-2.652 x h + 2.657 x e-0.139 x h. In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the i.v. administration the urinary excretion of loxiglumide and of its metabolites accounted for 11.13% of the administered dose. After oral administration loxiglumide appeared in plasma with a lag time of 14 min, reached the peak 34 min after administration, being eliminated with an initial fast and a terminal slow elimination rate. The plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = -46.72 x e-8.765 x (h-0.23) + 40.660 x e-1.383 x (h-0.23) + 6.057 x e-0.120 x (h-0.23). In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the oral administration the excretion of loxiglumide and of its metabolites accounted for 7.67% of the administered dose. The absolute bioavailability of loxiglumide was calculated comparing the AUC(0-inf) found after oral and after i.v. administration and was estimated as 0.967, with p = 0.05 fiducial limit of 0.656-1.278.

  18. Dose-dependent effects of intravenous alcohol administration on cerebral blood flow in young adults.

    PubMed

    Strang, Nicole M; Claus, Eric D; Ramchandani, Vijay A; Graff-Guerrero, Ariel; Boileau, Isabelle; Hendershot, Christian S

    2015-02-01

    Functional magnetic resonance imaging (fMRI) studies involving alcohol challenge are important for identifying neural correlates of alcohol's psychopharmacological effects. However, evaluating acute alcohol effects on blood oxygen level-dependent (BOLD) signal change is complicated by alcohol-related increases in cerebral blood flow (CBF). The present study aimed to further characterize acute alcohol effects on CBF using intravenous alcohol administration to maximize control over brain alcohol exposure. Twenty heavy-drinking young adults (M = 19.95 years old, SD = 0.76) completed alcohol and placebo imaging sessions in a within-subject, counter-balanced, placebo-controlled design. Arterial spin labeling (ASL) provided estimates of perfusion change at two target blood alcohol concentrations (40 and 80 mg%) relative to baseline and relative to a saline control infusion. Voxel-wise analyses showed widespread and dose-dependent effects of alcohol on CBF increase. Region-of-interest analyses confirmed these findings, also indicating regional variation in the magnitude of perfusion change. Additional findings indicated that lower self-reported sensitivity to alcohol corresponded with reduced perfusion change during alcohol administration. This study provides further evidence for widespread effects of acute alcohol on cerebral perfusion, also demonstrating regional, dose-dependent, and inter-individual variation. Further research is needed to evaluate implications of these effects for the design and interpretation of pharmacological fMRI studies involving alcohol challenge.

  19. Pharmacokinetics of danofloxacin after single dose intravenous, intramuscular and subcutaneous administration to loggerhead turtles Caretta caretta.

    PubMed

    Marín, Pedro; Bayón, Alejandro; Fernández-Varón, Emilio; Escudero, Elisa; Clavel, Cristina; Almela, Ramon; Cárceles, Carlos M

    2008-12-22

    The single-dose disposition kinetics of the antibiotic danofloxacin were determined in clinically normal loggerhead turtles (n = 6) after intravenous (IV), subcutaneous (SC) and intramuscular (IM) administration of 6 mg kg(-1) bodyweight. Danofloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. The concentration-time data were analyzed by non-compartmental kinetic methods. Steady-state volume of distribution, and total body clearance of danofloxacin after IV administration were estimated to be 1.02 +/- 0.17 1 kg(-1) and 0.11 +/- 0.01 1 h(-1) kg(-1), respectively. Following IM and SC administration, danofloxacin achieved maximum plasma concentrations of 10.25 +/- 4.59 and 10.35 +/- 4.45 mg l(-1) at 1.20 +/- 0.52 and 1.46 +/- 0.48 h, respectively. The absolute bioavailabilities after SC and IM routes were 98.72 +/- 11.73 and 104.81 +/- 14.97%, respectively. Danofloxacin shows a favourable pharmacokinetic profile in loggerhead turtles reflected by parameters such as a long half-life and a high bioavailability following a single dose of 6 mg kg(-1) by IM and SC routes; thus, it is likely that this treatment will be effective in loggerhead turtles with bacterial infections.

  20. Induced liver injury after high-dose methylprednisolone in a patient with multiple sclerosis.

    PubMed

    Oliveira, Ana Torres; Lopes, Sandra; Cipriano, Maria Augusta; Sofia, Carlos

    2015-07-21

    A 33-year-old woman with multiple sclerosis, medicated with high doses of methylprednisolone, cyclophosphamide and glatiramer acetate, was referred to our department due to acute liver injury. The laboratory investigation was normal except for weakly positive antinuclear antibodies. Cyclophosphamide and glatiramer acetate were suspended, and intravenous immunoglobulin with maintenance of high doses of methylprednisolone was initiated. The patient developed another episode of acute hepatitis so the immunoglobulin was stopped. After that, she had three more episodes of elevation of liver enzymes with no hepatic insufficiency while medicated only with high doses of methylprednisolone. At this time, liver biopsy showed focal centrilobubar hepatocyte necrosis with minimal interface hepatitis. After the high doses of methylprednisolone were suspended, the patient remained asymptomatic, with normal hepatic enzymes. This case emphasises that, although rare, induced liver injury after high doses of methylprednisolone can occur. 2015 BMJ Publishing Group Ltd.

  1. Contamination study of multiple-dose vials.

    PubMed

    Melnyk, P S; Shevchuk, Y M; Conly, J M; Richardson, C J

    1993-03-01

    To document the number of opened, dated, and expired multiple-dose vials (MDVs) in patient-care areas and to determine what proportion of MDVs were contaminated with bacteria or cellular debris. Every tenth opened MDV (69/656) identified on the wards was collected, ensuring representation from each nursing unit. Contents were examined for contamination. Medical-school-affiliated, tertiary care center. (1) Visual inspection for debris, medication type, location, lot number, manufacturer's expiration date, and date of opening; (2) culture in solid and broth media for bacterial growth; and (3) staining and microscopic examination for cellular constituents. No vials had been dated after opening and 4.6 percent were expired according to the manufacturer's expiration date. No bacterial contamination was evident; however, one vial was contaminated with red blood cells. Transmission of infection via contaminated MDVs has been well documented and contamination with red blood cells raises concerns about potential for transmission of bloodborne pathogens. Recommendations include dating MDVs after opening, emphasizing the need for proper aseptic technique, and discarding MDVs on the manufacture's date of expiration.

  2. Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil citrate

    PubMed Central

    Muirhead, Gary J; Rance, David J; Walker, Donald K; Wastall, Philip

    2002-01-01

    Aims To characterize the absorption, metabolism and excretion of an oral and intravenous (IV) dose of radiolabelled [14C]-sildenafil citrate in healthy male subjects. Specific objectives were to measure the cumulative amount of drug-related radiolabelled material excreted in the urine and faeces to characterize urinary and faecal radioactivity as unchanged sildenafil or its metabolites, and to quantify blood and plasma total radioactivity and unchanged drug concentrations. Methods Six healthy male subjects between the ages of 45 and 58 years were enrolled in an open-label, parallel-group study; three subjects received the oral dose and three received the IV dose. Oral drug was administered as a single dose of 50-mg [14C]-sildenafil, and IV drug was administered as a single dose of 25-mg [14C]-sildenafil infused over 25 min. Each dosage form contained 50 µCi of radioactivity. For radioactivity assays, whole blood, plasma, urine and faeces samples were taken predose and at specified intervals up to 5 days postdose. Plasma samples were assayed for sildenafil and the metabolites UK-103,320 and UK-150,564. Metabolite profiling was also performed in plasma, faeces and urine. Results Absorption of sildenafil after oral administration was rapid and approximately 92% whilst the absolute bioavailability was limited to 38%, due to first-pass metabolism. Mean AUCt values showed that sildenafil accounted for about 60% of the total circulating radioactivity in the plasma after IV administration and for 32% after oral administration. Concentrations of radioactivity in whole blood were lower than in plasma, indicating limited penetration of sildenafil into blood cells. No unchanged sildenafil was detected in either urine or faeces, demonstrating that metabolism was the major mechanism of drug clearance. The principal routes of metabolism were N-demethylation, oxidation and aliphatic dehydroxylation. Sildenafil was well tolerated, with treatment-related adverse events reported by

  3. Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil.

    PubMed

    Muirhead, Gary J; Rance, David J; Walker, Donald K; Wastall, Philip

    2002-01-01

    To characterize the absorption, metabolism and excretion of an oral and intravenous (IV) dose of radiolabelled [14C]-sildenafil citrate in healthy male subjects. Specific objectives were to measure the cumulative amount of drug-related radiolabelled material excreted in the urine and faeces to characterize urinary and faecal radioactivity as unchanged sildenafil or its metabolites, and to quantify blood and plasma total radioactivity and unchanged drug concentrations. Six healthy male subjects between the ages of 45 and 58 years were enrolled in an open-label, parallel-group study; three subjects received the oral dose and three received the IV dose. Oral drug was administered as a single dose of 50-mg [14C]-sildenafil, and IV drug was administered as a single dose of 25-mg [14C]-sildenafil infused over 25 min. Each dosage form contained 50 microCi of radioactivity. For radioactivity assays, whole blood, plasma, urine and faeces samples were taken predose and at specified intervals up to 5 days postdose. Plasma samples were assayed for sildenafil and the metabolites UK-103,320 and UK-150,564. Metabolite profiling was also performed in plasma, faeces and urine. Absorption of sildenafil after oral administration was rapid and approximately 92% whilst the absolute bioavailability was limited to 38%, due to first-pass metabolism. Mean AUCt values showed that sildenafil accounted for about 60% of the total circulating radioactivity in the plasma after IV administration and for 32% after oral administration. Concentrations of radioactivity in whole blood were lower than in plasma, indicating limited penetration of sildenafil into blood cells. No unchanged sildenafil was detected in either urine or faeces, demonstrating that metabolism was the major mechanism of drug clearance. The principal routes of metabolism were N-demethylation, oxidation and aliphatic dehydroxylation. Sildenafil was well tolerated, with treatment-related adverse events reported by three subjects

  4. Preliminary study of intravenous amantadine treatment for ataxia management in patients with probable multiple system atrophy with predominant cerebellar ataxia.

    PubMed

    Youn, Jinyoung; Shin, Hyeeun; Kim, Ji Sun; Cho, Jin Whan

    2012-05-01

    Multiple system atrophy with predominant cerebellar ataxia is a disabling neurologic disease. However, effective management has not yet been established. We conducted a short-term, open-label preliminary study to assess the benefits of intravenous amantadine treatment in patients with probable multiple system atrophy with predominant cerebellar ataxia. Twenty patients (10 male, 10 female) with probable multiple system atrophy with predominant cerebellar ataxia received 400 mg of amantadine by intravenous per day for 5 days. Ataxia severity was evaluated by the International Cooperative Ataxia Rating Scale before and after intravenous amantadine therapy and all subjects reported subjective improvement after intravenous amantadine treatment using a patient global impression scale. We analyzed the total and subscale scores by the ataxia scale and patient global impression scale. The mean age was 57.4 years (range: 47-72) and the mean disease duration was 30.8 months (range: 11-79). The ataxia severity significantly decreased after intravenous amantadine therapy from 42.5 to 37.3 (p < 0.001). The mean patient global impression scale for improvement was 2.9 and there were no side effects of intravenous amantadine treatment observed. When we assessed responders, the duration of intravenous amantadine effect was more than 1 month in 4 subjects of 7 responders. Our findings suggest that intravenous amantadine treatment can be a safe management option in cerebellar ataxia, although the mechanism is unclear. Thus, further double-blind, long-term studies with a larger sample size are needed.

  5. Catastrophic demyelinating encephalomyelitis after intrathecal and intravenous stem cell transplantation in a patient with multiple sclerosis.

    PubMed

    Alderazi, Yazan J; Coons, Stephen W; Chapman, Kevin

    2012-05-01

    Stem cell transplantation is an investigational therapy for multiple sclerosis. The authors describe a case of catastrophic demyelinating encephalomyelitis following stem cell transplantation in a 17-year-old girl. Nine months after an initial diagnosis of multiple sclerosis, she underwent stem cell transplantation in Costa Rica. Subsequently, she deteriorated and was transported back to the United States with headache and vomiting progressing to quadriparesis, locked-in syndrome, and superimposed encephalopathy. Magnetic resonance imaging and brain biopsy were consistent with fulminant demyelinating encephalomyelitis with enhancing parenchyma and leptomeninges. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis and high protein. The protracted illness required tracheostomy and gastrostomy. After methyleprednisone, intravenous immunoglobulin, and cyclophosphamide, she improved during 2.5 months to an ambulatory, functionally independent state. Subsequently, typical less severe multiple sclerosis relapses occurred. This case demonstrates that stem cell transplantation may provoke life-threatening encephalomyelitis in patients with multiple sclerosis. This highlights the need to restrict transplantation to trials with appropriate safety controls.

  6. Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to dairy goats.

    PubMed

    Courtin, F; Craigmill, A L; Wetzlich, S E; Gustafson, C R; Arndt, T S

    1997-10-01

    Twelve (12) lactating dairy goats (46-71 kg body wt at study initiation) were divided into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two route (intravenous, i.v.; intramuscular, i.m.), two-period crossover design, with a 2-week washout between injections. After another 2-week washout period, the goats were dosed with ceftiofur sodium i.m. for 5 consecutive days at either 1.1 or 2.2 mg CFAE/kg. The goats from the 2.2 mg/kg multiple dose group were dried off and the i.v. kinetic study repeated. After all injections, blood samples were obtained serially for determination of combined serum concentrations of ceftiofur and metabolites. After intravenous doses of 1.1 and 2.2 mg/kg, the harmonic means of the terminal phase half-lives were 171.8 and 233 min, respectively, for lactating does. The harmonic mean of the terminal phase half-life after an i.v. dose of 2.2 mg/kg in non-lactating does was 254 min. The AUC0-infinity was significantly less and the clearance significantly greater during lactation. After i.m. doses of 1.1 and 2.2 mg/kg, the harmonic mean terminal phase half-lives were 163 and 156 min, respectively. The i.m. bioavailability of ceftiofur sodium in goats was 100%, and the AUC0-infinity was dose-proportional from 1.1-2.2 mg CFAE/kg body weight. After five daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE, there was minimal accumulation of drug in serum as assessed by Cmax, and serum concentrations were dose-proportional after the multiple dosing regimen.

  7. Comparison between two intraoperative intravenous loading doses of paracetamol on pain after minor hand surgery: two grams versus one gram.

    PubMed

    Cornesse, D; Senard, M; Hans, G A; Ledoux, D; Kirsch, M; Hick, G; Hallet, C; Joris, J

    2010-01-01

    Paracetamol (acetaminophen) is widely used for postoperative analgesia at a recommended dose of 1 g every six hours in adult patients. Increasing the loading dose to 2 g was suggested to improve immediate postoperative analgesia without increased toxicity in healthy adult patients. We tested the hypothesis that a loading dose of 2 g of intravenous paracetamol results in better postoperative analgesia after surgery as compared with a dose of 1 g. Sixty adult patients scheduled for minor hand surgery under intravenous regional anaesthesia were randomized into two groups. The first group received 1 g of intravenous paracetamol before surgery while the second group received 2 g. Verbal numeric pain score, analgesic consumption, first night sleep quality, and patient's satisfaction were recorded during the first 24 hours. Verbal numeric pain scores during the first 24 hours after surgery were significantly lower in the 2 g paracetamol group as compared to the 1 g paracetamol group. No differences were found between the two groups with regard to rescue analgesic consumption, sleep quality and patient's satisfaction. An intraoperative loading dose of 2 g paracetamol improves postoperative analgesia after minor hand surgery as compared to 1 g paracetamol.

  8. Single-dose pharmacokinetics of intravenous ampicillin plus sulbactam in healthy elderly and young adult subjects.

    PubMed

    Rho, J P; Jones, A; Woo, M; Castle, S; Smith, K; Bawdon, R E; Norman, D C

    1989-10-01

    The pharmacokinetics of intravenous ampicillin and sulbactam, a beta-lactamase inhibitor, were evaluated in two different age groups. Twelve healthy elderly subjects (age 65-93 years) and 12 healthy young adult subjects (age 20-35 years) received both a dose of ampicillin 1 g plus sulbactam 0.5 g and a higher dose of ampicillin 2 g plus sulbactam 1 g after a one-week period between doses. A reverse-phase high-pressure liquid chromatography method was used for the quantitation of ampicillin and sulbactam in serum and urine. The pharmacokinetic parameters for both ampicillin and sulbactam were calculated by computer-based two-compartment nonlinear model. After a 30-min infusion, serum concentrations of both drugs declined in a biexponential manner for both doses. Elderly subjects demonstrated significantly lower total clearances (Clt) than young adult subjects of ampicillin 1 g (220.0 +/- 104.2 vs 360.0 +/- 95.8 ml/min/1.73 m2), ampicillin 2 g (72.6 +/- 36.6 vs 306.8 +/- 109.77 ml/min/1.73 m2), sulbactam 0.5 g (122.3 +/- 47.8 vs 263.9 +/- 93.7 ml/min/1.73 m2), and sulbactam 1 g (171.2 +/- 85.8 vs 391.7 +/- 70.8 ml/min/1.73 m2), respectively. Significance was defined as P less than 0.05. Renal clearance was also significantly reduced in the elderly subjects. Area under the curve was found to be significantly increased in the elderly subjects compared to the young subjects for both ampicillin and sulbactam as were the beta elimination half-lives. No significant difference in the apparent volume of distribution, when adjusted for body weight, was found for either sulbactam (P greater than 0.95) or ampicillin (P greater than 0.95) between the two groups. Linear regression analysis revealed that age was significantly correlated with the Clt of ampicillin 1 g (r = 0.85, P less than 0.001), ampicillin 2 g (r = 0.90, P less than 0.001), sulbactam 0.5 g (r = 0.80, P less than 0.001), and sulbactam 1 g (r = 0.93, P less than 0.001). A multivariate analysis showed a slight

  9. [Treatment of iron deficiency in predialysis state by low molecular weight iron dextran high doses intravenously].

    PubMed

    Fievet, Patrick; Coppin, Mathilde; Brazier, François; Lefèvre, Magali; Stephan, Robin; Demontis, Renato

    2012-02-01

    Anemia is a common complication of chronic kidney disease (CKD) in predialysis stage. Iron deficiency is more common than in normal patients and plays a key role in the genesis of anemia. Its correction avoids the use of erythropoiesis stimulating agents (ESA) or reduces their dosage. Treatment with oral iron is often poorly tolerated and ineffective, necessitating the use of intravenous iron. New forms of injectable iron allow the use of high doses and correct iron deficiency in a single administration with consequent preservation of venous capital and lower costs. We studied the effectiveness of iron dextran of low molecular weight (LMWID) in high doses to correct iron deficiency and treat anemia in predialysis CKD patients. Twenty-nine doses of 500 to 1600 mg were administered to 25 patients followed for CKD (GFR between 60 and 10 ml/min per 1.73 m(2)), selected on biological criteria of iron deficiency defined by a ratio of transferrin saturation (TSAT) <20% and/or serum ferritin of less than 100 μg/L. Patients received treatment by ESA in 16 cases out of 29. One month after treatment, hemoglobin (Hb) increased significantly (11.4±1.6 vs 10.4±1.4 g/dL, P=0.0003) along with a significant increase in TSAT (21.3±7.3 vs 13.3±3.8%, P=0.000003) and serum ferritin (286±253 vs 91±60 μg/L, P=0.00005). Six patients had a serum ferritin greater than 500 μg/L after treatment, which may put them at risk of iron overload. Their serum ferritin was higher than the rest of the population before treatment, while the TSAT was no different, reflecting a functional deficiency. Their hemoglobin did not increase after treatment in contrast to the rest of the population suggesting the unavailability of iron for erythropoiesis with accumulation in the reticuloendothelial system. Renal function did not change significantly and there were no cases of acute renal failure. No immediate side effect was observed. Three patients presented delayed reactions to such self

  10. Single-dose intravenous iron for iron deficiency: a new paradigm.

    PubMed

    Auerbach, Michael; Deloughery, Thomas

    2016-12-02

    Iron-deficiency anemia is the most common hematologic problem in the world. Although oral iron is often viewed as front-line therapy, extensive published evidence has accumulated that IV iron is superior, in both efficacy and safety, to oral iron in many clinical situations and should be introduced much sooner in the treatment paradigm of iron-deficient patients. In this chapter, we will review the formulations of IV iron that allow total complete replacement doses in 1 or 2 sessions including practical tips for administration. We realize safety concerns abound and therefore will analyze evidence based overstated concerns regarding serious adverse events highlighting unnecessary interventions for minor, self-limiting infusion reactions, which infrequently occur with intravenous iron administration. Recent data for the use of IV iron in a variety of clinic situations will be reviewed including women with heavy uterine bleeding, pregnancy, bariatric surgery, inflammatory bowel disease, and restless legs syndrome. Briefly discussed is the new frontier of IV iron's use in the prevention of acute (high altitude) mountain sickness. It is clear that in many clinical situations IV iron is a new and improved standard of care offering advantages over oral iron in efficacy, toxicity, and convenience to patients and health care providers. © 2016 by The American Society of Hematology. All rights reserved.

  11. Pharmacokinetics of doxycycline after a single intravenous, oral or intramuscular dose in Muscovy ducks (Cairina moschata).

    PubMed

    Yang, F; Sun, N; Zhao, Z S; Wang, G Y; Wang, M F

    2015-01-01

    1. The pharmacokinetics of doxycycline in ducks were investigated after a single intravenous (IV), intramuscular (IM) or oral (PO) dose at 20 mg/kg body weight. 2. The concentrations of doxycycline in plasma samples were assayed using a high performance liquid chromatography method, and pharmacokinetic parameters were calculated using a non-compartmental model. 3. After IV administration, doxycycline had a mean (±SD) distribution volume (Vz) of 1761.9 ± 328.5 ml/kg and was slowly eliminated with a terminal half-life (t₁/₂λz) of 21.21±1.47 h and a total body clearance (Cl) of 57.51 ± 9.50 ml/h/kg. Following PO and IM administration, doxycycline was relatively slowly absorbed - the peak concentrations (Cmax) were 17.57 ± 4.66 μg/ml at 2 h and 25.01 ± 4.18 μg/ml at 1.5 h, respectively. The absolute bioavailabilities (F) of doxycycline after PO and IM administration were 39.13% and 70.71%, respectively. 4. The plasma profile of doxycycline exhibited favourable pharmacokinetics characteristics in Muscovy ducks, such as wide distribution, relatively slow absorption and slow elimination, though oral bioavailability was low.

  12. Pharmacokinetics of lansoprazole and its main metabolites after single intravenous doses in healthy Chinese subjects.

    PubMed

    Zhang, Dan; Yang, Man; Liu, Man; Zhang, Yanan; Wang, Xiaolin; Xiao, Xue; Liu, Huichen

    2012-11-01

    The aim of the study was to evaluate the pharmacokinetics (PK) of lansoprazole (LPZ) and its main metabolites 5'-hydroxy lansoprazole (HLPZ) and lansoprazole sulphone (LPZS) after single intravenous (i.v.) doses of LPZ in healthy Chinese subjects, and the relationship between the cytochrome P450 (CYP) 2C19 phenotypes and the plasma concentrations of LPZS at the time-points in the elimination phase of LPZ. Twelve subjects were given lansoprazole by i.v. infusion. Blood samples were collected at designated time points up to 24 h. Plasma concentrations of LPZ, HLPZ and LPZS were quantified by a selective and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. After single i.v. doses of 15, 30 and 60 mg LPZ, C(max) and area under the plasma concentration-time curve (AUC(0-t)) of LPZ were 725 ± 151, 1480 ± 190, 3130 ± 480 µg · L(-1) and 1690 ± 1210, 3630 ± 2530, 8080 ± 4550 µg · h · L(-1), respectively. LPZ was generally well tolerated in healthy Chinese subjects, and displayed linear PK in the range of 15-60 mg. There were significant differences in the elimination of LPZ and the formation of LPZS between the single CYP2C19 poor metabolizer (PM) and the CYP2C19 extensive metabolizers (EM). The concentration of LPZS at the time-points in the elimination phase of LPZ could be monitored for CYP2C19 phenotyping. As a probe drug for CYP2C19 phenotyping, LPZ for injection might be more suitable than LPZ oral formulations.

  13. Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis.

    PubMed

    Moretti, Michele; Buiatti, Alessandra; Merlo, Marco; Massa, Laura; Fabris, Enrico; Pinamonti, Bruno; Sinagra, Gianfranco

    2013-11-01

    The management of refractory recurrent pericarditis is challenging. Previous clinical reports have noted a beneficial effect of high-dose intravenous human immunoglobulins (IvIgs) in isolated and systemic inflammatory disease-related forms. In this article, we analyzed retrospectively our clinical experience with IvIg therapy in a series of clinical cases of pericarditis refractory to conventional treatment. We retrospectively analyzed 9 patients (1994 to 2010) with refractory recurrent pericarditis, who received high-dose IvIg as a part of their medical treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine treatment was not discontinued during IvIg treatment. No patients had a history of autoimmune or connective tissue diseases. During an average period of 11 months from the first recurrence, patients had experienced a mean of 5 relapses before the first IvIg treatment. In 4 cases, patients showed complete clinical remission with no further relapse after the first IvIg cycle. Two patients experienced a single minor relapse, responsive to short-term nonsteroidal anti-inflammatory drugs. In 2 patients, we performed a second cycle of IvIg after a recurrence of pericarditis, with subsequent complete remission. One patient did not respond to 3 cycles of IvIg and subsequently underwent pericardial window and long-term immunosuppressive treatment. No major adverse effect was observed in consequence of IvIg administration in all the cases. In conclusion, although IvIg mode of action is still poorly understood in this setting, this treatment can be considered as an option in patients with recurrent pericarditis refractory to conventional medical treatment and, in our small series, has proved to be effective in 8 of 9 cases. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Intravenous topiramate: safety and pharmacokinetics following a single dose in patients with epilepsy or migraines taking oral topiramate.

    PubMed

    Clark, Anne M; Kriel, Robert L; Leppik, Ilo E; White, James R; Henry, Thomas R; Brundage, Richard C; Cloyd, James C

    2013-06-01

    Although topiramate is widely prescribed for epilepsy and migraine, there is no intravenous product. We have developed an injectable topiramate formulation in which the drug is solubilized in a cyclodextrin matrix, Captisol(®) (Ligand Pharmaceuticals, Inc., La Jolla, CA). Our long-term goal is to evaluate intravenous topiramate for the treatment of neonatal seizures. Prior to studies in newborns, we carried out an investigation of injectable topiramate's safety and pharmacokinetics in adult patients. Twenty adult volunteers with epilepsy or migraine on stable, on maintenance topiramate therapy were given 25 mg of a stable-labeled intravenous topiramate over 10 min, followed by their usual oral doses. Vital signs were taken, electrocardiography studies (ECGs) were recorded, and the infusion sites were periodically examined prior to and up to 24 h after dosing. Blood samples were collected prior to administration and serially for 96 h thereafter. Plasma concentrations of both stable-labeled and regular topiramate were measured using liquid chromatography-mass spectrometry (LC-MS). Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2 (Pharsight Corporation, Mountain View, CA, U.S.A.). Seven patients experienced one or more of the following minor adverse events including nausea and vomiting (1), tingling around the lips (1), paresthesia in the arms and legs (1), and a mild vasovagal response with intravenous catheter placement (1). Included in the adverse events were four patients with epilepsy who had seizures consistent with their histories. There were no changes in heart rate, blood pressure, or ECG results, and there were no infusion site reactions. Pharmacokinetic parameters (mean ± standard deviation [SD]) determined following the intravenous dose included absolute bioavailability: 110 ± 16%, distribution volume: 0.79 ± 0.22 L/kg, clearance: 2.03 ± 1.07 L/h, and elimination half-life: 27.6 ± 9.7 h. Distribution volume

  15. [Immunomodulation in severe leptospirosis with multiple organ failure: plasma exchange, intravenous immunoglobulin or corticosteroids?].

    PubMed

    Meaudre, E; Asencio, Y; Montcriol, A; Martinaud, C; Graffin, B; Palmier, B; Goutorbe, P

    2008-02-01

    We report a case of severe leptospirosis complicated with a multiple organ failure syndrome. A 62-year-old patient presented a picture associating fever, asthenia and myalgias, particularly intense on the calves. The assessment showed acute renal failure, hyperbilirubinemia, severe rhabdomyolysis and thrombocytopenia. Although initial management associating amoxicilline and continuous veino-venous hemodiafiltration, evolution was unfavourable, with SDRA and increase of hyperbilirubinemia. Administration of a bolus of 500 mg of methylprednisolone, associated with intravenous immunoglobulin (0,4 g/kg per day during five days), led to a rapid clinical and biological improvement. Immunomodulation aspects during leptospirosis are discussed.

  16. Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

    PubMed Central

    Zhao, Wei; Qi, Tengfei; Shi, Mei; Guan, Zhifang; Lu, Haikong; Long, Fuquan; Gao, Zixiao; Zhang, Sufang; Zhou, Pingyu

    2017-01-01

    Background Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. Methodology/Principal findings Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38–4.13%) and 0.35% (95% CI: 0.06–1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. Conclusions/Significance Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use

  17. Safety and Dose Escalation Study of Intravenous Zinc Supplementation in Pediatric Critical Illness.

    PubMed

    Cvijanovich, Natalie Z; King, Janet C; Flori, Heidi R; Gildengorin, Ginny; Vinks, Alexander A; Wong, Hector R

    2016-08-01

    Critically ill children have low plasma zinc (pZn), correlating with organ failure. Since Zn influences inflammation, immune function, and glucose control, Zn supplementation is a plausible therapeutic modality. We sought to determine a safe dose of intravenous (IV) Zn to restore pZn in critically ill children. Stepwise dose escalation study of IV Zn supplementation at a tertiary children's hospital. All children (<10 years) admitted to the pediatric intensive care unit with a Pediatric Risk of Mortality III score >5, or ≥1 new organ failure were eligible. After consent, patients were sequentially enrolled into 4 dosing groups: (1) no zinc, (2) Zn250: 250 mcg/kg/d ZnSO4, (3) Zn500: 500 mcg/kg/d ZnSO4, or (4) Zn750: 750 mcg/kg/d ZnSO4 ZnSO4 was administered 3 times daily for 7 days. pZn was measured at baseline, end of first ZnSO4 infusion, 1 hour postinfusion, and 7 hours postinfusion on day 1, then daily through days 2-7. Interleukin-6 (IL-6), C-reactive protein (CRP), and lymphocyte subsets were measured on days 1 and 3. Glucose was measured 3 times daily for 7 days. Twenty-four patients were enrolled. Baseline demographics were similar among groups. Baseline pZn was low in all patients (mean [SD], 41.8 [16.0] mcg/dL). pZn increased over the study period in supplemented groups; however, mean pZn in the Zn750 group exceeded the 50th percentile. pZn was not associated with IL-6, CRP, or lymphocyte subsets among groups. Degree of hyperglycemia did not differ among groups. No patient had a study-related adverse event. IV zinc supplementation at 500 mcg/kg/d restores pZn to near the 50th percentile and is well tolerated. © 2015 American Society for Parenteral and Enteral Nutrition.

  18. Population pharmacokinetic modeling and Monte Carlo simulation of varying doses of intravenous metronidazole.

    PubMed

    Sprandel, Kelly A; Drusano, George L; Hecht, David W; Rotschafer, John C; Danziger, Larry H; Rodvold, Keith A

    2006-08-01

    Population pharmacokinetic modeling and Monte Carlo simulation (MCS) are approaches used to determine probability of target attainment (PTA) of antimicrobial therapy. The objectives of this study were 1) to determine a population pharmacokinetic model (PPM) using metronidazole and hydroxy-metronidazole concentrations from healthy subjects and critically ill patients, and 2) to determine the probability of attaining the pharmacodynamic target area under the plasma concentration (AUC)/MIC ratio >or=70 against 218 clinical isolates of Bacteroides fragilis using MCS. Eighteen healthy subjects were randomized to 3 dosages of intravenous metronidazole (500 mg every 8 h, 1000 mg day(-1), 1500 mg day(-1)) in an open-label 3-way crossover fashion. Serial blood samples were collected over 25.5 h on the 3rd day of each study period. An additional of 8 critically ill patients received intravenous metronidazole 500 mg every 8 h. Serial blood samples were collected over 8 h after the 2nd day of dosing. Plasma metronidazole and hydroxy-metronidazole concentrations were analyzed using a high-performance liquid chromatographic assay. The 834 plasma concentrations from 62 data sets were simultaneously modeled with Non-Parametric Adaptive Grid population modeling program. A 4-compartment model with a metabolite and zero-order infusion into the central compartment was used. The mean parameter vector and covariance matrix from PPM were inserted into the simulation module of ADAPT II. A 10,000-subject MCS was performed to determine the probability of PTA for a total drug AUC to MIC ratio >or=70 against 218 isolates of B. fragilis (MIC range, 0.125-2.0 mg L(-1)). Mean parameter values were CL(non-OH), 3.08 L h(-1); Vc, 35.4 L; K(OH), 0.04 h(-1); CL(OH), 2.78 L h(-1); and V(OH), 9.66 L. The regression values of the observed versus predicted concentrations (r2) of metronidazole and hydroxy-metronidazole were 0.972 and 0.980, respectively. The PTA for metronidazole 1500 mg day(-1) or 500 mg

  19. Effect of polyaspartic acid on pharmacokinetics of gentamicin after single intravenous dose in the dog.

    PubMed Central

    Whittem, T; Parton, K; Turner, K

    1996-01-01

    The effects of poly-L-aspartic acid on the pharmacokinetics of gentamicin were examined by using a randomized crossover trial design with the dog. When analyzed according to a three-compartment open model, poly-L-aspartic acid reduced some first-order rate equation constants (A3, lambda 1, and lambda 3), the deep peripheral compartment exit microconstant (k31), the elimination rate constant (k(el)), and the area under the concentration-time curve from 0 to 480 h (AUC0-480) (0.21-, 0.60-, 0.26-, 0.27-, 0.72-, and 0.76-fold, respectively; P < 0.05) but increased the volume of distribution at steady state (Vss), the volume of distribution calculated by the area method (V(area)), the apparent volume of the peripheral compartment (Vp), and all mean time parameters. These results suggested that poly-L-aspartic acid increased the distribution of gentamicin to or binding within the deep peripheral compartment and that poly-L-aspartic acid may have delayed gentamicin transit through the peripheral tissues. In contrast, poly-L-aspartic acid did not alter pharmacokinetic parameters relevant to the central or shallow peripheral compartments to a clinically significant extent. Although gentamicin's pharmacokinetic parameters of relevance to therapeutic drug monitoring were not directly altered, this study has provided pharmacokinetic evidence that poly-L-aspartic acid alters the peripheral distribution of gentamicin. This pharmacokinetic interaction occurred after a single intravenous dose of each drug. Therefore, this interaction should be investigated further, before polyaspartic acid can be considered for use as a clinical nephroprotectant. PMID:8723473

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

    PubMed

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

    2016-04-01

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

  1. The effects of intravenous dexmedetomidine on spinal anesthesia: comparision of different dose of dexmedetomidine

    PubMed Central

    Lee, Mi Hyeon; Ko, Jae Houn; Kim, Eun Mi; Cheung, Mi Hwa; Choi, Young Ryong

    2014-01-01

    Background In this prospective, randomized, double-blind, placebo-controlled trial, we tried to find out appropriate amounts of single-dose dexmedetomidine to prolong the duration of spinal anesthesia in a clinical setting. Methods Sixty patients who were scheduled for unilateral lower limb surgery under spinal anesthesia were randomized into three groups receiving normal saline (control group, n = 20) or 0.5 or 1.0 ug/kg dexmedetomidine (D-0.5 group, n = 20; D-1, n = 20) intravenously prior to spinal anesthesia with 12 mg of bupivacaine. The two-dermatome pinprick sensory regression time, duration of the motor block, Ramsay sedation score (RSS), and side effects of dexmedetomidine were assessed. Results The two-dermatome pinprick sensory regression time (57.6 ± 23.2 vs 86.5 ± 24.3 vs 92.5 ± 30.7, P = 0.0002) and duration of the motor block (98.8 ± 34.1 vs 132.9 ± 43.4 vs 130.4 ± 50.4, P = 0.0261) were significantly increased in the D-0.5 and D-1 groups than in the control group. The RSS were significantly higher in the D-0.5 and D-1 groups than in the control group. However, there were no patients with oxygen desaturation in dexmedetomidine groups. The incidences of hypotension and bradycardia showed no differences among the three groups. Conclusions Both 0.5 and 1.0 ug/kg of dexmedetomidine administered as isolated boluses in the absence of maintenance infusions prolonged the duration of spinal anesthesia. PMID:25368783

  2. False-Photosensitivity and Transient Hemiparesis Following High-Dose Intravenous and Intrathecal Methotrexate for Treatment of Acute Lymphoblastic Leukemia

    PubMed Central

    Shah, Nilay; Zambidis, Elias T.

    2011-01-01

    We describe a patient who was treated with high-dose intravenous and intrathecal methotrexate for acute lymphoblastic leukemia, and who manifested a false photosensitivity reaction with no prior evidence of sun exposure. This patient later experienced delayed transient hemiparesis following methotrexate administration, although without long-term sequelae. The etiology of these events is obscure, but suggestive of a vasculitic or immune-mediated reaction to methotrexate. PMID:19326416

  3. Comparison of high-dose and low-dose insulin by continuous intravenous infusion in the treatment of diabetic ketoacidosis in children.

    PubMed

    Burghen, G A; Etteldorf, J N; Fisher, J N; Kitabchi, A Q

    1980-01-01

    We studied the efficacy of low-dose (0.1 U/kg/h) and high-dose (1..0 U/kg/h) insulin, given randomly to children with diabetic ketoacidosis (DKA) by continuous intravenous infusion without a loading dose. Plasma glucose reached 250 mg/dl in 3.4 +/- 0.4 h with the high-dose insulin group compared with 5.4 +/- 0.5 h with the low-dose insulin group (P < 0.01). During the first 12 h of therapy, plasma glucose fell below 100 mg/dl in 2 of 16 in the low-dose compared with 12 of 16 in the high-dose patients. The decrement of ketone bodies, cortisol, and glucagon was similar in both groups. The number of hours required for HCO3(-) greater than or equal to meq/l and arterial blood pH greater than or equal to 7.30 were not significantly different in the two groups. Hypokalemia (K < 3.4 meq/L) occurred in 3 of 16 low-dose and 10 of 16 high-dose patients. The data show that low-dose insulin, with a slower rate of glucose decrease, is as effective as a high dose for the treatment of DKA in children with less incidence of hypokalemia and decreased potential for hypoglycemia.

  4. Safety of intravenously applied mistletoe extract - results from a phase I dose escalation study in patients with advanced cancer.

    PubMed

    Huber, Roman; Schlodder, Dietrich; Effertz, Carola; Rieger, Sabine; Tröger, Wilfried

    2017-09-18

    Mistletoe extracts have anti-tumor properties and are approved for subcutaneous use in cancer patients. Data on Intravenous application are limited. An aqueous extract from pine-mistletoe was used to investigate maximum tolerable dose (MTD) and safety of intravenous application. It was infused once weekly for 3 weeks in patients with advanced cancer. Any type of cancer was included; relevant exclusion criteria were concurrent chemo- or radiation therapy. The classical phase I 3 + 3 dose escalation scheme was followed. Predefined dose groups were 200, 400, 700, 1200 and 2000 mg. Maximum planned dose was 2000 mg. With the MTD three more patients should be treated for 9 weeks in order to evaluate intermediate term tolerability. Weekly during the treatment and 1 week later tolerability, clinical status, safety laboratory parameters and adverse events were documented. Twenty-one patients (3 in the dose groups 200, 400, 700 and 1200 mg, respectively, 9 in the dose group 2000 mg) were included. MTD was not reached. Because one dose-limiting toxicity (DLT), an allergic reaction, occurred during infusion of 2000 mg, three more patients had to be included in this dose group and tolerated it, as well as the three patients who received 2000 mg for 9 weeks. Occasionally in the dose group 2000 mg mild to moderate fever occurred. Weekly infusions of 2000 mg of the pine-mistletoe extract were tolerated and can be used in further studies but had a risk for allergic reactions and fever. German Clinical Trials Register (Trial registration number DRKS00005028).

  5. An Exploratory Dose-Escalating Study Investigating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous Atacicept in Patients with Systemic Lupus Erythematosus

    PubMed Central

    Pena-Rossi, C; Nasonov, E; Stanislav, M; Yakusevich, V; Ershova, O; Lomareva, N; Saunders, H; Hill, J; Nestorov, I

    2009-01-01

    Atacicept, a recombinant fusion protein containing the extracellular, ligand-binding portion of the transmembrane activator and calcium modulator and cyclophilin-ligand interactor receptor, and the Fc portion of human immunoglobulin (Ig) G, is designed to block the activity of B-lymphocyte stimulator and a proliferation-inducing ligand, and may have utility as a treatment for B-cellmediated diseases, such as systemic lupus erythematosus (SLE). This Phase Ib study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of intravenous (i.v.) atacicept in patients with mild-to-moderate SLE. Patients (n = 24) were randomised (5:1) to receive atacicept (single dose: 3, 9 or 18 mg/kg; or multiple dose: 2 × 9 mg/kg) or matching placebo. Patients were followed for 6 weeks after dosing (9 weeks in the 2 × 9 mg/kg cohort). Local tolerability of atacicept was comparable with that of placebo, with only mild injection-site reactions reported with atacicept. Atacicept i.v. was generally well tolerated, both systemically and locally, in patients with mild-to-moderate SLE. Atacicept displayed non-linear PK, which was predictable across doses and between single and repeat doses. The biological activity of atacicept was demonstrated by its marked effect in reducing B-cells and Ig levels in patients with SLE. This supports the utility of this therapeutic approach in the treatment of autoimmune diseases, such as SLE. PMID:19395457

  6. Timing or Dosing of Intravenous Proton Pump Inhibitors in Acute Upper Gastrointestinal Bleeding Has Low Impact on Costs.

    PubMed

    Lu, Yidan; Adam, Viviane; Teich, Vanessa; Barkun, Alan

    2016-10-01

    High-dose intravenous proton pump inhibitors (PPIs) post endoscopy are recommended in non-variceal upper gastrointestinal bleeding (UGIB), as they improve outcomes of patients with high-risk lesions. Determine the budget impact of using different PPI regimens in treating non-variceal UGIB, including pre- and post-endoscopic use, continuous infusion (high dose), and intermittent bolus (twice daily) dosing. A budget impact analysis using a decision model informed with data from the literature adopting a US third party payer's perspective with a 30-day time horizon was used to determine the total cost per patient (US$2014) presenting with acute UGIB. The base-case employing high-dose pre- and post-endoscopic IV PPI was compared with using only post-endoscopic PPI. For each, continuous or intermittent dosing regimens were assessed with associated incremental costs. Deterministic and probabilistic sensitivity analyses were performed. The overall cost per patient is $11,399 when high-dose IV PPIs are initiated before endoscopy. The incremental costs are all inferior in alternate-case scenarios: $106 less if only post-endoscopic high-dose IVs are used; with intermittent IV bolus dosing, the savings are $223 if used both pre and post endoscopy and $191 if only administered post endoscopy. Subgroup analysis suggests cost savings in patients with clean-base ulcers who are discharged early after endoscopy. Results are robust to sensitivity analysis. The incremental costs of using different IV PPI regimens are modest compared with total per patient costs.

  7. Effect of Admission Oral Diuretic Dose on Response to Continuous versus Bolus Intravenous Diuretics in Acute Heart Failure: An Analysis from DOSE-AHF

    PubMed Central

    Shah, Ravi V.; McNulty, Steven; O'Connor, Christopher M.; Felker, G. Michael; Braunwald, Eugene; Givertz, Michael M.

    2014-01-01

    Background Results from the Diuretic Optimization Strategies in Acute Heart Failure (DOSE-AHF) study suggest that an initial continuous infusion of loop diuretics is not superior to bolus dosing with regard to clinical endpoints in AHF. We hypothesized that outpatient furosemide dose was associated with congestion and poorer renal function, and explored the hypothesis that a continuous infusion may be more effective in patients on higher outpatient diuretic doses. Methods DOSE-AHF randomized 308 patients within 24 hours of admission to high vs. low initial intravenous diuretic dose given as either a continuous infusion or bolus. We compared baseline characteristics and assessed associations between mode of administration (bolus vs. continuous) and outcomes in patients receiving high-dose (≥120 mg furosemide equivalent, n=177) versus low-dose (<120 mg furosemide equivalent, n=131) outpatient diuretics. Results Patients on higher doses of furosemide were less frequently on renin-angiotensin system inhibitors (P=.01), and had worse renal function and more advanced symptoms. There was a significant interaction between outpatient dose and mode of therapy (P=0.01) with respect to net fluid loss at 72 hours after adjusting for creatinine and intensification strategy. Admission diuretic dose was associated with an increased risk of death or rehospitalization at 60 days (adjusted HR=1.08 per 20-mg increment in dose, 95% CI 1.01–1.16, P=.03). Conclusions In acute HF, patients on higher diuretic doses have greater disease severity, and may benefit from an initial bolus strategy. PMID:23194486

  8. Standard-dose intravenous anti-D immunoglobulin versus intravenous immunoglobulin in the treatment of newly diagnosed childhood primary immune thrombocytopenia.

    PubMed

    Papagianni, Andromachi; Economou, Marina; Tragiannidis, Athanasios; Karatza, Eliza; Tsatra, Ioanna; Gombakis, Nikolaos; Athanassiadou-Piperopoulou, Fani; Athanasiou-Metaxa, Miranda

    2011-05-01

    We conducted a study to evaluate the efficacy of intravenous (IV) anti-D against IV immunoglobulin (IVIG) in newly diagnosed immune thrombocytopenia (ITP) in children and to identify the clinical characteristics of the children most likely to benefit from one or the other treatment. Children (6 mo to 14 y) with newly diagnosed ITP and a platelet count <20,000/μL were treated either with a single bolus dose of 50 μg/kg IV anti-D or with 0.8 to 1 g/kg IVIG in a randomized manner. Twenty-five patients, mean age of 6.8 years, were treated either with IV anti-D (n=10) or with IVIG (n=15). Both drugs were equally efficient in raising the platelet count above 20,000/μL at 24 hours posttreatment. Children who presented with bleeding stage 1 or 2 (no mucosal bleeding) responded better to IVIG treatment, in terms of an increase in platelet count at 24 hours posttreatment (P=0.04). Hemoglobin drop was greater in the anti-D group (P=0.002). A single bolus dose of 50 μg/kg of IV anti-D is a safe and effective first-line treatment in newly diagnosed ITP in childhood and mucosal bleeding is a poor prognostic factor for treatment with IVIG.

  9. Phase I study of intravenous low-dose granulocyte colony-stimulating factor in acute and subacute ischemic stroke.

    PubMed

    Moriya, Yusuke; Mizuma, Atsushi; Uesugi, Tsuyoshi; Ohnuki, Yoichi; Nagata, Eiichiro; Takahashi, Wakoh; Kobayashi, Hiroyuki; Kawada, Hiroshi; Ando, Kiyoshi; Takagi, Shigeharu; Takizawa, Shunya

    2013-10-01

    Granulocyte colony-stimulating factor (G-CSF; filgrastim) may be useful for the treatment of acute ischemic stroke because of its neuroprotective and neurogenesis-promoting properties, but an excessive increase of neutrophils may lead to brain injury. We examined the safety and tolerability of low-dose G-CSF and investigated the effectiveness of G-CSF given intravenously in the acute phase (at 24 hours) or subacute phase (at 7 days) of ischemic stroke. Three intravenous dose regimens (150, 300, or 450 μg/body/day, divided into 2 doses for 5 days) of G-CSF were examined in 18 patients with magnetic resonance imaging (MRI)-confirmed infarct in the territory of the middle cerebral artery. Nine patients received the first dose at 24 hours poststroke (acute group) and 9 patients received the first dose on day 7 poststroke (subacute group; n = 3 at each dose in each group). A scheduled administration of G-CSF was skipped if the patient's leukocyte count exceeded 40,000/μL. Patients received neurologic and MRI examinations. We found neither serious adverse event, drug-related platelet reduction nor splenomegaly. Leukocyte levels remained below 40,000/μL at 150 and 300 μg G-CSF/body/day, but rose above 40,000/μL at 450 μg G-CSF/body/day. Neurologic function improvement between baseline and day 90 was more marked after treatment in the acute phase versus the subacute phase (Barthel index 49.4 ± 28.1 v 15.0 ± 22.0; P < .01). Low-dose G-CSF (150 and 300 μg/body/day) was safe and well tolerated in ischemic stroke patients, and leukocyte levels remained below 40,000/μL. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  10. Comparison of effectiveness of high-dose intracoronary adenosine versus intravenous administration on the assessment of fractional flow reserve in patients with coronary heart disease.

    PubMed

    López-Palop, Ramón; Carrillo, Pilar; Frutos, Araceli; Cordero, Alberto; Agudo, Pilar; Mashlab, Samer; Bertomeu-Martínez, Vicente

    2013-05-01

    Intravenous adenosine is considered the drug of choice to obtain maximum hyperemia in the measurement of the fractional flow reserve (FFR). However, comparative studies performed between intravenous and intracoronary administration have not used high doses of intracoronary adenosine. The present study compared the efficacy and safety of high doses of intracoronary adenosine to intravenous administration when calculating the FFR. Intracoronary bolus doses of 60, 180, 300, and 600 μg adenosine were compared to an intravenous administration of 140 μg/kg/min, 200 μg/kg/min, and 140 μg/kg/min plus an intracoronary bolus of 120 μg. All the cases were performed using the radial approach. FFR was assessed in 102 patients with 108 intermediate lesions by an intracoronary pressure wire. The intracoronary dose of 60 μg was associated with a significantly greater FFR compared to the intravenous infusion (0.02 ± 0.03, p = 0.001). The intracoronary doses of 300 (-0.01 ± 0.00; p = 0.006) and 600 μg (-0.02 ± 0.00; p <0.0005) were significantly associated with a smaller FFR compared to the intravenous infusion. An intracoronary dose of 600 μg revealed a significantly greater percentage of lesions with an FFR <0.80 compared to intravenous infusion at 140 μg/kg/min (37.6 vs 31.5%; p <0.05) and 200 μg/kg/min (37.6 vs 32.4%; p <0.05) and compared to intracoronary doses of 60 (26.9%) and 180 μg (31.5%). In conclusion, an intracoronary bolus dose >300 μg can be equal to or more effective than an intravenous infusion of adenosine in achieving maximum hyperemia when calculating the FFR. Its use could simplify these procedures without having an effect on safety.

  11. Study of Intravenous Single-Dose Toxicity Test of Bufonis venonum Pharmacopuncture in Sprague-Dawley Rats

    PubMed Central

    Kwon, Ki-Rok; Yu, Jun-Sang; Sun, Seung-Ho; Lee, Kwang-Ho

    2016-01-01

    Objectives: Bufonis venonum (BV) is toad venom and is the dried, white secretions of the auricular and the skin glands of toads. This study was performed to evaluate the toxicity of intravenous injection of Bufonis venonum pharmacopuncture (BVP) through a single- dose test with sprague-dawley (SD) rats. Methods: Twenty male and 20 female 6-week-old SD rats were injected intravenously in the caudal vein with BVP or normal saline. The animals were divided into four groups with five female and five male rats per group: the control group injected with normal saline, the low-dosage group injected with 0.1 mL/animal of BVP, the medium-dosage group injected with 0.5 mL/ animal of BVP and the high-dosage group injected with 1.0 mL/animal of BVP. We performed clinical observations every day and body weight measurements on days 3, 7 and 14 after the injection. We also conducted hematology, serum biochemistry, and histological observations immediately after the observation period. Results: No mortalities were observed in any experimental group. Paleness occurred in the medium- and the high-dosage groups, and congestion on tails was observed in females in the medium- and the high-dosage groups. No significant changes in weight, hematology, serum biochemistry, and histological observations that could be attributed to the intravenous injection of BVP were observed in any experimental group. Conclusion: The lethal dose of intravenously-administered BVP in SD rats is over 1.0 mL/animal. PMID:27386149

  12. The assesment of effectiveness of plasmonic resonance photothermal therapy in tumor-bearing rats after multiple intravenous administration of gold nanorods

    NASA Astrophysics Data System (ADS)

    Bucharskaya, Alla B.; Maslyakova, Galina N.; Navolokin, Nikita A.; Terentyuk, Georgy S.; Khlebtsov, Boris N.; Khlebtsov, Nikolai G.; Bashkatov, Alexey N.; Genina, Elina A.; Tuchin, V. V.

    2017-03-01

    To assess the effectiveness of plasmonic photothermal therapy (PPT) multiple intravenous strategy of gold nanorods (GNRs) administration was used before laser exposure. The model of alveolar liver cancer PC-1 was used in male outbred albino rats, which were intravenously administrated by single and multiple injections of GNRs and then were treated by PPT. The gold dosage was 400 μg (single injection group), 800 μg (double injection group), 1200 μg (triple injection group), and absorption maximum of gold nanorods suspension was at the wavelength of 808 nm. 24 hours after last injection the tumors were irradiated by the 808-nm diode laser during 15 min at power density 2.3 W/cm2. Temperature control of the tumor heating was provided by IR imager. 24 hours after the PPT the half of animals from each group was withdrawn from the experiments and the sampling tumor tissue for morphological study was performed. In survived animals the growth of tumors was evaluated during 21 days after the PPT. The antitumor effects of PPT after triple intravenous injection were comparable with those obtained at direct intratumoral administration of similar total dose of GNRs. The effectiveness of PPT depended on gold accumulation in tumor, probably, due to sufficient vascularization of tumor tissue.

  13. Evolution of carfilzomib dose and schedule in patients with multiple myeloma: a historical overview.

    PubMed

    Jakubowiak, Andrzej J

    2014-07-01

    Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to its target. In July 2012, carfilzomib received accelerated approval in the United States for the treatment of relapsed and refractory multiple myeloma. Based on emerging preclinical data and clinical results, the total dose, infusion time, and administration schedule of carfilzomib have evolved during phase I and phase II clinical studies, with the aim of optimizing the risk-benefit profile of the agent. Based on in vitro and in vivo findings and encouraging phase I tolerability data, a consecutive-day, twice-weekly dosing schedule was implemented early in the development program. Other phase II studies have led to further refinements in the dosing schedule of carfilzomib, resulting in the current approved schedule for carfilzomib to be administered intravenously over 2-10 min on 2 consecutive days each week for 3 weeks of a 28-day cycle. Prolonged infusion over 30 min has also been assessed in clinical studies to enable the use of higher carfilzomib doses with the aim of improving drug tolerability and efficacy. These data collectively informed the dosing and scheduling schemas for carfilzomib in ongoing trials, including phase I and II studies of combination regimens, and the randomized phase III trials ASPIRE, FOCUS, ENDEAVOR, and CLARION. Additional studies are underway to examine alternative dosing schedules (e.g., once-weekly dosing [CHAMPION-1]).

  14. Comparing low-dose intravenous ketamine-midazolam with intravenous morphine with respect to pain control in patients with closed limb fracture.

    PubMed

    Ahmadi, Omid; Isfahani, Mehdi Nasr; Feizi, Awat

    2014-06-01

    We assessed the effects of low-dose IV ketamine-midazolam versus morphine on pain control in patients with closed limb fracture(s); and also compared the incidence of adverse events (cardio-pulmonary) between two groups. This prospective, single-blind, non-inferiority trial randomized consecutive emergency department (ED) patients aged 18-60 years to two groups: Receiving 300-500 mcg/kg ketamine plus 0.03 mg/kg midazolam, or 0.05-0.1 mg/kg morphine. Visual analogue score (VAS) and adverse events were verified during an interval of 30 minutes. Two hundred and thirty - six patients were selected, among whom 207 were males (87.3%). The average age was 29 ± 2, (range, 18-60 years). The VAS score at T30 (i.e., 30 minutes after initial analgesic dose) was significantly decreased compared with VAS score at T0, in both groups. No statistically significant difference, however, was observed between the two groups (-6.1 ± 1.1 versus -6.2 ± 1.0; P = 0.16). With regard to systolic blood pressure and respiratory rate, however, a meaningful difference was noted between the two groups (1.5 ± 6.4 versus -2.1 ± 6.6; P = 0.000 for SBP, and -0.2 ± 1.1 versus -1.1 ± 6.1; P = 0.048 for RR). Low-dose intravenous ketamine plus midazolam has the same analgesic effects as morphine on pain control in trauma patients with closed limb fracture(s), in addition to less respiratory adverse events.

  15. Effect of intravenous fructose on the P-31 MR spectrum of the liver: dose response in healthy volunteers.

    PubMed

    Terrier, F; Vock, P; Cotting, J; Ladebeck, R; Reichen, J; Hentschel, D

    1989-05-01

    Dynamic phosphorus-31 magnetic resonance (MR) spectroscopy of the liver after intravenous administration of fructose has been suggested as a test of liver function. To establish dose-response curves of the phosphorus metabolites in the normal human liver, each of four healthy volunteers was given two to four different fructose doses on separate days: 62.5, 125, 250, 375, or 500 mg per kilogram of body weight. P-31 MR spectra of the liver were acquired with a 2-T whole-body magnetic, both before and after fructose administration, at 2.5-minute intervals over at least 30 minutes. The fructose load caused a significant, linearly dose-dependent accumulation of phosphomonoesters (r = .72, P less than .01) and a decrease in inorganic phosphate (r = .78, P less than .005) and adenosine triphosphate (r = .73, P less than .01). On the basis of these experiments, dynamic P-31 MR spectroscopy seems promising in the assessment of liver function.

  16. Population pharmacokinetics of intravenous busulfan in children: revised body weight-dependent NONMEM® model to optimize dosing.

    PubMed

    Diestelhorst, Christian; Boos, Joachim; McCune, Jeannine S; Hempel, Georg

    2014-07-01

    We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time data. PopPK analyses were done with NONMEM® 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation). The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dose[mg]=target AUC[mg×h/L]×3.04L/h×(ABW/16.1)0.797. Compared to other dosing strategies, differences were observed for the very small and obese patients. We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed.

  17. May early intervention with high dose intravenous immunoglobulin pose a potentially successful treatment for severe cases of tick-borne encephalitis?

    PubMed Central

    2013-01-01

    Background Arthropod-borne viral encephalitis of diverse origins shows similar clinical symptoms, histopathology and magnetic resonance imaging, indicating that the patho mechanisms may be similar. There is no specific therapy to date. However, vaccination remains the best prophylaxis against a selected few. Regardless of these shortcomings, there are an increasing number of case reports that successfully treat arboviral encephalitis with high doses of intravenous immunoglobulins. Discussion To our knowledge, high dose intravenous immunoglobulin has not been tested systematically for treating severe cases of tick-borne encephalitis. Antibody-dependent enhancement has been suspected, but not proven, in several juvenile cases of tick-borne encephalitis. Although antibody-dependent enhancement during secondary infection with dengue virus has been documented, no adverse effects were noticed in a controlled study of high dose intravenous immunoglobulin therapy for dengue-associated thrombocytopenia. The inflammation-dampening therapeutic effects of generic high dose intravenous immunoglobulins may override the antibody-dependent enhancement effects that are potentially induced by cross-reactive antibodies or by virus-specific antibodies at sub-neutralizing levels. Summary Analogous to the increasing number of case reports on the successful treatment of other arboviral encephalitides with high dose intravenous immunoglobulins, we postulate whether it may be possible to also treat severe cases of tick-borne encephalitis with high dose intravenous immunoglobulins as early in the course of the disease as possible. PMID:23822550

  18. Biological dose optimization with multiple ion fields.

    PubMed

    Gemmel, A; Hasch, B; Ellerbrock, M; Weyrather, W K; Krämer, M

    2008-12-07

    We describe a method to irradiate arbitrarily shaped target volumes with simultaneously optimized multiple fields of fast carbon ions, explicitly taking into account sparing of organs at risk. The method was developed with realistic technical boundary conditions in mind, so that irradiations can be executed with devices like the GSI raster scanner or its successors at the upcoming dedicated ion-beam radiotherapy facilities. By virtue of the local effect model (LEM) biological effects are fully taken into account. Several minimization algorithms were investigated, and plain gradient search was found to be more effective than methods based on conjugate gradients or Newton's root finding algorithm. Two sets of cell survival experiments for the experimental verification of patient-like treatment plans were performed. Chinese hamster cells were used for quasi two-dimensional biological dosimetry. The plans combine a very good target conformation with an excellent sparing of organs-at-risk which was verified by the measurements. The results are compared to predictions of the local effect model in its original formulation and a modified version taking additional effects of clustered DNA damage into account. The new method is implemented in GSI's TRiP98 treatment planning system. It has already been applied clinically for planning and irradiating selected patients within the GSI pilot project.

  19. Immediate hypersensitivity to iodinated contrast media: diagnostic accuracy of skin tests and intravenous provocation test with low dose.

    PubMed

    Sesé, L; Gaouar, H; Autegarden, J-E; Alari, A; Amsler, E; Vial-Dupuy, A; Pecquet, C; Francès, C; Soria, A

    2016-03-01

    The diagnosis of HSR to iodinated contrast media (ICM) is challenging based on clinical history and skin tests. This study evaluates the negative predictive value (NPV) of skin tests and intravenous provocation test (IPT) with low-dose ICM in patients with suspected immediate hypersensitivity reaction (HSR) to ICM. Thirty-seven patients with suspected immediate hypersensitivity reaction to ICM were included retrospectively. Skin tests and a single-blind placebo-controlled intravenous provocation test (IPT) with low-dose iodinated contrast media (ICM) were performed. Skin tests with ICM were positive in five cases (one skin prick test and five intradermal test). Thirty-six patients were challenged successfully by IPT, and only one patient had a positive challenge result, with a grade I reaction by the Ring and Messmer classification. Ten of 23 patients followed up by telephone were re-exposed to a negative tested ICM during radiologic examination; two experienced a grade I immediate reaction. For immediate hypersensitivity reaction to ICM, the NPV for skin tests and IPT with low dose was 80% (95% CI 44-97%). © 2016 John Wiley & Sons Ltd.

  20. Pharmacokinetics and Bioavailability of a Fixed-Dose Combination of Ibuprofen and Paracetamol after Intravenous and Oral Administration.

    PubMed

    Atkinson, Hartley C; Stanescu, Ioana; Frampton, Chris; Salem, Isam I; Beasley, Charles P H; Robson, Richard

    2015-10-01

    Previously published studies have suggested the lack of a pharmacokinetic interaction between ibuprofen and paracetamol when they are delivered as a fixed-dose oral combination. The aim of this study was to determine the pharmacokinetic profile and safety of a fixed-dose intravenous (IV) combination, containing 3 mg/mL ibuprofen and 10 mg/mL paracetamol, in comparison with its individual components. The study also assessed the relative bioavailability of the same doses of the active ingredients when they were administered as an oral formulation. A single-dose, open-label, randomized, five-period cross-over sequence pharmacokinetic study was undertaken in 30 healthy volunteers. Serial plasma samples were assayed for both paracetamol and ibuprofen concentrations, using validated liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were computed using standard non-compartmental analyses. Adverse events were also assessed. The ratios of the maximum measured plasma concentration (C max), the area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable plasma concentration (AUCt ) and AUC from time zero to infinity (AUC∞) were analysed for bioequivalence as determined by 90% confidence intervals. The pharmacokinetic parameters of ibuprofen and paracetamol were very similar for the combination and monotherapy IV preparations; the ratios of the C max, AUC t and AUC∞ values fell within the 80-125% acceptable bioequivalence range. Precise dose proportionality for both compounds was also determined for the half dose of the IV formulation in comparison with the full dose. The relative bioavailability of paracetamol (93.78%) and ibuprofen (96.45%) confirmed the pharmacokinetic equivalence of the oral and IV formulations of the fixed-dose combination. Concomitant administration of 3 mg/mL ibuprofen and 10 mg/mL paracetamol in a fixed-dose IV combination does not alter the pharmacokinetic profiles of

  1. WE-G-218-02: The Measurement of Absorbed Dose to Active Intravenous Cardiac Devices in Patients Undergoing Radiotherapy.

    PubMed

    Reft, C

    2012-06-01

    Radiotherapy departments are seeing an increasing number of patients presenting for treatment with active intravenous cardiac devices (AICDs). This is due to an increasing aging population and technology advances in these devices. The AAPM TG-34 addressed the radiation effects in these devices and provided recommendations for patients with these devices undergoing radiotherapy. The current devices utilizing CMOS technology are more sensitive to radiation then the older bipolar devices. Therefore, it is important to estimate the dose to the device to ensure that the radiation does not adversely affect the performance of the device. This is particularly important for patients dependent on their accurate functioning. The dose to the device is generally from secondary radiation and is typically below 0.05 Gy with most of it coming from lower energy scatter radiation. Treatment planning systems can be used to estimate the dose to the device. However, these systems do not accurately calculate doses at distances more than 2-3 cm from the field edge. For these out-of-field dose measurements the dosimeter requires a high sensitivity and a relatively flat energy response. Thermoluminescent detectors and optically stimulated luminescent detectors satisfy these requirements and they are relatively unobtrusive. The newer formulations of radiochromic film with higher sensitivity can also be used. The detector should be place under 0.5 to 1.0 cm of bolus to minimize the contaminating head-scatter electrons provide a more realistic measurement of the dose to the device. 1. List the reasons for estimating the dose to the AICDs 2. Provide a discussion on the various methods which include calculations and measurements to estimate the dose to the device as well as the uncertainties in these estimates. 3. Identify detectors that satisfy the requirements for these in-vivo out-of-field dose measurements as well as describe the appropriate correction factors to apply for accurate dose

  2. Efficacy of high-dose intravenous immunoglobulins in two patients with idiopathic recurrent pericarditis refractory to previous immunosuppressive treatment.

    PubMed

    Tona, Francesco; Bellotto, Fabio; Laveder, Francesco; Meneghin, Alessia; Sinagra, Gianfranco; Marcolongo, Renzo

    2003-01-01

    Although idiopathic acute pericarditis is usually a self-limiting disease, in many patients it may recur over a period of months or years. Even if some evidence seems to suggest the possible role of a deranged immune reactivity in the pathogenesis of idiopathic recurrent pericarditis, the etiology of the disease is still unknown. Furthermore, while some trial data confirm the usefulness of colchicine, its medical treatment is not yet clearly established. We here report the clinical history of 2 patients with idiopathic recurrent pericarditis resistant to prednisone, colchicine and other immunosuppressive drugs, who have been successfully treated with high-dose intravenous immunoglobulins.

  3. [Treatment of multiple myeloma with intravenous pamidronate. Pain prevention and suppression of hypercalcemia risk].

    PubMed

    Díaz, Carlos; Soutelo, María J; Quiroga, Luis; Palmer, Luis; Lutfi, Rubén

    2004-01-01

    In a prospective clinical study, with the patient as its own control, we selected patients with stage III multiple myeloma. We treated them monthly with intravenous (i.v.) Disodic Pamidronate: 90 mg in 2 to 21 cycles. Four patients died during the study. The remaining 13 patients presented reduced bone resorption urinary markers (D-Pyr mainly) as well as urinary calcium (bone turnover reduction). Both effects (metabolic interchange reduction and calcium variation) did not show a direct relationship, being the 1st magnitude proportional to the baseline level and the 2nd independent from it. We noted pain reduction (VAS: visual analogs scale), low analgesic consumption, and the absence of future skeletal problems. The treatment tolerance was good. All these factors contribute to justify the welfare of the patient demonstrated by ECOG (Eastern Cooperative Oncology Group), not only improving the average results but also extending this improvement to future results. Our observation suggests that under strict procedures, this treatment could be very adequate in patients with advanced multiple myeloma independent of the state of the disease at the beginning of the study.

  4. Effect of Single Compared to Repeated Doses of Intravenous S(+) Ketamine on the Release of Pro-inflammatory Cytokines in Patients Undergoing Radical Prostatectomy.

    PubMed

    Ali, Hassan Mohamed; Mokhtar, Ali M

    2017-01-01

    Radical prostatectomy is a major surgical procedure that is associated with marked inflammatory response and impairment of the immune system which may affect the postoperative outcome. The aim of this study was to evaluate the effect of preincision single or multiple doses of S(+) ketamine on the pro-inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). This is a randomized controlled trial including 60 American Society of Anesthesiologists Physical Status I and II patients scheduled for radical prostatectomy under combined general-epidural anesthesia in Cairo university Teaching Hospital. Patients were randomly divided into three groups each of twenty patients: Group I received no S(+) ketamine (control group), Group II received S(+) ketamine as a single preincision dose, and Group III received preincision and repeated doses of S(+) ketamine. S(+) ketamine was injected as a single intravenous dose of 0.5 mg/kg in Group II and III, repeated as 0.2 mg/kg at 20 min interval until 30 min before the end of surgery. The three groups were comparable in age, weight, and duration of the operation. The study also revealed that a single preincision dose of S(+) ketamine decreased TNF-α to reach 1027.04 ± 50.13 μ/ml and IL-6 to reach 506.89 ± 25.35 pg/ml whereas the repeated doses of S(+) ketamine decreased TNF-α to reach 905.64 ± 35065 μ/ml and IL-6 to reach 412.79 ± 16.5 pg/ml (P < 0.05). S(+) ketamine suppresses pro-inflammatory cytokine production, especially when given in repeated doses.

  5. Ketamine augmentation for outpatients with treatment-resistant depression: Preliminary evidence for two-step intravenous dose escalation.

    PubMed

    Cusin, Cristina; Ionescu, Dawn Flosnik; Pavone, Kara Jean; Akeju, Oluwaseun; Cassano, Paolo; Taylor, Norman; Eikermann, Matthias; Durham, Kelley; Swee, Michaela Ballentyne; Chang, Trina; Dording, Christina; Soskin, David; Kelley, John; Mischoulon, David; Brown, Emery Neal; Fava, Maurizio

    2017-01-01

    Preliminary evidence supports the safety and efficacy of subanesthetic ketamine as an experimental antidepressant, although its effects are often not sustained beyond one week. Studies are lacking that have examined the sustained effects of escalating ketamine doses as augmentation in outpatients with treatment-resistant depression. Therefore, the aims of this study were twofold: (1) to assess the safety and antidepressant efficacy of two-step, repeated-dose ketamine augmentation and (2) to assess the duration of ketamine's antidepressant efficacy as augmentation to ongoing antidepressant pharmacotherapy for 3 months after the final infusion. Fourteen patients with treatment-resistant depression were eligible to receive augmentation with six open-label intravenous ketamine infusions over 3 weeks. For the first three infusions, ketamine was administered at a dose of 0.5 mg/kg over 45 minutes; the dose was increased to 0.75 mg/kg over 45 minutes for the subsequent three infusions. The primary outcome measure was response (as measured on Hamilton Depression Rating Scale-28 items). After the completion of three ketamine infusions, 7.1% (1/14) responded; after all six ketamine infusions, 41.7% (5/12) completers responded and 16.7% (2/12) remitted. Intent-to-treat response and remission rates at the end of the final infusion were 35.7% (5/14) and 14.3% (2/14), respectively. However, all but one responder relapsed within 2 weeks after the final infusion. Repeated, escalating doses of intravenous ketamine augmentation were preliminarily found to be feasible, efficacious and well tolerated. Interaction with concomitant medications and elevated level of treatment resistance are possible factors for non-response.

  6. Prospective validation of a novel dosing scheme for intravenous busulfan in adult patients undergoing hematopoietic stem cell transplantation

    PubMed Central

    Cho, Sang-Heon; Lee, Jung-Hee; Lim, Hyeong-Seok; Lee, Kyoo-Hyung; Kim, Dae-Young; Choe, Sangmin; Lee, Je-Hwan

    2016-01-01

    The objective of this study was to externally validate a new dosing scheme for busulfan. Thirty-seven adult patients who received busulfan as conditioning therapy for hematopoietic stem cell transplantation (HCT) participated in this prospective study. Patients were randomized to receive intravenous busulfan, either as the conventional dosage (3.2 mg/kg daily) or according to the new dosing scheme based on their actual body weight (ABW) (23×ABW0.5 mg daily) targeting an area under the concentration-time curve (AUC) of 5924 µM·min. Pharmacokinetic profiles were collected using a limited sampling strategy by randomly selecting 2 time points at 3.5, 5, 6, 7 or 22 hours after starting busulfan administration. Using an established population pharmacokinetic model with NONMEM software, busulfan concentrations at the available blood sampling times were predicted from dosage history and demographic data. The predicted and measured concentrations were compared by a visual predictive check (VPC). Maximum a posteriori Bayesian estimators were estimated to calculate the predicted AUC (AUCPRED). The accuracy and precision of the AUCPRED values were assessed by calculating the mean prediction error (MPE) and root mean squared prediction error (RMSE), and compared with the target AUC of 5924 µM·min. VPC showed that most data fell within the 95% prediction interval. MPE and RMSE of AUCPRED were -5.8% and 20.6%, respectively, in the conventional dosing group and −2.1% and 14.0%, respectively, in the new dosing scheme group. These fi ndings demonstrated the validity of a new dosing scheme for daily intravenous busulfan used as conditioning therapy for HCT. PMID:27162478

  7. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial.

    PubMed

    Motov, Sergey; Rockoff, Bradley; Cohen, Victor; Pushkar, Illya; Likourezos, Antonios; McKay, Courtney; Soleyman-Zomalan, Emil; Homel, Peter; Terentiev, Victoria; Fromm, Christian

    2015-09-01

    We assess and compare the analgesic efficacy and safety of subdissociative intravenous-dose ketamine with morphine in emergency department (ED) patients. This was a prospective, randomized, double-blind trial evaluating ED patients aged 18 to 55 years and experiencing moderate to severe acute abdominal, flank, or musculoskeletal pain, defined as a numeric rating scale score greater than or equal to 5. Patients were randomized to receive ketamine at 0.3 mg/kg or morphine at 0.1 mg/kg by intravenous push during 3 to 5 minutes. Evaluations occurred at 15, 30, 60, 90, and 120 minutes. Primary outcome was reduction in pain at 30 minutes. Secondary outcome was the incidence of rescue analgesia at 30 and 60 minutes. Forty-five patients per group were enrolled in the study. The primary change in mean pain scores was not significantly different in the ketamine and morphine groups: 8.6 versus 8.5 at baseline (mean difference 0.1; 95% confidence interval -0.46 to 0.77) and 4.1 versus 3.9 at 30 minutes (mean difference 0.2; 95% confidence interval -1.19 to 1.46; P=.97). There was no difference in the incidence of rescue fentanyl analgesia at 30 or 60 minutes. No statistically significant or clinically concerning changes in vital signs were observed. No serious adverse events occurred in either group. Patients in the ketamine group reported increased minor adverse effects at 15 minutes post-drug administration. Subdissociative intravenous ketamine administered at 0.3 mg/kg provides analgesic effectiveness and apparent safety comparable to that of intravenous morphine for short-term treatment of acute pain in the ED. Copyright © 2015 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

  8. Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

    PubMed Central

    Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas

    2015-01-01

    The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions. PMID:26073995

  9. Effect of Intravenous High Dose Vitamin C on Postoperative Pain and Morphine Use after Laparoscopic Colectomy: A Randomized Controlled Trial

    PubMed Central

    Jeon, Younghoon; Park, Jun Seok; Moon, Suyoung

    2016-01-01

    Background and Objective. Vitamin C has antioxidant, neuroprotective, and neuromodulating effects. Recently, it showed antinociceptive effect as a result of the antioxidant properties. Therefore, we designed this study to assess the effect of intravenous vitamin C on opiate consumption and pain in patients undergoing laparoscopic colectomy. Methods. A total of 100 patients were enrolled and allocated to receive 50 mg/kg vitamin C or placebo by intravenous infusion immediately after induction of anesthesia. Morphine consumption and scores of pain were assessed at 2, 6, and 24 h after completion of surgery. Results. There were 97 patients included in the analysis. Patients who received vitamin C had higher plasma concentrations of vitamin C at the end of surgery, significantly lower morphine consumption at the 2 h after end of surgery, and significantly lower pain scores at rest during first 24 h postoperatively. There was no significant difference between groups in side effects, fatigue score, or pain score during cough. Conclusion. This study shows high dose vitamin C infusion decreased postoperative pain during the first 24 h and reduced morphine consumption in the early postoperative period. Additional research needed to examine whether higher doses of vitamin C and longer infusion times can amplify these effects. PMID:27872555

  10. Pharmacokinetics and selected pharmacodynamics of romifidine following low-dose intravenous administration in combination with exercise to quarter horses.

    PubMed

    Knych, H K; Stanley, S D; McKemie, D S; Steinmetz, S J

    2017-10-01

    Romifidine is an alpha-2 adrenergic agonist used for sedation and analgesia in horses. As it is a prohibited substance, its purported use at low doses in performance horses necessitates further study. The primary goal of the study reported here was to describe the serum concentrations and pharmacokinetics of romifidine following low-dose administration immediately prior to exercise, utilizing a highly sensitive liquid chromatography-tandem mass spectrometry assay that is currently employed in many drug testing laboratories. An additional objective was to describe changes in heart rate and rhythm following intravenous administration of romifidine followed by exercise. Eight adult Quarter Horses received a single intravenous dose of 5 mg (0.01 mg/kg) romifidine followed by 1 h of exercise. Blood samples were collected and drug concentrations measured at time 0 and at various times up to 72 h. Mean ± SD systemic clearance, steady-state volume of distribution and terminal elimination half-life were 34.1 ± 6.06 mL/min/kg and 4.89 ± 1.31 L/kg and 3.09 ± 1.18 h, respectively. Romifidine serum concentrations fell below the LOQ (0.01 ng/mL) and the LOD (0.005 ng/mL) by 24 h postadministration. Heart rate and rhythm appeared unaffected when a low dose of romifidine was administered immediately prior to exercise. © 2017 John Wiley & Sons Ltd.

  11. Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.

    PubMed

    Pegram, Mark D; Borges, Virginia F; Ibrahim, Nuhad; Fuloria, Jyotsna; Shapiro, Charles; Perez, Susan; Wang, Karen; Schaedli Stark, Franziska; Courtenay Luck, Nigel

    2009-01-01

    MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy. Patients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied. Twenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half-life of 115.4 +/- 37.1 hours

  12. Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer

    PubMed Central

    2009-01-01

    Introduction MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy. Methods Patients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied. Results Twenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half

  13. Radiological Dose Assessment - Nonuniform Skin Dose, Radioactive Skin Contamination, and Multiple Dosimetry

    SciTech Connect

    W. C. Inkret; M. E. Schillaci

    1999-03-01

    Radioactive skin contamination with {beta}- and {gamma}-emitting radionuclides may result in biologically significant absorbed doses to the skin. A specific exposure scenario of interest is a nonuniform skin dose delivered by {beta}- and {gamma}-emissions from radioactive skin contamination. The United States Department of Energy requires a formal evaluation and reporting of nonuniform skin doses. The United States Department of Energy also requires specific, formal procedures for evaluating the results from the placement or use of multiple dosimeters. Action levels relative to potential absorbed doses for the contamination survey instrumentation in use at Los Alamos and formal procedures for evaluating nonuniform skin doses and multiple dosimeters are developed and presented here.

  14. Contamination of multiple-dose vials in a veterinary hospital

    PubMed Central

    Sabino, Catherine V.; Weese, J Scott

    2006-01-01

    Bacterial contamination of multiple-dose saline bottles and medication vials in a veterinary teaching hospital was evaluated. Bacterial contamination was identified in 16/88 (18%) containers, with no difference in contamination between the large animal clinic, small animal clinic, and ruminant ambulatory clinic. Contamination of multiple-dose containers containing substances for injection was common, and potential pathogens were present in many situations. While the clinical significance is not resolved at this point, infection control practices should address this potential source of nosocomial infection. PMID:16933556

  15. Pharmacokinetics and Pharmacodynamics of Sustained Low-Dose Intravenous Infusions of Pyridostigmine

    DTIC Science & Technology

    1993-05-17

    over 20 years. This drug is used routinely in several daily doses for years in treating patients with a disease called myasthenia gravis . This drug...smaller than the dose usually used in treating patients with myasthenia gravis . Patients take over 20 times more of the drug each day than you will in

  16. Pharmacokinetics and effects after intravenous administration of high-dose boron to rat.

    PubMed

    Tagawa, T; Kono, K; Dote, T; Usuda, K; Nishiura, H; Koizumi, C; Saito, M; Nakaya, H; Nagaie, H

    2000-06-01

    Boron (B) compounds have been widely used in the chemical industry, agriculture, and environmental science. The kinetics and toxicity of B were studied by analyzing several serum and urine parameters after a single intravenous injection of sodium tetraborate solution (B: 85.7 mg/kg) in Wistar male rats. Blood samples were removed at 0, 1, 2, 4, and 6 h after injection. The serum parameters studied included: B, Na, Ca, K, P, Mg, gamma-GTP, AST, ALT, BUN, Cr, CK, LDH and ALD. Plasma concentration-time profiles of B were evaluated by a nonlinear least-squares method for fitting data to polyexponential equations and calculation of relevant pharmacokinetic parameters. Urine samples were collected from the bladder following infusion. The urinary parameters that were studied included urine volume and excretion of B, Cr and NAG. Results indicated that a two-compartment model could describe the elimination of B from plasma after intravenous administration. Urine volume significantly increased. A diuretic effect of B was noted.

  17. Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality.

    PubMed

    Bailie, George R; Larkina, Maria; Goodkin, David A; Li, Yun; Pisoni, Ronald L; Bieber, Brian; Mason, Nancy; Tong, Lin; Locatelli, Francesco; Marshall, Mark R; Inaba, Masaaki; Robinson, Bruce M

    2015-01-01

    Intravenous (IV) iron is required for optimal management of anemia in the majority of hemodialysis (HD) patients. While IV iron prescription has increased over time, the best dosing strategy is unknown and any effect of IV iron on survival is unclear. Here we used adjusted Cox regression to analyze associations between IV iron dose and clinical outcomes in 32,435 HD patients in 12 countries from 2002 to 2011 in the Dialysis Outcomes and Practice Patterns Study. The primary exposure was total prescribed IV iron dose over the first 4 months in the study, expressed as an average dose/month. Compared with 100-199 mg/month (the most common dose range), case-mix-adjusted mortality was similar for the 0, 1-99, and 200-299 mg/month categories but significantly higher for the 300-399 mg/month (HR of 1.13, 95% CI of 1.00-1.27) and 400 mg/month or more (HR of 1.18, 95% CI of 1.07-1.30) groups. Convergent validity was proved by an instrumental variable analysis, using HD facility as the instrument, and by an analysis expressing IV iron dose/kg body weight. Associations with cause-specific mortality (cardiovascular, infectious, and other) were generally similar to those for all-cause mortality. The hospitalization risk was elevated among patients receiving 300 mg/month or more compared with 100-199 mg/month (HR of 1.12, 95% CI of 1.07-1.18). In light of these associations, a well-powered clinical trial to evaluate the safety of different IV iron-dosing strategies in HD patients is urgently needed.

  18. Intraosseous concentration and inhibitory effect of different intravenous cefazolin doses used in preoperative prophylaxis of total knee arthroplasty.

    PubMed

    Angthong, Chayanin; Krajubngern, Pongpaibool; Tiyapongpattana, Warawut; Pongcharoen, Boonchana; Pinsornsak, Piya; Tammachote, Nattapol; Kittisupaluck, Wanna

    2015-12-01

    The aim of this study was to compare the intraosseous concentrations and the inhibitory effects on the growth of Staphylococcus aureus of 1 g versus 2 g of intravenous (IV) prophylactic cefazolin in total knee arthroplasty (TKA). Eighteen patients (21 knees) with primary knee osteoarthritis were divided into two groups receiving 1 g (12 patients: 14 knees) versus 2 g (six patients: seven knees) IV prophylactic cefazolin prior to the incision in TKA. Subchondral bone samples (proximal tibia, distal femur) were taken during the operation. These samples were analyzed for intraosseous concentration of cefazolin and their inhibitory effects on the growth of S. aureus, using high-performance liquid chromatography (HPLC) and agar disc diffusion bioassays. The mean intraosseous concentration in the 2 g dose group was significantly higher than in the 1 g dose group in the proximal tibia (p = 0.007) and distal femur (p = 0.016). There were no significant differences between the two groups in terms of mean inhibitory effects in the proximal tibia or distal femur (p > 0.05). No significant correlations were found between the intraosseous concentrations and inhibitory effects in the proximal tibia (r = 0.18, p = 0.52) and distal femur (r = -0.29, p = 0.30). IV cefazolin at a dose of 2 g produced greater intraosseous concentrations overall than a dose of 1 g. However, the higher intraosseous concentrations did not correlate with higher inhibitory effects.

  19. Evaluation of a Single Dose Intravenous Paracetamol for Pain Relief After Maxillofacial Surgery: A Randomized Clinical Trial Study.

    PubMed

    Eftekharian, Hamidreza; Tabrizi, Reza; Kazemi, Hamidreza; Nili, Mahsa

    2014-12-01

    The aim of this study was to evaluate, using a single dose of intravenous paracetamol, pain relief after maxillofacial surgery. This is a controlled, randomized, uni- blind, clinical trial study to evaluate using a single dose of IV paracetamol for pain relief after maxillofacial surgery. The subjects were randomly divided into two groups with 40 subjects in each: group I received paracetamol (Apotel)* as a single dose and group II received placebo. Subjects were randomly allocated according to randomization lists. Paracetamol was used as a single dose (20 mg/kg in 100 cc of normal saline which was infused for 10 min after surgery in recovery room just before discharging). We used a visual analogue scale to investigate pain relief at various times. Analysis of the data, did not show any significant difference for age, sex and weight between the treatment group and the control group. Pain decreased 6 h after paracetamol infusion; then it increased mildly. In the control group, pain severity increased after operation, then it decreased mildly. Results showed a correlation between duration of surgery and pain severity in both the groups. Paracetamol is effective on pain relief after maxillofacial surgeries. Operation time may be an important factor for induction of pain after the surgeries.

  20. Effect of heparin dose and infusion rate on lipid clearance and bilirubin binding in premature infants receiving intravenous fat emulsions.

    PubMed

    Spear, M L; Stahl, G E; Hamosh, M; McNelis, W G; Richardson, L L; Spence, V; Polin, R A; Pereira, G R; Hamosh, P

    1988-01-01

    The effect of heparin dose and infusion rate on plasma lipids, lipases, and unbound bilirubin was investigated in 22 premature infants with physiologic jaundice. Infants were randomly assigned to receive low or high intravenous doses (24 vs 137.3 U/day) of heparin. Each patient then received 2 g/kg/day of 10% Intralipid on 2 successive days: one day during a 15-hour period and the other day over 24 hours, with the order assigned randomly. The results demonstrate a significantly greater change in serum-free fatty acids in infants receiving the high heparin dose during the 15-hour lipid infusion period. Lipoprotein lipase activity rose more with the high heparin dose and equally at either infusion rate. We conclude that lipid infusions of 2 g/kg/day with low heparin dosage infused over 24 hours resulted in less elevation in serum-free fatty acids. There were no adverse effects on unbound bilirubin at either infusion rate or heparin dosage.

  1. Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits

    PubMed Central

    Cox, Daniel T. C.; Shanahan, Danielle F.; Hudson, Hannah L.; Fuller, Richard A.; Anderson, Karen; Hancock, Steven; Gaston, Kevin J.

    2017-01-01

    Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare. PMID:28208789

  2. Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits.

    PubMed

    Cox, Daniel T C; Shanahan, Danielle F; Hudson, Hannah L; Fuller, Richard A; Anderson, Karen; Hancock, Steven; Gaston, Kevin J

    2017-02-09

    Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare.

  3. Intravenous Sedation with Low-Dose Dexmedetomidine: Its Potential for Use in Dentistry

    PubMed Central

    Ogawa, Sachie; Seino, Hiroaki; Ito, Hiroshi; Yamazaki, Shinya; Ganzberg, Steven; Kawaai, Hiroyoshi

    2008-01-01

    This study investigated the physiologic and sedative parameters associated with a low-dose infusion of dexmedetomidine (Dex). Thirteen healthy volunteers were sedated with Dex at a loading dose of 6 mcg/kg/h for 5 minutes and a continuous infusion dose of 0.2 mcg/kg/h for 25 minutes. The recovery process was observed for 60 minutes post infusion. The tidal volume decreased significantly despite nonsignificant changes in respiratory rate, minute ventilation, oxygen saturation, and end-tidal carbon dioxide. The mean arterial pressure and heart rate also decreased significantly but within clinically acceptable levels. Amnesia to pin prick was present in 69% of subjects. A Trieger dot test plot error ratio did not show a significant change at 30 minutes post infusion despite a continued significant decrease in bispectral index. We conclude that sedation with a low dose of Dex appears to be safe and potentially efficacious for young healthy patients undergoing dental procedures. PMID:18788843

  4. New Advances in the Treatment of Neurological Diseases Using High Dose Intravenous Immunoglobulins

    PubMed Central

    2008-01-01

    Since the incidental discovery in 1981 that intravenous immunoglobulins (IVIg) are immunomodulatory, they have been investigated in a large number of putative autoimmune diseases. This has led to licensing for idiopathic thrombocytopenic purpura, Kawasaki disease, and in neurological disorders for Guillain-Barré syndrome (GBS). Although not licensed, randomized controlled trials have also shown IVIg efficacy in other neuroimmunological diseases such as multifocal motor neuropathy (MMN), chronic inflammatory demyelinating neuropathy (CIDP), myasthenia gravis, dermatomyositis, and stiff-person syndrome. However, other indications are currently being explored including Alzheimer's disease, postpolio syndrome, and narcolepsy. There are even reports from experimental studies in stroke. The results of recently published clinical trials in both the classical neuroimmunological disorders as well as for new indications are reported and their role in clinical practice is discussed. PMID:21180569

  5. Oxytetracycline hydrochloride in the horse: serum, synovial, peritoneal and urine concentrations after single dose intravenous administration.

    PubMed

    Brown, M P; Stover, S M; Kelly, R H; Farver, T B; Knight, H D

    1981-03-01

    Six adult mares were given a single intravenous injection of oxytetracycline HCl (50 mg/ml) at a dosage of 5 mg/kg. Serum, synovial fluid, peritoneal fluid, and urine oxytetracycline concentrations were measured serially over a 48-h period. The highest measured serum oxytetracycline concentration was 8.01 mcg/ml at 1/2 h. Oxytetracycline was detected in synovial fluid and peritoneal fluid, which obtained mean peak oxytetracycline concentrations of 4.43 mcg/ml and 4.20 mcg/ml, at 1/2 h and 1 h, respectively. These concentrations steadily declined in parallel with serum concentrations and were not measurable at 48 h. Urine oxytetracycline concentration was relatively high, with a peak concentration of 1565.2 mcg/ml at 1/2 h after drug administration.

  6. Responses to low dose intravenous perindoprilat infusion in salt deplete/salt replete normotensive volunteers.

    PubMed Central

    MacFadyen, R J; Lees, K R; Reid, J L

    1994-01-01

    1. Intravenous ACE inhibitor therapy appears to have a role in the treatment of acute heart failure and early after myocardial infarction. Practical experience with intravenous administration with activation of renin is limited. We report responses to perindoprilat (Pt, 0.67 mg) or placebo (P) infused over 4 h in normotensive male volunteers (n = 12, 19-28 years, 53-77 kg) with double-blind, placebo controlled salt depletion (SD) or salt repletion (SR) as a model of the activated renin system. 2. Salt depletion caused no significant fall in serum sodium (P, 139.4 +/- 2.4; Pt, 138.3 +/- 1.9) compared with salt replete preparation (P, 139.9 +/- 1.2; Pt, 139.7 +/- 0.9) but elevation of plasma renin activity 2-3-fold. Pretreatment baseline systolic blood pressure following salt depletion (P, 121 +/- 9.3/71 +/- 7.9; Pt, 121.5 +/- 9.6/69 +/- 8.1) was higher than following salt replete preparation (P, 114 +/- 9.5/61 +/- 7.2; Pt, 116.9 +/- 6.9/67 +/- 7.2). 3. Baseline corrected supine SBP fell significantly and to a similar extent following active treatment regardless of activation of the renin system (SD, -14.6 +/- 9.5/-9.4 +/- 6.4; SR, -12 +/- 14/-10.1 +/- 6.6) compared with placebo (SD, -6.1 +/- 6/-3.7 +/- 5.6; SR, -4.7 +/- 10/-1.3 +/- 6.5). Heart rate was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7833222

  7. Prolonged high-dose intravenous magnesium therapy for severe tetanus in the intensive care unit: a case series

    PubMed Central

    2010-01-01

    Introduction Tetanus rarely occurs in developed countries, but it can result in fatal complications including respiratory failure due to generalized muscle spasms. Magnesium infusion has been used to treat spasticity in tetanus, and its effectiveness is supported by several case reports and a recent randomized controlled trial. Case presentations Three Caucasian Greek men aged 30, 50 and 77 years old were diagnosed with tetanus and admitted to a general 12-bed intensive care unit in 2006 and 2007 for respiratory failure due to generalized spasticity. Intensive care unit treatment included antibiotics, hydration, enteral nutrition, early tracheostomy and mechanical ventilation. Intravenous magnesium therapy controlled spasticity without the need for additional muscle relaxants. Their medications were continued for up to 26 days, and adjusted as needed to control spasticity. Plasma magnesium levels, which were measured twice a day, remained in the 3 to 4.5 mmol/L range. We did not observe hemodynamic instability, arrhythmias or other complications related to magnesium therapy in these patients. All patients improved, came off mechanical ventilation, and were discharged from the intensive care unit in a stable condition. Conclusion In comparison with previous reports, our case series contributes the following meaningful additional information: intravenous magnesium therapy was used on patients already requiring mechanical ventilation and remained effective for up to 26 days (significantly longer than in previous reports) without significant toxicity in two patients. The overall outcome was good in all our patients. However, the optimal dose, optimal duration and maximum safe duration of intravenous magnesium therapy are unknown. Therefore, until more data on the safety and efficacy of magnesium therapy are available, its use should be limited to carefully selected tetanus cases. PMID:20356376

  8. The dipeptidyl peptidase-4 inhibitor linagliptin exhibits time- and dose-dependent localization in kidney, liver, and intestine after intravenous dosing: results from high resolution autoradiography in rats.

    PubMed

    Greischel, Andreas; Binder, Rudolf; Baierl, Juergen

    2010-09-01

    Linagliptin is an orally active dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes and shows dose-dependent pharmacokinetics in rats and humans. With microscopic autoradiography, the dose dependence of cellular distribution of [(3)H]linagliptin-related radioactivity was investigated in kidney at 3 h after intravenous injection of 7.4, 100, and 2000 microg/kg [(3)H]linagliptin. Furthermore, distribution of radioactivity in kidney, liver, and small intestine was investigated in relation to time (2 min, 3 h, and 192 h) after intravenous injection of 7.4 microg/kg [(3)H]linagliptin. The localization of radioactivity in the kidney at 3 h after administration of 7.4, 100, and 2000 microg/kg [(3)H]linagliptin changed with increasing dose from cortical glomeruli and parts of proximal tubule parts to parts of medullar proximal tubule. In addition, the compound distribution in the kidney shifted with time after administration of 7.4 microg/kg [(3)H]linagliptin from glomeruli (2 min) to the lower parts of proximal tubules (192 h). The radioactivity within proximal tubules was located primarily in the brush border. In the liver, the radioactivity persisted mainly around the portal triads and in the bile duct from 2 min to 192 h. In the small intestine, the radioactivity shifted from the lamina propria (2 min) to the surface of the villi and/or intestinal lumen (192 h). In conclusion, the cellular distribution pattern of [(3)H]linagliptin-related radioactivity reflected the known distribution of DPP-4. Together with the persistence of binding, this result supports the high relevance of DPP-4 binding of linagliptin for its pharmacokinetics and pharmacodynamics.

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

    PubMed

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

    2010-01-01

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

  10. Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels

    PubMed Central

    Hyun, Seung Won; Wong, Weng Kee

    2016-01-01

    We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs. PMID:26565557

  11. Pharmacokinetics of high doses of cyanocobalamin administered by intravenous injection for 26 weeks in rats.

    PubMed

    Nava-Ocampo, Alejandro A; Pastrak, Aleksandra; Cruz, Tony; Koren, Gideon

    2005-01-01

    1. High doses of vitamin B12 (cyanocobalamin) may be therapeutically effective to treat neurological alterations secondary to a wide range of disease states. The aim of the present study was to evaluate the effect of dose and repeated administration on the pharmacokinetics of cyanocobalamin in rats. 2. Forty-eight rats were randomly assigned to receive 1, 5, 25 or 100 mg/kg cyanocobalamin for 182 days (26 weeks). Cyanocobalamin plasma levels were quantified by HPLC on days 1, 85 and 182 of treatment and were analysed by means of non-compartment pharmacokinetic (PK) analysis. In addition, population PK analysis was used to fit cyanocobalamin plasma concentrations to time by means of a two-compartment model for intravascular administration. 3. The half-life of cyanocobalamin ranged from approximately 20 to 50 min, clearance ranged from 4.5 to 9 mL/min and the volume of distribution at steady state ranged from 140 to 470 mL. A statistically significant negative relationship existed between the dose of cyanocobalamin and the normalized area under the plasma concentration-time curve (AUC). This non-linearity was not exhibited in population PK analysis. No evidence of toxicity was observed. 4. At very high and prolonged doses (up to 100 mg/kg for 26 weeks), intravascular administration of cyanocobalamin in rats follows a two-compartment kinetic model and cyanocobalamin undergoes extensive extravascular distribution. The negative relationship between dose and normalized AUC is compatible with possible saturation of tubular reabsorption, thus increasing renal clearance at higher doses.

  12. A case of anorexia nervosa with Marchiafava-Bignami Disease that responded to high-dose intravenous corticosteroid administration.

    PubMed

    Tao, Hiroki; Kitagawa, Nobuki; Kako, Yuki; Yamanaka, Hiroyoshi; Ito, Koichi; Denda, Kenzo; Koyama, Tsukasa

    2007-11-15

    We report the first known case of anorexia nervosa (AN) with Marchiafava-Bignami Disease (MBD) that responded to high-dose intravenous corticosteroid administration. A 16-year-old Japanese female with AN was diagnosed with MBD after rapid weight loss. During the acute stage, she suffered from a sudden onset of coma. After regaining consciousness, she presented with lack of movement, apathy, labile affect, and poverty of speech. On admission, magnetic resonance imaging showed an area of demyelination in the splenium of the corpus callosum. Positron emission tomography obtained 7 days after admission showed areas of hypoperfusion in the medial temporal lobe and in regions anterior and posterior to the central sulcus.

  13. Dose-response of intrathecal morphine when administered with intravenous ketorolac for post-cesarean analgesia: a two-center, prospective, randomized, blinded trial.

    PubMed

    Berger, J S; Gonzalez, A; Hopkins, A; Alshaeri, T; Jeon, D; Wang, S; Amdur, R L; Smiley, R

    2016-12-01

    The appropriate dose of intrathecal morphine for post-cesarean analgesia is unclear. With the inclusion of routine non-steroidal anti-inflammatory drugs, the required dose of morphine may be significantly less than the 200-300μg common a decade ago. We performed a two-center, prospective, randomized, blinded trial comparing three doses of intrathecal morphine, combined with routine intravenous ketorolac, in 144 healthy women undergoing elective cesarean delivery. Patients received an intrathecal injection of hyperbaric bupivacaine 12mg, fentanyl 15μg and a randomized dose of 50, 100, or 150μg morphine in a volume of 2.2mL. Patients received intravenous ketorolac 30mg before leaving the operating room and 15mg intravenously every 6h for the duration of the study (24h). All received postoperative patient-controlled intravenous morphine. The primary endpoint was total intravenous morphine administered postoperatively over 24h, analyzed using mixed model regression. There were no differences between dose groups (or institutions) in intravenous morphine use over 24h. Visual analog scale scores for pain and nausea did not differ. Pruritus was greater in the 100 and 150μg groups than the 50μg group at 6h and 12h, but there was no difference between groups in nausea or pruritus treatments. Respiratory depression or significant sedation did not occur. The dose-response relationship of intrathecal morphine for multimodal post-cesarean analgesia suggests that 50μg produces analgesia similar to that produced by either 100μg or 150μg. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Calculating the Dose of Subcutaneous Immunoglobulin for Primary Immunodeficiency Disease in Patients Switched From Intravenous to Subcutaneous Immunoglobulin Without the Use of a Dose-Adjustment Coefficient

    PubMed Central

    Fadeyi, Michael; Tran, Tin

    2013-01-01

    Primary immunodeficiency disease (PIDD) is an inherited disorder characterized by an inadequate immune system. The most common type of PIDD is antibody deficiency. Patients with this disorder lack the ability to make functional immunoglobulin G (IgG) and require lifelong IgG replacement therapy to prevent serious bacterial infections. The current standard therapy for PIDD is intravenous immunoglobulin (IVIG) infusions, but IVIG might not be appropriate for all patients. For this reason, subcutaneous immunoglobulin (SCIG) has emerged as an alternative to IVIG. A concern for physicians is the precise SCIG dose that should be prescribed, because there are pharmacokinetic differences between IVIG and SCIG. Manufacturers of SCIG 10% and 20% liquid (immune globulin subcutaneous [human]) recommend a dose-adjustment coefficient (DAC). Both strengths are currently approved by the FDA. This DAC is to be used when patients are switched from IVIG to SCIG. In this article, we propose another dosing method that uses a higher ratio of IVIG to SCIG and an incremental adjustment based on clinical status, body weight, and the presence of concurrent diseases. PMID:24391400

  15. Photon dose calculation based on electron multiple-scattering theory: primary dose deposition kernels.

    PubMed

    Wang, L; Jette, D

    1999-08-01

    The transport of the secondary electrons resulting from high-energy photon interactions is essential to energy redistribution and deposition. In order to develop an accurate dose-calculation algorithm for high-energy photons, which can predict the dose distribution in inhomogeneous media and at the beam edges, we have investigated the feasibility of applying electron transport theory [Jette, Med. Phys. 15, 123 (1988)] to photon dose calculation. In particular, the transport of and energy deposition by Compton electron and electrons and positrons resulting from pair production were studied. The primary photons are treated as the source of the secondary electrons and positrons, which are transported through the irradiated medium using Gaussian multiple-scattering theory [Jette, Med. Phys. 15, 123 (1988)]. The initial angular and kinetic energy distribution(s) of the secondary electrons (and positrons) emanating from the photon interactions are incorporated into the transport. Due to different mechanisms of creation and cross-section functions, the transport of and the energy deposition by the electrons released in these two processes are studied and modeled separately based on first principles. In this article, we focus on determining the dose distribution for an individual interaction site. We define the Compton dose deposition kernel (CDK) or the pair-production dose deposition kernel (PDK) as the dose distribution relative to the point of interaction, per unit interaction density, for a monoenergetic photon beam in an infinite homogeneous medium of unit density. The validity of this analytic modeling of dose deposition was evaluated through EGS4 Monte Carlo simulation. Quantitative agreement between these two calculations of the dose distribution and the average energy deposited per interaction was achieved. Our results demonstrate the applicability of the electron dose-calculation method to photon dose calculation.

  16. Comparative molecular field analysis to derive pharmacophore maps for induction doses of intravenous anaesthetic agents.

    PubMed

    Sear, J W

    2011-03-01

    The present study examines the molecular basis of induction of anaesthesia by i.v. hypnotic agents using comparative molecular field analysis (CoMFA). ED(50) induction doses for 14 i.v. anaesthetics in human subjects (expressed as molar dose per kilogram body weight) were obtained from the literature. Immobilizing potency data for the same 14 agents (expressed as the EC(50) plasma free drug concentrations that abolish movement in response to a noxious stimulus in 50% patients) were taken from our previous publication. These data were used to form CoMFA models for the two aspects of anaesthetic activity. Molecular alignment was achieved by field-fit minimization techniques. The lead structure for both models was eltanolone. The final CoMFA model for the ED(50) induction dose was based on two latent variables, and explained 99.3% of the variance in observed activities. It showed good intrinsic predictability (cross-validated q(2)=0.849). The equivalent model for immobilizing activity was also based on two latent variables, with r(2)=0.988 and q(2)=0.852. Although there was a correlation between -log ED(50) and -log EC(50) (r(2)=0.779), comparison of the pharmacophore maps showed poor correlation for both electrostatic and steric regions when isocontours were constructed by linking lattice grid points, making the greatest 40% contributions; the relative contributions of electrostatic and steric interactions differing between the models (induction dose: 2.5:1; immobilizing activity 1.8:1). Comparison of two CoMFA activity models shows only small elements of commonality, suggesting that different molecular features may be responsible for these two properties of i.v. anaesthetics.

  17. Disposition, behavioural and physiological effects of escalating doses of intravenously administered fentanyl to young foals.

    PubMed

    Knych, H K; Steffey, E P; Casbeer, H C; Mitchell, M M

    2015-09-01

    Foal responses to a broader range of plasma fentanyl concentrations than currently reported are desirable to support (or not) clinical use. To describe fentanyl plasma concentrations following an escalating i.v. fentanyl dosing schedule in foals aged 5-13 days and describe selected, associated dose- and time-related behavioural and physiological responses to plasma fentanyl concentration. Experimental. Fentanyl was administered i.v. in an escalating fashion (2, 4, 8, 16 and 32 μg/kg bwt) at 10-min intervals. Blood samples were collected before and at selected times until 24 h post administration. Blood samples were analysed for fentanyl and metabolite concentrations and correlated with behavioural and physiological observations and selected blood analytes. Foals mostly appeared to be unaffected following 2 μg/kg bwt (1.09 ± 0.41 μg/l; average maximal plasma concentration) of fentanyl, but 6 of the 8 foals appeared to be sedated following 4 μg/kg bwt (3.07 ± 1.11 μg/l). Ataxia with increased locomotor activity, muscle rigidity and head pressing posture was observed in many foals at 8 (7.24 ± 3.22 μg/l) and 16 μg/kg bwt (17.4 ± 5.67 μg/l). All foals were heavily sedated after 32 μg/kg bwt (34.5 ± 10.3 μg/l); 3 of the 8 foals became recumbent. The average (± s.d.) terminal half-life following administration of the final dose was 44.2 ± 9.85 min. Behavioural and physiological responses to i.v. fentanyl in young foals are dose related. As with mature horses, the window of fentanyl plasma concentrations related to possible clinically desirable actions appears relatively narrow. © 2014 EVJ Ltd.

  18. Intravenous paracetamol with a lower dose is also effective for the treatment of patent ductus arteriosus in pre-term infants.

    PubMed

    Tekgündüz, Kadir Şerafettin; Ceviz, Naci; Caner, İbrahim; Olgun, Haşim; Demirelli, Yaşar; Yolcu, Canan; Şahin, İrfan Oğuz; Kara, Mustafa

    2015-08-01

    Haemodynamically significant patent ductus arteriosus is a significant cause of morbidity and mortality in pre-term infants. This retrospective study was conducted to investigate the usefulness of lower-dose paracetamol for the treatment of patent ductus arteriosus in pre-term infants. A total of 13 pre-term infants who received intravenous paracetamol because of contrindications or side effects to oral ibuprofen were retrospectively enrolled. In the first patient, the dose regimen was 15 mg/kg/dose, every 6 hours. As the patient developed significant elevation in transaminase levels, the dose was decreased to 10 mg/kg/dose, every 8 hours in the following 12 patients. Echocardiographic examination was conducted daily. In case of closure, it was repeated after 2 days and when needed thereafter in terms of reopening. A total of 13 patients received intravenous paracetamol. Median gestational age was 29 weeks ranging from 24 to 31 weeks and birth weight was 950 g ranging from 470 to 1390 g. The median postnatal age at the first intravenous paracetamol dose was 3 days ranging from 2 to 9 days. In 10 of the 13 patients (76.9%), patent ductus arteriosus was closed at the median 2nd day of intravenous paracetamol ranging from 1 to 4 days. When the patient who developed hepatotoxicity was eliminated, the closure rate was found to be 83.3% (10/12). Intravenous paracetamol may be a useful treatment option for the treatment of patent ductus arteriosus in pre-term infants with contrindication to ibuprofen. In our experience, lower-dose paracetamol is effective in closing the patent ductus arteriosus in 83.3% of the cases.

  19. Prenatal intravenous cocaine and the heart rate-orienting response: a dose-response study.

    PubMed

    Foltz, Tara L; Snow, Diane M; Strupp, Barbara J; Booze, Rosemarie M; Mactutus, Charles F

    2004-01-01

    Attentional dysfunction is a persistent behavioral abnormality that is emerging as one of the cardinal features in the investigations of the teratogenic effects of cocaine in humans and rodents. The present study sought to extend this work by using a dose-response design with an alternate strain of rat. Virgin Long-Evans female rats, implanted with an IV access port prior to breeding were administered saline, 0.5, 1.0, or 3.0 mg/kg of cocaine HCl from gestational day (GD) GD8-21 (1x per day-GD8-14, 2x per day-GD15-21). Cocaine had no significant effect on maternal or litter parameters. At 14-15 days of age, 1 male and 1 female from each litter were tested to evaluate the heart rate orienting response (HR-OR). Following 20 min for acclimation, pups were presented an olfactory stimulus for 20s per trial, across four trials, and with an intertrial interval of 2 min. The initial baseline HR was not significantly different across the treatment groups, although cocaine did alter the stability of the QRS complex duration. The magnitude of the HR-OR averaged across trials increased as a linear function of dosage of cocaine. A more complex (quadratic) interaction between cocaine dose and sex of the offspring was also noted. When examined across trials, the controls failed to display any significant within-session variation in the HR-OR; in contrast all of the prenatal cocaine treated groups displayed either sensitization (low and high dose) or habituation of the response (middle dose). Analysis of the peak HR-OR confirmed that the controls were indeed displaying the response on at least one trial of the session, albeit not consistently on any specific trial. The more vigorous HR-OR of the prenatal cocaine groups, relative to vehicle controls, most likely reflects an alteration in development of the neural basis of response; as previously shown, the most vigorous response to the olfactory stimulus is seen early (12 days of age) and progressively decreases across the

  20. Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma.

    PubMed

    Boyé, Pierre; Serres, François; Marescaux, Laurent; Hordeaux, Juliette; Bouchaert, Emmanuel; Gomes, Bruno; Tierny, Dominique

    2017-01-01

    Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans' solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas.

  1. Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma

    PubMed Central

    Hordeaux, Juliette; Bouchaert, Emmanuel; Gomes, Bruno

    2017-01-01

    Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans’ solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas. PMID:28505195

  2. Attenuation of haemodynamic responses to laryngoscopy and endotracheal intubation with intravenous dexmedetomidine: A comparison between two doses

    PubMed Central

    Sebastian, Bon; Talikoti, Anand T; Krishnamurthy, Dinesh

    2017-01-01

    Background and Aims: Laryngoscopic manipulation and endotracheal intubation are noxious stimuli capable of producing tachycardia, arrhythmias and hypertension. The aim of this study was to arrive at an optimal dose of dexmedetomidine by comparing two doses with placebo to attenuate stress response during laryngoscopy and endotracheal intubation. Methods: It was a randomised, prospective, double-blind placebo-controlled study. After Institutional Ethical Committee clearance, ninety patients of American Society of Anesthesiologists Physical Status 1 were enrolled in the study and divided into three equal groups. Group A received normal saline, Group B received injection dexmedetomidine 0.5 μg/kg and Group C received injection dexmedetomidine 0.75 μg/kg as infusion over 10 min. The general anaesthesia technique was standardised for all three groups. The primary outcome measures were haemodynamic response at 1, 3 and 5 min after intubation. The secondary outcome measures were to note down any adverse effects associated with drugs. The statistical package used was SPSS version 15. Results: Groups were well matched for their demographic data. There was a statistically significant difference (P < 0.05) between dexmedetomidine and normal saline in heart rate, systolic, diastolic and mean arterial pressures at all time points after tracheal intubation with dexmedetomidine 0.75 μg/kg being most effective. Sedation scores were more with dexmedetomidine. None of the patients had any adverse effects such as hypotension, bradycardia, respiratory depression and fall in oxygen saturation. Conclusion: Dexmedetomidine in a dose of 0.75 μg/kg intravenous is the optimal dose to attenuate stress response to laryngoscopy and endotracheal intubation. PMID:28216704

  3. Pharmacokinetics and pharmacodynamics of ramipril and ramiprilat after intravenous and oral doses of ramipril in healthy horses.

    PubMed

    Serrano-Rodríguez, J M; Gómez-Díez, M; Esgueva, M; Castejón-Riber, C; Mena-Bravo, A; Priego-Capote, F; Serrano Caballero, J M; Muñoz, A

    2016-02-01

    The pharmacokinetics and pharmacodynamics (PK/PD) of the angiotensin-converting enzyme inhibitor (ACEI) ramiprilat after intravenous (IV) and oral (PO) administration of ramipril have not been evaluated in horses. This study was designed to establish PK profiles for ramipril and ramiprilat as well as to determine the effects of ramiprilat on serum angiotensin converting enzyme (ACE) and to select the most appropriate ramipril dose that suppresses ACE activity. Six healthy horses in a cross-over design received IV ramipril 0.050 mg/kg, PO at a dose of 0 (placebo), and 0.050, 0.10, 0.20, 0.40 and 0.80 mg/kg ramipril. Blood pressures were measured and blood samples obtained at different times. Serum ramipril and ramiprilat concentrations and serum ACE activity were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and spectrophotometry, respectively. Systemic bioavailability of ramiprilat after PO ramipril was 6-9%. Percentages of maximum ACE inhibitions from baseline were 98.88 (IV ramipril), 5.31 (placebo) and 27.68, 39.27, 46.67, 76.13 and 84.27 (the five doses of PO ramipril). Blood pressure did not change during the experiments. Although oral availability of ramiprilat was low, ramipril has sufficient enteral absorption and bioconversion to ramiprilat to induce serum ACE inhibitions of almost 85% after a dose of 0.80 mg/kg ramipril. Additional research on ramipril administration in equine patients is indicated. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Analgesic efficacy and safety of intravenous paracetamol (acetaminophen) administered as a 2 g starting dose following third molar surgery.

    PubMed

    Juhl, Gitte I; Norholt, Sven E; Tonnesen, Else; Hiesse-Provost, Odile; Jensen, Troels S

    2006-05-01

    The recommended dose for intravenous (IV) paracetamol injection in adults is 1g, however pharmacokinetic and pharmacodynamic findings suggest that a better analgesia could be obtained with a 2 g starting dose. A single-centre, randomised, double-blind, placebo-controlled, 3-parallel group study was performed to demonstrate the analgesic efficacy and safety of IV paracetamol 2 g. Following third molar surgery, patients reporting moderate to severe pain received a single 15-min infusion of either IV paracetamol 2 g, IV paracetamol 1g or placebo. Efficacy and safety were evaluated over 8 h. Laboratory tests were performed before and 48 h after drug administration. Two hundred and ninety seven patients (132 = IV paracetamol 2g; 132 = IV paracetamol 1g; 33 = placebo) were randomised and completed the study. The summed pain relief over 6h (TOTPAR6) was significantly superior with IV paracetamol 2 g as compared to IV paracetamol 1g and placebo (p < 0.0001). Pain relief scores of IV paracetamol 2g were significantly superior to IV paracetamol 1g and to placebo from T30' to T8h (p < 0.0001). Median duration of analgesia was significantly longer following IV paracetamol 2 g compared to IV paracetamol 1g and placebo (p < 0.0001). Adverse events occurred with the same frequency in the 3 treatment groups. No clinically significant changes from baseline were observed for vital signs or laboratory tests. The analgesic efficacy of a 2 g starting dose of IV paracetamol was superior over the recommended dose of 1g in terms of magnitude and duration of analgesic effect for postoperative pain following third molar surgery, with no significant difference between groups regarding safety.

  5. Adverse effects of high doses of intravenous alpha lipoic Acid on liver mitochondria.

    PubMed

    Vigil, Michael; Berkson, Burton M; Garcia, Ana Patricia

    2014-01-01

    Alpha lipoic acid (ALA, thioctic acid), among other actions, is an essential coenzyme in the conversion of pyruvate to acetyl co-enzyme A. Therefore, it is necessary for the production of energy for aerobic organisms. Scientists have found that it can be used medically to help regenerate liver tissue, reverse the complications of diabetes mellitus, slow or stop the growth of cancer cells, and chelate heavy metals, among other actions. In this article, the authors describe the cellular mitochondrial damage from excessively high doses of this beneficial agent.

  6. Long-term outcome of Graves' orbitopathy following high-dose intravenous glucocorticoids and orbital radiotherapy.

    PubMed

    Sisti, E; Menconi, F; Leo, M; Profilo, M A; Mautone, T; Mazzi, B; Rocchi, R; Latrofa, F; Nardi, M; Vitti, P; Marcocci, C; Marinò, M

    2015-06-01

    Intravenous (iv) glucocorticoids (GC) (ivGC) and orbital radiotherapy (ORT) are commonly used in active Graves' orbitopathy (GO), with favorable outcomes in up to 80% of patients. However, little is known on the factors that may affect GO outcome in the long term, an issue that we investigated here. We studied retrospectively 96 untreated patients with GO, identified out of 787 consecutive patients who came to our GO Clinic for a follow-up visit between September 2010 and June 2013. After the first observation, patients were treated with ivGC and ORT and were then re-examined after a median period of 55.5 months. The primary end-point was the possible relation between GO outcome and several individual variables. Exophthalmometry, eyelid aperture, CAS, diplopia and visual acuity (the latter only in patients with an initial reduction) improved significantly after treatment. Overall, 67.7% of patients had improved and were considered as responders, whereas the remaining (29.1% stable and 4.5% worsened) were considered as non-responders. Age, smoking, thyroid volume, thyroid treatment, serum anti-TSH receptor autoantibodies and individual GO features at first observation did not affect the outcome of GO, which, in contrast, was affected by gender and by the time elapsed between first and last observation. Thus, the prevalence of responders was higher in females (76.4 vs 48% in males, P = 0.02) and the time elapsed between first and last observation was greater in responders (58 vs 39 months in non-responders, P = 0.02). Whereas the prevalence of responders and non-responders was similar up to 36 months, there was an increase in responders beginning between 37 and 48 months and reaching a peak of ~80% between 61 and 72 months, to plateau thereafter. Given the limitations of retrospective investigations, our study confirms that the combination of GC and ORT is effective in GO and shows that females have greater chances to respond to treatment. The notorious tendency of

  7. Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice

    SciTech Connect

    Iwai, Hiroyuki; Matsuno, Etsuko ); Sasai, Keisuke; Abe, Mitsuyuki; Shibamoto, Yuta )

    1994-06-15

    In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined. The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions [times] three fractions/48 h or 5 Gy/fractions [times] five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three, or four times at 2-h intervals. At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter. Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity. 12 refs., 5 figs., 1 tab.

  8. Optimal Dose and Method of Administration of Intravenous Insulin in the Management of Emergency Hyperkalemia: A Systematic Review

    PubMed Central

    Harel, Ziv; Kamel, Kamel S.

    2016-01-01

    Background and Objectives Hyperkalemia is a common electrolyte disorder that can result in fatal cardiac arrhythmias. Despite the importance of insulin as a lifesaving intervention in the treatment of hyperkalemia in an emergency setting, there is no consensus on the dose or the method (bolus or infusion) of its administration. Our aim was to review data in the literature to determine the optimal dose and route of administration of insulin in the management of emergency hyperkalemia. Design, Setting, Participants, & Measurements We searched several databases from their date of inception through February 2015 for eligible articles published in any language. We included any study that reported on the use of insulin in the management of hyperkalemia. Results We identified eleven studies. In seven studies, 10 units of regular insulin was administered (bolus in five studies, infusion in two studies), in one study 12 units of regular insulin was infused over 30 minutes, and in three studies 20 units of regular insulin was infused over 60 minutes. The majority of included studies were biased. There was no statistically significant difference in mean decrease in serum potassium (K+) concentration at 60 minutes between studies in which insulin was administered as an infusion of 20 units over 60 minutes and studies in which 10 units of insulin was administered as a bolus (0.79±0.25 mmol/L versus 0.78±0.25 mmol/L, P = 0.98) or studies in which 10 units of insulin was administered as an infusion (0.79±0.25 mmol/L versus 0.39±0.09 mmol/L, P = 0.1). Almost one fifth of the study population experienced an episode of hypoglycemia. Conclusion The limited data available in the literature shows no statistically significant difference between the different regimens of insulin used to acutely lower serum K+ concentration. Accordingly, 10 units of short acting insulin given intravenously may be used in cases of hyperkalemia. Alternatively, 20 units of short acting insulin may be

  9. Effects of a single bolus intravenous dose of tramadol on minimum alveolar concentration (MAC) of sevoflurane in dogs.

    PubMed

    Itami, Takaharu; Kawase, Kodai; Tamaru, Naomichi; Ishizuka, Tomohito; Tamura, Jun; Miyoshi, Kenjirou; Umar, Mohammed A; Inoue, Hiroki; Yamashita, Kazuto

    2013-01-01

    Tramadol is an atypical opioid analgesic widely used in small animal practice. This study was designed to determine the effect of a single intravenous (IV) dose of tramadol on the minimum alveolar concentration (MAC) of sevoflurane in dogs. Six beagle dogs were anesthetized twice to determine the sevoflurane MAC with or without an administration of tramadol (4 mg/kg, IV) at 7 days interval. The sevoflurane MAC was determined using a tail clamp method in each dog ventilated with positive pressure ventilation. The tramadol administration produced a significant reduction in the sevoflurane MAC by 22.3 ± 12.2% (1.44 ± 0.28% with tramadol versus 1.86 ± 0.30% without tramadol, P=0.010). This MAC reduction had been determined from 122 ± 19 to 180 ± 41 min following the tramadol administration. During this period, the plasma concentrations of tramadol and its metabolite, O-desmethyltramadol (M1), decreased from 429 ± 64 to 332 ± 55 ng/ml and from 136 ± 24 to 114 ± 68 ng/ml, respectively, but these changes were not statistically significant. There was no significant difference in heart rate, mean arterial blood pressure and SpO2 between the control and tramadol treatment. The dogs that received tramadol treatment sometimes breathed spontaneously. Therefore, their respiratory rates significantly increased, and PETCO2 decreased during the MAC determination. In conclusion, the single IV dose of tramadol produced a significant reduction in the sevoflurane MAC in dogs.

  10. Pharmacokinetics of doxycycline after administration as a single intravenous bolus and intramuscular doses to non-lactating Egyptian goats.

    PubMed

    Abd El-Aty, A M; Goudah, A; Zhou, H-H

    2004-05-01

    The pharmacokinetics of doxycycline hydrochloride (DoxHcl) at a dose of 5 mg kg-1 BW was studied after an intravenous (i.v.) bolus and intramuscular (i.m.) injections in non lactating goats. A microbiological assay employing Bacillus subtilis as the test organism was used to measure its concentrations in serum and urine. Following a single i.v. injection, the serum concentration-time curves of doxycycline hydrochloride were best represented by a two-compartment open model. The drug was rapidly distributed and slowly eliminated with half-lives of distribution (t1/2 alpha) and elimination (t1/2 beta) of 0.52 and 4.62 h, respectively. After i.m. injection of the same dose, the peak serum concentration C(max) was 1.60 microg ml-1 attained at 0.86 h (Tmax). Following i.v. and i.m. injections, the concentrations of doxycycline in urine were much higher than that in serum. Urinary drug concentrations decreased gradually till reaching its lowest detectable level 12 and 24h post-injections, respectively. The extent of serum protein binding percent was 32.8% and the systemic bioavailability was 99.40% after i.m. injection of 5 mg kg-1 BW

  11. A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers.

    PubMed

    Tett, S E; Cutler, D J; Day, R O; Brown, K F

    1988-09-01

    1. The pharmacokinetics of hydroxychloroquine were studied in five healthy volunteers following an intravenous infusion of 155 mg (2.47 +/- 0.25 mg kg-1) racemic hydroxychloroquine. Four of these volunteers also received a further 310 mg (4.92 +/- 0.45 mg kg-1) infusion of hydroxychloroquine and evidence of nonlinearities in the pharmacokinetics of hydroxychloroquine were sought. 2. No nonlinear elimination or distribution processes appeared to be operating at the doses of hydroxychloroquine used in this study, supporting the hypothesis that in the therapeutic dosing range the pharmacokinetics of hydroxychloroquine are linear. 3. Half-life and mean residence time were long (around 40 days) and large volumes of distribution were calculated (5,522 l from blood, 44,257 l from plasma). Sequestration into the tissues is an important feature of the disposition of hydroxychloroquine. The persistence of hydroxychloroquine in the body is due primarily to this extensive tissue distribution, rather than to low clearance (667 ml min-1 based on plasma data, 96 ml min-1 based on blood data). 4. Plasma data were more variable than blood data. Blood to plasma concentration ratios were not constant (mean +/- s.d.: 7.2 +/- 4.2). The data indicate that it is preferable to measure whole blood concentrations of hydroxychloroquine, rather than plasma concentrations, in pharmacokinetic studies. 5. The pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.

  12. Pharmacokinetics of a single intravenous enrofloxacin dose in scimitar-horned oryx (Oryx dammah).

    PubMed

    Gamble, K C; Boothe, D M; Jensen, J M; Heatley, J J; Helmick, K E

    1997-03-01

    Based on a 1.3 mg/kg mean dosage determined by metabolic energy scaling, enrofloxacin pharmacokinetics of a single i.v. dose of enrofloxacin in five adult scimitar-horned oryx (Oryx dammah) were determined. Drug concentration versus time curves were best fit by residual analysis to a one-compartment open model with a maximum (mean +/- SD) serum concentration after distribution of 1.887 +/- 0.632 micrograms/ml and an elimination half-life of 41.2 +/- 27.5 min. Model-independent parameters were area under the curve (173.63 +/- 147.5 micrograms.min/ml), mean volume of distribution (steady state) (0.80 +/- 0.30 L/kg), clearance (12.07 +/- 7.12 ml/min/kg), and residence time (77.22 +/- 72.8 min). Mean serum enrofloxacin concentrations reached the recommended minimum inhibitory concentration (1.0 micrograms/ml). Drug concentrations remained above the minimum inhibitory concentration of most sensitive bacteria (0.5 micrograms/ml) consistently for 90 min. Based on this study, enrofloxacin would have to be administered parenterally to scimitar-horned oryx at 1.6 mg/kg every 6-8 hr (minimally) to maintain appropriate serum concentrations against susceptible bacteria. The metabolic energy scaled dosed regiment from this study appeared to be too low for the oryx.

  13. Pharmacokinetics of single doses of gentamicin given by intravenous and intramuscular routes to lactating cows.

    PubMed

    Haddad, N S; Ravis, W R; Pedersoli, W M; Carson, R L

    1986-04-01

    Healthy mature lactating cows (n = 6) were given gentamicin (5 mg/kg of body weight) by IV route and another dose 19 days later by IM route. Serum gentamicin concentrations were determined over a period of 48 hours after each drug dosing, using radioimmunoassay. With the aid of a nonlinear least-square regression analysis program, the combined data of the IV and IM treatments were best fitted by a 2-compartment open model, as indicated by residual trends and improvements in the sum of squares by F test and the SD of the estimated values. The distribution phase half-life was 0.25 +/- 0.12 hour, and postdistribution half-life was 1.83 +/- 0.18 hours. The volume of the central compartment was 0.10 +/- 0.02 L/kg, volume of distribution at steady state was 0.16 +/- 0.03 L/kg, and the total body clearance was 1.32 +/- 0.17 ml/min/kg. Intramuscular absorption was rapid, with a half-life for absorption of 0.63 +/- 0.28 hour. The extent of IM absorption was 92% +/- 15%. The percentage of the IM dose eliminated in the urine during the first 8 hours was 83 +/- 8. Gentamicin was detected in milk for 48 hours. Kinetic calculations predicted that IM injection of gentamicin at a dosage of 3.5 mg/kg of body weight every 8 hours would provide average steady-state serum drug concentrations of 5.08 micrograms/ml, with minimum and maximum steady-state concentrations of 1.03 and 12.05 micrograms/ml, respectively, whereas an IM injection of a 5 mg/kg dosage every 8 hours would provide average steady-state serum concentrations of 7.26 micrograms/ml, with minimum and maximum steady-state serum concentrations of 1.47 and 17.21 micrograms/ml, respectively.

  14. Nosocomial transmission of hepatitis B virus infection through multiple-dose vials.

    PubMed

    Kidd-Ljunggren, K; Broman, E; Ekvall, H; Gustavsson, O

    1999-09-01

    The source of acute hepatitis B virus (HBV) infection in two women (55 and 72 years old) was investigated. They displayed no risk factors for acquiring HBV infection, other than treatment with local anaesthetic injections some months previously. The HBV strains were sequenced and showed distinct homology to strains seen in Swedish intravenous drug users (IVDU). Prior to these patients' acute infection, an outbreak of HBV had occurred among IVDU in the same county. Analysis of the HBV strains from six of these IVDUs showed their core promoter, precore and pre-S sequences (679 nucleotides) to be identical to those from the two patients. Cross-contamination between samples was excluded and the most likely source of infection was thought to be multiple-dose vials of local anaesthetic that had been contaminated with the HBV strain circulating among the IVDU population in the community. We believe that multiple-dose vials have no place in modern healthcare and recommend sequence homology analysis as an alternative or additional way to trace a source of HBV infection.

  15. A system for individualized dosing of intravenous aminophylline using a programmable calculator.

    PubMed

    Mitsuoka, J C; Fleck, R J

    1984-01-01

    A program that calculates a value of clearance for an individual patient prior to reaching steady state in the early stages of aminophylline therapy is presented. The program is written for the Texas Instruments TI-59 programmable calculator and may be used with or without the PC-100C printer. The program can provide clinically useful information concerning projected plasma concentrations prior to reaching steady state with an accurate history of the dose administration and serum concentration determination. If the patient has not received xanthene therapy prior to admission, only one serum sample is required. If there has been prior drug exposure, a second serum sample is required. An iterative technique, which would be impractical to use without calculator assistance, is employed to make these determinations.

  16. Factors associated with acute-phase response of bisphosphonate-naïve or pretreated women with osteoporosis receiving an intravenous first dose of zoledronate or ibandronate.

    PubMed

    Popp, A W; Senn, R; Curkovic, I; Senn, C; Buffat, H; Popp, P F; Lippuner, K

    2017-03-15

    A first intravenous dose of bisphosphonates may be associated with an acute-phase response (APR). In bisphosphonate-naïve women with postmenopausal osteoporosis, the characteristics and frequency of APR may differ by compound. Prior bisphosphonate exposure was predictive of APR risk and severity.

  17. Intravenous aminophylline in patients already taking oral theophylline: effect on calculated dose of knowledge of serum theophylline concentration on admission.

    PubMed Central

    Wiggins, J; Arbab, O A; Stableforth, D E; Ayres, J G

    1986-01-01

    Measurement of serum theophylline concentration is usually recommended before intravenous aminophylline is given to patients taking oral theophylline. Fifty patients with worsening airflow obstruction, all of whom were taking oral theophyllines and who had no contraindication to the use of parenteral aminophylline, were randomly allocated into two groups before treatment was given. The dose of aminophylline was calculated without (group A) and with (group B) knowledge of admission serum theophylline concentration. In group A a regimen incorporating corrections to account for factors affecting theophylline clearance was used in an attempt to represent a "knowledgeable" approach; in group B a formula incorporating the known serum theophylline concentration at the time of admission was used. All loading doses were given over 30 minutes as "mini infusions." The two groups were well matched for age, blood gas tensions, and severity of airflow obstruction. The results for four patients (one from group A and three from group B) were excluded from analysis after completion of the study. In each group the mean admission serum theophylline concentration measured (group A: 8.4 (SD 6.0)mg/l; group B: 7.2 (5.7)mg/l) and the aminophylline doses used (group A: loading bolus 172 (45.5)mg, infusion 815 (198)mg; group B: loading bolus 233(189)mg, infusion 788(214)mg) were similar. Mean serum theophylline concentrations during 24 hours' aminophylline treatment, number of patients with a serum theophylline concentration greater than 20 mg/l, symptoms of toxicity, and outcome were also similar in the two groups. Although satisfactory use of parenteral aminophylline was achieved for most patients without knowledge of serum theophylline concentration at the time of admission to hospital (with the aid of a "knowledgeable" clinical approach and constant infusion pumps), prompt measurement of serum theophylline concentration at the time of admission identified patients with either

  18. The use of intraarticular tramadol for postoperative analgesia after arthroscopic knee surgery: a comparison of different intraarticular and intravenous doses.

    PubMed

    Alagöl, A; Calpur, O U; Kaya, G; Pamukçu, Z; Turan, F N

    2004-05-01

    We aimed to determine the optimal dose of tramadol when administered intraarticularly after arthroscopic knee surgery under general anesthesia in patients with an American Society of Anesthesiologists (ASA) physical status score of I-II. When the surgical procedure was completed, patients were assigned to one of seven groups ( n=30 for each) in a double-blinded and randomized manner according to a table of random numbers. Group I received 100 mg tramadol, Group II received 50 mg tramadol, Group III received 20 mg tramadol and Group IV received 0.9% NaCl intraarticularly in 20 ml solutions. Group V received 100 mg tramadol, Group VI received 50 mg tramadol and Group VII received 20 mg tramadol intravenously. Pain was evaluated by using the Visual Analogue Scale (VAS) at 0 min (when the patient was cooperated after extubation), 30 min, 1 h, 4 h, 6 h, 12 h, 18 h and 24 h postoperatively. Patients were administered diclofenac sodium 75 mg intravenously (i.m.) when they experienced pain. The intraarticular tramadol groups had longer duration of analgesia than i.v. tramadol groups who were administered the same doses (I vs V; II vs VI; III vs VII; p <0.001). Group I had the longest duration of analgesia ( p<0.001). Group II had a longer time to the first analgesic request than all other groups ( p<0.001) except Group I. Consequently, Group I and II needed less analgesics than other groups ( p<0.001). Pain scores were 0-3 on the VAS in Groups I, II and V at first assessment, in Groups I and II at 30 min and 1 h, and in Group I at 4 h and 6 h postoperatively ( p<0.01). In Group V, vomiting was more a more frequent complication than with other groups ( p<0.05). It is concluded that tramadol provides analgesia with a peripheral mechanism when administered intraarticularly. The side effects of intraarticular 100 mg tramadol were no more severe than those for intraarticular 50 mg tramadol. Moreover, intraarticular 100 mg tramadol provided excellent analgesia after arthroscopic

  19. Single-dose intravenous iron infusion or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled trial.

    PubMed

    Holm, C; Thomsen, L L; Norgaard, A; Langhoff-Roos, J

    2017-04-01

    To evaluate the clinical efficacy of a single-dose intravenous infusion of iron isomaltoside compared with current treatment practice with oral iron measured by physical fatigue in women after postpartum haemorrhage. Single-centre, open-label, randomized controlled trial. Participants received intravenous iron (n = 97) or oral iron (n = 99), and completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale, and haematological and iron parameters were measured. Primary outcome was the aggregated change in physical fatigue score from baseline to 12 weeks postpartum. The difference in physical fatigue score was -0·97 (95% CI: -1·65; -0·28, P = 0·006) in favour of intravenous iron, but did not meet the predefined difference of 1·8. Across visits, we found statistically significant differences in fatigue and depression scores, as well as in haematological and iron parameters, all in favour of intravenous iron. There were no serious adverse reactions. A single dose of intravenous iron was associated with a statistically significant reduction in aggregated physical fatigue within 12 weeks after postpartum haemorrhage compared to standard medical care with oral iron below the prespecified criteria of clinical superiority. As patient-reported outcomes improved significantly and intravenous iron resulted in a fast hematopoietic response without serious adverse reactions, intravenous iron may be a useful alternative after postpartum haemorrhage if oral iron is not absorbed or tolerated. © 2017 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.

  20. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers.

    PubMed

    Ramakrishnan, Rohini; Cheung, Wing K; Wacholtz, Mary C; Minton, Neil; Jusko, William J

    2004-09-01

    This study describes a pharmacokinetic (PK) model to account for serum recombinant human erythropoietin (rHuEpo) concentrations in healthy volunteers following intravenous (IV) and subcutaneous (SC) dosing; it also characterizes the pharmacodynamics (PD) of SC rHuEpo effects on reticulocytes, red blood cells (RBC), and hemoglobin (Hb) in blood. Data were obtained from 4 clinical studies carried out in healthy volunteers. Epoetin alfa (rHuEpo) was administered as 5 single IV doses ranging from 10 to 500 IU/kg, as 8 single SC doses ranging from 300 to 2400 IU/kg, and as 2 multiple SC dosage regimens (150 IU/kg/3 times a week [tiw] and 600 IU/kg/wk). A dual-absorption rate model (fast zero-order and slow first-order inputs) with nonlinear disposition characterized the PK of SC rHuEpo. A high K(m) value was obtained indicating that clearance was mildly nonlinear. Absorption was slow (t(max) approximately 24 hours), and the bioavailability of SC rHuEpo increased with dose (ranging from 46%-100%). A catenary cell production and loss model with a feedback down regulation component was used to fit the reticulocyte data yielding estimates of the stimulatory capacity (S(max)), sensitivity (SC(50)), and life span parameters. These parameters were used for simulations of RBC and Hb profiles. An SC(50) of 27 to 61 IU/L was estimated indicating that low physiological plasma rHuEpo concentrations were sufficient to produce pharmacological effects. No marked sex-dependent differences in clinical responses to rHuEpo therapy were found despite baseline differences. Realistic pharmacokinetic and physiological models accounted for clinical responses from a wide array of dosing conditions with rHuEpo. The rationale for greater efficacy of SC administration of rHuEpo compared to IV was ascertained.

  1. Disposition and tissue distribution of imatinib in a liposome formulation after intravenous bolus dose to mice.

    PubMed

    Moo, Kai Shing; Radhakrishnan, Shantini; Teoh, Magdalene; Narayanan, Prasad; Bukhari, Nadeem Irfan; Segarra, Ignacio

    2010-07-01

    Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest. We assess the pharmacokinetic and tissue distribution profile of imatinib in a liposome formulation. Its single dose (6.25 mg x kg(-1)) in a liposome formulation was administered iv to male mice. Imatinib concentration was measured in plasma, spleen, liver, kidney and brain using a HPLC assay. Non-compartmental pharmacokinetic approach was used to assess the disposition parameters. The plasma disposition profile was biphasic with a plateau-like second phase. The AUC(0-->infinity) was 11.24 microg x h x mL(-1), the elimination rate constant (k(el)) was 0.348 h(-1) and the elimination half life (t(1/2)) was 2.0 h. The mean residence time (MRT) was 2.59 h, V(SS) was 1.44 L x kg(-1) and clearance was 0.56 L x h x kg(-1). Liver achieved the highest tissue exposure: CMAX = 18.72 microg x mL(-1); AUC(0-->infinity)= 58.18 microg x h x mL(-1) and longest t(1/2) (4.29 h) and MRT (5.31 h). Kidney and spleen AUC(0-->infinity) were 47.98 microg x h x mL(-1) and 23.46 microg x h x mL(-1), respectively. Half-life was 1.83 h for the kidney and 3.37 h for the spleen. Imatinib penetrated into the brain reaching approximately 1 microg x g(-1). Upon correction by organ blood flow the spleen showed the largest uptake efficiency. Liposomal imatinib presented extensive biodistribution. The drug uptake kinetics showed mechanism differences amongst the tissues. These findings encourage the development of novel imatinib formulations to treat other cancers.

  2. Efficacy of a single high dose versus multiple low doses of LLLT on wounded skin fibroblasts

    NASA Astrophysics Data System (ADS)

    Hawkins, Denise H.; Abrahamse, Heidi

    2007-07-01

    Background/purpose: In vivo studies have demonstrated that phototherapy accelerates wound healing in the clinical environment; however the exact mechanism is still not completely understood. The main focus of this study was to use in vitro laboratory results to establish an effective treatment regimen that may be practical and applicable to the clinical environment. This in vitro study aimed to compare the cellular responses of wounded fibroblasts following a single exposure of 5 J/cm2 or multiple exposures of low doses (2.5 J/cm2 or 5 J/cm2) on one day of the week to a single application of a higher dose (16 J/cm2) on day 1 and day 4. Methodology: Cellular responses to Helium-Neon (632.8 nm) laser irradiation were evaluated by measuring changes in cell morphology, cell viability, cell proliferation, membrane integrity and DNA damage. Results: Wounded cells exposed to 5 J/cm2 on day 1 and day 4 showed an increase in cell viability, increase in the release of bFGF, increase in cell density, decrease in ALP enzyme activity and decrease in caspase 3/7 activity indicating a stimulatory effect. Wounded cells exposed to three doses of 5 J/cm2 on day 1 showed a decrease in cell viability and cell proliferation and an increase in LDH cytotoxicity and DNA damage indicating an inhibitory effect. Conclusion: Results indicate that cellular responses are influenced by the combination of dose administered, number of exposures and time between exposures. Single doses administered with sufficient time between exposures is more beneficial to restoring cell function than multiple doses within a short period. Although this work confirms previous reports on the cumulative effect of laser irradiation it provides essential information for the initiation of in vivo clinical studies.

  3. Recurrent Coagulopathy after Rattlesnake Bite Requiring Continuous Intravenous Dosing of Antivenom

    PubMed Central

    2015-01-01

    Context. Snakebite envenomation is common and may result in systemic coagulopathy. Antivenom can correct resulting laboratory abnormalities; however, despite antivenom use, coagulopathy may recur, persist, or result in death after a latency period. Case Details. A 50-year-old previously healthy man presented to the emergency department after a rattlesnake bite to his right upper extremity. His presentation was complicated by significant glossal and oropharyngeal edema requiring emergent cricothyrotomy. His clinical course rapidly improved with the administration of snake antivenom (FabAV); the oropharyngeal and upper extremity edema resolved within several days. However, over the subsequent two weeks, he continued to have refractory coagulopathy requiring multiple units of antivenom. The coagulopathy finally resolved after starting a continuous antivenom infusion. Discussion. Envenomation may result in latent venom release from soft tissue depots that can last for two weeks. This case report illustrates the importance of close hemodynamic and laboratory monitoring after snakebites and describes the administration of continuous antivenom infusion, instead of multidose bolus, to neutralize latent venom release and correct residual coagulopathy. PMID:25664187

  4. Serum ascorbic acid concentrations in previously unsupplemented greyhounds after administration of a single dose of ascorbic acid intravenously or per os.

    PubMed

    Scott, K C; Hill, R C; Lewis, D D; Gronwall, R; Sundstrom, D A; Jones, G L; Harper, J

    2002-08-01

    Plasma vitamin C concentrations (mean + SD) were measured after a large (1 g) dose of vitamin C was administered orally or intravenously to each of four trained greyhounds in a randomized cross-over design. Concentrations increased (p<0.05) for 2 h but returned to baseline by 6 h after supplementation. Peak concentrations were greater (p<0.01) after intravenous than oral administration (6.1+/-1.2 vs. 0.54+/-0.23 mg/dl). This suggests that vitamin C must be administered many times daily to maintain plasma concentrations above normal.

  5. Pharmacokinetics of the individual enantiomer S-(+)-ketoprofen after intravenous and oral administration in dogs at two dose levels.

    PubMed

    Serrano-Rodríguez, J M; Serrano, J M; Rodríguez, J Morgaz; Machuca, M M Granados; Gómez-Villamandos, R J; Navarrete-Calvo, R

    2014-06-01

    The pharmacokinetic of the individual S-(+)-enantiomer of ketoprofen, S-(+)-ketoprofen, after intravenous (IV) and oral (PO) administration was determined in six dogs at 1 and 3 mg/kg. Plasma concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration-time curves were analyzed by non-compartmental methods. Steady-state volume of distribution (Vss) and clearance (Cl) of S-(+)-ketoprofen after IV administration were 0.22 ± 0.07 and 0.19 ± 0.03 L/kg, and 0.10 ± 0.02 and 0.09 ± 0.01 L/h/kg, at 1 and 3 mg/kg, respectively. Following PO administration, S-(+)-ketoprofen achieved maximum plasma concentrations of 4.91 ± 0.76 and 12.47 ± 0.62 μg/ml, at two dose levels, respectively. The absolute bioavailability after PO route was 88.66 ± 12.95% and 85.36 ± 13.90%, respectively.

  6. Intravenous and intramuscular pharmacokinetics of a single-daily dose of disodium-fosfomycin in cattle, administered for 3 days.

    PubMed

    Sumano, L H; Ocampo, C L; Gutierrez, O L

    2007-02-01

    Pharmacokinetic parameters of fosfomycin in cattle were determined after administration of buffered disodium fosfomycin either intravenously (i.v.) or intramuscularly (i.m.) at a dose of 20 mg/kg/day for 3 days. Calculated concentrations at time zero and maximum serum concentrations were 34.42 and 10.18 mug/mL, respectively. The variables determined, the elimination half-life of the drug remained unchanged during the 3 days ( = 1.33 +/- 0.3 h for the i.v. route and = 2.17 +/- 0.4 h for the i.m. route). Apparent volumes of distribution suggest moderated distribution out of the central compartment (V(darea) = 673 mL +/- 27 mL/kg and V(dss) = 483 +/- 11 mL/kg). Bioavailability after i.m. administration was 74.52%. Considering fosfomycin as a time-dependent antibacterial drug, plasma concentration vs. time profiles obtained in this study, suggest that clinically effective plasma concentrations of fosfomycin could be obtained for up to 8 h following i.v. administration and approximately 10 h after i.m. injection of 20 mg/kg, for susceptible bacteria. In addition to residue studies in milk and edible tissues, a series of clinical assessments, using fosfomycin at 20 mg/kg b.i.d. or t.i.d. are warranted before this antibacterial drug should be considered for use in cattle.

  7. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen.

    PubMed

    Singla, Neil K; Parulan, Cherri; Samson, Roselle; Hutchinson, Joel; Bushnell, Rick; Beja, Evelyn G; Ang, Robert; Royal, Mike A

    2012-09-01

    This is the first study to compare plasma and cerebrospinal fluid (CSF) pharmacokinetics of intravenous (IV), oral (PO), or rectal (PR) formulations of acetaminophen. Healthy male subjects (N = 6) were randomized to receive a single dose of IV (OFIRMEV(®) ; Cadence) 1,000 mg (15 minute infusion), PO (2 Tylenol(®) 500 mg caplets; McNeil Consumer Healthcare), or PR acetaminophen (2 Feverall(®) 650 mg suppositories; Actavis) with a 1-day washout period between doses. The 1,300 mg PR concentrations were standardized to 1,000 mg. Acetaminophen plasma and CSF levels were obtained at T0, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours. IV acetaminophen showed earlier and higher plasma and CSF levels compared with PO or PR administration. CSF bioavailability over 6 hours (AUC(0-6)) for IV, PO, and PR 1 g was 24.9, 14.2, and 10.3 μg·h/mL, respectively. No treatment-related adverse events were reported. One subject was replaced because of premature failure of his lumbar spinal catheter. The mean CSF level in the IV group was similar to plasma from 3 to 4 hours and higher from 4 hours on. Absorption phase, variability in plasma, and CSF were greater in PO and PR groups than variability with IV administration. These results demonstrate that earlier and greater CSF penetration occurs as a result of the earlier and higher plasma peak with IV administration compared with PO or PR. © 2012 Lotus Clinical Research, LLC. Pain Practice © 2012 World Institute of Pain.

  8. Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after intravenous and subcutaneous dose administration in cynomolgus monkeys.

    PubMed

    Ramakrishnan, Rohini; Cheung, Wing K; Farrell, Francis; Joffee, Linda; Jusko, William J

    2003-07-01

    The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEpo) were investigated in monkeys. A two-compartment model with dual input and nonlinear disposition could adequately characterize the PK of rHuEpo upon three intravenous and six s.c. administrations. The kinetic model suggests rapid zero-order absorption of part of the s.c. dose (35%) followed by a slow first-order entry through the lymphatics. The s.c. treatments caused a delayed dose-dependent rise in reticulocyte numbers peaking between 100 and 200 h and returning to baseline by 300 to 400 h. This was followed by steady rises in red blood cell (RBC) and hemoglobin counts. A physiological catenary model based on a life span concept with rHuEpo stimulating the production of two cell populations (progenitor cells and erythroblasts) was applied. The model could adequately describe the reticulocyte responses upon the various s.c. treatments, giving estimates of maturation times for cells in the various stages of differentiation including the early progenitor cells (70.4 h), erythroblasts (15.0 h), and reticulocytes (141.6 h) that are close to the literature reported values. An Smax of 3.13 was estimated indicating a moderate maximum stimulation of erythropoiesis, whereas the SC50 was 842 IU/l. The model was used to effectively predict the increases in RBC and hemoglobin counts as well. In conclusion, the physiological PK/PD model developed could adequately describe the time course of rHuEpo effects, yielding realistic estimates of cell life span parameters.

  9. Effect of admission oral diuretic dose on response to continuous versus bolus intravenous diuretics in acute heart failure: an analysis from diuretic optimization strategies in acute heart failure.

    PubMed

    Shah, Ravi V; McNulty, Steven; O'Connor, Christopher M; Felker, G Michael; Braunwald, Eugene; Givertz, Michael M

    2012-12-01

    Results from the DOSE-AHF study suggest that an initial continuous infusion of loop diuretics is not superior to bolus dosing with regard to clinical endpoints in acute heart failure. We hypothesized that outpatient furosemide dose was associated with congestion and poorer renal function and explored the hypothesis that a continuous infusion may be more effective in patients on higher outpatient diuretic doses. The DOSE-AHF study randomized 308 patients within 24 hours of admission to high versus low initial intravenous diuretic dose given as either a continuous infusion or bolus. We compared baseline characteristics and assessed associations between mode of administration (bolus vs continuous) and outcomes in patients receiving high-dose (≥120 mg furosemide equivalent, n = 177) versus low-dose (<120 mg furosemide equivalent, n = 131) outpatient diuretics. Patients on higher doses of furosemide were less frequently on renin-angiotensin system inhibitors (P = .01) and had worse renal function and more advanced symptoms. There was a significant interaction between outpatient dose and mode of therapy (P = .01) with respect to net fluid loss at 72 hours after adjusting for creatinine and intensification strategy. Admission diuretic dose was associated with an increased risk of death or rehospitalization at 60 days (adjusted hazard ratio 1.08 per 20-mg increment in dose, 95% CI 1.01-1.16, P = .03). In acute heart failure, patients on higher diuretic doses have greater disease severity and may benefit from an initial bolus strategy. Copyright © 2012 Mosby, Inc. All rights reserved.

  10. Exact analysis of dose response for multiple correlated binary outcomes.

    PubMed

    Han, Karen E; Catalano, Paul J; Senchaudhuri, Pralay; Mehta, Cyrus

    2004-03-01

    The neurotoxicity of a substance is often tested using animal bioassays. In the functional observational battery, animals are exposed to a test agent and multiple outcomes are recorded to assess toxicity, using approximately 40 animals measured on up to 30 different items. This design gives rise to a challenging statistical problem: a large number of outcomes for a small sample of subjects. We propose an exact test for multiple binary outcomes, under the assumption that the correlation among these items is equal. This test is based upon an exponential model described by Molenberghs and Ryan (1999, Environmetrics 10, 279-300) and extends the methods developed by Corcoran et al. (2001, Biometrics 57, 941-948) who developed an exact test for exchangeably correlated binary data for groups (clusters) of correlated observations. We present a method that computes an exact p-value testing for a joint dose-response relationship. An estimate of the parameter for dose response is also determined along with its 95% confidence bound. The method is illustrated using data from a neurotoxicity bioassay for the chemical perchlorethylene.

  11. Hanford Technical Basis for Multiple Dosimetry Effective Dose Methodology

    SciTech Connect

    Hill, Robin L.; Rathbone, Bruce A.

    2010-08-01

    The current method at Hanford for dealing with the results from multiple dosimeters worn during non-uniform irradiation is to use a compartmentalization method to calculate the effective dose (E). The method, as documented in the current version of Section 6.9.3 in the 'Hanford External Dosimetry Technical Basis Manual, PNL-MA-842,' is based on the compartmentalization method presented in the 1997 ANSI/HPS N13.41 standard, 'Criteria for Performing Multiple Dosimetry.' With the adoption of the ICRP 60 methodology in the 2007 revision to 10 CFR 835 came changes that have a direct affect on the compartmentalization method described in the 1997 ANSI/HPS N13.41 standard, and, thus, to the method used at Hanford. The ANSI/HPS N13.41 standard committee is in the process of updating the standard, but the changes to the standard have not yet been approved. And, the drafts of the revision of the standard tend to align more with ICRP 60 than with the changes specified in the 2007 revision to 10 CFR 835. Therefore, a revised method for calculating effective dose from non-uniform external irradiation using a compartmental method was developed using the tissue weighting factors and remainder organs specified in 10 CFR 835 (2007).

  12. Pharmacokinetics and disposition of monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) after intravenous dosing of antiseptic XueBiJing injection in human subjects and rats

    PubMed Central

    Cheng, Chen; Lin, Jia-zhen; Li, Li; Yang, Jun-ling; Jia, Wei-wei; Huang, Yu-hong; Du, Fei-fei; Wang, Feng-qing; Li, Mei-juan; Li, Yan-fen; Xu, Fang; Zhang, Na-ting; Olaleye, Olajide E.; Sun, Yan; Li, Jian; Sun, Chang-hai; Zhang, Gui-ping; Li, Chuan

    2016-01-01

    Aim: Monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides. Methods: Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro. Results: A total of 18 monoterpene glycosides were detected in XueBiJing injection (content levels, 0.001–2.47 mmol/L), and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2–1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorin increased proportionally as the dose was increased. Rat lung, heart, and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability. Conclusion: Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance. PMID:26838074

  13. Safety and Pharmacokinetics of Multiple Dose myo-Inositol in Preterm Infants

    PubMed Central

    Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Nolen, Tracy L.; Watterberg, Kristi L.; Oh, William; Goedecke, Michael; Ehrenkranz, Richard A.; Fennell, Timothy; Poindexter, Brenda B.; Cotten, C. Michael; Hallman, Mikko; Frantz, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; Lacy, Conra Backstrom; Walsh, Michele C.; Carlo, Waldemar A.; Sánchez, Pablo J.; Bell, Edward F.; Shankaran, Seetha; Carlton, David P.; Chess, Patricia R.; Higgins, Rosemary D.

    2016-01-01

    BACKGROUND Preterm infants with RDS given inositol had reduced BPD, death and severe ROP. We assessed the safety and pharmacokinetics(PK) of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS Infants ≤29wks GA (n=122, 14 centers) were randomized and treated with placebo or inositol at 10, 40 or 80mg/kg/day. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 weeks, 34weeks PMA or discharge. Serum collection employed a sparse sampling population PK design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS At 80mg/kg/day mean serum levels reached 140mg/L, similar to Hallman’s findings. Levels declined after 2 weeks, converging in all groups by 6 wks. Analyses showed a mean volume of distribution 0.657 L/kg, clearance 0.058 L/kg/hr, and half-life 7.90 hr. Adverse events and co-morbidities were fewer in the inositol groups, but not significantly so. CONCLUSIONS Multiple dose inositol at 80mg/kg/day was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a Phase 3 trial. PMID:27074126

  14. Pharmacokinetics of temafloxacin in humans after multiple oral doses.

    PubMed Central

    Granneman, G R; Carpentier, P; Morrison, P J; Pernet, A G

    1992-01-01

    The multiple-dose pharmacokinetics and tolerance of temafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Temafloxacin was found to be well tolerated when administered orally every 12 h for 7 days at doses of 100, 200, 300, 400, 600, and 800 mg. Steady-state maximum and minimum concentrations in plasma were proportional to dose, averaging slightly over 1.0 and 0.5 microgram/ml/100 mg administered. Analyses of variance found no significant differences among the dosage groups in total apparent clearances (CLT/F), renal clearances (CLR), or nonrenal clearances, which averaged 197, 119, and 78 ml/min, respectively. The half-life increased slightly with dose, averaging 8.4 h overall. The extent of absorption of temafloxacin was quite reproducible, with day-to-day intrasubject variability in minima averaging under 10%. Renal glomerular filtration of unbound drug was the dominant elimination process; however, tubular secretion and reabsorption also appear to occur. Secretion was estimated to account for about 12% of CLT/F during a regimen of 600 mg every 12 h. CLR was relatively constant for urine flow rates above 1 ml/min, but reabsorption appeared to occur under low-flow conditions, resulting in day-versus-night differences in CLR. Intersubject variability in CLT/F over the eightfold range in dosage was only 20%, and 60% of this variance was accounted for by differences in body surface area (or lean body mass), concentration in plasma, and urine flow rate. Overall, it appears that the pharmacokinetics of temafloxacin are essentially linear, reproducible within a subject, and predictable among subjects. PMID:1318680

  15. Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin.

    PubMed Central

    Richter, C; Schnabel, A; Csernok, E; De Groot, K; Reinhold-Keller, E; Gross, W L

    1995-01-01

    In this uncontrolled study 15 patients with ANCA-associated systemic vasculitis, who were poor responders to conventional therapy, were treated with single or multiple courses of intravenous immunoglobulin (IVIG), 30 g/day over 5 days. Clinical and serological evaluation was performed before and 4 weeks after IVIG. Six of the 15 patients experienced clinically significant benefit from IVIG. Improvement was confined to single organ manifestations (skin, ENT findings), no improvement was seen with conjunctivitis and scleritis, pericarditis or nephritis. No patient experienced complete remission after IVIG. Repeated courses of IVIG at 4-week intervals were no more effective than single courses. In six anti-proteinase 3 (PR3)-positive patients pretreatment sera were incubated with F(ab')2 fragments of the IVIG preparation in vitro to measure the inhibitory effect of IVIG on anti-PR3 activity. An inhibition of anti-PR3 activity by 25-70% was observed; this did not correlate with clinical effects. Approximately 40% of patients benefited from IVIG treatment, though complete remission of disease activity did not occur. Neither clinical characteristics nor the inhibitory effect of the IVIG preparation on serum anti-PR3 activity in vitro predicted clinical response to this treatment modality. PMID:7621588

  16. Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin.

    PubMed

    Richter, C; Schnabel, A; Csernok, E; De Groot, K; Reinhold-Keller, E; Gross, W L

    1995-07-01

    In this uncontrolled study 15 patients with ANCA-associated systemic vasculitis, who were poor responders to conventional therapy, were treated with single or multiple courses of intravenous immunoglobulin (IVIG), 30 g/day over 5 days. Clinical and serological evaluation was performed before and 4 weeks after IVIG. Six of the 15 patients experienced clinically significant benefit from IVIG. Improvement was confined to single organ manifestations (skin, ENT findings), no improvement was seen with conjunctivitis and scleritis, pericarditis or nephritis. No patient experienced complete remission after IVIG. Repeated courses of IVIG at 4-week intervals were no more effective than single courses. In six anti-proteinase 3 (PR3)-positive patients pretreatment sera were incubated with F(ab')2 fragments of the IVIG preparation in vitro to measure the inhibitory effect of IVIG on anti-PR3 activity. An inhibition of anti-PR3 activity by 25-70% was observed; this did not correlate with clinical effects. Approximately 40% of patients benefited from IVIG treatment, though complete remission of disease activity did not occur. Neither clinical characteristics nor the inhibitory effect of the IVIG preparation on serum anti-PR3 activity in vitro predicted clinical response to this treatment modality.

  17. Naturally Existing Oncolytic Virus M1 Is Nonpathogenic for the Nonhuman Primates After Multiple Rounds of Repeated Intravenous Injections.

    PubMed

    Zhang, Haipeng; Lin, Yuan; Li, Kai; Liang, Jiankai; Xiao, Xiao; Cai, Jing; Tan, Yaqian; Xing, Fan; Mai, Jialuo; Li, Yuan; Chen, Wenli; Sheng, Longxiang; Gu, Jiayu; Zhu, Wenbo; Yin, Wei; Qiu, Pengxin; Su, Xingwen; Lu, Bingzheng; Tian, Xuyan; Liu, Jinhui; Lu, Wanjun; Dou, Yunling; Huang, Yijun; Hu, Bing; Kang, Zhuang; Gao, Guangping; Mao, Zixu; Cheng, Shi-Yuan; Lu, Ling; Bai, Xue-Tao; Gong, Shoufang; Yan, Guangmei; Hu, Jun

    2016-09-01

    Cancers figure among the leading causes of morbidity and mortality worldwide. The number of new cases is expected to rise by about 70% over the next 2 decades. Development of novel therapeutic agents is urgently needed for clinical cancer therapy. Alphavirus M1 is a Getah-like virus isolated from China with a genome of positive single-strand RNA. We have previously identified that alphavirus M1 is a naturally existing oncolytic virus with significant anticancer activity against different kinds of cancer (e.g., liver cancer, bladder cancer, and colon cancer). To support the incoming clinical trial of intravenous administration of alphavirus M1 to cancer patients, we assessed the safety of M1 in adult nonhuman primates. We previously presented the genome sequencing data of the cynomolgus macaques (Macaca fascicularis), which was demonstrated as an ideal animal species for virus infection study. Therefore, we chose cynomolgus macaques of either sex for the present safety study of oncolytic virus M1. In the first round of administration, five experimental macaques were intravenously injected with six times of oncolytic virus M1 (1 × 10(9) pfu/dose) in 1 week, compared with five vehicle-injected control animals. The last two rounds of injections were further completed in the following months in the same way as the first round. Body weight, temperature, complete blood count, clinical biochemistries, cytokine profiles, lymphocytes subsets, neutralizing antibody, and clinical symptoms were closely monitored at different time points. Magnetic resonance imaging was also performed to assess the possibility of encephalitis or arthritis. As a result, no clinical, biochemical, immunological, or medical imaging or other pathological evidence of toxicity was found during the whole process of the study. Our results in cynomolgus macaques suggested the safety of intravenous administration of oncolytic virus M1 in cancer patients in the future.

  18. Nicotine and cocaine self-administration using a multiple schedule of intravenous drug and sucrose reinforcement in rats.

    PubMed

    Stairs, Dustin J; Neugebauer, Nichole M; Bardo, Michael T

    2010-05-01

    There appears to be a relatively narrow range of contingencies in which intravenous (i.v) infusions of nicotine will maintain responding in rats. The schedule of reinforcement typically used when investigating i.v. nicotine self-administration is a simple fixed-ratio (FR) schedule. This study determined if responding in rats could be established using a multiple schedule of either i.v. cocaine or nicotine and sucrose reinforcement. Following training of individual components with each reinforcer, rats were placed on an FR15 60-s timeout multiple schedule of cocaine (0.3 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement or an FR5 60-s timeout multiple schedule of nicotine (0.03 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement. Both cocaine and nicotine maintained significant levels of responding under the multiple schedule. Pretreatment with the dopamine D1 antagonist SCH 23390 increased cocaine-maintained responding, but not sucrose responding. Acute pretreatment with the nicotinic antagonist mecamylamine or SCH 23390 specifically decreased nicotine self-administration. Extinction of the individual nicotine and sucrose components resulted in decreases in responding in each component under extinction. These results indicate that i.v. nicotine maintains responding under a multiple schedule. This procedure may be useful when studying the specificity of drug pretreatments on nicotine self-administration.

  19. Pharmacokinetics of ginkgolides A, B and K after single and multiple intravenous infusions and their interactions with midazolam in healthy Chinese male subjects.

    PubMed

    Shao, Feng; Zhang, Hongwen; Xie, Lijun; Chen, Juan; Zhou, Sufeng; Zhang, Jinsong; Lv, Jinru; Hao, Weiwen; Ma, Yunsu; Liu, Yun; Ou, Ning; Xiao, Wei

    2017-05-01

    Ginkgo terpene lactones meglumine injection (GMI) is a novel preparation of traditional Chinese medicine that contains ginkgolides A, B and K (GA, GB, GK, respectively) as its primary components. In this study we evaluated the safety, tolerability and pharmacokinetics of these three ginkgolides after single and multiple intravenous infusions of GMI. We also investigated the effect of GMI on cytochrome P450 3A4 (CYP3A4) in healthy Chinese volunteers. In this open-label, placebo-controlled study 15 subjects were randomly assigned to receive GMI or matched placebo (4:1 ratio). All subjects first received midazolam (MDZ) on day 1, followed by a 6-day washout. On Day 8, the subjects were started on once-daily dosing of either GMI or placebo for 14 days. Lastly, on Day 22 the subjects were given second dose of MDZ + GMI or MDZ + placebo. Plasma concentrations of ginkgolides, MDZ and its metabolite 1-hydroxy midazolam were quantified. The steady-state conditions of GA, GB and GK were achieved after 6 days of daily dosing. Following a single dose of GMI (Day 8) the area under the concentration-timecurve from zero to 24 h after administration (AUC0-24h) of GA, GB and GK (arithmetic ± standard deviation) was 4.10 ± 1.06, 4.61 ± 1.31 and 0.127 ± 0.102 h μg/mL, respectively; the corresponding values following multiple doses of GMI (Day 19) were 3.94 ± 1.16, 5.00 ± 1.55 and 0.118 ± 0.096 h μg/mL, respectively. The mean accumulation ratios were 0.95, 1.08 and 0.89 for GA, GB and GK, respectively. Additionally, the geometric mean [peak concentration (Cmax) and AUC0-24h] ratios of MDZ and 1-hydroxy midazolam were all within the specified acceptance ranges in the MDZ + placebo treatment and MDZ + GMI treatment. Our results show that GMI was well tolerated during the entire study. There was no systemic accumulation and no significant effects on the pharmacokinetics of MDZ in healthy Chinese male subjects after repeated dosing of GMI.

  20. Intravenous lipid emulsion and high-dose insulin as adjunctive therapy for propranolol toxicity in a pediatric patient.

    PubMed

    Thompson, Amanda M; Franco Palacios, Carlos R; Henriksen, Maria N

    2016-06-15

    The concurrent use of intravenous lipid emulsion (ILE) and high-dose insulin (HDI) for the management and treatment of propranolol toxicity in a pediatric patient is described. A seven-month-old infant (weight, 6.1 kg) was admitted to a hospital emergency department with lethargy and bradycardia after an unintentional overdose of propranolol suspension, which had been prescribed several days previously for treatment of a scalp hemangioma. Notable physical examination and laboratory findings were as follows: blood pressure, 121/84 mm Hg (normal range, 90 ± 30/60 ± 10 mm Hg); heart rate, 62 beats/min (normal range, 100-150 beats/min); respiratory rate, 24 breaths/min (normal range, 25-35 breaths/min); oxygen saturation, 100% on room air; and rectal temperature, 35.7 °C (normal range, 36.6-38.0 °C). The patient was lethargic. Treatment included i.v. fluid boluses of 0.9% sodium chloride injection and i.v. boluses and continuous infusions of HDI, dextrose, and ILE. After the completion of these treatments, hemodynamic stability was regained. The case is believed to be the first reported case in which a pediatric patient less than one year of age regained hemodynamic stability after administration of ILE and HDI rescue therapy. Monitoring blood glucose frequently with HDI is essential to avoid hypoglycemia. The rationale for using ILE and HDI for reversal of drug toxicities is discussed. A symptomatic pediatric patient with acute propranolol toxicity exhibited clinical improvement with the administration of ILE in conjunction with HDI. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  1. Lidocaine infusion adjunct to total intravenous anesthesia reduces the total dose of propofol during intraoperative neurophysiological monitoring.

    PubMed

    Sloan, Tod B; Mongan, Paul; Lyda, Clark; Koht, Antoun

    2014-04-01

    Total intravenous anesthesia (TIVA) with propofol and opioids is frequently utilized for spinal surgery where somatosensory evoked potentials (SSEP) and motor evoked potentials (tcMEP) are monitored. Lidocaine infusions can contribute to antinociception and unconsciousness, thus allowing for a reduction in the total dose of propofol. We examined our recent experience with lidocaine infusions to quantify this effect. After institutional review board approval, we conducted a retrospective review of propofol usage in propofol-opioid TIVA (with and without lidocaine) for spine cases monitored with SSEP and tcMEP over a 7 months period. The propofol infusion rate, cortical amplitudes of the SSEP (median nerve, posterior tibial nerve), amplitudes and stimulation voltage of the tcMEP (adductor pollicis brevis, tibialis anterior) were evaluated. The savings of propofol and sufentanil were estimated based on utilization in 50 milliliter (ml) bottles and 5 ml ampules, respectively. 129 cases were evaluated. Propofol infusion rates were reduced with lidocaine infusion from an average of 115-99 μg/kg/min (p = 0.00038) and sufentanil infusions from an average of 0.36-0.29 μg/kg/h (p = 0.0059). This reduction in propofol infusion was also seen when the cases were divided into anterior cervical, posterior cervical, or posterior thoraco-lumbar procedures. No significant differences in the cortical SSEP or tcMEP amplitudes or the tcMEP stimulation voltages used were observed. No complications were associated with the use of the lidocaine infusion. The total estimated drug savings included 104 50 ml bottles of propofol and 5 5 ml ampules of sufentanil. These cases indicate that a lidocaine infusion can be effectively utilized in spine surgery with SSEP and tcMEP monitoring as a means to reduce propofol and sufentanil usage without a negative effect on the monitoring.

  2. Single-dose pharmacokinetics of ampicillin/sulbactam (2:1) combination after intravenous administration to sheep and goats.

    PubMed

    Carceles, C M; Espuny, A; Vicente, M S; Diaz, M S; Escudero, E

    1996-09-01

    The pharmacokinetic behaviour of a combination of ampicillin and sulbactam (2:1) in six sheep and six goats after single intravenous doses of 20 mg kg body weight-1 (13.33 mg kg-1 of ampicillin and 6.67 mg kg-1 of sulbactam) was investigated by using a high-performance liquid chromatographic method for determining plasma concentrations. The objective was to determine whether there are differences between sheep and goats in the disposition kinetics of ampicillin and sulbactam. The plasma concentration-time curves were analysed by compartmental pharmacokinetic and non-compartmental methods. The disposition curves for both drugs were best described by a biexponential equation (two-compartment open model) in both sheep and goats. The mean (SD) elimination half-lives of ampicillin were 0.32 (0.05) h in sheep and 0.32 (0.04) h in goats, and the half-lives of sulbactam were 0.74 (0.10) h and 0.79 (0.18) h in sheep and goats, respectively. The apparent volumes of distribution of ampicillin and sulbactam were similar in the two species. Mean (SD) body clearances of ampicillin were 0.69 (0.07) litre h-1 kg-1 in sheep and 0.72 (0.11) litre h-1 kg-1 in goats, and the body clearances of sulbactam were 0.38 (0.03) and 0.38 (0.07) litre h-1 kg-1 in sheep and goats, respectively. There were no significant differences between any of the pharmacokinetic parameters of ampicillin and sulbactam in the sheep and goats.

  3. Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation

    PubMed Central

    Grover, Anita; Benet, Leslie Z.

    2013-01-01

    Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives. PMID:21499748

  4. High dose thiamine improves fatigue in multiple sclerosis

    PubMed Central

    Costantini, Antonio; Nappo, Agostino; Pala, Maria Immacolata; Zappone, Antonietta

    2013-01-01

    The majority of the patients with multiple sclerosis (MS) experience fatigue. Some observations indicate that fatigue and related manifestations concomitant with MS could be associated with an intracellular mild thiamine deficiency. We recruited 15 patients with MS who also experience fatigue and assessed the severity of the fatigue using the Fatigue Severity Scale. Although blood thiamine and thiamine pyrophosphate levels were within normal limit in all the patients, high-dose thiamine therapy administered orally or parenterally led to an appreciable improvement of the fatigue. The absence of apparent decrease in blood thiamine despite the presence of symptoms referable to a mild thiamine deficiency suggests that these patients may have a dysfunction of the mechanisms of intracellular transport or structural enzymatic abnormalities. The administration of large quantities of thiamine was effective in reversing the fatigue in MS, suggesting that the abnormalities in thiamine-dependent processes could be overcome by diffusion-mediated transport at supranormal thiamine concentrations. PMID:23861280

  5. Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial.

    PubMed

    Motov, Sergey; Yasavolian, Matthew; Likourezos, Antonios; Pushkar, Illya; Hossain, Rukhsana; Drapkin, Jefferson; Cohen, Victor; Filk, Nicholas; Smith, Andrew; Huang, Felix; Rockoff, Bradley; Homel, Peter; Fromm, Christian

    2017-08-01

    Nonsteroidal anti-inflammatory drugs are used extensively for the management of acute and chronic pain, with ketorolac tromethamine being one of the most frequently used parenteral analgesics in the emergency department (ED). The drugs may commonly be used at doses above their analgesic ceiling, offering no incremental analgesic advantage while potentially adding risk of harm. We evaluate the analgesic efficacy of 3 doses of intravenous ketorolac in ED patients with acute pain. We conducted a randomized, double-blind trial to assess the analgesic efficacy of 3 doses of intravenous ketorolac (10, 15, and 30 mg) in patients aged 18 to 65 years and presenting to the ED with moderate to severe acute pain, defined by a numeric rating scale score greater than or equal to 5. We excluded patients with peptic ulcer disease, gastrointestinal hemorrhage, renal or hepatic insufficiency, allergies to nonsteroidal anti-inflammatory drugs, pregnancy or breastfeeding, systolic blood pressure less than 90 or greater than 180 mm Hg, and pulse rate less than 50 or greater than 150 beats/min. Primary outcome was pain reduction at 30 minutes. We recorded pain scores at baseline and up to 120 minutes. Intravenous morphine 0.1 mg/kg was administered as a rescue analgesic if subjects still desired additional pain medication at 30 minutes after the study drug was administered. Data analyses included mixed-model regression and ANOVA. We enrolled 240 subjects (80 in each dose group). At 30 minutes, substantial pain reduction was demonstrated without any differences between the groups (95% confidence intervals 4.5 to 5.7 for the 10-mg group, 4.5 to 5.6 for the 15-mg group, and 4.2 to 5.4 for the 30-mg group). The mean numeric rating scale pain scores at baseline were 7.7, 7.5, and 7.8 and improved to 5.1, 5.0, and 4.8, respectively, at 30 minutes. Rates of rescue analgesia were similar, and there were no serious adverse events. Secondary outcomes showed similar rates of adverse effects per

  6. Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

    PubMed Central

    Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

    2015-01-01

    TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats. PMID:26877840

  7. Tranexamic Acid Administration in Primary Total Hip Arthroplasty: A Randomized Controlled Trial of Intravenous Combined with Topical Versus Single-Dose Intravenous Administration.

    PubMed

    Yi, Zeng; Bin, Shen; Jing, Yang; Zongke, Zhou; Pengde, Kang; Fuxing, Pei

    2016-06-15

    The use of tranexamic acid (TXA) in primary total hip arthroplasty is well documented. However, considering the potential side effects, including deep vein thrombosis and pulmonary embolism, the ideal method of providing TXA to patients undergoing total hip arthroplasty remains controversial. The objective of this trial was to assess the efficacy and safety of intravenous (IV) administration combined with topical administration of TXA regarding postoperative blood loss and transfusion rates in patients treated with primary unilateral total hip arthroplasty. In this prospective, randomized controlled trial, 150 patients were divided into three groups: the combined group (IV administration of 15 mg/kg of TXA combined with topical administration of 1 g/100 mL of TXA), the single IV group (IV administration of 15 mg/kg of TXA), and the placebo group. The primary outcomes included blood-loss variables (total, intraoperative, and drainage blood loss; changes in hemoglobin, hematocrit, and platelet concentration; and amount of IV transfusion fluid) and transfusion values (frequency of transfusion and number of transfused blood units). The secondary outcomes included the length of the hospital stay, range of hip motion, Harris hip score, and prevalences of deep vein thrombosis and pulmonary embolism. The total blood loss in the combined group (mean and standard deviation, 835.49 ± 343.50 mL) was significantly reduced (p < 0.05) in comparison with that in the single IV group (1002.62 ± 366.85 mL) and placebo group (1221.11 ± 386.25 mL). The combined group also had fewer transfusions in comparison with the single IV and placebo groups (1, 8, and 19, respectively; p < 0.05). There was no difference among the 3 groups with regard to the rates of deep vein thrombosis or pulmonary embolism. Intravenous combined with topical administration of TXA in patients undergoing a primary unilateral total hip arthroplasty significantly reduced postoperative bleeding and the transfusion

  8. Pharmacokinetics of single-dose intravenous, oral, and intraperitoneal pefloxacin in patients on chronic ambulatory peritoneal dialysis.

    PubMed Central

    Schmit, J L; Hary, L; Bou, P; Renaud, H; Westeel, P F; Andrejak, M; Fournier, A

    1991-01-01

    Comparison of plasma and dialysate concentrations of pefloxacin after intravenous, oral, or intraperitoneal administration shows excellent bidirectional diffusion of the quinolone through the peritoneal membrane, demonstrating that therapeutical concentrations can be achieved in the dialysate after intravenous or oral administration. In this study, the half-life of the drug was 18.8 +/- 1.4 h, i.e., apparently longer than that reported for normal controls or uremic patients on hemodialysis. PMID:1929314

  9. Comparative pharmacokinetics and bile transformation of R-enantiomer and racemic bambuterol after single-dose intravenous, oral administration in rats and beagle dogs.

    PubMed

    Guan, Su; Hu, Chun-Yun; He, Meng-Ying; Yang, Ying-Ying; Tang, Yu-Xin; Chen, Jie-di; Huang, Li-Jie; Tan, Wen

    2015-12-01

    This study was to compare pharmacokinetics and bile transformation of R-enantiomer bambuterol with its racemate. Pharmacokinetics of R-enantiomer was investigated after single-dose intravenous and three doses of oral administration to rats and beagle dogs. To compare the pharmacokinetics with racemic bambuterol, the same oral doses of racemic bambuterol were also administrated; the blood and bile samples were collected by cannulation. A validated LC-MS/MS method was used to assess the level of bambuterol in plasma and bile. After single intravenous administration, no significant differences were observed between the two drugs in pharmacokinetic data. After oral dosing of R-bambuterol, the AUCs of R-enantiomer presented linear correlation. After same oral dosing of R-enantiomer and its racemate, all the pharmacokinetic parameters were equivalent. However, the clearance and apparent distribution had different results due to species and administration route difference. The bile transformation of these two compounds was similar and implicated that liver transformation accounted for the major metabolism of them. The bioavailability of R-enantiomer and racemate were comparative and relatively high in beagle dogs. Thus, R-enantiomer had a comparative pharmacokinetic profile and bile transformation with racemic bambuterol in rats and beagle dogs. These findings provided references for further clinical study.

  10. Single- vs multiple-dose pharmacokinetics of clozapine in psychiatric patients.

    PubMed

    Choc, M G; Hsuan, F; Honigfeld, G; Robinson, W T; Ereshefsky, L; Crismon, M L; Saklad, S R; Hirschowitz, J; Wagner, R

    1990-04-01

    Clozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose-multiple dose-single dose). Each patient received a single 75-mg dose (3 x 25 mg) with clozapine tablets, and serial plasma samples were collected over 48 hr after the dose. At 48 hr, a multiple-dose regimen was started, consisting of an initial dose escalation period followed by dosing at a constant regimen for at least 6 days. After the last dose, serial plasma samples were again obtained over 72 hr. Drug was then withheld for at least 7 days, a final single 75-mg dose was given, and plasma sampling was repeated. A subset of the patient population (N = 7) was used to test for a food effect during the single-dose treatments. The pharmacokinetic parameters between the initial and the final single dose periods were not significantly different. Similarly, there were no differences within patients when given the dose after fasting (fed 1 hr after dose) or with a meal. In contrast, the terminal elimination rate differed between the single-dose and the multiple-dose treatments (t1/2 m3 = 7.9 hr single dose and 14.2 hr multiple dose) (P less than 0.05) and the dose-normalized area under the plasma concentration/time curves increased 27% with multiple dosing. Since a previous study in patients (Choc et al., Pharm. Res. 4:402-405, 1987) showed dose proportionality of clozapine plasma concentrations during multiple-dose regimens, the present results cannot be described by Michaelis-Menten kinetics.

  11. Multiple intravenous injections of allogeneic equine mesenchymal stem cells do not induce a systemic inflammatory response but do alter lymphocyte subsets in healthy horses.

    PubMed

    Kol, Amir; Wood, Joshua A; Carrade Holt, Danielle D; Gillette, Jessica A; Bohannon-Worsley, Laurie K; Puchalski, Sarah M; Walker, Naomi J; Clark, Kaitlin C; Watson, Johanna L; Borjesson, Dori L

    2015-04-15

    Intravenous (IV) injection of mesenchymal stem cells (MSCs) is used to treat systemic human diseases and disorders but is not routinely used in equine therapy. In horses, MSCs are isolated primarily from adipose tissue (AT) or bone marrow (BM) and used for treatment of orthopedic injuries through one or more local injections. The objective of this study was to determine the safety and lymphocyte response to multiple allogeneic IV injections of either AT-derived MSCs (AT-MSCs) or BM-derived MSCs (BM-MSCs) to healthy horses. We injected three doses of 25 × 10(6) allogeneic MSCs from either AT or BM (a total of 75 × 10(6) MSCs per horse) into five and five, respectively, healthy horses. Horses were followed up for 35 days after the first MSC infusion. We evaluated host inflammatory and immune response, including total leukocyte numbers, serum cytokine concentration, and splenic lymphocyte subsets. Repeated injection of allogeneic AT-MSCs or BM-MSCs did not elicit any clinical adverse effects. Repeated BM-MSC injection resulted in increased blood CD8(+) T-cell numbers. Multiple BM-MSC injections also increased splenic regulatory T cell numbers compared with AT-MSC-injected horses but not controls. These data demonstrate that multiple IV injections of allogeneic MSCs are well tolerated by healthy horses. No clinical signs or clinico-pathologic measurements of organ toxicity or systemic inflammatory response were recorded. Increased numbers of circulating CD8(+) T cells after multiple IV injections of allogeneic BM-MSCs may indicate a mild allo-antigen-directed cytotoxic response. Safety and efficacy of allogeneic MSC IV infusions in sick horses remain to be determined.

  12. Effects of age on the pharmacokinetics of single dose ceftiofur sodium administered intramuscularly or intravenously to cattle.

    PubMed

    Brown, S A; Chester, S T; Robb, E J

    1996-02-01

    The effects of maturation on the intravenous (IV) and intramuscular (IM) pharmacokinetics of ceftiofur sodium following a dose of 2.2 mg ceftiofur equivalents/kg body weight were evaluated in 16 one-day-old Holstein bull calves (33-53 kg body weight initially; Group 1) and 14 six-month-old Holstein steers (217-276 kg body weight initially; Group 2). Group 1 calves were fed unmedicated milk replacer until 30 days of age and were then converted to the same roughag/concentrate diet as Group 2. Groups 1-IV and 2-IV received ceftiofur sodium IV, and Groups 1-IM and 2-IM received ceftiofur sodium IM. Group 1 calves were dosed at 7 days of age and at 1 and 3 months of age; group 2 calves were dosed at 6 and 9 months of age. Blood samples were obtained serially from each calf, and plasma samples were analysed using an HPLC assay that converts ceftiofur and all desfuroylceftiofur metabolites to desfuroylceftiofur acetamide. Cmax values were similar in all calves, and were no higher in younger calves than in older calves. Plasma concentrations remained above 0.150 microgram ceftiofur free acid equivalents/mliter for 72 h in 7-day-old calves, but were less than 0.150 microgram/mliter within 48 h following IV or IM injection for 6- and 9-month-old calves. Intramuscular bioavailability, assessed by comparing the model-derived area under the curve (AUCmod) from IM and IV injection at each age, appeared to be complete. After IV administration, the AUCmod in 7-day-old and 1-month-old calves (126.92 +/- 21.1 micrograms.h/mliter and 135.0 +/- 21.6 micrograms.h/mliter, respectively) was significantly larger than in 3-, 6- and 9-month-old calves (74.0 +/- 10.7 micrograms.h/mliter, 61.0 +/- 17.7 micrograms.h/mliter and 68.5 +/- 12.8 micrograms.h/mliter, respectively; P < 0.0001). The Vd(ss) decreased linearly within the first 3 months of life in cattle (0.345 +/- 0.0616 L/kg, 0.335 +/- 0.919 L/kg and 0.284 +/- 0.0490 L/kg, respectively; P = 0.031), indicative of the decreasing

  13. Influence of high-dose intraoperative remifentanil with intravenous ibuprofen on postoperative morphine consumption in patients undergoing pancreaticoduodenectomy: a randomized trial.

    PubMed

    Koo, Chang-Hoon; Cho, Youn Joung; Hong, Deok Man; Jeon, Yunseok; Kim, Tae Kyong

    2016-12-01

    High-dose remifentanil during surgery paradoxically increases postoperative pain intensity and morphine consumption. Cyclooxygenase inhibitors decrease prostaglandin synthesis, thereby antagonizing N-methyl-d-aspartate receptor activation, and may reduce hyperalgesia. This study was performed to evaluate whether postoperative morphine consumption increased following intraoperative continuous remifentanil infusion and whether this could be prevented by intravenous ibuprofen pretreatment. A randomized controlled study. Single university hospital, study period from September 2014 to March 2015. One hundred and twenty patients undergoing pancreaticoduodenectomy. After induction of anesthesia, patients received remifentanil target-controlled infusion (effect site concentration of 4 ng/mL or 1 ng/mL) with or without intravenous ibuprofen (800 mg). Postoperative cumulative total morphine consumption and pain intensity were assessed. Intraoperative remifentanil use in patients receiving high-dose remifentanil was more than 3-fold higher than that in patients receiving low-dose remifentanil (2666.8 ± 858.4 vs 872.0 ± 233.3 μg, respectively; P< .001). However, cumulative total morphine consumption at postoperative 1, 3, 6, 12, 24, and 48 hours did not differ among the groups. There were no differences among the groups in the self-administered analgesic dose by the patients using a controlled analgesia device, number of self-administration attempts, numerical rating scale for pain, or analgesic side effects. We found no influence on postoperative pain after high-dose remifentanil in patients undergoing pancreaticoduodenectomy. Addition of intravenous ibuprofen did not reduce postoperative morphine consumption or pain intensity. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Pharmacokinetics and pharmacodynamics of high doses of pharmaceutically prepared heroin, by intravenous or by inhalation route in opioid-dependent patients.

    PubMed

    Rook, Elisabeth J; van Ree, Jan M; van den Brink, Wim; Hillebrand, Michel J X; Huitema, Alwin D R; Hendriks, Vincent M; Beijnen, Jos H

    2006-01-01

    A pharmacokinetic-pharmacodynamic study was performed in opioid-dependent patients in the Netherlands, who were currently treated with high doses of pharmaceutically prepared heroin on medical prescription. Besides intravenous heroin, heroin was prescribed for inhalation by "chasing the dragon" method. In this technique, heroin base is heated on aluminium foil, and heroin vapours are inhaled into the lungs. Not much is known about the pharmacokinetics profile and bioavailability of this specific administration method. Therefore, a study was performed on pharmacokinetics and pharmacodynamics of heroin inhalation and intravenous use. Eleven patients who injected heroin and 9 patients who inhaled heroin entered the study. They were on steady-state heroin treatment for at least 12 months. For safety reasons, there was no crossing-over between heroin injection or inhalation. In a double-blind randomised study, 67-100-150% of the regular heroin maintenance dose was administered to each patient. Maximal single heroin dose was 450 mg. Plasma concentrations of heroin and its metabolites 6-monoacetylmorphine, morphine and morphine-glucuronides were analysed using LC-MS-MS. Blood pressure, heart rate, skin temperature and reaction time were assessed. Furthermore, visual analogue scales regarding craving and appreciation of heroin effect were scored by the subjects. Both in inhaling and injecting patients, the areas under curve of heroin and all measured metabolites were linearly related to heroin dose. Mean C(max) of heroin and its metabolites were 2-6 times lower after inhalation, than after intravenous injection. Bioavailability (F) of heroin inhalation was estimated as 52% (95% CI 44-61%). Heroin was rapidly cleared from plasma. Cl/F was 930 l/hr (95% CI 799-1061 l/hr) after intravenous administration, and 1939 l/hr (95% CI 1661-2217 l/hr) after inhalation. Heroin Cl and Vd were correlated to body weight (R(2) 15-19%). Morphine-glucuronides levels were inversely related to

  15. Effects of single-dose preemptive intravenous ibuprofen on postoperative opioid consumption and acute pain after laparoscopic cholecystectomy.

    PubMed

    Ahiskalioglu, Elif Oral; Ahiskalioglu, Ali; Aydin, Pelin; Yayik, Ahmet Murat; Temiz, Ayetullah

    2017-02-01

    Although studies involving intravenous (IV) ibuprofen are still limited, it has been shown to have a potential role in the treatment of postoperative pain. The primary objective of this study was to investigate the effects of preemptive IV ibuprofen on postoperative 24 hour opioid consumption and postoperative pain in patients undergoing laparoscopic cholecystectomy. Following ethical committee approval, 60 patients aged 18 to 65, American Society of Anesthesiology (ASA) I-II, and scheduled for laparoscopic cholecystectomy were included in this prospective, randomized, double-blinded study. Patients were randomly divided into 1 of 2 groups. The control group (n = 30) received 100 mL saline solution 30 minutes before surgery, while the ibuprofen group (n = 30) received 400 mg IV ibuprofen in 100 mL saline. The same general anesthesia protocol was applied in both groups, and all operations were performed by the same surgeon using the same technique. Postoperative analgesia was assessed using a visual analogue pain scale (VAS) with active and passive movements. Twenty-four hour postoperative fentanyl consumption with patient-controlled analgesia and additional analgesia requirements were recorded. Postoperative analgesia was established with 1000 mg paracetamol once every 6 hours and patient-controlled IV fentanyl. Compared with the control group, VAS scores in the IV ibuprofen group were statistically lower at postoperative 30 minutes and 1, 2, 4, 8, 12, and 24 hours (P < 0.001). Twenty-four hour opioid consumption was statistically significantly higher in the control group compared to the ibuprofen group (553.00 ± 257.04 and 303.33 ± 132.08 μcq, respectively, P < 0.001). Additional analgesia use was statistically significantly higher in the control group than in the ibuprofen group (14/30 vs 5/30, respectively, P < 0.001). The rates of nausea and vomiting were higher in group control than in group ibuprofen (13/30 vs

  16. Pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol following a single induction dose administered intravenously in cats.

    PubMed

    Griffenhagen, Gregg M; Rezende, Marlis L; Gustafson, Daniel L; Hansen, Ryan J; Lunghofer, Paul J; Mama, Khursheed R

    2015-09-01

    To compare the pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol administered intravenously (IV) as a single induction dose in cats. Prospective experimental study. Six healthy adult cats, three female intact, three male castrated, weighing 4.8 ± 1.8 kg. Cats received 8 mg kg(-1) IV of propofol (P) or propofol with 2% benzyl alcohol (P28) using a randomized crossover design. Venous blood samples were collected at predetermined time points to 24 hours after drug administration to determine drug plasma concentrations. Physiologic and behavioral variables were also recorded. Propofol and benzyl alcohol concentrations were determined using high pressure liquid chromatography with fluorescence detection. Pharmacokinetic parameters were described using a 2-compartment model. Pharmacokinetic and pharmacodynamic parameters were analyzed using repeated measures anova (p < 0.05). Plasma concentrations of benzyl alcohol were below the lower limits of quantification (LLOQ) at all time points for two of the six cats (33%), and by 30 minutes for the remaining four cats. Propofol pharmacokinetics, with or without 2% benzyl alcohol, were characterized by rapid distribution, a long elimination phase, and a large volume of distribution. No differences were noted between treatments with the exception of clearance from the second compartment (CLD2), which was 23.6 and 38.8 mL kg(-1)  minute(-1) in the P and P28 treatments, respectively. Physiologic and behavioral variables were not different between treatments with the exception of heart rate at 4 hours post administration. The addition of 2% benzyl alcohol as a preservative minimally altered the pharmacokinetics and pharmacodynamics of propofol 1% emulsion when administered as a single IV bolus in this group of cats. These data support the cautious use of propofol with 2% benzyl alcohol for induction of anesthesia in healthy cats. © 2014 Association of Veterinary Anaesthetists and the

  17. Modified total lymphoid irradiation and low dose corticosteroids in progressive multiple sclerosis.

    PubMed

    Cook, S D; Devereux, C; Troiano, R; Wolansky, L; Guarnaccia, J; Haffty, B; Bansil, S; Goldstein, J; Sheffet, A; Zito, G; Jotkowitz, A; Boos, J; Dowling, P; Rohowsky-Kochan, C; Volmer, T

    1997-11-25

    In a double-blind prospective randomized trial, we assessed the efficacy and safety of modified total lymphoid irradiation (TLI) plus low dose prednisone (TLI-LDP) as compared to sham TLI plus identical prednisone therapy (sham TLI-LDP) in 46 patients with progressive forms of multiple sclerosis (MS). No significant difference existed between groups at study entry in patient age, sex, duration of MS, or disability status. However, following treatment, significantly fewer TLI patients showed a sustained one point decline in the Expanded Disability Status Scale, the primary study endpoint, as compared to the sham TLI group using the Kaplan-Meier Product-limit survival analysis, (P<0.005). Risk for relapse requiring treatment with intravenous methylprednisolone was reduced by 54% in the TLI-treated group (P<0.05). Significantly fewer TLI-LDP patients had gadolinium enhancing plus new T2-weighted lesions (P=0.018) when compared to the sham group post-treatment. There was also a substantial and significant decrease in blood lymphocytes in the TLI-LDP group when compared to either pretreatment values or to sham TLI-LDP through at least 12 months post-therapy. Side effects secondary to TLI were generally mild and well-tolerated. These results further support the hypothesis that TLI and systemic immunosuppression have a beneficial effect in progressive forms of MS.

  18. Multiple doses of contrast medium from a single container: bacteriological studies.

    PubMed

    Tress, B M; Hellyar, A G; Pennington, J; Thomson, K R; Desmond, P M; Martinkus, J; Lavan, J J

    1994-05-01

    Preparations of Iopromide (Ultravist 370; Schering Pty Ltd, Sydney, NSW, Australia), brain/heart infusion broth (BHI; positive growth control) and distilled water (negative control) were inoculated with 10(3) to 10(4) Pseudomonas aeruginosa, Escherichia coli or Staphylococcus aureus cells and incubated at 37 degrees C. Slow decreases (up to one log) were observed in each organism's count in Iopromide and distilled water at room temperature and in S. aureus and E. coli in Iopromide and distilled water at 35 degrees C until 6-8 h, when counts stabilized. BHI cultures showed logarithmic increases. P. aeruginosa counts increased (half log over 8 h) in Ultravist at 37 degrees C. Radiology laboratories were shown to have similar airborne bacterial loads to operating theatres. Samples from repeatedly entered Iopromide bottles showed no contamination. Multiple intravenous doses from a single bottle of non-ionic contrast medium can safely be used as a cost-saving measure provided scrupulous attention is paid to aseptic preparation. Unused decanted contrast medium should be discarded after 4 h.

  19. ASSESSING POPULATION EXPOSURES TO MULTIPLE AIR POLLUTANTS USING A MECHANISTIC SOURCE-TO-DOSE MODELING FRAMEWORK

    EPA Science Inventory

    The Modeling Environment for Total Risks studies (MENTOR) system, combined with an extension of the SHEDS (Stochastic Human Exposure and Dose Simulation) methodology, provide a mechanistically consistent framework for conducting source-to-dose exposure assessments of multiple pol...

  20. ASSESSING POPULATION EXPOSURES TO MULTIPLE AIR POLLUTANTS USING A MECHANISTIC SOURCE-TO-DOSE MODELING FRAMEWORK

    EPA Science Inventory

    The Modeling Environment for Total Risks studies (MENTOR) system, combined with an extension of the SHEDS (Stochastic Human Exposure and Dose Simulation) methodology, provide a mechanistically consistent framework for conducting source-to-dose exposure assessments of multiple pol...

  1. Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis.

    PubMed

    Cohen, Jeffrey A; Imrey, Peter B; Planchon, Sarah M; Bermel, Robert A; Fisher, Elizabeth; Fox, Robert J; Bar-Or, Amit; Sharp, Susan L; Skaramagas, Thomai T; Jagodnik, Patricia; Karafa, Matt; Morrison, Shannon; Reese Koc, Jane; Gerson, Stanton L; Lazarus, Hillard M

    2017-04-01

    Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest. To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS. Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0-6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1-2 × 10(6) MSCs/kg were thawed and administered IV. In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1-3 passages) was 1.9 × 10(6) MSCs/kg (range, 1.5-2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation. Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.

  2. Comparison of postoperative analgesic efficacy of intraoperative single-dose intravenous administration of dexketoprofen trometamol and diclofenac sodium in laparoscopic cholecystectomy.

    PubMed

    Anıl, Ali; Kaya, Fatma Nur; Yavaşcaoğlu, Belgin; Mercanoğlu Efe, Esra; Türker, Gürkan; Demirci, Abdurrahman

    2016-08-01

    The aim of this study is to compare the effects of intravenous single-dose dexketoprofen trometamol and diclofenac sodium 30 minutes before the end of the surgery on relief of postoperative pain in patients undergoing laparoscopic cholecystectomy. A randomized fashion. Sixty (American Society of Anesthesiologist class I-II) patients undergoing laparoscopic cholecystectomy were divided into 2 groups Patients in group DT received 50 mg dexketoprofen trometamol, whereas patients in group DS received 75 mg diclofenac sodium, intravenously 30 minutes before the end of surgery. Postoperative pain intensity, morphine consumption with patient-controlled analgesia, time to first analgesic requirement, complications, rescue analgesic (intravenous tenoxicam 20 mg) requirement, and duration of hospital stay were recorded. Postoperative pain visual analog scale scores were similar in the follow-up periods (P > .05). Patient-controlled analgesia morphine consumption was significantly less in group DT compared with group DS in all postoperative follow-up periods (2 and 4 hours: P < .01; 8, 12, 18, and 24 hours: P < .001). In the postoperative period, the first analgesic requirement time was significantly longer in group DT compared with group DS (P < .01). In addition, the number of patients requiring rescue analgesic was higher in group DS compared with group DT (P < .01). Other follow-up parameters were similar. In our study, administration of intravenous single-dose dexketoprofen trometamol 30 minutes before the end of surgery provided effective analgesia with reduced consumption of opioids and requirement for rescue analgesic compared with diclofenac sodium in patients undergoing laparoscopic cholecystectomy. For this reason, we believe that, as a part of multimodal analgesia, dexketoprofen trometamol provides more effective analgesia than diclofenac sodium in patients undergoing laparoscopic cholecystectomy. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Multiple-dose and double-dose versus single-dose administration of methotrexate for the treatment of ectopic pregnancy: a systematic review and meta-analysis.

    PubMed

    Yang, Chun; Cai, Jing; Geng, Yuhong; Gao, Ying

    2017-04-01

    In this systematic review and meta-analysis, the effectiveness and safety among different dosage of methotrexate protocols for the treatment of unruptured tubal ectopic pregnancy was evaluated. Six studies of randomized contorlled trials were identified through searches conducted on PubMed, Embase and Cochrane Library between January 1974 and March 2016. The overall success rate of multiple-dose protocol was similar to the single-dose protocol (RR 1.07, 95% CI 0.99 to 1.17, I(2) = 0%). The difference between double-dose and single-dose groups was not significant (RR 1.09, 95% CI 0.98 and 1.20, I(2) = 0%). The incidence of side-effects of double-dose regimen was similar with single-dose regimen. Side-effects, however, are more common in multiple-dose regimen (RR 1.64, 95% CI 1.15 to 2.34, P = 0.006, I(2) = 0%). This meta-analysis indicated that the incidence of side-effects of multiple-dose protocol was significantly higher than single-dose protocol, and the success rates between them were similar. The double-dose regimen was an efficient and safe alternative to the single-dose protocol. Further high-quality researches are needed to confirm our findings and to develop the optimal protocol.

  4. Intracoronary versus intravenous high-dose bolus plus maintenance administration of tirofiban in patients undergoing primary percutaneous coronary intervention for acute ST elevation myocardial infarction.

    PubMed

    Candemir, Basar; Kilickap, Mustafa; Ozcan, Ozgur Ulas; Kaya, Cansin Tulunay; Gerede, Menekse; Ozdemir, Aydan Ongun; Ozdol, Cagdas; Kumbasar, Deniz; Erol, Cetin

    2012-07-01

    We aimed to examine whether intracoronary high-dose bolus of tirofiban plus maintenance would result in improved clinical outcome in STEMI patients undergoing primary PCI in this pilot trial. A total of 56 patients were enrolled to receive either intracoronary high-dose bolus plus maintenance (n = 34) or intravenous high-dose bolus plus maintenance (n = 22) of tirofiban. Pre and post intervention TIMI flow grades, myocardial blush grades, peak CKMB and troponin levels, time to peak CKMB and troponin, time to 50% ST resolution and major composite adverse cardiac event rates at 30 days were recorded. Although incidence of major adverse cardiac events was not different, post intervention TIMI flow and TIMI blush grades, peak CKMB and troponin levels, and time to peak CKMB and time to peak troponin were significantly different, favoring intracoronary strategy. In conclusion, this regimen improved myocardial reperfusion and coronary flow, and reduced myocardial necrosis, but failed to improve clinical outcomes at 30 days.

  5. High dose Intravenous Anti-D Immune Globulin is More Effective and Safe in Indian Paediatric Patients of Immune Thrombocytopenic Purpura

    PubMed Central

    Jena, Rabindra Kumar; Swain, Kali Prasanna

    2016-01-01

    Introduction Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. Aim To compare the safety and efficacy of higher dose (75μg/kg) intravenous Anti-D immune globulin against the standard dose of 50μg/kg for the management of ITP in Indian patients. Materials and Methods One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50μg/kg (standard dose) or 75μg /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. Results Seventy one out of 84 patients treated with Anti-D at 75μg/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50μg/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. Conclusion A 75μg/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50μg dose for treatment of newly diagnosed Indian patients of ITP. PMID:28208873

  6. Effect of multiple intravenous injections of butaphosphan and cyanocobalamin on the metabolism of periparturient dairy cows.

    PubMed

    Fürll, M; Deniz, A; Westphal, B; Illing, C; Constable, P D

    2010-09-01

    Numerous adjunct therapeutic agents have been investigated for the treatment or control of fat mobilization syndrome in periparturient dairy cows. The aim of this study was to determine the effects of multiple i.v. injections of 10% butaphosphan and 0.005% cyanocobalamin combination (Catosal, Bayer Animal Health, Leverkusen, Germany) between 1 and 2 wk antepartum (a.p.) on the metabolism and health of dairy cows. Forty-five late-gestation Holstein-Friesian cows (second pregnancy) were allocated randomly to 1 of 3 groups with 15 cows/group: group C6 (6 daily i.v. injections of butaphosphan at 10 mg/kg of body weight (BW) and cyanocobalamin at 5 microg/kg of BW in the last 2 wk of gestation); group C3 (3 daily i.v. injections of butaphosphan at 10 mg/kg of BW and cyanocobalamin at 5 microg/kg of BW in the last week of gestation); and group C0 (equivolume daily i.v. injections of 0.9% NaCl solution). Serum biochemical analysis was performed on jugular venous blood samples that were periodically obtained a.p. and postpartum (p.p.). Health status and milk production were monitored p.p. Serum cyanocobalamin concentration increased in groups C6 and C3 p.p. Multiple daily i.v. injections of Catosal before parturition increased p.p. glucose availability, as evaluated by p.p. serum glucose concentration, and decreased peripheral fat mobilization and ketone body formation, as evaluated by p.p. serum nonesterified fatty acid and beta-OH butyrate concentrations. The number of puerperal infections in the first 5 d after calving was decreased in group C6, relative to group C0. We conclude that multiple injections of Catosal during the close-up period have a beneficial effect on the metabolism of periparturient dairy cows. Our results are consistent with the hypothesis that high-producing dairy cows in early lactation may have a relative or actual deficiency of cyanocobalamin.

  7. Reduction of circulating regulatory T cells by intravenous high-dose interferon alfa-2b treatment in melanoma patients.

    PubMed

    Mozzillo, Nicola; Ascierto, Paolo

    2012-10-01

    High-dose interferon alfa-2b (IFNα-2b) is the only approved adjuvant systemic therapy for resected, high risk melanoma in the United States (Fecher and Flaherty, in Natl Compr Cancer Netw 7:295-304, 2009). Recently, two important meta-analyses of randomized trials (Wheatley et al., in J Clin Oncol, 2007; Mocellin et al. in J Natl Cancer Inst, 2010) investigating IFNα-2b versus observation in high risk melanoma patients, showed that adjuvant IFNα-2b has an impact both on relapse-free survival (RFS) and overall survival (OS) independently by dosage, duration and route compared with observation in high risk melanoma patients. Despite of an absolute benefits of 3 % (Wheatley et al., in J Clin Oncol, 2007), this treatment is associated with significant toxicity, which impacts on patient quality of life. A better understanding of the mechanism of action may help to potentiate the clinical efficacy and reduce the toxicity of IFNα-2b/Peg-IFNα-2b. Numerous studies suggest that interferon's mechanism of action in melanoma is primarily immunomodulatory (Table 1) (de La Salmoniere, in Clin Cancer Res 6:4713-4718, 2000; Stuckert, in J Clin Oncol 25:8506, 2007; Gogas et al., in N Engl J Med 354:709-718, 2006; Moschos et al., in J Clin Oncol 24:3164-3171, 2006; Ascierto and Kirkwood, in J Transl Med 6:62, 2008) Recent efforts to elucidate the mechanism of action for interferon have focused upon signal transducers and activators of transcription (STAT) (Simons et al., in J Transl Med 9:52, 2011) signaling and immunoregulatory responses mediated by regulatory T cells (Tregs) (Wang et al., in Clin Cancer Res 13:1523-1531, 2007; Clin Cancer Res 14:8314-8320, 2008). Tregs are a suppressive CD4+ T cell population that is present, along with primed effector T cells, in tumor and tumor-draining lymph nodes (Hiura et al. in J Immunol 175:5058-5066, 2005). Tregs express high levels of surface antigens such as CD25, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), and

  8. Population Pharmacokinetics of High-dose Methotrexate After Intravenous Administration in Chinese Osteosarcoma Patients from a Single Institution

    PubMed Central

    Zhang, Wei; Zhang, Qing; Tian, Xiaohuang; Zhao, Haitao; Lu, Wei; Zhen, Jiancun; Niu, Xiaohui

    2015-01-01

    Background: High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is the gold standard therapy in the treatment of osteosarcoma. The plasma concentration of MTX is closely related to efficacy and toxicity. There are large individual differences. Many authors have described the pharmacokinetic (PK) profile of MTX regarding osteosarcoma under a variety of circumstances. However, no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models (NONMEM) have been previously reported. The goals of this study were to establish the population pharmacokinetics (PPK) of HD-MTX treatment in Chinese osteosarcoma patients, and to explore the influence of patient covariates and between-occasion variability on drug disposition. Methods: An intravenous HD-MTX solution (10 g/m2) was given 274 times to 148 osteosarcoma patients. MTX plasma concentrations were measured at 0, 6, 12, 24, 48 and 72 h after commencement of the infusion, and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations. The PPK model and parameters were estimated using NONMEM software. The effects of fixed-effect factors were evaluated, and the final regression model was obtained. Results: The following population parameters were obtained using a two-compartment model: CL1 (clearance of central compartment): (CL1)i = CL1TV × [1- θCL1 −MTXNUM × MTXNUM]×[1-θCL1 −CrCI1 × (CrCl1 −1.89)]×eηCL1i (L/h). V1 (central volume): (V1)i = V1TV × eηV1i (L). CL2 (clearance of peripheral compartment): (CL2)i = CL2TV ×[1- θCL2 −BODYAREA × (bodyarea − 1.62)]×eηCL2i (L/h). V2(peripheral compartment): (V2)i = V2TV ×[1 − θV2−bodyarea × (bodyarea-1.62)]× eηV2i (L). The PPK parameters (RSD%) were CL1, V1, CL2 and V2 with values of 6.20 L/h (8.48%), 19.6 L (extremely small), 0.0172 L/h (50.9%) and 0.515 L (39.1%), respectively. Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a

  9. Effects of multiple doses of isoprinosine on Echinococcus multilocularis metacestodes.

    PubMed Central

    Sarciron, M E; Delabre, I; Walbaum, S; Raynaud, G; Petavy, A F

    1992-01-01

    Isoprinosine was given at daily doses of 0.5, 1, 2, and 4 g kg-1 of body weight to jirds that were infected for 3 months with Echinococcus multilocularis metacestodes. The effects of the different drug doses on metacestodes were studied by transmission electron microscopy and biochemical methods. At lower doses, increases in uric acid and adenosine deaminase activity were noted. At 4 g kg-1 of body weight, marked ultrastructural damage with metabolic perturbations was observed. Images PMID:1375448

  10. Multiple-dose pharmacokinetics confirm no accumulation and dose proportionality of the novel promotile drug tegaserod (HTF 919).

    PubMed

    Appel-Dingemanse, S; Hirschberg, Y; Osborne, S; Pommier, F; McLeod, J

    2001-03-01

    To evaluate the steady-state pharmacokinetics (PK) and dose proportionality of the selective 5-HT4 receptor partial agonist tegaserod (HTF 919) in healthy subjects. Eighteen subjects were given 2, 6, or 12-mg doses of tegaserod twice daily (b.i.d.) for 5 days, with PK and safety assessments made during the 12 h or 24 h following first administration, and 12 h after the final dose. Tegaserod was rapidly absorbed [time to reach measured maximum plasma concentration after multiple administrations (tmax,ss) 1 h]. Steady-state PK were consistent with single-dose PK characteristics supporting that there was no accumulation of tegaserod in plasma based on systemic exposure. Mean measured maximum plasma concentration after multiple administrations (Cmax,ss) and area under the plasma concentration-time curve over one dosing interval (tau, 0-12 h after drug administration, AUC tau) were between 0.7 +/- 0.3 ng/ml and 5.6 +/- 2.9 ng/ml and 2.4 +/- 1.3 h.ng/ml and 20.4 +/- 14.0 h.ng/ml, respectively, indicating dose-proportional PK of tegaserod in the range 2-12 mg b.i.d. Tegaserod was safe and well tolerated. No serious adverse events were reported. Tegaserod exhibits no accumulation and dose-proportional PK after multiple doses.

  11. Pharmacokinetics of marbofloxacin in pigs after intravenous and intramuscular administration of a single dose of 8 mg/kg: dose proportionality, influence of the age of the animals and urinary elimination

    PubMed Central

    Schneider, M; Paulin, A; Dron, F; Woehrlé, F

    2014-01-01

    The pharmacokinetics of marbofloxacin in pigs were evaluated as a function of dose and animal age following intravenous and intramuscular administration of a 16% solution (Forcyl®). The absolute bioavailability of marbofloxacin as well as the dose proportionality was evaluated in 27-week-old fattening pigs. Blood PK and urinary excretion of marbofloxacin were evaluated after a single intramuscular dose of 8 mg/kg in 16-week-old male pigs. An additional group of 12-week-old weaned piglets was used for the evaluation of age-related kinetics. The plasma and urine concentration of marbofloxacin was determined using a HPLC method. Pharmacokinetic parameters were calculated using noncompartmental methods. After intravenous administration in 27-week-old fattening pigs, the total body clearance was 0.065 L/h·kg. After intramuscular administration to the same animals, the mean observed Cmax was 6.30 μg/mL, and the AUCINF was 115 μg·h/mL. The absolute bioavailability was 91.5%, and dose proportionality was shown within the dose range of 4–16 mg/kg. The renal clearance was about half of the value of the total clearance. The total systemic clearance values significantly decreased as a function of age, being 0.092 L/h·kg and 0.079 L/h·kg in pigs aged 12 and 16 weeks, respectively. PMID:24666477

  12. Pharmacokinetics of marbofloxacin in pigs after intravenous and intramuscular administration of a single dose of 8 mg/kg: dose proportionality, influence of the age of the animals and urinary elimination.

    PubMed

    Schneider, M; Paulin, A; Dron, F; Woehrlé, F

    2014-12-01

    The pharmacokinetics of marbofloxacin in pigs were evaluated as a function of dose and animal age following intravenous and intramuscular administration of a 16% solution (Forcyl(®) ). The absolute bioavailability of marbofloxacin as well as the dose proportionality was evaluated in 27-week-old fattening pigs. Blood PK and urinary excretion of marbofloxacin were evaluated after a single intramuscular dose of 8 mg/kg in 16-week-old male pigs. An additional group of 12-week-old weaned piglets was used for the evaluation of age-related kinetics. The plasma and urine concentration of marbofloxacin was determined using a HPLC method. Pharmacokinetic parameters were calculated using noncompartmental methods. After intravenous administration in 27-week-old fattening pigs, the total body clearance was 0.065 L/h·kg. After intramuscular administration to the same animals, the mean observed Cmax was 6.30 μg/mL, and the AUCINF was 115 μg·h/mL. The absolute bioavailability was 91.5%, and dose proportionality was shown within the dose range of 4-16 mg/kg. The renal clearance was about half of the value of the total clearance. The total systemic clearance values significantly decreased as a function of age, being 0.092 L/h·kg and 0.079 L/h·kg in pigs aged 12 and 16 weeks, respectively.

  13. Intravenous anakinra can achieve experimentally effective concentrations in the central nervous system within a therapeutic time window: results of a dose-ranging study.

    PubMed

    Galea, James; Ogungbenro, Kayode; Hulme, Sharon; Greenhalgh, Andrew; Aarons, Leon; Scarth, Sylvia; Hutchinson, Peter; Grainger, Samantha; King, Andrew; Hopkins, Stephen J; Rothwell, Nancy; Tyrrell, Pippa

    2011-02-01

    The naturally occurring antagonist of interleukin-1, IL-1RA, is highly neuroprotective experimentally, shows few adverse effects, and inhibits the systemic acute phase response to stroke. A single regime pilot study showed slow penetration into cerebrospinal fluid (CSF) at experimentally therapeutic concentrations. Twenty-five patients with subarachnoid hemorrhage (SAH) and external ventricular drains were sequentially allocated to five administration regimes, using intravenous bolus doses of 100 to 500 mg and 4 hours intravenous infusions of IL-1RA ranging from 1 to 10 mg per kg per hour. Choice of regimes and timing of plasma and CSF sampling was informed by pharmacometric analysis of pilot study data. Data were analyzed using nonlinear mixed effects modeling. Plasma and CSF concentrations of IL-1RA in all regimes were within the predicted intervals. A 500-mg bolus followed by an intravenous infusion of IL-1RA at 10 mg per kg per hour achieved experimentally therapeutic CSF concentrations of IL-1RA within 45 minutes. Experimentally, neuroprotective CSF concentrations in patients with SAH can be safely achieved within a therapeutic time window. Pharmacokinetic analysis suggests that IL-1RA transport across the blood-CSF barrier in SAH is passive. Identification of the practicality of this delivery regime allows further studies of efficacy of IL-1RA in acute cerebrovascular disease.

  14. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening

    PubMed Central

    Park, Yoon-Dong; Sun, Wei; Salas, Antonio; Antia, Avan; Carvajal, Cindy; Wang, Amy; Xu, Xin; Meng, Zhaojin; Zhou, Ming; Tawa, Gregory J.; Dehdashti, Jean; Zheng, Wei; Henderson, Christina M.; Zelazny, Adrian M.

    2016-01-01

    ABSTRACT Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. PMID:27486194

  15. Microfluidic Thrombosis under Multiple Shear Rates and Antiplatelet Therapy Doses

    PubMed Central

    Ku, David N.; Forest, Craig R.

    2014-01-01

    The mainstay of treatment for thrombosis, the formation of occlusive platelet aggregates that often lead to heart attack and stroke, is antiplatelet therapy. Antiplatelet therapy dosing and resistance are poorly understood, leading to potential incorrect and ineffective dosing. Shear rate is also suspected to play a major role in thrombosis, but instrumentation to measure its influence has been limited by flow conditions, agonist use, and non-systematic and/or non-quantitative studies. In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s−1) and therapy concentrations (0–2.4 µM for eptifibatide, 0–2 mM for acetyl-salicylic acid (ASA), 3.5–40 Units/L for heparin) using a microfluidic device. We also measured complete blood counts (CBC) and platelet activity using whole blood impedance aggregometry. Effects of shear rate and dose were analyzed using general linear models, logistic regressions, and Cox proportional hazards models. Shear rates have significant effects on thrombosis/dose-response curves for all tested therapies. ASA has little effect on high shear occlusion times, even at very high doses (up to 20 times the recommended dose). Under ASA therapy, thrombi formed at high shear rates were 4 times more prone to detachment compared to those formed under control conditions. Eptifibatide reduced occlusion when controlling for shear rate and its efficacy increased with dose concentration. In contrast, the hazard of occlusion from ASA was several orders of magnitude higher than that of eptifibatide. Our results show similar dose efficacy to our low shear measurements using whole blood aggregometry. This quantitative and statistically validated study of the effects of a wide range of shear rate and antiplatelet therapy doses on occlusive thrombosis contributes to more accurate understanding of thrombosis and to models for optimizing patient treatment. PMID:24404131

  16. Thoracic paravertebral block versus intravenous patient-controlled analgesia for pain treatment in patients with multiple rib fractures.

    PubMed

    Yeying, Ge; Liyong, Yuan; Yuebo, Chen; Yu, Zhang; Guangao, Ye; Weihu, Ma; Liujun, Zhao

    2017-01-01

    Objectives To assess the effect of thoracic paravertebral block (PVB) on pain management and preservation of pulmonary function compared with intravenous, patient-controlled analgesia (IVPCA) in patients with multiple rib fractures (MRFs). Methods Ninety patients with unilateral MRFs were included in this prospective study and randomly assigned to the TPVB or IVPCA group. The visual analogue scale (VAS) pain score, blood gas analysis, and bedside spirometry were measured and recorded at different time points after analgesia. Results TPVB and IVPCA provided good pain relief. VAS scores were significantly lower in the TPVB group than in the IVPCA group at rest and during coughing ( P < 0.05). Patients in the TPVB group had a higher PaO2 and PaO2/FiO2 and lower P(A-a)O2 compared with the IVPCA group ( P < 0.05). Moreover, patients in the TPVB group showed higher FVC, FEV1/FVC, and PEFR, and fewer complications than did the IVPCA group ( P < 0.05). Conclusion TPVB is superior to IVPCA in pain relief and preservation of pulmonary function in patients with MRFs.

  17. Nicotine and cocaine self-administration using a multiple schedule of intravenous drug and sucrose reinforcement in rats

    PubMed Central

    Stairs, D.J.; Neugebauer, N.M.; Bardo, M.T.

    2011-01-01

    There appears to be a relatively narrow range of contingencies in which intravenous (i.v) infusions of nicotine will maintain responding in rats. The schedule of reinforcement typically used when investigating i.v. nicotine self-administration is a simple fixed-ratio (FR) schedule. The current study determined if responding in rats could be established using a multiple (Mult) schedule of either i.v. cocaine or nicotine and sucrose reinforcement. Following training of individual components with each reinforcer, rats were placed on an FR15 60-sec timeout Mult schedule of cocaine (0.3 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement or an FR5 60-sec timeout Mult schedule of nicotine (0.03 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement. Both cocaine and nicotine maintained significant levels of responding under the Mult schedule. Pretreatment with the dopamine D1 antagonist SCH 23390 increased cocaine-maintained responding, but not sucrose responding. Acute pretreatment with the nicotinic antagonist mecamylamine or SCH 23390 specifically decreased nicotine self-administration. Extinction of the individual nicotine and sucrose components resulted in decreases in responding in each component under extinction. These results indicate that i.v. nicotine maintains responding under a Mult schedule. This procedure may be useful when studying the specificity of drug pretreatments on nicotine self-administration. PMID:20440201

  18. Prophylactic intravenous immunoglobulin during autologous haemopoietic stem cell transplantation for multiple myeloma is not associated with reduced infectious complications.

    PubMed

    Blombery, Piers; Prince, H Miles; Worth, Leon J; Main, Jo; Yang, Melissa; Wood, Erica M; Westerman, David A

    2011-10-01

    Patients with multiple myeloma undergoing autologous haemopoietic stem cell transplantation (ASCT) are at high risk for infectious complications. Peri-transplant intravenous immunoglobulin (IVIG) has been used with the aim of reducing these risks. Our retrospective, non-randomised study of peri-transplant IVIG use and effect on infectious complications in 266 ASCTs for myeloma from 2000 to 2009 at a major metropolitan referral centre for haematological malignancies found no difference between those receiving peri-transplant IVIG (0.4 g/kg) (n=130) and those who were not (n=110) with regard to bloodstream infections, pneumonia, urinary tract or gastrointestinal infections. When analysed according to pre-transplant therapy (conventional chemotherapy versus novel agents), there was no significant difference in infectious complications between those who did or did not receive peri-transplant IVIG. In conclusion, our study did not show a benefit for the use of peri-transplant IVIG (0.4 g/kg) to reduce infectious complications in a large cohort of patients with myeloma undergoing ASCT. In the absence of data supporting efficacy in this context, there appears to be no benefit in the routine use of IVIG for this purpose.

  19. Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine.

    PubMed

    Cairney, David G; Beckwith, Hannah K S; Al-Hourani, Khalid; Eddleston, Michael; Bateman, D Nicholas; Dear, James W

    2016-06-01

    Paracetamol (acetaminophen) overdose is a common reason for emergency hospital admission in the UK and the leading cause of acute liver failure in the Western world. Currently, the antidote acetylcysteine (NAC) is administered at a dose determined only by body weight without regard for the body burden of paracetamol. To determine whether higher plasma paracetamol concentrations are associated with increased risk of liver injury despite prompt treatment with intravenous NAC. Patients admitted to hospital for treatment with intravenous NAC following a single acute paracetamol overdose entered the study if NAC was commenced within 24 h of drug ingestion (N = 727 hospital presentations). Based on the plasma paracetamol concentration at first presentation to hospital, a series of nomograms were created: 0-100, 101-150, 151-200, 201-300, 301-500 and over 501 mg/L. The primary endpoints were acute liver injury (ALI - peak serum ALT activity >150 U/L and double the admission value) and hepatotoxicity (peak ALT >1000 U/L). ALI and hepatotoxicity were more common in patients with higher admission plasma paracetamol concentrations despite NAC treatment (ALI: nomogram 0-100: 6%, 101-150: 3%, 151-200: 3%, 201-300: 9%, 301-500: 13%, over 501 mg/dL: 27%. p < 0.0001). This dose-response relationship between paracetamol concentration and ALI persisted even in patients treated with NAC within 8 h of overdose (nomogram 0-100: 0%, 101-150: 0.8%, 151-200: 2%, 201-300: 3.6%, 301-500: 12.5%, over 501mg/L: 33%. p < 0.0001) and in patients with normal ALT activity at first presentation (nomogram: 0-100: 0%, 101-150: 1.2%, 151-200: 1.5%, 201-300: 5.3%, 301-500: 10.8% p < 0.0001). Patients with increased concentrations of plasma paracetamol at hospital presentation are at higher risk of liver injury even when intravenous NAC is promptly administered before there is biochemical evidence of toxicity. This study supports theoretical concerns that the current

  20. Incidence of infection according to intravenous immunoglobulin use in autologous hematopoietic stem cell transplant recipients with multiple myeloma.

    PubMed

    Park, S; Jung, C W; Jang, J H; Kim, S J; Kim, W S; Kim, K

    2015-10-01

    Although intravenous immunoglobulin (IVIG) is not routinely recommended, many centers still use IVIG during the post-hematopoietic stem cell transplant (HSCT) period. A total of 162 multiple myeloma (MM) patients who underwent autologous (auto-) HSCT between January 2008 and June 2013 were retrospectively reviewed. Primary objective was determination of the impact of IVIG on post-transplant infection, and secondary objectives included identification of overall incidence of infection, type of infection, and risk factors for infection after auto-HSCT in MM patients. After auto-HSCT, 53 of 162 patients (32.7%) experienced 104 infectious events. Upper respiratory infection was most common (n = 31, 29.8%) and pneumonia (n = 27, 26.0%) and herpes zoster (n = 15, 14.4%) came next. Among the identifiable organisms causing respiratory infection, influenza virus (n = 10) and Pneumococcus (n = 9) were predominant. Incidence of infection was not statistically different according to IVIG use (34.8% in IVIG (-) vs. 31.3% in IVIG (+), P = 0.631). Incidence of infection requiring hospitalization and multiple episodes of infection showed no difference between the groups (P = 0.147, P = 0.156). In a Cox proportional hazard model, none of the factors including age, gender, type of disease, stage, tandem (vs. single) transplantation,and IVIG was prognostic for infectious event after auto-HSCT (P = 0.955, hazard ratio 0.980 with 95% confidence interval 0.481-1.997 for IVIG). In auto-HSCT recipients with MM, incidence of post-transplant infection was not different according to prophylactic IVIG use. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection.

    PubMed

    Kohno, Shigeru; Yen, Muh-Yong; Cheong, Hee-Jin; Hirotsu, Nobuo; Ishida, Tadashi; Kadota, Jun-ichi; Mizuguchi, Masashi; Kida, Hiroshi; Shimada, Jingoro

    2011-11-01

    Antiviral medications with activity against influenza viruses are important in controlling influenza. We compared intravenous peramivir, a potent neuraminidase inhibitor, with oseltamivir in patients with seasonal influenza virus infection. In a multinational, multicenter, double-blind, double-dummy randomized controlled study, patients aged ≥ 20 years with influenza A or B virus infection were randomly assigned to receive either a single intravenous infusion of peramivir (300 or 600 mg) or oral administration of oseltamivir (75 mg twice a day [b.i.d.] for 5 days). To demonstrate the noninferiority of peramivir in reducing the time to alleviation of influenza symptoms with hazard model analysis and a noninferiority margin of 0.170, we planned to recruit 1,050 patients in South Korea, Japan, and Taiwan. A total of 1,091 patients (364 receiving 300 mg and 362 receiving 600 mg of peramivir; 365 receiving oseltamivir) were included in the intent-to-treat infected population. The median durations of influenza symptoms were 78.0, 81.0, and 81.8 h in the groups treated with 300 mg of peramivir, 600 mg of peramivir, and oseltamivir, respectively. The hazard ratios of the 300- and 600-mg-peramivir groups compared to the oseltamivir group were 0.946 (97.5% confidence interval [CI], 0.793, 1.129) and 0.970 (97.5% CI, 0.814, 1.157), respectively. Both peramivir groups were noninferior to the oseltamivir group (97.5% CI, <1.170). The overall incidence of adverse drug reactions was significantly lower in the 300-mg-peramivir group, but the incidence of severe reactions in either peramivir group was not different from that in the oseltamivir group. Thus, a single intravenous dose of peramivir may be an alternative to a 5-day oral dose of oseltamivir for patients with seasonal influenza virus infection.

  2. Routine use of intravenous low-dose recombinant tissue plasminogen activator in Japanese patients: general outcomes and prognostic factors from the SAMURAI register.

    PubMed

    Toyoda, Kazunori; Koga, Masatoshi; Naganuma, Masaki; Shiokawa, Yoshiaki; Nakagawara, Jyoji; Furui, Eisuke; Kimura, Kazumi; Yamagami, Hiroshi; Okada, Yasushi; Hasegawa, Yasuhiro; Kario, Kazuomi; Okuda, Satoshi; Nishiyama, Kazutoshi; Minematsu, Kazuo

    2009-11-01

    A retrospective, multicenter, observational study was conducted to document clinical outcomes and to identify outcome predictors in patients treated with low-dose intravenous recombinant tissue plasminogen activator (0.6 mg/kg alteplase), which was approved in Japan in 2005, within 3 hours of stroke onset. Consecutive patients with stroke treated with recombinant tissue plasminogen activator in 10 Japanese stroke centers were included. A total of 600 patients (377 men, 72+/-12 years old) were studied. Median National Institutes of Health Stroke Scale scores decreased from 13 before recombinant tissue plasminogen activator to 8 at 24 hours later. Symptomatic intracerebral hemorrhage within 36 hours with a >or=1-point increase from the baseline National Institutes of Health Stroke Scale score developed in 23 patients (3.8%; 95% CI, 2.6% to 5.7%). At 3 months, 43 patients had died (7.2%; 5.4% to 9.5%), and 199 patients (33.2%; 29.5% to 37.0%) had a modified Rankin Scale score intravenous antihypertensives just before recombinant tissue plasminogen activator were independently related to a 3-month modified Rankin Scale score dose intravenous recombinant tissue plasminogen activator therapy in the present study were similar to those from postmarketing surveys using 0.9 mg/kg alteplase.

  3. Comparison of intravenous immune globulin and high dose anti-D immune globulin as initial therapy for childhood immune thrombocytopenic purpura.

    PubMed

    Kane, Ian; Ragucci, Dominic; Shatat, Ibrahim F; Bussel, James; Kalpatthi, Ram

    2010-04-01

    This report documents our experience with intravenous immune globulin (IVIG) (1 g/kg, iv) and high-dose, anti-D immune globulin (anti-D) (75 microg/kg) as initial treatment for childhood immune thrombocytopenic purpura (ITP). The medical records of children diagnosed with ITP at a single institution between January 2003 and May 2008 were retrospectively reviewed. Participants received either IVIG or high-dose anti-D immune globulin as their initial treatment for ITP. For the 53 patients included for analysis, there was no statistical difference in efficacy between each group; however, patients who received anti-D experienced a higher rate of adverse drug reactions (ADRs), particularly chills and rigours, and 2 of 24 patients in the anti-D group developed severe anaemia requiring medical intervention. Patients who presented with mucosal bleeding had higher rates of treatment failure (32%) compared to those who presented with dry purpura (6%), regardless of treatment. Both IVIG and high-dose anti-D are effective first-line therapies for childhood ITP. However, we observed increased ADRs in the high-dose anti-D group in contrast to previously published reports. Further studies are needed to evaluate safety and premedications for high-dose anti-D and to determine the utility of using the presence of mucosal bleeding to predict treatment failure.

  4. A 12-week dose-escalating study of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese hemodialysis patients
.

    PubMed

    Yokoyama, Keitaro; Fukagawa, Masafumi; Shigematsu, Takashi; Akiba, Takashi; Fujii, Akifumi; Odani, Motoi; Akizawa, Tadao

    2017-08-01

    To evaluate dose-escalation of etelcalcetide (ONO-5163/AMG 416), a novel, intravenous (IV), long-acting calcium-sensing receptor agonist, for treatment of secondary hyperparathyroidism (SHPT) in Japanese hemodialysis patients. In this multicenter study, IV injections of etelcalcetide (3 times a week for 12 weeks) were administered, with dose escalation every 4 weeks depending on changes in serum intact parathyroid hormone (iPTH) and corrected calcium (cCa). A total of 24 patients participated in this study. Serum iPTH was reduced in a time- and dose-dependent manner, with reductions (in pg/mL) at 12 weeks of -226.1 ± 125.3, -362.5 ± 161.5, and -412.4 ± 130.2, respectively, for maximum doses of 5, 10, and 15 mg. At the end of the treatment, 50% of patients had serum iPTH levels within the target range (60 - 240 pg/mL). Serum cCa and phosphorus were reduced in parallel with iPTH. Adverse events (AEs) occurred in 20 patients (83.3%). The most frequently observed AEs (> 10%) were either mild or moderate nasopharyngitis (29.2%), decreased serum calcium (16.7%), and vomiting (12.5%). Dose-escalated triweekly etelcalcetide was effective for SHPT in Japanese hemodialysis patients and was satisfactorily tolerated.
.

  5. [Toxicity studies of landiolol hydrochloride (ONO-1101) (3). 4-week repeated dose intravenous toxicity study in dogs with 4-week recovery test].

    PubMed

    Yamaguchi, K; Yanagi, H; Shichino, Y; Shimizu, K; Ueda, H; Oida, H; Tanaka, M; Suzuki, Y; Yonezawa, H; Fujita, T

    1997-12-01

    4-week repeated dose toxicity study with 4-week recovery test of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in beagle dogs. ONO-1101 was administered intravenously to dogs of both sexes at a dose level of 0 (control), 12.5, 25 or 50 mg/kg/day. No deaths occurred throughout the treatment period. Transitory licking chops, vomiting, nausea, diarrhea and soft feces were observed occasionally in both sexes dosed 25 and 50 mg/kg/day and the incidence seemed dose-dependent. However, those incidence declined in the course of the treatment period. Hematology showed a decrease in red blood cell count, hematocrit and hemoglobin value in both sexes receiving 25 and 50 mg/kg/day. ONO-1101 did not effect on body weight, food consumption, respiratory rate, pulse, rectal temperature, heart rate, blood pressure, electrocardiography, renal or hepatic function, ophthalmology, urinalysis, occult blood in feces, blood chemistry, organ weights, necropsy and microscopic findings at any doses. These results indicate that the no-adverse-effect level of ONO-1101 in dogs is 12.5 mg/kg/day for both sexes in this study.

  6. Unpredictability of intravenous busulfan pharmacokinetics in children undergoing hematopoietic stem cell transplantation for advanced beta thalassemia: limited toxicity with a dose-adjustment policy.

    PubMed

    Chiesa, Robert; Cappelli, Barbara; Crocchiolo, Roberto; Frugnoli, Ilaria; Biral, Erika; Noè, Anna; Evangelio, Costanza; Fossati, Marco; Roccia, Tito; Biffi, Alessandra; Finizio, Valentina; Aiuti, Alessandro; Broglia, Monica; Bartoli, Antonella; Ciceri, Fabio; Roncarolo, Maria Grazia; Marktel, Sarah

    2010-05-01

    beta-thalassemia is a major health problem worldwide, and stem cell transplantation (SCT) is the only curative option. Oral Busulfan (Bu) based conditioning is widely used in this setting. Due to the variability of Bu systemic exposure, intravenous (i.v.) Bu has been proposed as a standard of care, with no need for drug monitoring and dose adjustment. Patients with beta-thalassemia from countries with limited resources might be at higher risk of erratic Bu metabolism because of liver dysfunction, severe iron overload, and specific ethnic/genetic features. We studied Bu pharmacokinetics in 53 children with advanced beta-thalassemia from Middle Eastern countries who underwent a total of 57 matched related donor SCTs. Forty-two percent of the children required dose adjustment because they did not achieve the therapeutic window after the first dose. With a Bu dose-adjustment policy, regimen-related toxicity was limited. At a median follow-up of 564 days, the probabilities of 2-year survival, current thalassemia-free survival, rejection, and treatment-related mortality were 96%, 88%, 21%, and 4%, respectively. Conditioning with i.v. Bu and dose adjustment is feasible and well tolerated, although recurrence of thalassemia remains an unsolved problem in children with advanced disease. Copyright 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  7. High-Dose Intravenous Vitamin C Treatment of a Child with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Case Report

    PubMed Central

    Mikirova, Nina; Hunnunghake, Ronald; Scimeca, Ruth C.; Chinshaw, Charles; Ali, Faryal; Brannon, Chris; Riordan, Neil

    2016-01-01

    Patient: Male, 1 Final Diagnosis: Optic glioma Symptoms: Visual problems Medication: — Clinical Procedure: Intravenous vitamin C Specialty: Oncology Objective: Unusual clinical course Background: In neurofibromatosis type 1 (NF1) disease, the loss of the tumor suppressor function of the neurofibromin gene leads to proliferation of neural tumors. In children, the most frequently identified tumor is the optic pathway glioma. Case Report: We describe the case of a 5-year-old child who was diagnosed with NF1 and optic pathway tumor onset at the age of 14 months. Because of the tumor progression, chemotherapy with carboplatin and vincristine was prescribed at this early age and continued for one year. As the progression of disease continued after chemotherapy, the child, at the age of 2.8 years, was started on high-dose intravenous vitamin C (IVC) treatment (7–15 grams per week) for 30 months. After 30 months, the results of IVC treatments demonstrated reduction and stabilization of the tumors in the optic chiasm, hypothalamus, and left optic nerve according to radiographic imaging. The right-sided optic nerve mass seen before IVC treatment disappeared by the end of the treatment. Conclusions: This case highlights the positive effects of treating NF1 glioma with IVC. Additional studies are necessary to evaluate the role of high-dose IVC in glioma treatment. PMID:27773919

  8. High-dose intravenous pulse steroid therapy for optic disc swelling and subretinal fluid in non-arteritic anterior ischemic optic neuropathy

    PubMed Central

    Takayama, Kei; Kaneko, Hiroki; Kachi, Shu; Ra, Eimei; Ito, Yasuki; Terasaki, Hiroko

    2017-01-01

    ABSTRACT Non-arteritic anterior ischemic optic neuropathy (NAION) is a disease with microvascular abnormality that causes acute optic disc swelling (ODS) and, in severe cases, subretinal fluid (SRF) accumulation. ODS causes compartment syndrome and subsequent axonal degeneration and loss of retinal ganglion cells by apoptosis. No treatment modalities have been effective, although some cases improved after the intake of oral systemic steroids. We reported a case of a 72-year-old man who was referred due to a visual defect in the right eye. At first presentation, visual acuity and visual field were disturbed; critical flicker frequency (CFF) was decreased; and optic coherence tomography (OCT) showed ODS and SRF. Microscopic examination revealed parapapillary hemorrhage and fluorescence angiography showed non-filling, temporal-superior choroidal lesion adjacent to the optic disc at an early phase. After high-dose intravenous steroid treatment, SRF and ODS were decreased, and completely resolved after 30 days. Visual acuity and CFF were improved, and visual field was enlarged. High-dose intravenous steroids could possibly resolve SRF and ODS and improve visual function of patients with NAION. Some cases in NAION improved visual acuity and visual function in natural course, more cases were needed to evaluate the efficiency. PMID:28303068

  9. Pharmacokinetics, Biotransformation, and Excretion of [(14)C]Etelcalcetide (AMG 416) Following a Single Microtracer Intravenous Dose in Patients with Chronic Kidney Disease on Hemodialysis.

    PubMed

    Subramanian, Raju; Zhu, Xiaochun; Hock, M Benjamin; Sloey, Bethlyn J; Wu, Benjamin; Wilson, Sarah F; Egbuna, Ogo; Slatter, J Greg; Xiao, Jim; Skiles, Gary L

    2017-02-01

    Etelcalcetide (AMG 416) is a novel synthetic peptide calcium-sensing receptor activator in clinical development as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. Etelcalcetide is composed of seven D-aminoacids with an L-cysteine linked to a D-cysteine by a disulfide bond. A single intravenous dose of [(14)C]etelcalcetide (10 mg; 26.3 kBq; 710 nCi) was administered to patients with CKD on hemodialysis to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in this setting. Blood, dialysate, urine, and feces were collected to characterize the pharmacokinetics, biotransformation product profiles, mass balance, and formation of anti-etelcalcetide antibodies. Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [(14)C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces. Biotransformation resulted from disulfide exchange with endogenous thiols, and preserved the etelcalcetide D-amino acid backbone. Drug-related radioactivity circulated primarily as serum albumin peptide conjugate (SAPC). Following removal of plasma etelcalcetide by hemodialysis, re-equilibration occurred between SAPC and L-cysteine present in blood to partially restore the etelcalcetide plasma concentrations between dialysis sessions. No unanticipated safety signals or anti-etelcalcetide or anti-SAPC antibodies were detected.

  10. Incidence and risk factors of acute kidney injury associated with continuous intravenous high-dose vancomycin in critically ill patients

    PubMed Central

    Lacave, Guillaume; Caille, Vincent; Bruneel, Fabrice; Palette, Catherine; Legriel, Stéphane; Grimaldi, David; Eurin, Mathilde; Bedos, Jean-Pierre

    2017-01-01

    Abstract For vancomycin therapy of severe infections, the Infectious Diseases Society of America recommends high vancomycin trough levels, whose potential for inducing nephrotoxicity is controversial. We evaluated the incidence and risk factors of acute kidney injury (AKI) in critically ill patients given continuous intravenous vancomycin with target serum vancomycin levels of 20 to 30 mg/L. We retrospectively studied 107 continuous intravenous vancomycin treatments of ≥48 hours’ duration with at least 2 serum vancomycin levels ≥20 mg/L in critically ill patients. Nephrotoxicity was defined according to the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for AKI (ie, serum creatinine elevation by ≥26.5 μmoL/L or to ≥1.5 times baseline). Risk factors for AKI were identified by univariate and multivariate analyses. AKI developed in 31 (29%) courses. Higher serum vancomycin levels were associated with AKI (P < 0.01). Factors independently associated with AKI were highest serum vancomycin ≥40 mg/L (odds ratio [OR], 3.75; 95% confidence interval [CI], 1.40–10.37; P < 0.01), higher cumulative number of organ failures (OR, 2.63 95%CI, 1.42–5.31; P < 0.01), and cirrhosis of the liver (OR, 5.58; 95%CI, 1.08–31.59; P = 0.04). In this study, 29% of critically ill patients had AKI develop during continuous intravenous vancomycin therapy targeting serum levels of 20 to 30 mg/L. Serum vancomycin level ≥40 mg/L was independently associated with AKI. PMID:28207512

  11. Dose titration of the clinical efficacy of intravenously administered flunixin meglumine in a reversible model of equine foot lameness.

    PubMed

    Foreman, J H; Bergstrom, B E; Golden, K S; Roark, J J; Coren, D S; Foreman, C R; Schumacher, S A

    2012-12-01

    There are no refereed controlled documentations of the skeletal analgesic efficacy of different dosages of flunixin meglumine (FM). The objective of this experiment was to compare the efficacy of various dosages of FM with a negative control. The hypothesis was that higher doses would result in improved efficacy in a dose-dependent manner when tested in a reversible model of foot lameness. Ten horses shod with adjustable heart bar shoes had weekly modified AAEP grade 4.0/5.0 lameness induced by tightening a set screw against the heart bar. Heart rate (HR) and lameness score (LS) were monitored by one double-blinded investigator at rest; every 20 min after lameness induction for 5 h and hourly for another 8 h. One hour after lameness induction, treatments were administered i.v. in a randomised order: negative control (isotonic saline: SAL) or FM at 0.55 (half-dose), 1.1 (single-dose) or 2.2 (double-dose) mg/kg bwt. Results were compared using RM ANOVA and Student-Newman-Keul's test with the level of significance set at P < 0.05. Compared to SAL, half-dose FM reduced HR at 2.33, 2.67, 4.0-8.0, and 10.0 h and LS at 1.33-12.0 h (P < 0.05). Single- and double-dose FM reduced HR from 0.67 to 12.0 h and LS from 1.0 to 12.0 h post administration (P < 0.05). Compared with half-dose FM, single- and double-dose LS were further decreased from 1.67 to 12.0 h post administration (P < 0.05). Mean peak and decaying plasma FM concentrations were different between dosages in a dose-dependent manner through 6 h post administration (P < 0.05). Flunixin meglumine administration affected dependent variables in a dose-dependent manner with half-dose FM clinically effective for a shorter period. Higher dosages did not perform differently from one another. Practitioners must be aware that half-doses of FM are less efficacious than single doses but double doses are not more efficacious and yet are potentially more toxic.

  12. Effects of alfaxalone administered intravenously to healthy yearling loggerhead sea turtles (Caretta caretta) at three different doses.

    PubMed

    Phillips, Brianne E; Posner, Lysa P; Lewbart, Gregory A; Christiansen, Emily F; Harms, Craig A

    2017-04-15

    OBJECTIVE To compare physiologic and anesthetic effects of alfaxalone administered IV to yearling loggerhead sea turtles (Caretta caretta) at 3 different doses. DESIGN Randomized crossover study. ANIMALS 9 healthy yearling loggerhead sea turtles. PROCEDURES Animals received each of 3 doses of alfaxalone (3 mg/kg [1.4 mg/lb], 5 mg/kg [2.3 mg/lb], or 10 mg/kg [4.5 mg/lb]) administered IV in randomly assigned order, with a minimum 7-day washout period between doses. Endotracheal intubation was attempted following anesthetic induction, and heart rate, sedation depth, cloacal temperature, and respirations were monitored. Times to first effect, induction, first voluntary muscle movement, first respiration, and recovery were recorded. Venous blood gas analysis was performed at 0 and 30 minutes. Assisted ventilation was performed if apnea persisted 30 minutes following induction. RESULTS Median anesthetic induction time for all 3 doses was 2 minutes. Endotracheal intubation was accomplished in all turtles following induction. Heart rate significantly increased after the 3- and 5-mg/kg doses were administered. Median intervals from alfaxalone administration to first spontaneous respiration were 16, 22, and 54 minutes for the 3-, 5-, and 10-mg/kg doses, respectively, and median intervals to recovery were 28, 46, and 90 minutes, respectively. Assisted ventilation was required for 1 turtle after receiving the 5-mg/kg dose and for 5 turtles after receiving the 10-mg/kg dose. The 10-mg/kg dose resulted in respiratory acidosis and marked hypoxemia at 30 minutes. CONCLUSIONS AND CLINICAL RELEVANCE IV alfaxalone administration to loggerhead sea turtles resulted in a rapid anesthetic induction and dose-dependent duration of sedation. Assisted ventilation is recommended if the 10 mg/kg dose is administered.

  13. Understanding the Recent Increase in Ferritin Levels in United States Dialysis Patients: Potential Impact of Changes in Intravenous Iron and Erythropoiesis-Stimulating Agent Dosing

    PubMed Central

    Zee, Jarcy; Morgenstern, Hal; Nolen, Jacqueline G.; Hakim, Raymond; Kalantar-Zadeh, Kamyar; Zager, Philip; Pisoni, Ronald L.; Port, Friedrich K.; Robinson, Bruce M.

    2015-01-01

    Background and objectives Anemia management changed substantially among dialysis patients in the United States around the time of implementation of the new Centers for Medicare & Medicaid Services bundled payment system and erythropoiesis-stimulating agent (ESA) label change in 2011. Among these, average ferritin levels increased dramatically and have remained high since; this study sought to gain understanding of this sustained rise in ferritin levels. Design, setting, participants, & measurements Trends in mean ferritin, hemoglobin, IV iron dose, and ESA dose from 2009 to 2013 were examined in 9735 patients from 91 United States Dialysis Outcomes and Practice Patterns Study facilities. Linear mixed models were used to assess the extent to which intravenous (IV) iron and ESA dose accounted for patients’ changes in ferritin over time. Results Mean ESA dose and hemoglobin levels declined throughout the study. Mean IV iron dose increased from 210 mg/mo in 2009–2010 to a peak of 280 mg/mo in 2011, then declined back to 200 mg/mo and remained stable from 2012 to 2013. Mean ferritin increased from 601 ng/ml in the third quarter of 2009 to 887 ng/ml in the first quarter of 2012; models suggest that higher IV iron dosing was a primary determinant during 2011, but lower ESA doses contributed to the sustained high ferritin levels thereafter. In a subset of 17 facilities that decreased IV iron dose in 2011, mean ferritin rose by 120 ng/ml to 764 ng/ml, which appeared to be primarily due to ESA reduction. Together, changes in IV iron and ESA doses accounted for 46% of the increase in ferritin over the study period. Conclusions In contrast to expectations, the rise in average IV iron dose did not persist beyond 2011. The sustained rise in ferritin levels in United States dialysis patients after policy changes in 2011, to average levels well in excess of 800 ng/ml, appeared to be partly due to reductions in ESA dosing and not solely IV iron dosing practices. The effect of

  14. High-dose intravenously administered iron versus orally administered iron in blood donors with iron deficiency: study protocol for a randomised, controlled trial.

    PubMed

    Macher, Susanne; Drexler, Camilla; Lindenau, Ines; Sareban, Nazanin; Schlenke, Peter; Amrein, Karin

    2016-10-28

    About 2-3 % of the population participates in blood donation programmes. Each whole blood donation or ten apheresis donations cause a loss of 200-250 mg of iron. As a result, one of the most common risks of regular blood donors is iron deficiency. Although this has been known for decades, in most countries, iron status is currently not assessed or treated in this population. Premenopausal women are particularly affected, as they have lower iron reserves and higher daily requirements. Besides anaemia, iron deficiency may lead to fatigue and impaired cognitive and physical performance. Current iron preparations for intravenous administration are well tolerated and allow for application of large doses up to 1 g in one visit. Our hypothesis is that in blood donors with iron deficiency, intravenously administered iron is more efficient and as safe as oral iron supplementation. Since anaemia is one of the most frequent reasons for permanent or intermittent donor deferral, maintaining an iron-replete donor pool may help to prevent shortages in blood supply and to avoid iron deficiency-related comorbidities. In this randomised clinical trial we include male and female blood donors aged ≥18 and ≤65 years with a ferritin value of ≤30 ng/ml. Stratified by gender, participants are randomized with a web-based randomisation tool in a 1:1 ratio to either 1 g of intravenously administered ferric carboxymaltose or 10 g of iron fumarate supplements at one to two daily doses of 100 mg each. Eight to 12 weeks after the first visit, iron status, blood count and symptoms are assessed in both groups. The primary endpoint is the difference in transferrin saturation (%) following the intervention between both groups. Secondary endpoints include other parameters of iron metabolism and red blood cell count, the number of patients with drug-related adverse events, and subjective symptoms including those of the restless legs syndrome, quality of life, and fatigue. Iron

  15. Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir ▿

    PubMed Central

    Huang, Fenglei; Drda, Kristin; MacGregor, Thomas R.; Scherer, Joseph; Rowland, Lois; Nguyen, Thuy; Ballow, Charles; Castles, Mark; Robinson, Patrick

    2009-01-01

    The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID. Following oral dosing, BILR 355 was rapidly absorbed, with the mean time to maximum concentration of drug in serum reached within 1.3 to 5 h and a mean half-life of 16 to 20 h. BILR 355 exhibited an approximately linear pharmacokinetics for doses of 5 to 50 mg when given as a solution; in contrast, when given as tablets, BILR 355 displayed a dose-proportional pharmacokinetics, with a dose range of 50 to 100 mg; from 100 to 150 mg, a slightly downward nonlinear pharmacokinetics occurred. The exposure to BILR 355 was maximized at 150 mg and higher due to a saturated dissolution/absorption process. After oral dosing of BILR 355/r, 150/100 mg BID, the values for the maximum concentration of drug in plasma at steady state, the area under the concentration-time curve from 0 to the dose interval at steady state, and the minimum concentration of drug in serum at steady state were 1,500 ng/ml, 12,500 h·ng/ml, and 570 ng/ml, respectively, providing sufficient suppressive concentration toward human immunodeficiency virus type 1. Based on pharmacokinetic modeling along with the in vitro virologic data, several BILR 355 doses were selected for phase II trials using Monte Carlo simulations. Throughout the study, BILR 355 was safe and well tolerated. PMID:18955519

  16. Multiple-Dose Pharmacokinetics of Fluvoxamine in Children and Adolescents.

    ERIC Educational Resources Information Center

    Labellarte, Michael; Biederman, Joseph; Emslie, Graham; Ferguson, James; Khan, Arifulla; Ruckle, Jon; Sallee, Randy; Riddle, Mark

    2004-01-01

    Objective: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. Method: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder…

  17. Multiple-Dose Pharmacokinetics of Fluvoxamine in Children and Adolescents.

    ERIC Educational Resources Information Center

    Labellarte, Michael; Biederman, Joseph; Emslie, Graham; Ferguson, James; Khan, Arifulla; Ruckle, Jon; Sallee, Randy; Riddle, Mark

    2004-01-01

    Objective: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. Method: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder…

  18. Estimation of pharmacokinetic parameters of sodium tungstate after multiple-dose during preclinical studies in beagle dogs.

    PubMed

    Le Lamer, S; Cros, G; Serrano, J J; Piñol, C; Fernändez-Alvarez, J; Bressolle, F

    2001-12-01

    In this paper, an empirical Bayes methodology was used to determine the pharmacokinetic profile of sodium tungstate in beagle dogs after multiple oral dosing using the P-PHARM computer program. The population estimation algorithm used in P-PHARM is an EM-type procedure. Sodium tungstate was administered orally, three times a day, (i) for 11 days (21 and 42 mg/kg per day) to 18 dogs (nine males and nine females) and (ii) for 13 weeks (15, 30 and 60 mg/kg per day) to 28 dogs (14 males, 14 females). Six other dogs received the compound intravenously (25 and 50 mg/kg). Plasma concentration profiles versus time were compatible with a two-compartment model and first-order kinetics. After oral administration, F (0.61+/-0.086 vs. 0.48+/-0.093), and normalized (to a 7-mg/kg dose of sodium tungstate) AUC (54+/-8.4 vs. 41.2+/-8.5 mg/l x h), C(max) (10.6+/-0.49 vs. 8.5+/-0.57 microg/ml) and C(min) (3.04+/-0.23 vs. 2.04+/-0.22 microg/ml), were higher in male than in female dogs. However, the introduction of the gender in the final model did not contribute statistically to an improvement of the fit of the population pharmacokinetic model. In males, t(1/2) elimination averaged 3.1+/-0.56 vs. 2.6+/-0.18 h in females. The duration of treatment did not modify statistically the pharmacokinetic parameters. After repeated multiple oral administration of 15-60 mg/kg per day of sodium tungstate, tungsten plasma concentrations increased in proportion to dose. No dose-dependent changes in pharmacokinetic parameters occurred.

  19. Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products.

    PubMed

    García-Arieta, Alfredo; Morales-Alcelay, Susana; Herranz, Marta; de la Torre-Alvarado, José María; Blázquez-Pérez, Antonio; Suárez-Gea, Ma Luisa; Alvarez, Covadonga

    2012-02-28

    In the European Union multiple dose bioequivalence studies are required for the approval of generic prolonged-release products, but they are not required by the US-FDA. In order to investigate if the multiple dose bioequivalence studies are necessary, the bioequivalence studies assessed in the Spanish Agency for Medicines and Health Care Products in the last 10 years were searched to find all reasons for rejection and identify those cases where the multiple dose study had failed to show bioequivalence and the single dose study had shown bioequivalence. In these latter cases, the plasma concentration at the end of the dosing interval (C(τ)) in the single dose study was assessed to investigate its sensitivity to predict non-bioequivalence in the steady state. The search identified six cases where the non-equivalence in the multiple dose study was not detected by the corresponding single dose study. C(τ) was not able to detect the difference in five cases and in general it was more variable than conventional metrics. In conclusion, the multiple dose bioequivalence study is necessary to ensure therapeutic equivalence and the use of C(τ) would be counterproductive, increasing the sample size of the studies without enough sensitivity to detect differences in the steady state.

  20. [Effect of intracoronary and intravenous administration of tirofiban loading dose in patients underwent percutaneous coronary interventions because of acute coronary syndrome].

    PubMed

    Turkmen, S; Fettser, D V; Kagliian, K É; Serchelik, A; Arystanova, A Zh; Tekin, K; Balli, M; Batyraliev, T A; Samko, A N; Sidorenko, B A

    2013-01-01

    Aim of this multicenter retrospective study was assessment of effect of intracoronary administration of tirofiban loading dose in troponin positive patients with acute coronary syndrome (ACS). We analyzed multicenter data base of patients subjected to percutaneous coronary interventions (PCI) because of ST-elevation or non-ST elevation ACS from October 2010 to October 2011. Patients who received loading doses of aspirin (300 mg) and clopidogrel (600 mg) before PCI and tirofiban (10 mg/kg bolus with subsequent infusion 0.15 mg/kg/min for 24 h) were selected for the study (n=133, 89 with intravenous and 44 - intracoronary administration of tirofiban loading dose). We assessed hospital mortality, myocardial reinfarctions (reMI), necessity of target vessel revascularization (TVR) and pronounced bleedings. There were no significant differences in mortality, reMI, and TVR between two groups. However major adverse cardiac events was significantly less in patients who received intracoronary tirofiban (6.8 vs. 21.3% in i.v. group; p=0.046). Hospital stay was significantly shorter in intracoronary compared with i.v. group (3.84+/-0.96 vs. 4.55+/-1.11 days; p=0.001). Rates of bleedings did not differ significantly between groups. Thus compared with i.v. intracoronary administration of tirofiban loading dose allows lower rate of major adverse cardiac events as well as to shorten length of hospital stay of patients with ACS.

  1. Clinical experience with repository corticotropin injection in patients with multiple sclerosis experiencing mood changes with intravenous methylprednisolone: a case series

    PubMed Central

    Murray, Stacey; Woo, Andrew

    2015-01-01

    The elevated prevalence of neuropsychiatric symptoms and disorders among patients with multiple sclerosis (MS) is well recognized, as are potential neuropsychiatric side effects of treatment with corticosteroids. Both methylprednisolone (MP) and repository corticotropin injection (HP Acthar® gel) have demonstrated efficacy in reducing short-term disability after exacerbations of MS. Although historical data are limited, repository corticotropin injection has not generally been associated with detrimental neuropsychiatric effects. We describe six cases of patients with relapsing-remitting MS who had previously experienced detrimental mood changes with MP treatment. Some of these patients had previous histories of mood disorders or other neuropsychiatric symptoms prior to MS diagnosis. All six patients were subsequently treated with repository corticotropin injection for MS exacerbations and each demonstrated improvements in MS symptoms. This clinical experience suggests that repository corticotropin injection should be considered as an alternative for patients who do not tolerate corticosteroids or have difficulties associated with intravenous medication. Furthermore, the rate of neuropsychiatric side effects observed in these patients was low. These observations support repository corticotropin injection as a viable alternative for the treatment of acute exacerbations of MS, particularly in patients who have a history of neuropsychiatric disorders or symptoms either independently or in response to MP treatment. In reviewing both the published data and our own clinical experience regarding potential neuropsychiatric adverse events with treatment for MS exacerbations, we hope to stimulate further research into the potential efficacy and safety of repository corticotropin injection among patients with some form of neuropsychiatric complications that must be considered when establishing a treatment plan for MS. PMID:27134674

  2. Salvage therapy with high dose Intravenous Immunoglobulins in acquired Von Willebrand Syndrome and unresponsive severe intestinal bleeding

    PubMed Central

    2014-01-01

    A 91-year-old woman affected with acquired Von Willebrand (VW) syndrome and intestinal angiodysplasias presented with severe gastrointestinal bleeding (hemoglobin 5 g/dl). Despite replacement therapy with VW factor/factor VIII concentrate qid, bleeding did not stop (eleven packed red blood cell units were transfused over three days). High circulating levels of anti-VW factor immunoglobulin M were documented immunoenzimatically. Heart ultrasound showed abnormalities of the mitral and aortic valves with severe flow alterations. When intravenous immunoglobulins were added to therapy, prompt clinical and laboratory responses occurred: complete cessation of bleeding, raise in hemoglobin, VW factor antigen, VW ristocetin cofactor and factor VIII levels as well as progressive reduction of the anti-VWF autoantibody levels. PMID:24926417

  3. Failed heart rate control with oral metoprolol prior to coronary CT angiography: effect of additional intravenous metoprolol on heart rate, image quality and radiation dose.

    PubMed

    Jiménez-Juan, Laura; Nguyen, Elsie T; Wintersperger, Bernd J; Moshonov, Hadas; Crean, Andrew M; Deva, Djeven P; Paul, Narinder S; Torres, Felipe S

    2013-01-01

    The purpose of this study was to evaluate the effect of intravenous (i.v.) metoprolol after a suboptimal heart rate (HR) response to oral metoprolol (75-150 mg) on HR control, image quality (IQ) and radiation dose during coronary CTA using 320-MDCT. Fifty-three consecutive patients who failed to achieve a target HR of < 60 bpm after an oral dose of metoprolol and required supplementary i.v. metoprolol (5-20 mg) prior to coronary CTA were evaluated. Patients with HR < 60 bpm during image acquisition were defined as responders (R) and those with HR ≥ 60 bpm as non-responders (NR). Two observers assessed IQ using a 3-point scale (1-2, diagnostic and 3, non-diagnostic). Effective dose (ED) was estimated using dose-length product and a 0.014 mSV/mGy.cm conversion factor. Baseline characteristics and HR on arrival were similar in the two groups. 58% of patients didn't achieve the target HR after receiving i.v. metoprolol (NR). R had a significantly higher HR reduction after oral (mean HR 63.9 ± 4.5 bpm vs. 69.6 ± 5.6 bpm) (p < 0.005) and i.v. (mean HR 55.4 ± 3.9 bpm vs. 67.4 ± 5.3 bpm) (p < 0.005) doses of metoprolol. Studies from NR showed a significantly higher ED in comparison to R (8.0 ± 2.9 vs. 6.1 ± 2.2 mSv) (p = 0.016) and a significantly higher proportion of non-diagnostic coronary segments (9.2 vs. 2.5%) (p < 0.001). 58% of patients who do not achieve a HR of <60 bpm prior to coronary CTA with oral fail to respond to additional i.v. metoprolol and have studies with higher radiation dose and worse image quality.

  4. The importance of active learning and practice on the students' mastery of pharmacokinetic calculations for the intermittent intravenous infusion dosing of antibiotics

    PubMed Central

    2012-01-01

    Background Estimation of pharmacokinetic parameters after intermittent intravenous infusion (III) of antibiotics, such as aminoglycosides or vancomycin, has traditionally been a difficult subject for students in clinical pharmacology or pharmacokinetic courses. Additionally, samples taken at different intervals during repeated dose therapy require manipulation of sampling times before accurate calculation of the patient-specific pharmacokinetic parameters. The main goal of this study was to evaluate the effectiveness of active learning tools and practice opportunities on the ability of students to estimate pharmacokinetic parameters from the plasma samples obtained at different intervals following intermittent intravenous infusion. Methods An extensive reading note, with examples, and a problem case, based on a patient’s chart data, were created and made available to students before the class session. Students were required to work through the case before attending the class. The class session was devoted to the discussion of the case requiring active participation of the students using a random participation program. After the class, students were given additional opportunities to practice the calculations, using online modules developed by the instructor, before submitting an online assignment. Results The performance of students significantly (P < 0.001) improved from a baseline of 11.3% (pretest) to 60.3% (posttest) after the class discussion. The grades of students further improved (P < 0.001) to 89.3% on the take-home assignment after they had a chance to study on their own and work on the online practices. Finally, students scored 82.6% in a formal mid-term examination, suggesting significant retention of the materials. Conclusions Despite being a difficult subject, students achieve mastery of pharmacokinetic calculations for the topic of intermittent intravenous infusion when appropriate active learning strategies and practice opportunities are

  5. The Optimal Dose of Prophylactic Intravenous Naloxone in Ameliorating Opioid-Induced Side Effects in Children Receiving Intravenous Patient-Controlled Analgesia Morphine for Moderate to Severe Pain: A Dose Finding Study

    PubMed Central

    Monitto, Constance L.; Kost-Byerly, Sabine; White, Elizabeth; Lee, Carlton K. K.; Rudek, Michelle A.; Thompson, Carol; Yaster, Myron

    2015-01-01

    BACKGROUND Opioid-induced side effects, such as pruritus, nausea, and vomiting are common and may be more debilitating than pain itself. A continuous low-dose naloxone infusion (0.25 µg/kg/h) ameliorates some of these side effects in many but not all patients without adversely affecting analgesia. We sought to determine the optimal dose of naloxone required to minimize opioid-induced side effects and to measure plasma morphine and naloxone levels in a dose escalation study. METHODS Fifty-nine pediatric patients (24 male/35 female; average age 14.2 ± 2.2 years) experiencing moderate to severe postoperative pain were started on IV patient-controlled analgesia morphine (basal infusion 20 µg/kg/h, demand dose 20 µg/kg, 5 doses/h) and a low-dose naloxone infusion (initial cohort: 0.05 µg/kg/h; subsequent cohorts: 0.10, 0.15, 0.25, 0.40, 0.65, 1, and 1.65 µg/kg/h). If 2 patients developed intolerable nausea, vomiting, or pruritus, the naloxone infusion was increased for subsequent patients. Dose/treatment success occurred when 10 patients had minimal side effects at a naloxone dose. Blood samples were obtained for measurement of plasma morphine and naloxone levels after initiation of the naloxone infusion, processed, stored, and measured by tandem mass spectrometry with electrospray positive ionization. RESULTS The minimum naloxone dose at which patients were successfully treated with a <10% side effect/failure rate was 1 µg/kg/h; cohort size varied between 4 and 11 patients. Naloxone was more effective in preventing pruritus than nausea and vomiting. Concomitant use of supplemental medicines to treat opioid-induced side effects was required at all naloxone infusion rates. Plasma naloxone levels were below the level of assay quantification (0.1 ng/mL) for infusion rates ≤0.15 µg/kg/h. At rates >0.25 µg/kg/h, plasma levels increased linearly with increasing infusion rate. In each dose cohort, patients who failed therapy had comparable or higher plasma naloxone

  6. Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

    PubMed Central

    Hawke, Roy L.; Schrieber, Sarah J.; Soule, Tedi A.; Wen, Zhiming; Smith, Philip C.; Reddy, K. Rajender; Wahed, Abdus S.; Belle, Steven H.; Afdhal, Nezam H.; Navarro, Victor J.; Berman, Josh; Liu, Qi-Ying; Doo, Edward; Fried, Michael W.

    2011-01-01

    Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg. PMID:19841158

  7. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study.

    PubMed

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3(+), CD4(+), CD8(+), and CD19(+)) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs.

  8. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

    PubMed Central

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

  9. Gastric emptying and intestinal transit times of radiopaque markers in cats fed a high-fiber diet with and without low-dose intravenous diazepam.

    PubMed

    Chandler, M L; Guilford, W G; Lawoko, C R; Whittem, T

    1999-01-01

    Reference ranges for gastric emptying time (GET), small intestinal transit time (SITT), and colonic transit time of 1.5-mm and 5-mm radiopaque markers in healthy cats fed a high-fiber meal were determined, and the influence of low-dose diazepam intravenous injection on the gastrointestinal transit of the markers was examined. The mean GETs and SITTs, and the mean residence times (MRTs) and geometric centers (GCs) of markers in the colon were determined. The effect of intravenous diazepam injection and marker size on these parameters was examined. Diazepam injection had no significant influence on gastrointestinal transit. The GETs of the 1.5-mm markers were significantly more rapid than those of the 5.0-mm markers. There were no significant differences between the SITTs or GCs of the 1.5-mm and 5.0-mm markers. Reference values were developed for GET, SITT, and colonic transit of radiopaque markers for cats fed a high-fiber meal. Diazepam injection had no effect on these parameters.

  10. Evaluation of renal toxicity and antifungal activity of free and liposomal amphotericin B following a single intravenous dose to diabetic rats with systemic candidiasis.

    PubMed Central

    Wasan, K M; Conklin, J S

    1996-01-01

    Since fungal infections are prevalent in diabetic patients, in whom treatment is often complicated by underlying renal disease and dyslipidemias, the purpose of the present study was to determine if the antifungal activity and nephrotoxic effects of amphotericin B (AmB) and liposomal AmB (L-AmB) are different in nondiabetic (normolipidemic) rats compared with those in diabetic (dyslipidemic) rats with systemic candidiasis. Non diabetic and diabetic rats infected with Candida albicans received a single intravenous dose of either AmB (0.8 mg of AmB per kg of body weight), L-AmB (0.8, 2, or 4 mg of AmB per kg), or an equivalent volume of normal saline (1 ml). Renal function was assessed by insulin clearance, and antifungal activity was determined by measuring the numbers of CFU of C. albicans that were present in the right kidney following drug treatment. AmB at 0.8 mg/kg and L-AmB at 0.8, 2, and 4 mg/kg are effective antifungal agents in both diabetic and nondiabetic rats. However, while there was approximately a 4-fold decline in the mean number of CFU per gram of kidney in nondiabetic rats, there was only approximately a 2.5-fold decline for the comparable dose (AmB, 0.8 mg/kg) in diabetic rats. There also appeared to be a similar fold reduction of L-AmB at all of the dosages tested. AmB treatment significantly improved renal function in diabetic and nondiabetic rats with systemic candidiasis. Although L-AmB at all doses tested significantly improved renal function in diabetic rats with systemic candidiasis, only L-AmB at doses of 2 and 4 mg/kg significantly improved renal function in nondiabetic rats with systemic candidiasis. These findings suggest that following administration of a single intravenous dose, AmB and L-AmB appear to be less effective in killing C. albicans isolates in diabetic than in nondiabetic rats, while they were found to improve the renal functions of rats in both treatment groups. PMID:8843285

  11. Arterial occlusion sites on magnetic resonance angiography influence the efficacy of intravenous low-dose (0.6 mg/kg) alteplase therapy for ischaemic stroke.

    PubMed

    Nakashima, T; Toyoda, K; Koga, M; Matsuoka, H; Nagatsuka, K; Takada, T; Naritomi, H; Minematsu, K

    2009-12-01

    To determine the predictors of efficacy, including magnetic resonance imaging information, for low-dose intravenous alteplase therapy for stroke patients. Seventy-eight patients were prospectively enrolled in a single Stroke Unit (SU) receiving alteplase at a dose of 0.6 mg/kg during the initial 27 months after its approval in Japan. Ischaemic changes and vascular lesions were identified using computed tomography, diffusion-weighted magnetic resonance imaging, and magnetic resonance angiography. Early ischaemic signs were assessed using the Alberta Stroke Program Early CT Score. The median baseline National Institutes of Health Stroke Scale score of 78 patients was 12. In 19 patients (24%), the National Institutes of Health Stroke Scale score improved by >or=8 points at 24 h. After multivariate adjustment, occlusion at the internal carotid artery (odds ratio 11.82, 95% confidence interval 1.73-142.74), Alberta Stroke Program Early CT Score on diffusion-weighted imaging Intravenous alteplase therapy at a dose of 0.6 mg/kg resulted in a relatively good overall outcome when compared with outcomes reported by western studies using an alteplase dose of 0.9 mg/kg. However, patients with occlusion at the internal carotid artery did not

  12. Comparative trial of two intravenous doses of granisetron (1 versus 3 mg) in the prevention of chemotherapy-induced acute emesis: a double-blind, randomized, non-inferiority trial.

    PubMed

    Tsuji, Daiki; Kim, Yong-Il; Taku, Keisei; Nakagaki, Shigeru; Ikematsu, Yoshito; Tsubota, Hiromi; Maeda, Masato; Hashimoto, Naoya; Kimura, Masayuki; Daimon, Takashi

    2012-05-01

    A single 3 mg or 40 μg/kg intravenous dose of granisetron combined with dexamethasone is routinely used in several countries, although the antiemetic guidelines have recommended granisetron at the dose of 1 mg or 10 μg/kg. A randomized, multicenter trial was conducted to determine the optimal intravenous granisetron dose, 1 or 3 mg, in cancer patients receiving emetogenic chemotherapy. We enrolled 365 patients and randomly assigned them to receive intravenous granisetron 3 mg (3-mg group) or 1 mg (1-mg group), combined with dexamethasone at an adequate dose fixed as per the emetic risk category. The primary end point was the proportion of patients with a complete response during the first 24 h after chemotherapy. The study demonstrated that 1 mg of granisetron was not inferior in effect to 3 mg. For the primary end point, 359 patients were evaluable according to the modified intention-to-treat (ITT) analysis. Complete protection was achieved in the modified ITT population, 90.6% and 88.8% for the 3- and 1-mg groups, respectively (p < 0.01 for non-inferiority). This study showed that 1 mg granisetron is not inferior to 3 mg when both doses are combined with dexamethasone. Therefore, 1-mg dose of intravenous granisetron should be the recommended prophylactic regimen for the prevention of acute emesis.

  13. [Toxicity studies of landiolol hydrochloride (ONO-1101) (2). 4-week repeated dose intravenous toxicity study in rats with 4-week recovery test].

    PubMed

    Yamaguchi, K; Yanagi, H; Shimizu, K; Sakai, M; Nishibata, K; Oida, H; Shinomiya, K; Suzuki, Y; Yonezawa, H; Fujita, T

    1997-12-01

    4-week repeated dose toxicity study with 4-week recovery test of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously to rats of both sexes at a dose level of 0 (control), 12.5, 25, 50 or 100 mg/kg/day. In the 100 mg/kg/day group, bradypnea or dyspnea was seen in all animals, pale in ear, eye and foot, tremor, reddish lacrimation and loss of righting reflex were also observed in some animals right after administration, and then those signs disappeared within 1 min after administration. During the treatment period, 3/20 animals of each sex in the 100 mg/kg/day showed clonic convulsion and died within 2 min after administration. No clinical changes were seen in the 50 mg/kg/day group or lower. Histopathological findings showed atrophy of the submaxillary gland in females and vessel-wall thickening and perivascular fibrosis of the injection site (tail) in both sexes at 100 mg/kg/day, however those changes were reversible. ONO-1101 did not effect on body weight, food consumption, ophthalmology, urinalysis, hematology, blood chemistry, organ weights or necropsy at any doses. These results indicate that the no-adverse-effect level of ONO-1101 in rats is 50 mg/kg/day for both sexes in this study.

  14. Pharmacokinetics of a single dose of intravenous and oral meloxicam in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus).

    PubMed

    Lacasse, Claude; Gamble, Kathryn C; Boothe, Dawn M

    2013-09-01

    Pharmacokinetic data were determined after a single dose of meloxicam in red-tailed hawks (RTH; Buteo jamaicensis) and great horned owls (GHO; Bubo virginianus). In a nonrandomized crossover design, individual birds of each species received 1 dose of intravenous meloxicam (0.5 mg/kg i.v.; n = 7 for each species) followed by a 2-week washout period, and then each received 1 dose of oral meloxicam (0.5 mg/kg PO; n = 5 for each species). Blood samples were collected intermittently after administration, and meloxicam was detected in plasma by high-performance liquid chromatography. Time versus plasma concentration data were subjected to noncompartmental analysis. Red-tailed hawks were determined to have the shortest elimination half-life for meloxicam (0.49 +/- 0.5 hours) of any species documented. Great horned owls also eliminated meloxicam very rapidly (0.78 +/- 0.52 hours). Great horned owls achieved higher plasma concentrations (368 +/- 87 ng/mL) of meloxicam than RTH (182 +/- 167 ng/mL) after oral administration, although RTH had a markedly higher volume of distribution (832 +/- 711 mL/kg) than GHO (137.6 +/- 62.7 mL/kg). The differences in meloxicam pharmacokinetics between these 2 raptor species supports the need for species-dependent studies and underlines the challenges of extrapolating drug dosages between species. Results of this study suggest that the current recommended once-daily dosing interval of oral meloxicam is unlikely to maintain plasma concentrations anticipated to be therapeutic in either RTH or GHO, and practical dosing options are questionable for this nonsteriodal anti-inflammatory drug in these raptor species.

  15. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.

    PubMed

    Mercadante, S; Arcuri, E; Tirelli, W; Casuccio, A

    2000-10-01

    Pain not responsive to morphine is often problematic. Animal and clinical studies have suggested that N-methyl-D-aspartate (NMDA) antagonists, such as ketamine, may be effective in improving opioid analgesia in difficult pain syndromes, such as neuropathic pain. A slow bolus of subhypnotic doses of ketamine (0.25 mg/kg or 0.50 mg/kg) was given to 10 cancer patients whose pain was unrelieved by morphine in a randomized, double-blind, crossover, double-dose study. Pain intensity on a 0 to 10 numerical scale; nausea and vomiting, drowsiness, confusion, and dry mouth, using a scale from 0 to 3 (not at all, slight, a lot, awful); Mini-Mental State Examination (MMSE) (0-30); and arterial pressure were recorded before administration of drugs (T0) and after 30 minutes (T30), 60 minutes (T60), 120 minutes (T120), and 180 minutes (T180). Ketamine, but not saline solution, significantly reduced the pain intensity in almost all the patients at both doses. This effect was more relevant in patients treated with higher doses. Hallucinations occurred in 4 patients, and an unpleasant sensation ("empty head") was also reported by 2 patients. These episodes reversed after the administration of diazepam 1 mg intravenously. Significant increases in drowsiness were reported in patients treated with ketamine in both groups and were more marked with ketamine 0.50 mg/kg. A significant difference in MMSE was observed at T30 in patients who received 0.50 mg/kg of ketamine. Ketamine can improve morphine analgesia in difficult pain syndromes, such as neuropathic pain. However, the occurrence of central adverse effects should be taken into account, especially when using higher doses. This observation should be tested in studies of prolonged ketamine administration.

  16. Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats.

    PubMed

    Rajan, Balan; Sathish, Shanmugam; Balakumar, Subramanian; Devaki, Thiruvengadam

    2015-03-01

    Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days.

  17. An open-label, single-dose bioavailability study of the pharmacokinetics of CAT-354 after subcutaneous and intravenous administration in healthy males

    PubMed Central

    Oh, Chad K; Faggioni, Raffaella; Jin, Feng; Roskos, Lorin K; Wang, Bing; Birrell, Claire; Wilson, Rosamund; Molfino, Nestor A

    2010-01-01

    AIM To assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration. METHODS This was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20–54 years were randomly assigned to one of three dose groups (n= 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed. RESULTS CAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3–9 (median 5) days, with a mean elimination half-life of 19.2 ± 3.1 days (150 mg) and 19.4 ± 3.59 days (300 mg) after s.c. and 21.4 ± 2.46 days after i.v. administration. Volume of distribution at steady state (Vss) was 4960 ± 1440 ml kg−1 after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 ± 82.3 and 307 ± 109 ml day−1 after 150 and 300 mg s.c., respectively; systemic CL of 188 ± 84.0 ml day−1 after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception. CONCLUSIONS CAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects. PMID:20565456

  18. Pharmacokinetics, Distribution, Metabolism, and Excretion of Omadacycline following a Single Intravenous or Oral Dose of 14C-Omadacycline in Rats

    PubMed Central

    Lin, Wen; Flarakos, Jimmy; Du, Yancy; Hu, Wenyu; He, Handan; Mangold, James; Tanaka, S. Ken

    2016-01-01

    ABSTRACT The absorption, distribution, metabolism, and excretion (ADME) of omadacycline, a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography in male Long-Evans Hooded (LEH) rats. Following an intravenous (i.v.) dose of 5 mg/kg of body weight, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood concentration ratios (t/b) were observed in bone mineral, thyroid gland, and Harderian gland at 24 h post-i.v. dose. There was no evidence of stable accumulation in uveal tract tissue, suggesting the absence of a stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest t/b were observed in bone mineral, Harderian gland, liver, spleen, and salivary gland. The plasma protein binding levels were 26% in the rat and 15% to 21% in other species. Omadacycline plasma clearance was 1.2 liters/h/kg, and its half-life was 4.6 h; the steady-state volume of distribution (Vss) was 6.89 liters/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after i.v. administration. Fecal excretion was primarily the result of biliary excretion (∼40%) and direct gastrointestinal secretion (∼30%). However, urinary excretion (∼30%) was equally prominent after i.v. dosing. PMID:27821446

  19. Intravenous injection of low-dose flurbiprofen axetil for preventing post-ERCP pancreatitis in high-risk patients: An interim analysis of the trial

    PubMed Central

    Fujita, Yuji; Hasegawa, Sho; Kato, Yuri; Ishii, Ken; Iwasaki, Akito; Sato, Takamitsu; Sekino, Yusuke; Hosono, Kunihiro; Nakajima, Atsushi; Kubota, Kensuke

    2016-01-01

    Background and study aims: Several meta-analyses and randomized control trials have demonstrated the efficacy of rectal nonsteroidal anti-inflammatory drugs for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Diclofenac or indomethacin was administered at a dose of 100 mg in those studies, which may be too high for Asian population. In addition, rectal administration can be considered complicated. Patients and methods: This study was a prospective, randomized, placebo-controlled trial. Patients with a PEP risk score ≥ 1 were randomly assigned to receive intravenous injection of 50 mg flurbiprofen axetil (flurbiprofen group) or saline only (placebo group). The primary outcome was reduced PEP. The secondary outcome was amylase level after 2 hours of ERCP as a predictor of PEP. (Clinical Trials.gov, ID UMIN000011322) Results: In total, 144 patients were enrolled from August 2013 to March 2015. We performed an interim analysis of the first 100 patients: 47 received flurbiprofen axetil and 53 received placebo. PEP occurred in 11 patients (11 %): 2 of 47 (4.3 %) in the flurbiprofen group and 9 of 53 (17 %) in the placebo group (P = 0.042). Relative risk reduction was 62.4 %. Hyperamylasemia did not differ significantly (17.0 % vs. 26.4 %, P = 0.109). This analysis resulted in early termination of the study for ethical reasons. Conclusions: Intravenous injection of low-dose flurbiprofen axetil after ERCP can reduce the incidence of PEP in high-risk patients PMID:27747282

  20. Pharmacokinetics and hematotoxicity of a novel copper-based anticancer agent: casiopeina III-Ea, after a single intravenous dose in rats.

    PubMed

    Vértiz, Guadalupe; García-Ortuño, Luis Enrique; Bernal, Juan Pablo; Bravo-Gómez, María Elena; Lounejeva, Elena; Huerta, Amada; Ruiz-Azuara, Lena

    2014-02-01

    Casiopeina III-Ea is a mixed chelate copper (II) complex that has shown cytotoxic and antitumor activity in vitro and in vivo. The aim of this study was to investigate the pharmacokinetics of total copper derived from casiopeina III-Ea administered by intravenous bolus injection to Wistar rats. Other objective was to evaluate the hematotoxicity produced by this compound in those animals. Wistar rats received a single intravenous dose of 4 mg/kg of casiopeina III-Ea. Blood samples were taken and pharmacokinetics evaluated. Furthermore, erythrocyte copper levels were determined to identify a potential target and Zn levels were analyzed to determine a possible change. For the evaluation of hematotoxicity, both blood and urine samples were collected for hematological and biochemical analyses; moreover, Fe determination was performed. Blood copper and zinc levels, red blood cell copper levels as well as copper, zinc, and iron amounts excreted into urine were analyzed by ICP-MS. The blood concentration-time profile of copper derived from casiopeina III-Ea was fitted to a two-compartment model with a zero-order input. Cumulative amounts of Cu, Zn, and Fe excreted into rat urine after administration of casiopeina III-Ea were different with respect to control. Hematological and biochemical data indicated a hemolytic toxicity. Pharmacokinetic analysis of total copper derived from casiopeina III-Ea provided a general knowledge about distribution and elimination process of this compound. Additionally, the systemic exposure of the copper derived from casiopeina III-Ea accounts for the hematotoxicity of this complex at test dose.

  1. Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration of a single dose to American kestrels (Falco sparverius)

    USGS Publications Warehouse

    Guzman, David Sanchez-Migallon; KuKanich, Butch; Drazenovich, Tracy L.; Olsen, Glenn H.; Paul-Murphy, Joanne R.

    2014-01-01

    Results indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies regarding the effects of other doses, other administration routes, constantrate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels may be indicated.

  2. Phase I dose escalation study of high dose carfilzomib monotherapy for Japanese patients with relapsed or refractory multiple myeloma.

    PubMed

    Iida, Shinsuke; Tobinai, Kensei; Taniwaki, Masafumi; Shumiya, Yoshihisa; Nakamura, Toru; Chou, Takaaki

    2016-11-01

    We conducted a multicenter, open-label Phase I study of single-agent carfilzomib in Japanese patients with relapsed or refractory multiple myeloma. The primary endpoints were tolerability and safety. Carfilzomib was administrated for 30 min on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. In cycle 1, doses for days 1 and 2 were 20 mg/m(2), followed by 45 or 56 mg/m(2). Three and four subjects were enrolled in the 20/45 mg/m(2) cohort and 20/56 mg/m(2) cohort. No dose-limiting toxicity was observed, and the tolerability of carfilzomib was confirmed. Pyrexia, hypertension, nausea and vomiting were considered as noteworthy adverse events (AE) when carfilzomib was administered at high doses. Moreover, pyrexia, blood creatinine increased, and body weight gain were observed as acute dose effects. These findings suggest that addition of dexamethasone is important to alleviate acute dose effect. The overall response rates of the 20/45 mg/m(2) and 20/56 mg/m(2) cohort were 66.7 % (two out of three) and 50 % (two out of four), respectively. Carfilzomib administrated at up to 20/56 mg/m(2) was well tolerated and seemed active in Japanese patients with relapsed or refractory multiple myeloma.

  3. Short-term distribution of Cs in relation to Cr-EDTA after intravenous dose in goats.

    PubMed

    Kaikkonen, M; de Gritz, B; Eriksson, L

    2005-03-01

    The aim of this study was to gather information about the short-term rate of caesium uptake (incorporation) in different animal tissues and explain them with known physiological mechanisms affecting ion distribution. Six goats were given an intravenous bolus containing (134)Cs as a tracer and (51)Cr-EDTA as an extracellular marker. After 30 min, the animals were killed and the activity concentration of radioactive isotopes in different tissues and fluid compartments were measured. The highest relative activity concentration of (134)Cs was found in kidney cortex, with a tissue/plasma-ratio around 50. In urine, the ratio varied between 5 and 28. In the salivary gland, cardiac muscle and small intestine the ratio was around 11, 7 and 6, respectively. The contents of small intestine had an average activity concentration five times that of plasma. In skeletal muscle the terminal activity concentration was surprisingly low, with a tissue/plasma ratio mostly far less than unity. Even in connective tissue and cartilage the terminal activity concentration was generally higher than in skeletal muscle. The rate of uptake of caesium varies widely from tissue to tissue. Many of these differences can be explained with differences in Na,K-ATPase activity. Also, perfusion and accessibility play a role in some tissues, like brain and possibly part of the skeletal muscles. The short-term distribution of caesium differs distinctly from the long-term distribution reported in literature.

  4. Increased BK viremia and progression to BK-virus nephropathy following high-dose intravenous immunoglobulin for acute cellular rejection.

    PubMed

    Boonyapredee, Maytee; Knight, Kendral; Little, Dustin

    2014-06-01

    BK virus nephropathy and cellular rejection are common causes of allograft dysfunction in renal transplant recipients. The two can be difficult to distinguish on allograft biopsy and can be present simultaneously. Management of the patient with coexistent BK infection and rejection is complicated by the conflicting ideals of decreasing immunosuppression to treat the former and increasing immunosuppression to treat the latter. The authors present the case of a 57-year-old renal transplant recipient who underwent allograft biopsy 8 weeks post-transplant for evaluation of increased serum creatinine in the setting of BK viremia (BKV). Biopsy revealed Banff classification 1b acute cellular rejection, with insufficient evidence to diagnose BK virus-associated nephropathy. The patient was administered intravenous immune globulin (IVIG), with no other changes in immunosuppressive therapy. Plasma and urine BK increased exponentially following IVIG administration, and allograft function further deteriorated. Repeat biopsy showed overt BK viral nephropathy, and BKV and creatinine decreased only after reduction in immunosuppression and initiation of leflunomide. Although case series have suggested a potential role for IVIG in the setting of BK infection, further study is needed to define the safety and efficacy of this approach. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

  5. Rapid excretion of gallium-67 isotope in an iron-overloaded patient receiving high-dose intravenous deferoxamine

    SciTech Connect

    Baker, D.L.; Manno, C.S.

    1988-12-01

    A 23 year-old black male with homozygous sickle cell disease (Hb SS disease) and transfusional iron overload was admitted for evaluation of response to intravenous deferoxamine (DFO) therapy. Soon after admission, the patient suffered an intraventricular hemorrhage and during his subsequent hospitalization developed a persistent fever of undetermined origin (f.u.o.). Included in the diagnostic evaluation of fever was a gallium 67 scan (Ga-67), which was initially nondiagnostic because of Ga-67 citrate's preferential chelation by DFO. After DFO was discontinued, a repeat scan demonstrated a lesion above the left kidney. To our knowledge the unusual interaction in vivo of DFO with Ga-67 citrate has not been reported in the clinical literature. With the anticipated increased use of chelation therapy for patients with transfusional iron overload, this interaction may be encountered more frequently. DFO should be discontinued before the use of Ga-67 scanning in this clinical situation, or an alternative isotopic scan, such as indium-labelled white cells, should be considered.

  6. Intravenous augmentative citalopram versus clomipramine in partial/nonresponder depressed patients: a short-term, low dose, randomized, placebo-controlled study.

    PubMed

    Altamura, Alfredo Carlo; Dell'Osso, Bernardo; Buoli, Massimiliano; Zanoni, Silvia; Mundo, Emanuela

    2008-08-01

    The aim of the present study was to evaluate the efficacy of short-term low-dose intravenous augmentative citalopram (10 mg/d) versus clomipramine (25 mg/d) versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors (SSRIs). Fifty-four patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, MDE and partial or no response to SSRIs per os (21-item Hamilton Depression Rating Scale [HAM-D21] score reduction, <50% or < or =25%, respectively, compared with pretreatment scores) were selected and randomized to citalopram (n = 18), clomipramine (n = 18), or placebo (n = 18) intravenous augmentation. The augmentation regimen lasted 5 days during which patients were maintained on their previous treatment with oral SSRIs. Analyses of variance with repeated measures on HAM-D(21), collected daily in blind-raters design, were performed to detect any change of depressive symptoms between the 3 groups. In addition, the number of responders and remitters was computed in the 3 groups of treatment. At end point, a significant treatment effect (F= 4.57; P = 0.015) and time-by-treatment effect (F = 11.22; P < 0.0001) were found on HAM-D21 total scores in favor of citalopram and clomipramine versus placebo, with a superiority of citalopram over clomipramine on overall symptoms (P = 0.05) as well as on anxiety-somatization symptoms (P = 0.027). The number of responders was significantly superior in the active treatment groups versus the placebo group ([chi](2)(2) = 16.36; P < 0.0001). The same result was found, considering the number of remitters ([chi](2)(2) = 13.50; P < 0.0001). Present findings suggest that both clomipramine and citalopram intravenous augmentation at low doses and for a short period are well tolerated and superior to placebo in major depressives with partial or no response to oral SSRIs with a possible superiority of citalopram over clomipramine with regard to

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

    PubMed

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

    2012-08-01

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

  8. Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration of a single dose to American kestrels (Falco sparverius)

    USGS Publications Warehouse

    Sanchez-Migallon Guzman, David; KuKanich, Butch; Drazenovich, Tracy L.; Olsen, Glenn H.; Paul-Murphy, Joanne R.

    2014-01-01

    Conclusion and Clinical Relevance—Results indicated hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with a short terminal half-life, rapid plasma clearance, and large volume of distribution in American kestrels. Further studies regarding the effects of other doses, other administration routes, constantrate infusions, and slow release formulations on the pharmacokinetics of hydromorphone hydrochloride and its metabolites in American kestrels may be indicated.

  9. Recombinant T-Cell Receptor Ligand (RTL) for Treatment of Multiple Sclerosis: A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study

    PubMed Central

    Yadav, Vijayshree; Bourdette, Dennis N.; Bowen, James D.; Lynch, Sharon G.; Mattson, David; Preiningerova, Jana; Bever, Christopher T.; Simon, Jack; Goldstein, Andrew; Burrows, Gregory G.; Offner, Halina; Ferro, Al J.; Vandenbark, Arthur A.

    2012-01-01

    Background. Recombinant T-cell receptor ligand 1000 (RTL1000) is a single-chain protein construct containing the outer two domains of HLA-DR2 linked to myelin-oligodendrocyte-glycoprotein- (MOG-) 35–55 peptide. Analogues of RTL1000 induce T-cell tolerance, reverse clinical and histological disease, and promote repair in experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic, C57BL/6, and SJL/J mice. Objective. Determining the maximum tolerated dose, safety, and tolerability of RTL1000 in multiple sclerosis (MS) subjects. Methods. This was a multicenter, Phase I dose-escalation study in HLA-DR2+ MS subjects. Consecutive cohorts received RTL1000 doses of 2, 6, 20, 60, 200, and 100 mg, respectively. Subjects within each cohort randomly received a single intravenous infusion of RTL1000 or placebo at a 4 : 2 ratio. Safety monitoring included clinical, laboratory, and brain magnetic resonance imaging (MRI) evaluations. Results. Thirty-four subjects completed the protocol. All subjects tolerated the 2–60 mg doses of RTL1000. Doses ≥100 mg caused hypotension and diarrhea in 3 of 4 subjects, leading to discontinuation of further enrollment. Conclusions. The maximum tolerated dose of RTL1000 in MS subjects is 60 mg, comparable to effective RTL doses in EAE. RTL1000 is a novel approach for MS treatment that may induce immunoregulation without immunosuppression and promote neural repair. PMID:22548151

  10. High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial.

    PubMed

    Vial, Pablo A; Valdivieso, Francisca; Ferres, Marcela; Riquelme, Raul; Rioseco, M Luisa; Calvo, Mario; Castillo, Constanza; Díaz, Ricardo; Scholz, Luis; Cuiza, Analia; Belmar, Edith; Hernandez, Carla; Martinez, Jessica; Lee, Sang-Joon; Mertz, Gregory J

    2013-10-01

    Andes virus (ANDV)-related hantavirus cardiopulmonary syndrome (HCPS) has a 35% case fatality rate in Chile and no specific treatment. In an immunomodulatory approach, we evaluated the efficacy of intravenous methylprednisolone for HCPS treatment, through a parallel-group, placebo-controlled clinical trial. Patients aged >2 years, with confirmed or suspected HCPS in cardiopulmonary stage, admitted to any of 13 study sites in Chile, were randomized by study center in blocks of 4 with a 1:1 allocation and assigned through sequentially numbered envelopes to receive placebo or methylprednisolone 16 mg/kg/day (≤1000 mg) for 3 days. All personnel remained blinded except the local pharmacist. Infection was confirmed by immunoglobulin M antibodies or ANDV RNA in blood. The composite primary endpoint was death, partial pressure of arterial oxygen/fraction of inspired oxygen ratio ≤55, cardiac index ≤2.2, or ventricular tachycardia or fibrillation within 28 days. Safety endpoints included the number of serious adverse events (SAEs) and quantification of viral RNA in blood. Analysis was by intention to treat. Infection was confirmed in 60 of 66 (91%) enrollees. Fifteen of 30 placebo-treated patients and 11 of 30 methylprednisolone-treated patients progressed to the primary endpoint (P = .43). We observed no significant difference in mortality between treatment groups (P = .41). There was a trend toward more severe disease in placebo recipients at entry. More subjects in the placebo group experienced SAEs (P = .02). There were no SAEs clearly related to methylprednisolone administration, and methylprednisolone did not increase viral load. Although methylprednisolone appears to be safe, it did not provide significant clinical benefit to patients. Our results do not support the use of methylprednisolone for HCPS. NCT00128180.

  11. High-Dose Intravenous Methylprednisolone for Hantavirus Cardiopulmonary Syndrome in Chile: A Double-Blind, Randomized Controlled Clinical Trial

    PubMed Central

    Vial, Pablo A.; Valdivieso, Francisca; Ferres, Marcela; Riquelme, Raul; Rioseco, M. Luisa; Calvo, Mario; Castillo, Constanza; Díaz, Ricardo; Scholz, Luis; Cuiza, Analia; Belmar, Edith; Hernandez, Carla; Martinez, Jessica; Lee, Sang-Joon; Mertz, Gregory J.; Abarca, Juan; Tomicic, Vinko; Aracena, M. Eugenia; Rehbein, Ana Maria; Velásquez, Soledad; Lavin, Victoria; Garrido, Felipe; Godoy, Paula; Martinez, Constanza; Chamorro, Juan Carlos; Contreras, Jorge; Hernandez, Jury; Pino, Marcelo; Villegas, Paola; Zapata, Viviana; León, Marisol; Vega, Ivonne; Otarola, Irisol; Ortega, Carlos; Daube, Elizabeth; Huecha, Doris; Neira, Alda; Ruiz, Ines; Nuñez, M. Antonieta; Monsalve, Luz; Chabouty, Henriette; Riquelme, Lorena; Palma, Samia; Bustos, Raul; Miranda, Ruben; Mardones, Jovita; Hernandez, Nora; Betancur, Yasna; Sanhueza, Ligia; Inostroza, Jaime; Donoso, Solange; Navarrete, Maritza; Acuña, Lily; Manriquez, Paulina; Castillo, Fabiola; Unzueta, Paola; Aguilera, Teresa; Osorio, Carola; Yobanolo, Veronica; Mardones, Jorge; Aranda, Sandra; Carvajal, Soledad; Sandoval, Moisés; Daza, Soraya; Vargas, Felipe; Diaz, Violeta; Riquelme, Mauricio; Muñoz, Miriam; Carriel, Andrea; Lanino, Paola; Hernandez, Susana; Schumacher, Patricia; Yañez, Lia; Marco, Claudia; Ehrenfeld, Mildred; Delgado, Iris; Rios, Susana; Vial, Cecilia; Bedrick, Edward

    2013-01-01

    Background. Andes virus (ANDV)–related hantavirus cardiopulmonary syndrome (HCPS) has a 35% case fatality rate in Chile and no specific treatment. In an immunomodulatory approach, we evaluated the efficacy of intravenous methylprednisolone for HCPS treatment, through a parallel-group, placebo-controlled clinical trial. Methods. Patients aged >2 years, with confirmed or suspected HCPS in cardiopulmonary stage, admitted to any of 13 study sites in Chile, were randomized by study center in blocks of 4 with a 1:1 allocation and assigned through sequentially numbered envelopes to receive placebo or methylprednisolone 16 mg/kg/day (≤1000 mg) for 3 days. All personnel remained blinded except the local pharmacist. Infection was confirmed by immunoglobulin M antibodies or ANDV RNA in blood. The composite primary endpoint was death, partial pressure of arterial oxygen/fraction of inspired oxygen ratio ≤55, cardiac index ≤2.2, or ventricular tachycardia or fibrillation within 28 days. Safety endpoints included the number of serious adverse events (SAEs) and quantification of viral RNA in blood. Analysis was by intention to treat. Results. Infection was confirmed in 60 of 66 (91%) enrollees. Fifteen of 30 placebo-treated patients and 11 of 30 methylprednisolone-treated patients progressed to the primary endpoint (P = .43). We observed no significant difference in mortality between treatment groups (P = .41). There was a trend toward more severe disease in placebo recipients at entry. More subjects in the placebo group experienced SAEs (P = .02). There were no SAEs clearly related to methylprednisolone administration, and methylprednisolone did not increase viral load. Conclusions. Although methylprednisolone appears to be safe, it did not provide significant clinical benefit to patients. Our results do not support the use of methylprednisolone for HCPS. Clinical Trials Registration. NCT00128180. PMID:23784924

  12. Abnormalities in cadmium fluoride kinetics in serum, bile, and urine after single intravenous administration of toxic doses to rats.

    PubMed

    Dote, Tomotaro; Adachi, Kazuya; Yamadori, Emi; Imanishi, Masafumi; Tsuji, Hiroshi; Tanida, Eri; Kono, Koichi

    2008-01-01

    Cadmium fluoride (CdF2, CdF for short) is the most lethal and hepatotoxic of all Cd-containing compounds. The toxic effects of CdF appear to depend on its detoxification and elimination. This study was designed to determine the early dynamics of the absorption, systemic distribution, and metabolism of CdF. The kinetics of cadmium and fluoride were investigated in the blood, bile, and urine of rats as a model of accidental occupational exposure to CdF. The serum concentration-time profiles measured after intravenous CdF (1.34, 2.67 or 4.01 mg/ per kg body weight) administration were analyzed by compartmental modeling using the WinNonlin program. Bile and urine were collected for 300 min after the administration. The kinetic profiles indicate that the clearance of Cd was diminished in the 2.67 and 4.01 mg/kg groups, leading to a persistently high serum Cd level. The mean total biliary excretions of Cd in the 2.67 and 4.01 mg/kg groups were significantly higher than that in the 1.34 mg/kg group. The abnormal kinetics of Cd was attributable to severe hepatic injury that diminished the capacity for Cd accumulation. The elimination of serum F was delayed in the 4.01 mg/kg group. The mean urinary F excretion amount was not significantly higher in the 4.01 mg/kg group than in the 2.67 mg/kg group. The abnormal kinetics of F was attributable to nephrotoxicity that diminished its elimination from the kidney.

  13. Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens

    PubMed Central

    Riesenberg, Robert A.; Cassella, James V.

    2015-01-01

    Abstract This randomized, double‐blind, placebo‐controlled, parallel‐group study was to determine the pharmacokinetic characteristics, safety, and tolerability of multiple doses of inhaled loxapine aerosol in subjects on a stable, oral, chronic antipsychotic regimen. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Thirty‐two subjects were randomized 1:1:1:1 to receive inhaled loxapine (total doses of 15, 20, or 30 mg) or inhaled placebo administered in 3 divided doses, given 4 hours apart. Following inhalation, the median Tmax was 2 minutes, and concentrations declined to about half Cmax approximately 5 minutes later across the 3 dose levels. The dose proportionality across data from this study combined with data from the single‐dose study showed a slope (90%CI) of log AUCinf versus log dose of 0.818 (0.762–0.875) across the 8 doses (n = 60 subjects) studied, indicating reasonable dose proportionality. The most common adverse events were cough (3 of 32, 9%), sedation (3 of 32, 9%), and dysgeusia (2 of 32, 6%). The inhalation of multiple doses of inhaled loxapine were well tolerated in study subjects and provided a safe, well‐tolerated means for rapidly and reliably achieving therapeutic plasma concentrations of loxapine. ClinicalTrials.gov identifier: NCT00555412 PMID:25808074

  14. Pharmacokinetic Properties of Intravenous Ibuprofen in Healthy Chinese Volunteers.

    PubMed

    Shen, Yali; Nan, Feng; Li, Mei; Liang, Maozhi; Wang, Ying; Chen, Zhihui; Luo, Zhu

    2016-12-01

    No pharmacokinetic data of intravenous ibuprofen were available in a Chinese population and the published information remained inadequate. The present study aimed to investigate the pharmacokinetic properties of intravenous ibuprofen in healthy Chinese volunteers after single- and multiple-dose administration. Twelve subjects received single doses of 200, 400, and 800 mg intravenous ibuprofen, respectively, and multiple doses of 400 mg intravenous ibuprofen, four times per day (every 6 h) till the morning of the sixth day in each study period. After single doses of 200, 400 and 800 mg and multiple doses of 400 mg intravenous ibuprofen, the main pharmacokinetic parameters obtained were: maximum plasma concentration (C max) 23.05 ± 2.96, 41.90 ± 3.22, 76.06 ± 8.70, and 49.53 ± 3.92 μg/ml, respectively, which were achieved immediately at the end of the infusion; area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUC0-t ) 49.82 ± 10.92, 88.79 ± 12.43, 152.34 ± 25.23, and 106.68 ± 18.94 µg·h/mL, respectively; AUC from time zero to infinity (AUC0-∞) 51.91 ± 10.67, 91.46 ± 12.06, 155.04 ± 25.70, and 108.58 ± 19.49 µg·h/ml, respectively; half-life (t ½) 1.87 ± 0.30, 1.93 ± 0.24, 2.02 ± 0.38, and 1.74 ± 0.26 h, respectively. The accumulation index (AI) was 1.22 ± 0.17 after multiple doses. The most obvious accumulation was observed in males; other parameters revealed no significant differences. Similar pharmacokinetic properties of intravenous ibuprofen in healthy Chinese volunteers were observed to those reported in a Caucasian population. Multiple doses of intravenous ibuprofen every 6 h caused slight accumulation. Except for the AI, sex did not affect the pharmacokinetics of intravenous ibuprofen. CHICTR. ChiCTR-IIR-15007347.

  15. Statistical strategies for averaging EC50 from multiple dose-response experiments.

    PubMed

    Jiang, Xiaoqi; Kopp-Schneider, Annette

    2015-11-01

    In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.

  16. Computational determination of absorbed dose distributions from multiple volumetric gamma ray sources

    NASA Astrophysics Data System (ADS)

    Zhou, Chuanyu; Inanc, Feyzi

    2002-05-01

    Determination of absorbed dose distributions is very important in brachytherapy procedures. The typical computation involves superposition of absorbed dose distributions from a single seed to compute the combined absorbed dose distribution formed by multiple seeds. This approach does not account for the shadow effect caused by the metallic nature of volumetric radioactive seeds. Since this shadow effect will cause deviations from the targeted dose distribution, it may have important implications on the success of the procedures. We demonstrated accuracy of our deterministic algorithms for isotropic point sources in the past. We will show that we now have the capability of computing absorbed dose distributions from multiple volumetric seeds and demonstrate that our results are quite close to the results published in the literature.

  17. Pharmacokinetics of meloxicam after intravenous, intramuscular and oral administration of a single dose to African grey parrots (Psittacus erithacus).

    PubMed

    Montesinos, A; Ardiaca, M; Gilabert, J A; Bonvehí, C; Oros, J; Encinas, T

    2016-09-06

    Meloxicam is a nonsteroidal anti-inflammatory drug commonly used in avian species. In this study, the pharmacokinetic parameters for meloxicam were determined following single intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administrations of the drug (1 mg/kg·b.w.) in adult African grey parrots (Psittacus erithacus; n = 6). Serial plasma samples were collected and meloxicam concentrations were determined using a validated high-performance liquid chromatography assay. A noncompartmental pharmacokinetic analysis was performed. No undesirable side effects were observed during the study. After i.v. administration, the volume of distribution, clearance and elimination half-life were 90.6 ± 4.1 mL/kg, 2.18 ± 0.25 mL/h/kg and 31.4 ± 4.6 h, respectively. The peak mean ± SD plasma concentration was 8.32 ± 0.95 μg/mL at 30 min after i.m. administration. Oral administration resulted in a slower absorption (tmax  = 13.2 ± 3.5 h; Cmax  = 4.69 ± 0.75 μg/mL) and a lower bioavailability (38.1 ± 3.6%) than for i.m. (78.4 ± 5.5%) route. At 24 h, concentrations were 5.90 ± 0.28 μg/mL for i.v., 4.59 ± 0.36 μg/mL for i.m. and 3.21 ± 0.34 μg/mL for p.o. administrations and were higher than those published for Hispaniolan Amazon parrots at 12 h with predicted analgesic effects.

  18. Total ionizing dose effects in multiple-gate field-effect transistor

    NASA Astrophysics Data System (ADS)

    Gaillardin, Marc; Marcandella, Claude; Martinez, Martial; Raine, Mélanie; Paillet, Philippe; Duhamel, Olivier; Richard, Nicolas

    2017-08-01

    This paper focuses on total ionizing dose (TID) effects induced in multiple-gate field-effect transistors. The impact of device architecture, geometry and scaling on the TID response of multiple-gate transistors is reviewed in both bulk and silicon-on-insulator (SOI) complementary metal-oxide-semiconductor (CMOS) technologies. These innovating devices exhibit specific ionizing dose responses which strongly depend on their three-dimensional nature. Their TID responses may look like the one usually observed in planar two-dimensional bulk or SOI transistors, but multiple-gate devices can also behave like any other CMOS device.

  19. The effect of a single intravenous dose of metamizol 2 g, ketorolac 30 mg and propacetamol 1 g on haemodynamic parameters and postoperative pain after heart surgery.

    PubMed

    Avellaneda, C; Gómez, A; Martos, F; Rubio, M; Sarmiento, J; de la Cuesta, F S

    2000-02-01

    Although nonopiate analgesics may be particularly useful in the immediate postoperative period after major surgery, their use has been associated with haemodynamic adverse effects during postoperative pain treatment and in critically ill patients in intensive care. The effect of a single intravenous dose of metamizol (dipyrone) 2 g, ketorolac 30 mg and propacetamol 1 g on haemodynamic variables and pain control in the immediate postoperative period after heart surgery is compared. Seventy-two patients undergoing elective coronary and/or heart valve surgery, were included in a cohort study of 1-years duration (1998). After weaning from mechanical ventilation and extubation, haemodynamic variables and a 4-point verbal rating pain scale were asseseed at base-line and 60 min after the administration of a single doses of metamizol, ketorolac or propacetamol. The Student's t-test for paired samples was used to compare changes produced by the study medications. A significant, but small, decrease in radial artery blood pressure was observed in all treatment groups which had little clinical relevance; no vasodilator effects were observed and ventricular function showed only minor changes: propacetamol decreased cardiac index by 10% and a 15% decrease in right ventricular work was also observed. Metamizol and ketorolac produced a 10% decrease in the left ventricular work index. Pain scores showed a statistically significant decrease in all treatment groups. The analgesic effects of metamizol, ketorolac and propacetamol were not associated with a clinically significant impairment in haemodynamic function when administered to haemodynamically stable patients.

  20. Vaginal Dinoprostone Versus Intravenous Oxytocin for Labor Induction in Patients Not Responsive to a First Dose of Dinoprostone: A Randomized Prospective Study.

    PubMed

    Antonazzo, Patrizio; Laoreti, Arianna; Personeni, Carlo; Grossi, Elena; Martinelli, Anna; Cetin, Irene

    2016-06-01

    To evaluate the efficacy of 2 different regimens for labor induction in patients with unfavorable cervix not responsive to a first dose of dinoprostone vaginal insert. Between November, 2011 and June, 2014, 338 patients underwent induction of labor. After standard 24 hours treatment, 94 singleton term pregnancies remained with a Bishop score ≤6 and were randomized into 2 different regimens: repeated vaginal dinoprostone (group A, n = 47) or intravenous oxytocin (group B, n = 47). Primary outcome was vaginal delivery, and the secondary outcomes were interval between labor induction and delivery and operative delivery rates. Vaginal deliveries were significantly higher (group A: 26/47 (55.3%) and group B 16/47 (34.0%), P < .05), and cesarean sections were significantly lower (group A 21/47 (44.7%) and group B 31/47 (66%), P < .05) in patients who received a double dose of dinoprostone. The intervals between labor induction and onset of labor and between labor induction and delivery were lower in the group treated with oxytocin. Neonatal outcomes were similar in the 2 groups. A second dinoprostone vaginal insert is an effective and safe choice for patients with unfavorable cervix not responsive to a first 24 hours administration of dinoprostone for cervical ripening, and its use is associated with lower cesarean section rates. © The Author(s) 2015.

  1. CT of multiple sclerosis: reassessment of delayed scanning with high doses of contrast material

    SciTech Connect

    Spiegel, S.M.; Vinuela, F.; Fox, A.J.; Pelz, D.M.

    1985-09-01

    A prospective study involving 87 patients was carried out to evaluate the necessity for a high dose of contrast material in addition to delayed computed tomographic (CT) scanning for optimal detection of the lesions of multiple sclerosis in the brain. In patients with either clinically definite multiple sclerosis or laboratory-supported definite multiple sclerosis, CT scans were obtained with a uniform protocol. Lesions consistent with multiple sclerosis were demonstrated on the second scan in 54 patients. In 36 of these 54 patients, the high-dose delayed scan added information. These results are quite similar to those of a previous study from this institution using different patients, in whom the second scan was obtained immediately after the bolus injection of contrast material containing 40 g of organically bound iodine. The lack of real difference in the results of the two studies indicate that the increased dose, not just the delay in scanning, is necessary for a proper study.

  2. High-dose Melphalan-based Autotransplants for Multiple Myeloma

    PubMed Central

    Pineda-Roman, Mauricio; Barlogie, Bart; Anaissie, Elias; Zangari, Maurizio; Bolejack, Vanessa; van Rhee, Frits; Tricot, Guido; Crowley, John

    2013-01-01

    BACKGROUND In this report, the authors describe their collective experience with melphalan-based autotransplants since the inception of their program at the University of Arkansas for Medical Sciences in 1989. METHODS The authors evaluated the clinical outcomes of 3077 successive patients with multiple myeloma (MM) who underwent at least 1 melphalan-based autotransplantation at the University of Arkansas. Of these, 1078 patients were enrolled on front-line Total Therapy (TT) protocols (TT-P) TT1, TT2, and TT3; 1104 patients were entered on protocols for newly diagnosed or previously treated patients (non-TT-P); and 895 patients were treated off protocol (non-P). RESULTS The 10-year overall survival (OS) rates after first transplantation were 41%, 19%, and 11% (P < .001) for the TT-P, non-TT-P, and non-P groups, respectively. In the TT-P group, the median OS was 72 months on TT1, was not reached at ≥7 years on TT2, and was 88% at 2 years on TT3. Among 2683 patients with complete baseline data, absence of hypodiploidy/chromosome 13 deletion, β-2-microglobulin <3.0 mg/L, C-reactive protein <6 mg/L, albumin ≥3.0 g/dL, and platelet count ≥100,000/μL all were associated independently with superior OS (P < .001), event-free survival (P < .001), and duration of complete remission (P < .001). CONCLUSIONS The results from this large, single-institution experience demonstrated that >10-year OS was accomplished in >40% of all patients enrolled on TT-P, whereas such success was observed in only 15% of the remaining patients (including 25% in the presence of all 5 good-risk features). Superior outcomes with protocol-based, primary transplant regimens such as TT-P draw attention to the importance of applying the best available therapies upfront. PMID:18300230

  3. Generation of Composite Dose and Biological Effective Dose (BED) Over Multiple Treatment Modalities and Multistage Planning Using Deformable Image Registration

    SciTech Connect

    Zhang, Geoffrey Huang, T-C; Feygelman, Vladimir; Stevens, Craig; Forster, Kenneth

    2010-07-01

    Currently there are no commercially available tools to generate composite plans across different treatment modalities and/or different planning image sets. Without a composite plan, it may be difficult to perform a meaningful dosimetric evaluation of the overall treatment course. In this paper, we introduce a method to generate composite biological effective dose (BED) plans over multiple radiotherapy treatment modalities and/or multistage plans, using deformable image registration. Two cases were used to demonstrate the method. Case I was prostate cancer treated with intensity-modulated radiation therapy (IMRT) and a permanent seed implant. Case II involved lung cancer treated with two treatment plans generated on two separate computed tomography image sets. Thin-plate spline or optical flow methods were used as appropriate to generate deformation matrices. The deformation matrices were then applied to the dose matrices and the resulting physical doses were converted to BED and added to yield the composite plan. Cell proliferation and sublethal repair were considered in the BED calculations. The difference in BED between normal tissues and tumor volumes was accounted for by using different BED models, {alpha}/{beta} values, and cell potential doubling times. The method to generate composite BED plans presented in this paper provides information not available with the traditional simple dose summation or physical dose summation. With the understanding of limitations and uncertainties of the algorithms involved, it may be valuable for the overall treatment plan evaluation.

  4. Cerebral blood flow change during volatile induction in large-dose sevoflurane versus intravenous propofol induction: transcranial Doppler study

    PubMed Central

    Jung, Hwa Sung; Sung, Tae-Yun; Kang, Hyun; Kim, Jin Sun

    2014-01-01

    Background The impact of volatile induction using large-dose sevoflurane (VI-S) on cerebral blood flow has not been well investigated. The present study compared the changes in cerebral blood flow of middle cerebral artery using transcranial Doppler (TCD) during VI-S and conventional induction using propofol. Methods Patients undergoing elective lumbar discectomy were randomly allocated to receive either sevoflurane (8%, Group VI-S, n = 11) or target-controlled infusion of propofol (effect site concentration, 3.0 µg/ml; Group P, n = 11) for induction of anesthesia. The following data were recorded before and at 1, 2, and 3 min after commencement of anesthetic induction (T0, T1, T2, and T3, respectively): mean velocity of the middle cerebral artery (VMCA) by TCD, mean blood pressure (MBP), heart rate, bispectral index score (BIS) and end-tidal CO2 (ETCO2). Changes in VMCA and MBP from their values at T0 (ΔVMCA and ΔMBP) at T1, T2, and T3 were also determined. Results BISs at T1, T2 and T3 were significantly less than that at T0 in both groups (P < 0.05). ΔVMCA in Group VI-S at T2 and T3 (18.1% and 12.4%, respectively) were significantly greater than those in Group P (-7.6% and -19.8%, P = 0.006 and P < 0.001, respectively), whereas ETCO2 and ΔMBP showed no significant intergroup difference. Conclusions VI-S using large-dose sevoflurane increases cerebral blood flow resulting in luxury cerebral flow-metabolism mismatch, while conventional propofol induction maintains cerebral flow-metabolism coupling. This mismatch in VI-S may have to be considered in clinical application of VI-S. PMID:25473461

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

    PubMed

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

    2013-03-01

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

  6. Intravenous nicotine self-administration and cue-induced reinstatement in mice: Effects of nicotine dose, rate of drug infusion and prior instrumental training

    PubMed Central

    Fowler, Christie D.; Kenny, Paul J.

    2011-01-01

    Intravenous nicotine self-administration is the most direct measure of nicotine reinforcement in laboratory animals, but this procedure has proven difficult to establish in mice. We found that stable responding for nicotine in C57BL6/J mice was facilitated by prior instrumental training for food reward, initial exposure of mice to a lower unit dose of nicotine (0.03 mg/kg/infusion) before access to higher doses, a slower rate of drug delivery (3-sec versus 1-sec infusion), consistency in schedule of daily testing, and low extraneous noise during testing. Under these conditions, we found that mice lever-pressing for nicotine (0.03–0.4 mg/kg/infusion; 60-min test sessions) under a fixed-ratio 5 time-out 20-sec (FR5TO20) reinforcement schedule consumed the drug according to an inverted ‘U’-shaped dose-response curve. Mice switched their responding onto a previously non-reinforced lever to continue earning nicotine infusions when the active/inactive lever assignment was reversed. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased responding for nicotine, but not food rewards, verifying that nAChRs regulate nicotine self-administration in mice. The cue-light paired with nicotine delivery did not support responding when delivered independently of nicotine infusions, further verifying that mice responded selectivity for the drug. Nicotine-seeking responses extinguished when nicotine infusions and the cue-light were withheld, and exposure to the cue-light reinstated responding. Finally, mice without prior instrumental food training acquired stable responding for nicotine under the FR5TO20 schedule, but required a greater number of sessions. These data demonstrate that nicotine is an effective reinforcer in mice and establish conditions under which the drug is reliably self-administered by mice. PMID:21640128

  7. Dose-response characteristics of intravenous ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats.

    PubMed

    Radford, Kennett D; Park, Thomas Y; Lee, Bong Hyo; Moran, Sean; Osborne, Lisa A; Choi, Kwang H

    2017-02-01

    Clinicians administer subanesthetic intravenous (IV) ketamine infusions for treatment of refractory depression, chronic pain, and post-traumatic stress disorder in humans. However, ketamine is administered via the subcutaneous (SC) or intraperitoneal (IP) routes to rodents in most pre-clinical research, which may limit translational application. The present study characterized the dose-response of a subanesthetic IV ketamine bolus (2 and 5mg/kg) and 1-h infusion (5, 10, and 20mg/kg/h) on dissociative stereotypy, locomotion, sensorimotor gating, and thermal nociception in male Sprague-Dawley rats. The secondary aim was to measure ketamine and norketamine plasma concentrations following IV ketamine bolus at 1, 20, and 50min and at the conclusion of the 1-h infusion using liquid chromatography/mass spectrometry. The results showed that ketamine bolus and infusions produced dose-dependent dissociative stereotypy. Bolus (2 and 5mg/kg) and 20mg/kg/h infusion increased locomotor activity while 5mg/kg/h infusion decreased locomotor activity. Both 10 and 20mg/kg/h infusions reduced the acoustic startle reflex, while 5mg/kg bolus and 20mg/kg/h infusion impaired pre-pulse inhibition. Ketamine 5mg/kg bolus and the 10 and 20mg/kg/h infusions induced significant and prolonged antinociception to the hotplate test. Plasma concentrations of ketamine decreased quickly after bolus while norketamine levels increased from 1 to 20min and plateaued from 20 to 50min. The peak ketamine plasma concentrations [ng/ml] were similar between 5mg/kg bolus [4100] vs. 20mg/kg/h infusion [3900], and 2mg/kg bolus [1700] vs. 10mg/kg/h infusion [1500]. These results support the findings from previous ketamine injection studies and further validate the feasibility of administering subanesthetic doses of IV ketamine infusion to rats for neuropharmacological studies. Published by Elsevier Inc.

  8. Infusion of high-dose intravenous immunoglobulin fails to lower the strength of human leukocyte antigen antibodies in highly sensitized patients.

    PubMed

    Alachkar, Nada; Lonze, Bonnie E; Zachary, Andrea A; Holechek, Mary J; Schillinger, Karl; Cameron, Andrew M; Desai, Niraj M; Dagher, Nabil N; Segev, Dorry L; Montgomery, Robert A; Singer, Andrew L

    2012-07-27

    Human leukocyte antigen (HLA) sensitization presents a major obstacle for patients awaiting renal transplantation. HLA antibody reduction and favorable transplantation rates have been reported after treatment with high-dose intravenous immunoglobulin (IVIg). We enrolled 27 patients whose median flow cytometric calculated panel reactive antibody (CPRA) was 100% and mean wait-list time exceeded 4 years in a protocol whereby high-dose IVIg was administered, HLA antibody profiles of sera obtained before and after treatment were characterized, and cross-match tests were performed with all blood group identical kidney offers. Whereas 12.8% of a similarly sensitized historic control cohort underwent transplantation in the course of a year, 41% of the IVIg-treated group underwent transplantation during the study period. Surprisingly, HLA antibody profiles, measured by CPRA, showed no significant change in response to IVIg treatment. In fact, retrospective cross-match testing using pretreatment sera of those receiving deceased-donor allografts showed that all patients would have been eligible for transplantation with their respective donors before IVIg infusions. This study does not corroborate previous reports of CPRA reduction leading to increased deceased-donor transplantation rates in broadly sensitized patients undergoing desensitization with high-dose IVIg. The increased rate of transplantation relative to historic controls is not related to improved cross-match eligibility and likely resulted from frequent crossmatching using a cytotoxic strength threshold, improved medical readiness for transplantation, and newly recognized options for live-donor transplantation, all of which could have been achieved without IVIg treatment.

  9. Acute and chronic bioeffects of single and multiple doses of piezoelectric shockwaves (EDAP LT.01).

    PubMed

    Ryan, P C; Jones, B J; Kay, E W; Nowlan, P; Kiely, E A; Gaffney, E F; Butler, M R

    1991-02-01

    Piezoelectric second generation lithotriptors are an established means of administering extracorporeal shockwave lithotripsy (ESWL) enabling treatment to be performed without anaesthesia or analgesia, but higher shockwave doses and multiple or staged treatment are frequently required. The bioeffects of this modality of ESWL, therefore, require further assessment. Seven experimental groups of adult male rabbits were treated using the EDAP LT.01 in order to determine the acute and chronic bioeffects of clinical dose, excess dose, divided excess dose, high frequency and multiple treatment (X10) piezoelectric shockwaves (PSW). Renal function was measured before and after treatment using mercaptoacetyltriglycine (MAG 3) scans. Gross and histological morphological changes were assessed at one and 30 days following application of PSW. Application of single clinical dose PSW was not associated with any significant functional or morphological renal injury. Excess dose PSW caused transient gross renal contusion, which resolved in the majority of animals with no persistent microscopic abnormality. Divided excess dose PSW resulted in no gross or microscopic damage. High frequency PSW was associated with mild histological abnormality. Multiple PSW treatments caused small discrete fibrotic lesions in all cases, without any change in renal function.

  10. Prescription Dose Guideline Based on Physical Criterion for Multiple Metastatic Brain Tumors Treated With Stereotactic Radiosurgery

    SciTech Connect

    Sahgal, Arjun; Barani, Igor J.; Novotny, Josef; Zhang Beibei; Petti, Paula; Larson, David A.; Ma Lijun

    2010-10-01

    Purpose: Existing dose guidelines for intracranial stereotactic radiosurgery (SRS) are primarily based on single-target treatment data. This study investigated dose guidelines for multiple targets treated with SRS. Methods and Materials: A physical model was developed to relate the peripheral isodose volume dependence on an increasing number of targets and prescription dose per target. The model was derived from simulated and clinical multiple brain metastatic cases treated with the Leksell Gamma Knife Perfexion at several institutions, where the total number of targets ranged from 2 to 60. The relative increase in peripheral isodose volumes, such as the 12-Gy volume, was studied in the multitarget treatment setting based on Radiation Therapy Oncology Group 90-05 study dose levels. Results: A significant increase in the 12-Gy peripheral isodose volumes was found in comparing multiple target SRS to single-target SRS. This increase strongly correlated (R{sup 2} = 0.92) with the total number of targets but not the total target volumes (R{sup 2} = 0.06). On the basis of the correlated curve, the 12-Gy volume for multiple target treatment was found to increase by approximately 1% per target when a low target dose such as 15 Gy was used, but approximately 4% per target when a high dose such as 20-24 Gy was used. Reduction in the prescription dose was quantified for each prescription level in maintaining the 12-Gy volume. Conclusion: Normal brain dose increases predictably with increasing number of targets for multitarget SRS. A reduction of approximately 1-2 Gy in the prescribed dose is needed compared with single target radiosurgery.

  11. Acute Hemodynamic Changes After Rapid Intravenous Bolus Dosing of Dexmedetomidine in Pediatric Heart Transplant Patients Undergoing Routine Cardiac Catheterization

    PubMed Central

    Jooste, EH; Muhly, WT; Ibinson, JW; Suresh, T; Damian, D; Phadke, A; Callahan, P; Miller, S; Feingold, B; Lichtenstein, SE; Cain, JG; Chrysostomou, C; Davis, PJ

    2011-01-01

    Introduction Dexmedetomidine is a highly selective α2-adrenoceptor agonist with sedative, anxiolytic and analgesic properties that has minimal effects on respiratory drive. Its sedative and hypotensive effects are mediated via central α2A and imidazoline type 1 receptors while activation of peripheral α2B–adrenoceptors result in an increase in arterial blood pressure and systemic vascular resistance (SVR). In this randomized, prospective, clinical study we attempted to quantify the short-term hemodynamic effects resulting from a rapid IV bolus administration of dexmedetomidine in pediatric cardiac transplant patients. Methods Twelve patients, aged ≤10 years of age, weighing ≤40kg, presenting for routine surveillance of right and left heart cardiac catheterization after cardiac transplantation were enrolled. After an inhaled or IV induction, the tracheas were intubated and anesthesia was maintained with 1 minimum alveolar concentration of isoflurane in room air, fentanyl (1mcg/kg) and rocuronium (1mg/kg). At the completion of the planned cardiac catheterization, 100% oxygen was administered. After recording a set of baseline values that included heart rate (HR), systolic blood pressure, diastolic blood pressure, central venous pressure, systolic pulmonary artery pressure, diastolic pulmonary artery pressure, pulmonary artery wedge pressure and thermodilution-based cardiac output, a rapid IV dexmedetomidine bolus of either 0.25mcg/kg or 0.5mcg/kg was administered over 5 seconds. The hemodynamic measurements were repeated at 1 min and 5 mins. Results There were 6 patients in each group. Investigation suggested that systolic blood pressure, diastolic blood pressure, systolic pulmonary artery pressure, diastolic pulmonary artery pressure, pulmonary artery wedge pressure and systemic vascular resistance all increased at 1 minute after rapid IV bolus for both doses, and decreased significantly to near baseline for both doses by 5 minutes. The transient increase

  12. Dose-related modulation of event-related potentials to novel and target stimuli by intravenous Δ⁹-THC in humans.

    PubMed

    D'Souza, Deepak Cyril; Fridberg, Daniel J; Skosnik, Patrick D; Williams, Ashley; Roach, Brian; Singh, Nagendra; Carbuto, Michelle; Elander, Jacqueline; Schnakenberg, Ashley; Pittman, Brian; Sewell, R Andrew; Ranganathan, Mohini; Mathalon, Daniel

    2012-06-01

    Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ⁹-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ⁹-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory 'oddball' P300 task). Δ⁹-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ⁹-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ⁹-THC induced psychotomimetic effects, perceptual alterations, and subjective 'high' in a dose-dependent manner. Δ⁹-THC -induced reductions in P3b amplitude correlated with Δ⁹-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ(9)-THC, there were no dose-related effects of Δ⁹-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ⁹-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP

  13. Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans

    PubMed Central

    D'Souza, Deepak Cyril; Fridberg, Daniel J; Skosnik, Patrick D; Williams, Ashley; Roach, Brian; Singh, Nagendra; Carbuto, Michelle; Elander, Jacqueline; Schnakenberg, Ashley; Pittman, Brian; Sewell, R Andrew; Ranganathan, Mohini; Mathalon, Daniel

    2012-01-01

    Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory ‘oddball' P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective ‘high' in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact

  14. Combination with intravenous iron supplementation or doubling erythropoietin dose for patients with chemotherapy-induced anaemia inadequately responsive to initial erythropoietin treatment alone: study protocol for a randomised controlled trial

    PubMed Central

    Chen, Lin; Jiang, Hong; Gao, Wei; Tu, Ye; Zhou, Ying; Li, Xi; Zhu, Zhe; Jiang, Qixin; Zhan, Haifeng; Yu, Jiangming; Fu, Chuangang; Gao, Yong

    2016-01-01

    Introduction Erythropoietin (EPO) is a commonly used option in the treatment of chemotherapy-induced anaemia (CIA). However, ∼30–50% of patients fail to achieve an adequate response after initial treatment. Prior studies have demonstrated that intravenous iron might synergistically improve therapeutic response to EPO treatment in this patient population. Methods and analysis We will perform this multicentre, randomised, open-label, parallel-group, active controlled non-inferiority study to compare the two combination therapies of EPO plus intravenous iron regimen versus doubling the dose of EPO in patients with CIA who have an inadequate response to initial EPO treatment at a routine dose. A total of 603 patients with an increase in haemoglobin (Hb) <1 g/dL will be enrolled and randomised to one of the three study treatment groups at a 1:1:1 ratio Group 1: EPO treatment at the original dose plus intravenous iron dextran 200 mg every 3 weeks (Q3W) for 15 weeks; Group 2: EPO treatment at the original dose plus intravenous iron dextran 100 mg, twice a week for 5 weeks; Group 3: the control group, doubling the EPO dose without preplanned iron supplementation. The primary outcome measure to compare is the Hb response rate at week 15 and the secondary end points involve therapeutic blood transfusions. Time-to-progression, adverse events and quality of life will also be evaluated. Ethics and dissemination All participants will provide informed consent; the study protocol has been approved by the independent ethics committee of Shanghai East Hospital. This study would clearly demonstrate the potential benefit of combining epoetin treatment with intravenous iron supplementation. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of CIA in China. Trial registration number NCT02731378. PMID:27855097

  15. Intravenous Therapy.

    ERIC Educational Resources Information Center

    Galliart, Barbara

    Intended for teaching licensed practical nurses, this curriculum guide provides information related to the equipment and skills required for nursing care of patients needing intravenous (IV) therapy. It also explains the roles and responsibilities of the licensed practical nurse with regard to intravenous therapy. Each of the 15 instructional…

  16. Intravenous Therapy.

    ERIC Educational Resources Information Center

    Galliart, Barbara

    Intended for teaching licensed practical nurses, this curriculum guide provides information related to the equipment and skills required for nursing care of patients needing intravenous (IV) therapy. It also explains the roles and responsibilities of the licensed practical nurse with regard to intravenous therapy. Each of the 15 instructional…

  17. Multiple-Dose Safety and Pharmacokinetics of Oral Garenoxacin in Healthy Subjects

    PubMed Central

    Gajjar, D. A.; Bello, A.; Ge, Z.; Christopher, L.; Grasela, D. M.

    2003-01-01

    Garenoxacin (T-3811ME, BMS-284756) is a novel des-F(6) quinolone that has been shown to be effective in vitro against a wide range of clinically important pathogens, including gram-positive and gram-negative aerobes and anaerobes. This study was conducted to evaluate the safety and tolerability of multiple oral doses (100 to 1,200 mg/day) of garenoxacin in healthy subjects and to determine its multiple-dose pharmacokinetics. Forty healthy male and female subjects (18 to 45 years of age) were enrolled in this randomized, double-blind, placebo-controlled, sequential, multiple- and ascending-dose study. Each subject received a once-daily oral dose of garenoxacin (100, 200, 400, 800, or 1,200 mg) or a placebo for 14 days. Blood and urine samples were collected for measurements of garenoxacin by validated liquid chromatography with dual mass spectrometry, and plasma garenoxacin concentration-time data were analyzed by noncompartmental methods. The effects of garenoxacin on Helicobacter pylori, psychometric test performance, and electrocardiograms were assessed, as was drug safety. Over the 14 days of dosing, geometric mean peak concentrations of garenoxacin in plasma (Cmax) at the 100- and 1,200-mg doses were within the ranges of 1.2 to 1.6 and 16.3 to 24 μg/ml, respectively. The corresponding values for the geometric mean area under the concentration-time curve over the dosing interval (AUCτ) for garenoxacin in plasma at the 100- and 1,200-mg doses were within the ranges of 11.5 to 15.7 and 180 to 307 μg · h/ml, respectively. Increases in systemic exposure to garenoxacin in terms of AUC and Cmax were approximately dose proportional over the 100- to 400-mg dose range but demonstrated increases that were somewhat greater than the dose increments at the 800- and 1,200-mg doses. Median values for the time to achieve Cmax were in the range of 1.13 to 2.50 h for all doses. The mean elimination half-life for garenoxacin in plasma appeared to be independent of dose and

  18. Phase II Trial of Intravenous Low-Dose Granulocyte Colony-Stimulating Factor in Acute Ischemic Stroke.

    PubMed

    Mizuma, Atsushi; Yamashita, Toru; Kono, Syoichiro; Nakayama, Taira; Baba, Yasuhiko; Itoh, Shinji; Asakura, Kunihiko; Niimi, Yoshiki; Asahi, Takashi; Kanemaru, Kazuya; Mutoh, Tatsuro; Kuroda, Satoshi; Kinouchi, Hiroyuki; Abe, Koji; Takizawa, Shunya

    2016-06-01

    Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  19. Cognitive and Affective Symptoms Experienced by Cancer Patients Receiving High-Dose Intravenous Interleukin 2 Therapy: An Integrative Literature Review.

    PubMed

    Mann, Tara K; Dail, Robin B; Bailey, Donald E

    2016-01-01

    Alterations in cognitive/affective functioning are among the most challenging adverse effects experienced by 80% of patients with metastatic melanoma and metastatic renal cell carcinoma undergoing high-dose interleukin 2 (IL-2) therapy. The purpose of this literature review is to describe what is known about IL-2-induced cognitive/affective symptoms, their prevalence, and level of severity and synthesize findings to determine areas for future research to address symptom management challenges. This review describes the IL-2 patient experience and the pathophysiology leading to these changes. An online electronic search using PubMed was performed to identify relevant literature published between 1992 and 2015. Of the original 113 articles, information was extracted from 9 articles regarding cognitive symptoms, affective symptoms, sample size, research design, reliability, and validity. Our review suggests that the trajectories, breadth, and depth of cognitive/affective symptoms have yet to be described. Despite intervention studies designed to address the psychosocial complications of IL-2, an understanding of the level of altered cognitive/affective symptoms experienced by IL-2 patients remains unclear. Our literature review reveals a lack of standardization when assessing, reporting, and managing cognitive/affective symptoms. Patients/family members have reported cognitive/affective symptoms to be the most alarming and difficult symptoms, yet these symptoms are not adequately screened for, and patients were not informed about potential changes. Assessing patients for cognitive/affective alterations is important to reduce anxiety while improving outcomes. Education about the illness trajectory (what to expect during/after treatment) can help care partners/patients set realistic shared expectations and increase coping.

  20. Biodistribution and tissue toxicity of amphotericin B in mice following multiple dose administration of a novel oral lipid-based formulation (iCo-009).

    PubMed

    Gershkovich, Pavel; Sivak, Olena; Wasan, Ellen K; Magil, Alex B; Owen, David; Clement, John G; Wasan, Kishor M

    2010-12-01

    The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009). BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV. A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study. A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.

  1. Comparative analysis of transcriptional gene regulation indicates similar physiologic response in mouse tissues at low absorbed doses from intravenously administered 211At.

    PubMed

    Langen, Britta; Rudqvist, Nils; Parris, Toshima Z; Schüler, Emil; Helou, Khalil; Forssell-Aronsson, Eva

    2013-06-01

    (211)At is a promising therapeutic radionuclide because of the nearly optimal biological effectiveness of emitted α-particles. Unbound (211)At accumulates in the thyroid gland and in other vital normal tissues. However, few studies have been performed that assess the (211)At-induced normal-tissue damage in vivo. Knowledge about the extent and quality of resulting responses in various organs offers a new venue for reducing risks and side effects and increasing the overall well-being of the patient during and after therapy. Female BALB/c nude mice were injected intravenously with 0.064-42 kBq of (211)At or mock-treated, and the kidneys, liver, lungs, and spleen were excised 24 h after injection. A transcriptional gene expression analysis was performed in triplicate using RNA microarray technology. Biological processes associated with regulated transcripts were grouped into 8 main categories with 31 subcategories according to gene ontology terms for comparison of regulatory profiles. A substantial decrease in the total number of regulated transcripts was observed between 0.64 and 1.8 kBq of (211)At for all investigated tissues. Few genes were differentially regulated in each tissue at all absorbed doses. In all tissues, most of these genes showed a nonmonotonous dependence on absorbed dose. However, the direction of regulation generally remained uniform for a given gene. Few known radiation-associated genes were regulated on the transcriptional level, and their expression profile generally appeared to be dose-independent and tissue-specific. The regulatory profiles of categorized biological processes were tissue-specific and reflected the shift in regulatory intensity between 0.64 and 1.8 kBq of (211)At. The profiles revealed strongly regulated and nonregulated subcategories. The strong regulatory change observed between 0.64 and 1.8 kBq is hypothesized to result not only from low-dose effects in each tissue but also from physiologic responses to ionizing radiation

  2. Determination of the minimum infusion rate of alfaxalone during its co-administration with fentanyl at three different doses by constant rate infusion intravenously in goats.

    PubMed

    Dzikiti, Brighton T; Ndawana, Patience S; Zeiler, Gareth; Ferreira, Jacques P; Dzikiti, Loveness N

    2016-05-01

    To determine the minimum infusion rate (MIR) of alfaxalone required to prevent purposeful movement of the extremities in response to standardized noxious stimulation during its co-administration with fentanyl at three different doses by constant rate infusion (CRI) intravenously (IV) in goats. Prospective, blinded, randomized crossover, experimental. Eight healthy goats; four does and four wethers. For induction of anaesthesia, a bolus of fentanyl was administered at 0.005 mg kg(-1) (LFent), 0.015 mg kg(-1) (MFent) or 0.03 mg kg(-1) (HFent) followed by alfaxalone at 2.0 mg kg(-1) . For maintenance, the goats received alfaxalone at an initial infusion rate of 9.6 mg kg(-1)  hour(-1) and one of three fentanyl treatments: 0.005 mg kg(-1)  hour(-1) (LFent), 0.015 mg kg(-1)  hour(-1) (MFent) or 0.03 mg kg(-1) hour(-1) (HFent). The MIR of alfaxalone was determined during fentanyl CRI by testing for responses to stimulation (clamping on a digit with Vulsellum forceps) every 30 minutes. Some cardiopulmonary parameters were measured. The alfaxalone MIR median (range) was 6.7 (6.7-8.6), 2.9 (1.0-6.7) and 1.0 (1.0-4.8) mg kg(-1)  hour(-1) during LFent, MFent and HFent, respectively. Alfaxalone MIR was significantly lower during MFENT and HFENT compared to LFENT. Significantly low oxygen haemoglobin saturation (SaO2 ) and arterial oxygen partial pressure (PaO2 ), observed 2 minutes into anaesthesia after all fentanyl treatments, were the most remarkable adverse cardiopulmonary effects observed. Recovery from anaesthesia was severely affected by high doses of fentanyl with excitatory behavioural signs predominant for up to 2 hours post-administration after MFent and HFent. Fentanyl reduces alfaxalone MIR in goats in a dose-dependent manner. Immediate oxygen supplementation after induction of general anaesthesia is recommended to prevent hypoxaemia. Doses of fentanyl equal to or greater than 0.015 mg kg(-1)  hour(-1) tend to be associated with severe

  3. Cardiorespiratory and antinociceptive effects of two different doses of lidocaine administered to horses during a constant intravenous infusion of xylazine and ketamine

    PubMed Central

    2013-01-01

    Background This study investigated the antinociceptive effects of a constant rate infusion (CRI) of lidocaine during xylazine and ketamine anesthesia in horses and aimed to correlate these effects with cardiorespiratory variables, bispectral index (BIS) and plasma lidocaine concentrations. Six adult crossbred mares weighing 320–400 kg were anesthetized on three different occasions. Sedation was performed with xylazine (0.75 mg/kg IV) and anesthetic induction with guaifenesin (75 mg/kg IV) and ketamine (2 mg/kg IV). Anesthesia was maintained with 37.5 μg/kg/min of xylazine and 87.5 μg/kg/min of ketamine both administered intravenously for 75 min. The three treatments consisted of: lidocaine (loading dose: 5 mg/kg, CRI: 100 μg/kg/min; THL); lidocaine (loading dose: 2.5 mg/kg; CRI: 50 μg/kg/min: TLL); and saline (TS); all given 15 min after induction and maintained for 1 h. Antinociception was measured by response to electrical stimulation and bispectral index (BIS) was recorded during anesthesia. Parametric and non-parametric data were compared using ANOVA followed by Student-Newman-Keuls and Friedman tests, respectively. Results Plasma lidocaine concentrations peaked at the end of lidocaine loading dose and was greater in THL (9.61 ± 2.75 μg/mL) vs TLL (4.50 ± 3.34 μg/mL). Electrical noxious stimulation caused purposeful movement in all horses from TS, but no response in THL. The BIS was decreased in THL only and was less when compared to the other treatments throughout anesthesia. Blood pressure, PaO2 and PaCO2 increased and heart rate (HR), respiratory rate (RR), pH, total plasma protein and temperature decreased during anesthesia in all treatments. PaCO2 and HR were greater and RR and pH less in THL compared to TLL and TS at 30 min during anesthesia. All recoveries were considered excellent. Time to standing was longer after THL (60 ± 20 min) than following TLL and TS (32 ± 17 and 30 ± 15 min, respectively

  4. [The bioavailability and pharmacokinetics of two carbocysteine preparations after single and multiple dosing].

    PubMed

    Lutz, D; Gielsdorf, W; Rasper, J; Jaeger, H; Albring, M; Eisler, G; Niebch, G

    1985-01-01

    The relative bioavailabilities and pharmacokinetic profiles of 2 carbocisteine preparations (capsules, granulate) were evaluated in a single dose and a steady state study. 10 healthy volunteers took in a randomized, 2fold cross over design 750 mg 3-(carboxymethylthio)alanine (carbocisteine, Transbronchin) (1 portion of the granulate or 2 capsules) as a single dose or for 4 days 3 times a day (every 8 h) 1 portion of the granulate or 2 capsules, respectively. During the saturation phase the pre-dose serum levels in the morning were determined and on day 5 - after a last dosing the elimination kinetics were evaluated. The same time frame of blood withdrawals was used for the evaluation of serum kinetics after single dosing. The new developed gaschromatographic method for the rapid, sensitive and reliable quantitative determination of carbocisteine in serum saves not only a lot of time but also improves the detection limit and selectivity by a factor of approx. 10. The studies revealed bioequivalency of the carbocisteine granulate and capsule preparations. After multiple dosing, no cumulation of the carbocisteine serum levels occurred. A comparison of the AUCo-infinity and AUC tau (single/multiple dosing, respectively) showed linear pharmacokinetics without enzyme induction or saturation phenomena in man.

  5. Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation.

    PubMed

    Asuphon, O; Montakantikul, P; Houngsaitong, J; Kiratisin, P; Sonthisombat, P

    2016-09-01

    The purpose of the study was to determine the optimal dosing regimen of intravenous fosfomycin for the treatment of Pseudomonas aeruginosa (PA) based on PK/PD targets. A total of 120 PA isolates were recovered from various clinical specimens at university hospital in Thailand. Minimum Inhibitory Concentrations (MICs) of all the isolates were determined by the E-test method. PK parameters were obtained from a published study. Monte Carlo simulation was performed to calculate the percentage of target attainment (PTA) and cumulative fraction of response (CFR). MIC90 of fosfomycin alone, fosfomycin in combination with carbapenem, carbapenems alone and carbapenems in combination with fosfomycin were >1,024, 1,024, >32 and 32μg/ml, for multidrug resistant (MDR)-PA and 512, 128, 8 and 3μg/ml respectively, for non-MDR PA. Approximately 40% of the non-MDR PA were carbapenem-resistant strains. For non-MDR PA with CRPA, fosfomycin 16g continuous infusion in combination with carbapenems provided %PTA of approximately 80 and %CFR of > 88. While, %PTA and %CFR > 90 were achieved with fosfomycin 24g/day prolonged infusion in combination with carbapenem. Prolonged infusion of fosfomycin 16 - 24g combined with extended carbapenem infusion could be used in non-MDR PA treatment with CRPA. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. High-dose insulin and intravenous lipid emulsion therapy for cardiogenic shock induced by intentional calcium-channel blocker and Beta-blocker overdose: a case series.

    PubMed

    Doepker, Bruce; Healy, William; Cortez, Eric; Adkins, Eric J

    2014-04-01

    Recently, high-dose insulin (HDI) and intravenous lipid emulsion (ILE) have emerged as treatment options for severe toxicity from calcium-channel blocker (CCB) and beta blocker (BB). Our aim was to describe the use and effectiveness of HDI and ILE for the treatment of CCB and BB overdose. We describe 2 patients presenting to the emergency department after intentional ingestions of CCBs and BBs. A 35-year-old man presented in pulseless electrical activity after ingesting amlodopine, verapamil, and metoprolol. A 59-year-old man presented with cardiogenic shock (CS) after ingesting amlodopine, simvastatin, lisinopril, and metformin. Both patients were initially treated with glucagon, calcium, and vasopressors. Shortly after arrival, HDI (1 unit/kg × 1; 1 unit/kg/h infusion) and ILE 20% (1.5 mL/kg × 1; 0.25 mL/kg/min × 60 min) were initiated. This led to hemodynamic improvement and resolution of shock. At the time of hospital discharge, both patients had achieved full neurologic recovery. HDI effectively reverses CS induced by CCBs and BBs due to its inotropic effects, uptake of glucose into cardiac muscle, and peripheral vasodilatation. ILE is theorized to sequester agents dependent on lipid solubility from the plasma, preventing further toxicity. To our knowledge, these are the first two successful cases reported using the combination of HDI and ILE for reversing CS induced by intentional ingestions of CCBs and BBs. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Efficacy of a single 40-mg intravenous dose of parecoxib for postoperative pain control after elective cesarean delivery: A double-blind randomized placebo-controlled trial.

    PubMed

    Inthigood, Nittaya; Lertbunnaphong, Tripop; Jaishuen, Atthapon

    2017-01-01

    The aim of this study was to determine the efficacy of a single 40-mg intravenous (i.v.) dose of parecoxib as an adjunctive analgesia to intrathecal morphine after elective cesarean delivery (CD). A total of 82 low-risk term pregnant women who were scheduled for elective CD during the June 2014-June 2015 study period were enrolled. Two hours after surgery, subjects were randomly assigned to receive either i.v. injection of 2 mL (40 mg) parecoxib (study group; n = 41) or 2 mL normal saline solution (control group; n = 41). Patient randomization into groups was determined by the hospital's central computer system. Outcome measurements included total postoperative supplemental meperidine consumption, recorded pain score by numeric pain rating scale at 6, 12, 18, and 24 h, postoperatively, and patient satisfaction. Patient characteristics and pregnancy outcomes were comparable between groups. Total postoperative meperidine consumption was not significantly different between groups (12.7 ± 18.8 mg vs 8.3 ± 16.7 mg; P > 0.05). Compared with control, the study group was significantly less likely to experience moderate to severe postoperative pain (score ≥ 4) at 6 h (0% vs 21.9%; P = 0.002). Study group patients reported higher satisfaction than control group patients (median score: 8 vs 6; P < 0.01). No patients in either group reported adverse effects from their assigned intervention. Parecoxib did not demonstrate effectiveness in reducing patient requirement for supplementary meperidine after CD. However, administration of a single 40-mg dose of i.v. parecoxib after elective CD demonstrated effectiveness in reducing pain scores, with a resulting increase in patient satisfaction. © 2016 Japan Society of Obstetrics and Gynecology.

  8. Combination of oral clonidine and intravenous low-dose ketamine reduces the consumption of postoperative patient-controlled analgesia morphine after spine surgery.

    PubMed

    Nitta, Rie; Goyagi, Toru; Nishikawa, Toshiaki

    2013-03-01

    Because ketamine, clonidine, and morphine modulate nociceptive pain, coadministration of these drugs would augment the activity of postoperative analgesic drugs. The purpose of this study was to evaluate the effects of coadministration of ketamine and clonidine on postoperative morphine consumption in patients after spine surgery. The patients undergoing spine surgery were allocated randomly to one of the four study groups, which are as follows: group M (n = 12), intravenously (IV) administered patient-controlled analgesia (PCA) morphine alone; group MK (n = 12), IV-PCA morphine plus intra- and postoperative ketamine; group MC (n = 13), IV-PCA morphine plus oral clonidine premedication; group MCK (n = 12), IV-PCA morphine plus intra- and postoperative ketamine and clonidine premedication. The patients in the MC and MCK groups received 4 μg/kg clonidine orally, whereas those in the MK and MCK groups received IV bolus of ketamine (10 mg) at a rate of 2 mg/kg/hour during anesthesia. Patients were arranged to use IV-PCA mode for administration of drugs, which was programmed to deliver a bolus dose of 2-mg morphine (groups M and MC), or boluses of 2-mg morphine and 2-mg ketamine (groups MK and MCK). Scores of visual analog scale (VAS) for pain, morphine requirement, vital signs, nausea, sedation, and other side effects were followed up to 60 hours after surgery. Although there were significant differences in VAS pain scores at rest 24-48 hours after the surgery, the VAS pain score at movement was similar among the groups. The number of PCA request and cumulative morphine requirement were significantly lower in the MCK group than in the M group. This study results show that the administration of perioperative low-dose ketamine combined with clonidine premedication could reduce the consumption of postoperative PCA morphine following spine surgery. Copyright © 2013. Published by Elsevier B.V.

  9. Limited effects of high‐dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies

    PubMed Central

    Helmers, Sevim Barbasso; Dastmalchi, Maryam; Alexanderson, Helene; Nennesmo, Inger; Esbjörnsson, Mona; Lindvall, Björn; Lundberg, Ingrid E

    2007-01-01

    Objectives The study was conducted with the aim of achieving an improved understanding of the molecular mechanisms of high‐dose intravenous immunoglobulin (IVIG) in inflammatory myopathies by investigating the effects on muscle function and immunological molecules in skeletal muscle of polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) patients. Methods Thirteen treatment‐resistant patients, 6 PM, 4 DM, 2 IBM and 1 juvenile DM, were treated with 2 g/kg of IVIG, three times at monthly intervals. Functional Index in Myositis and serum creatinine kinase (CK) levels were determined, and muscle biopsies were performed before treatment and after the third IVIG infusion. Immunological molecules were also studied in biopsies taken 24–48 h after the first infusion. Results Improved muscle function was observed in three patients (1 PM, 1 DM and 1 IBM) and CK levels decreased in five. T cells, macrophages, major histocompatibility complex (MHC) class I antigen on muscle fibres, intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1) expression and membranolytic attack complex (MAC) deposits on capillaries were present to an equal degree in biopsies before and after IVIG treatment. No correlation between the clinical response and molecular changes was found. Conclusions The clinical effects of high‐dose IVIG on muscle function in patients with refractory inflammatory active myositis did not correspond to effects on any of the investigated molecules in our study. T cells, macrophages, phenotypical changes in muscle fibres and endothelial cell activation were still present after treatment. These observations question a role for IVIG as an immune‐modulating therapy in patients with inflammatory myopathies. PMID:17277004

  10. Effects of intravenous administration of high dose-diethylstilbestrol diphosphate on serum hormonal levels in patients with hormone-refractory prostate cancer.

    PubMed

    Kitahara, S; Umeda, H; Yano, M; Koga, F; Sumi, S; Moriguchi, H; Hosoya, Y; Honda, M; Yoshida, K

    1999-10-01

    The objective of this study was to elucidate the mechanism underlying the further suppression of serum testosterone (T) by diethylstilbestrol diphosphate (DES-DP) in patients with prostate cancer refractory to hormonal treatment. These patients received an LHRH agonist with or without a non-steroidal androgen-receptor blocker or a gestagen before DES-DP. We measured serum levels of total and free T, dihydrotestosterone (DHT), estradiol (E2), dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione, cortisol, aldosterone before and during intravenous administration of high doses of DES-DP (500 or 1000 mg/day). DES-DP administration suppressed the serum levels of FSH (p=0.04) and total T (p=0.02), and eliminated free T (p=0.04) and E2 (p=0.04) from serum, while reducing serum DHEA-S to approximately two-thirds of the pretreatment level (p=0.03). In contrast, serum levels of SHBG (p=0.02) and cortisol (p=0.02) were markedly increased after DES-DP administration. The latter had no significant effect on serum levels of LH, DHT, ACTH, 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone, DHEA, androstenedione, or aldosterone. The results suggest that the potent suppression of circulating total T by DES-DP is caused, in part, by the inhibitory effect of DES-DP on serum DHEA-S level. In most patients, high-dose DES-DP treatment completely suppressed the serum level of free T, while possibly elevating serum SHBG and decreasing serum total T. The mechanisms that maintain the serum level of serum DHT during DES-DP treatment require further elucidation.

  11. Attenuation of Multiple Organ Damage by Continuous Low-Dose Solvent-Free Infusions of Resveratrol after Severe Hemorrhagic Shock in Rats.

    PubMed

    Müller, Tobias; Kirsch, Michael; Petrat, Frank

    2017-08-17

    Therapeutic effects of continuous intravenous infusions of solvent-free low doses of resveratrol on organ injury and systemic consequences resulting from severe hemorrhagic shock in rats were studied. Hemorrhagic shock was induced by withdrawing arterial blood until a mean arterial blood pressure (MAP) of 25-30 mmHg was reached. Following a shock phase of 60 min, rats were resuscitated with the withdrawn blood plus lactated Ringer's. Resveratrol (20 or 60 μg/kg × h) was continuously infused intravenously starting with the resuscitation phase (30 min) and continued until the end of the experiment (total treatment time 180 min). Animals of the shock control group received 0.9% NaCl solution. After the observation phase (150 min), rats were sacrificed. Resveratrol significantly stabilized the MAP and peripheral oxygen saturation after hemorrhagic shock, decreased the macroscopic injury of the small intestine, significantly attenuated the shock-induced increase in tissue myeloperoxidase activity in the small intestine, liver, kidney and lung, and diminished tissue hemorrhages (particularly in the small intestine and liver) as well as the rate of hemolysis. Already very low doses of resveratrol, continuously infused during resuscitation after severe hemorrhagic shock, can significantly improve impaired systemic parameters and attenuate multiple organ damage in rats.

  12. Attenuation of Multiple Organ Damage by Continuous Low-Dose Solvent-Free Infusions of Resveratrol after Severe Hemorrhagic Shock in Rats

    PubMed Central

    Kirsch, Michael; Petrat, Frank

    2017-01-01

    Therapeutic effects of continuous intravenous infusions of solvent-free low doses of resveratrol on organ injury and systemic consequences resulting from severe hemorrhagic shock in rats were studied. Hemorrhagic shock was induced by withdrawing arterial blood until a mean arterial blood pressure (MAP) of 25–30 mmHg was reached. Following a shock phase of 60 min, rats were resuscitated with the withdrawn blood plus lactated Ringer’s. Resveratrol (20 or 60 μg/kg × h) was continuously infused intravenously starting with the resuscitation phase (30 min) and continued until the end of the experiment (total treatment time 180 min). Animals of the shock control group received 0.9% NaCl solution. After the observation phase (150 min), rats were sacrificed. Resveratrol significantly stabilized the MAP and peripheral oxygen saturation after hemorrhagic shock, decreased the macroscopic injury of the small intestine, significantly attenuated the shock-induced increase in tissue myeloperoxidase activity in the small intestine, liver, kidney and lung, and diminished tissue hemorrhages (particularly in the small intestine and liver) as well as the rate of hemolysis. Already very low doses of resveratrol, continuously infused during resuscitation after severe hemorrhagic shock, can significantly improve impaired systemic parameters and attenuate multiple organ damage in rats. PMID:28817064

  13. Dose-Response Modeling for Inhalational Anthrax in Rabbits Following Single or Multiple Exposures.

    PubMed

    Gutting, Bradford W; Rukhin, Andrey; Marchette, David; Mackie, Ryan S; Thran, Brandolyn

    2016-11-01

    There is a need to advance our ability to characterize the risk of inhalational anthrax following a low-dose exposure. The exposure scenario most often considered is a single exposure that occurs during an attack. However, long-term daily low-dose exposures also represent a realistic exposure scenario, such as what may be encountered by people occupying areas for longer periods. Given this, the objective of the current work was to model two rabbit inhalational anthrax dose-response data sets. One data set was from single exposures to aerosolized Bacillus anthracis Ames spores. The second data set exposed rabbits repeatedly to aerosols of B. anthracis Ames spores. For the multiple exposure data the cumulative dose (i.e., the sum of the individual daily doses) was used for the model. Lethality was the response for both. Modeling was performed using Benchmark Dose Software evaluating six models: logprobit, loglogistic, Weibull, exponential, gamma, and dichotomous-Hill. All models produced acceptable fits to either data set. The exponential model was identified as the best fitting model for both data sets. Statistical tests suggested there was no significant difference between the single exposure exponential model results and the multiple exposure exponential model results, which suggests the risk of disease is similar between the two data sets. The dose expected to cause 10% lethality was 15,600 inhaled spores and 18,200 inhaled spores for the single exposure and multiple exposure exponential dose-response model, respectively, and the 95% lower confidence intervals were 9,800 inhaled spores and 9,200 inhaled spores, respectively.

  14. Impact of concomitant dexamethasone dosing schedule on bortezomib-induced peripheral neuropathy in multiple myeloma.

    PubMed

    Kumar, Shaji K; Laubach, Jacob P; Giove, Thomas J; Quick, Maureen; Neuwirth, Rachel; Yung, Godwin; Rajkumar, S Vincent; Richardson, Paul G

    2017-09-01

    Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules. © 2017 John Wiley & Sons Ltd.

  15. Application of mathematical model to multiple-dose experimental chemotherapy for fatal murine pneumonia.

    PubMed Central

    Hishikawa, T; Kusunoki, T; Tsuchiya, K; Uzuka, Y; Sakamoto, T; Nagatake, T; Matsumoto, K

    1991-01-01

    Two beta-lactam antibiotics, cefazolin and cefmenoxime, were administered for 7 days to mice with pneumonia caused by Klebsiella pneumoniae by using dosage regimens that would simulate multiple dosing in usual clinical treatments at dosing intervals of 8 or 12 h. Viable numbers of the bacteria in the lungs were measured at 12- or 24-h intervals. The mathematical model established in a previous single-dose study was applied in this study to explain the time courses of the changes in bacterial count over 7 days. However, because the error in viable count measurements was larger than that in the previous study, the time course of the changes in mean viable count was not regular and the viable count reduction rate changed during multiple dosing, and therefore it was difficult to explain the time course by repeated application of the mathematical model described previously. This study suggests that the changes in pharmacokinetic and pharmacodynamic parameters during multiple dosing need to be considered. PMID:1929244

  16. Absence of sperm from the seminal receptacle of female Onchocerca volvulus following multiple doses of ivermectin.

    PubMed

    Chavasse, D C; Post, R J; Davies, J B; Whitworth, J A

    1993-09-01

    It is already known that multiple doses of ivermectin have a profound effect on embryonic development in Onchocerca volvulus and that this appears to operate mainly at the single cell stage. To investigate this further, we examined adult female O. volvulus originating from patients treated either with placebo or one, four or five doses of ivermectin. The reproductive organs were dissected out of the worm and examined for evidence of oogenesis and for the quantity of sperm and oocytes in the seminal receptacles. A single dose of ivermectin had no measurable effect on oogenesis or on the amount of sperm and oocytes compared to placebo. However after multiple doses of ivermectin a significantly lower proportion of seminal receptacles contained sperm and there was a significantly higher proportion of ovaries with impaired oogenesis compared to placebo. It is concluded that the reduction in the number of multicellular embryonic stages from worms exposed to multiple doses of ivermectin is due, at least in part, to a major reduction in the effective insemination of female worms and to a minor impairment of oogenesis.

  17. Multiple-dose pharmacokinetics of fesoterodine sustained-release in healthy Korean volunteers.

    PubMed

    Shin, Dongseong; Shin, Kwang-Hee; Lee, SeungHwan; Lim, Kyoung Soo; Cho, Joo-Youn; Jang, In-Jin; Shin, Sang-Goo; Yu, Kyung-Sang

    2012-10-01

    Fesoterodine is a pro-drug of the active metabolite 5-hydroxymethyl tolterodine (5-HMT), a muscarinic receptor antagonist. This study aimed to evaluate the safety profile and pharmacokinetic characteristics of multiple oral doses of sustained-release fesoterodine (fesoterodine SR) in healthy Korean males. A randomized, double-blind, placebo-controlled, multiple-dose study with two oral doses (4 mg and 8 mg) was conducted in healthy Korean male participants. The study drug was administered once daily for 5 days. The plasma concentration of 5-HMT was measured up to 72 hours after the last drug administration. The CYP2D6 genotype was analyzed using polymerase chain reaction (PCR) methods to assess the effect of genetic polymorphisms on the pharmacokinetic parameters. 20 participants completed the study. The mean (SD) areas under the plasma concentration-time curves during the dosing interval (AUCτ) of the 4 mg and 8 mg dose groups were 26.1 (8.0) and 64.2 (30.5) μg·h/ml and the mean peak concentrations (Cmax) were 2.6 (0.7) and 6.0 (2.0) μg/ml, respectively, at steady-state. The mean AUCτ and Cmax of 5-HMT increased in approximately the same proportion as the dose increased. Fesoterodine SR was well tolerated without any serious adverse events or abnormal clinical laboratory findings. Systemic 5-HMT exposure showed dose-proportional characteristics in the 4 mg to 8 mg dose range in healthy Korean males. Thus, 4 mg or 8 mg doses of fesoterodine SR taken once-daily were tolerable in healthy Korean males.

  18. Multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole)

    SciTech Connect

    Bleehen, N.M.; Newman, H.F.; Maughan, T.S.; Workman, P.

    1989-04-01

    The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

  19. Safety and efficacy of high-dose enteral, intravenous, and transdermal clonidine for the acute management of severe intractable childhood dystonia and status dystonicus: An illustrative case-series.

    PubMed

    Nakou, V; Williamson, K; Arichi, T; Lumsden, D E; Tomlin, Steve; Kaminska, M; Lin, J-P

    2017-07-28

    Acute dystonia in children is distressing, painful and can progress to life-threatening status dystonicus. Typical management involves benzodiazepines which can result in respiratory depression requiring PICU admission. Clonidine is less respiratory-depressant, and by facilitating sleep, switches dystonia off. It can also be administered via enteral, continuous intravenous infusion, and transdermal slow release routes. We describe the dose range and safety profile of clonidine management in a case-series of children with severe acute exacerbation of dystonia in a tertiary hospital setting. The management of 5 children (3 female, age range 8-14 years) suffering from an acute exacerbation of secondary dystonia requiring hospital admission at the Evelina London Children's Hospital was reviewed. The average and maximum dose of clonidine in mcg/kg/h and routes of administration were recorded for each day of hospital admission. Co-administration of any other medical treatments for dystonia and their route of administration were also recorded. Cardiovascular and respiratory clinical status were measured by recording the daily mean and maximum Paediatric Early Warning Scores (PEWS). Clonidine was administered via enteral, intravenous, and transdermal routes at a median dose of 2.5 mcg/kg/h (range 0.1-9 mcg/kg/h). Administration of high dose clonidine was associated with decreased use of benzodiazepines, morphine, and propofol: avoiding invasive respiratory support for ¾ cases during admission. Clonidine doses via all routes of administration did not correlate with poorer PEWS scores (p = 0.839). Both high dose intravenous and transdermal clonidine where found to be effective. High dose clonidine administered via different routes can be used in the acute management of severe exacerbations of dystonia. Its use in our cohort was not associated with significant cardio-respiratory depression even at doses as high as 9 mcg/kg/h. Copyright © 2017. Published by Elsevier

  20. Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing using microdialysis.

    PubMed

    Buerger, Cornelia; Plock, Nele; Dehghanyar, Pejman; Joukhadar, Christian; Kloft, Charlotte

    2006-07-01

    The antimicrobial agent linezolid is approved for the treatment of severe infections caused by, e.g., methicillin-resistant Staphylococcus strains. In order to evaluate the penetration of linezolid into the interstitial space fluid (ISF) of subcutaneous adipose tissue and skeletal muscle of the target population, a microdialysis study was performed with 12 patients with sepsis or septic shock after multiple intravenous infusions. Unbound linezolid concentrations were determined for plasma and microdialysates by use of a validated high-performance liquid chromatography method. Individual compartmental pharmacokinetic (PK) analysis was performed using WinNonlin. In vivo microdialysis was found to be feasible for the determination of unbound linezolid concentrations at steady state in the ISF of critically ill patients. On average, linezolid showed good distribution into ISF but with high interindividual variability. A two-compartment model was fitted to unbound concentrations in plasma with a geometric mean distribution volume of 62.9 liters and a mean clearance of 9.18 liters/h at steady state. However, disposition characteristics changed intraindividually within the time course. In addition, an integrated model for simultaneous prediction of concentrations in all matrices was developed and revealed similar results. Based on the model-predicted unbound concentrations in ISF, a scheme of more-frequent daily dosing of linezolid for some critically ill patients might be taken into consideration to avoid subinhibitory unbound concentrations in the infected tissue. The developed integrated model will be a valuable basis for further PK data analysis to explore refined dosing guidelines that achieve effective antimicrobial therapy in all patients by use of the population PK approach.

  1. Distribution of flunixin residues in muscles of dairy cattle dosed with lipopolysaccharide or saline and treated with flunixin by intravenous or intramuscular injection

    USDA-ARS?s Scientific Manuscript database

    Twenty dairy cows received flunixin meglumine at 2.2 mg/kg bw, administered once daily by either the intravenous (IV) or intra muscular (IM) route for three consecutive days with either intravenous normal saline (NS) or lipopolysaccharide (LPS) providing a balanced design with five animals per group...

  2. Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model

    PubMed Central

    Barnewall, Roy E.; Comer, Jason E.; Miller, Brian D.; Gutting, Bradford W.; Wolfe, Daniel N.; Director-Myska, Alison E.; Nichols, Tonya L.; Taft, Sarah C.

    2012-01-01

    Repeated low-level exposures to biological agents could occur before or after the remediation of an environmental release. This is especially true for persistent agents such as B. anthracis spores, the causative agent of anthrax. Studies were conducted to examine aerosol methods needed for consistent daily low aerosol concentrations to deliver a low-dose (less than 106 colony forming units (CFU) of B. anthracis spores) and included a pilot feasibility characterization study, acute exposure study, and a multiple 15 day exposure study. This manuscript focuses on the state-of-the-science aerosol methodologies used to generate and aerosolize consistent daily low aerosol concentrations and resultant low inhalation doses to rabbits. The pilot feasibility characterization study determined that the aerosol system was consistent and capable of producing very low aerosol concentrations. In the acute, single day exposure experiment, targeted inhaled doses of 1 × 102, 1 × 103, 1 × 104, and 1 × 105 CFU were used. In the multiple daily exposure experiment, rabbits were exposed multiple days to targeted inhaled doses of 1 × 102, 1 × 103, and 1 × 104 CFU. In all studies, targeted inhaled doses remained consistent from rabbit-to-rabbit and day-to-day. The aerosol system produced aerosolized spores within the optimal mass median aerodynamic diameter particle size range to reach deep lung alveoli. Consistency of the inhaled dose was aided by monitoring and recording respiratory parameters during the exposure with real-time plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over multiple exposure days. PMID:22919662

  3. An application of population kinetics analysis to estimate pharmacokinetic parameters of sodium tungstate after multiple-dose during preclinical studies in rats.

    PubMed

    Le Lamer, Sophie; Cros, Gérard; Piñol, Carmen; Fernández-Alvarez, Josepha; Bressolle, Françoise

    2002-02-01

    The purpose of this study was to use a population approach in the preclinical development program of sodium tungstate in the rat in order i) to compute individual pharmacokinetic parameters of this compound after repeated oral administrations, until the 4-week toxicology study, using an empirical Bayes methodology; and ii) to study the influence of the administered dose, of the gender and of the duration of treatment on the pharmacokinetic parameters. Four studies were used representing a mixture of single intravenous administration and multiple oral administrations. The treatment duration ranged from 7 to 28 days. Intravenous dose was 9 mg/kg; three different oral doses were tested, 50, 100 and 200 mg/kg/day. Plasma concentration profiles versus time were compatible with a two-compartment model. A significant gender effect was found on bioavailability. The duration of treatment and the administered dose did not significantly explain part of the interindividual variability of pharmacokinetic parameters. The absorption of tungsten was rapid (1-3 hr). Total plasma clearance and elimination half-life averaged 2.8 ml/min/kg and 3.04 hr in males, and 3 ml/min/kg and 2.74 hr in females. The bioavailability was on an average 70%; being significantly higher in females than in males (0.78 versus 0.61). This compartmental approach should be considered as complementary to the usual non-compartmental approach used for analysis of preclinical data and should be a valuable tool to characterise the pharacokinetic/pharmacodynamic behaviour of a drug.

  4. Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial

    PubMed Central

    Eddleston, Michael; Juszczak, Edmund; Buckley, Nick A; Senarathna, Lalith; Mohamed, Fahim; Dissanayake, Wasantha; Hittarage, Ariyasena; Azher, Shifa; Jeganathan, K; Jayamanne, Shaluka; Sheriff, MH Rezvi; Warrell, David A

    2008-01-01

    Summary Background The case-fatality for intentional self-poisoning in the rural developing world is 10–50-fold higher than that in industrialised countries, mostly because of the use of highly toxic pesticides and plants. We therefore aimed to assess whether routine treatment with multiple-dose activated charcoal, to interrupt enterovascular or enterohepatic circulations, offers benefit compared with no charcoal in such an environment. Methods We did an open-label, parallel group, randomised, controlled trial of six 50 g doses of activated charcoal at 4-h intervals versus no charcoal versus one 50 g dose of activated charcoal in three Sri Lankan hospitals. 4632 patients were randomised to receive no charcoal (n=1554), one dose of charcoal (n=1545), or six doses of charcoal (n=1533); outcomes were available for 4629 patients. 2338 (51%) individuals had ingested pesticides, whereas 1647 (36%) had ingested yellow oleander (Thevetia peruviana) seeds. Mortality was the primary outcome measure. Analysis was by intention to treat. The trial is registered with controlled-trials.com as ISRCTN02920054. Findings Mortality did not differ between the groups. 97 (6·3%) of 1531 participants in the multiple-dose group died, compared with 105 (6·8%) of 1554 in the no charcoal group (adjusted odds ratio 0·96, 95% CI 0·70–1·33). No differences were noted for patients who took particular poisons, were severely ill on admission, or who presented early. Interpretation We cannot recommend the routine use of multiple-dose activated charcoal in rural Asia Pacific; although further studies of early charcoal administration might be useful, effective affordable treatments are urgently needed. PMID:18280328

  5. Multiple Testing, Cumulative Radiation Dose, and Clinical Indications in Patients Undergoing Myocardial Perfusion Imaging

    PubMed Central

    Einstein, Andrew J.; Weiner, Shepard D.; Bernheim, Adam; Kulon, Michal; Bokhari, Sabahat; Johnson, Lynne L.; Moses, Jeffrey W.; Balter, Stephen

    2013-01-01

    Context Myocardial perfusion imaging (MPI) is the single medical test with the highest radiation burden to the US population. While many patients undergoing MPI receive repeat MPI testing, or additional procedures involving ionizing radiation, no data are available characterizing their total longitudinal radiation burden and relating radiation burden with reasons for testing. Objective To characterize procedure counts, cumulative estimated effective doses of radiation, and clinical indications, for patients undergoing MPI. Design, Setting, Patients Retrospective cohort study evaluating, for 1097 consecutive patients undergoing index MPI during the first 100 days of 2006 at Columbia University Medical Center, all preceding medical imaging procedures involving ionizing radiation undergone beginning October 1988, and all subsequent procedures through June 2008, at that center. Main Outcome Measures Cumulative estimated effective dose of radiation, number of procedures involving radiation, and indications for testing. Results Patients underwent a median (interquartile range, mean) of 15 (6–32, 23.9) procedures involving radiation exposure; 4 (2–8, 6.5) were high-dose (≥3 mSv, i.e. one year's background radiation), including 1 (1–2, 1.8) MPI studies per patient. 31% of patients received cumulative estimated effective dose from all medical sources >100mSv. Multiple MPIs were performed in 39% of patients, for whom cumulative estimated effective dose was 121 (81–189, 149) mSv. Men and whites had higher cumulative estimated effective doses, and there was a trend towards men being more likely to undergo multiple MPIs than women (40.8% vs. 36.6%, Odds ratio 1.29, 95% confidence interval 0.98–1.69). Over 80% of initial and 90% of repeat MPI exams were performed in patients with known cardiac disease or symptoms consistent with it. Conclusion In this institution, multiple testing with MPI was very common, and in many patients associated with very high cumulative

  6. Dose Distribution Analysis in Stereotactic Body Radiotherapy Using Dynamic Conformal Multiple Arc Therapy

    SciTech Connect

    Takeda, Atsuya; Kunieda, Etsuo Sanuki, Naoko; Ohashi, Toshio; Oku, Yohei; Sudo, Yasunobu; Iwashita, Hideo; Ooka, Yoshikazu; Aoki, Yosuke; Shigematsu, Naoyuki; Kubo, Atsushi

    2009-06-01

    Purpose: We have used dynamic conformal multiple arc therapy (DCMAT) for stereotactic body radiotherapy (SBRT) since 2001. We investigated the consistency of DCMAT for SBRT using dose-volume histogram analysis. Methods and Materials: A total of 50 patients with peripheral lung tumors underwent SBRT. The median tumor diameter was 2.4 cm (range, 0.9-5.9). Treatment planning was performed using a superposition algorithm. The prescribed 50 Gy dose was divided into five fractions. The prescribed dose was defined as 80% of the maximal dose in the planning target volume (PTV), and the leaf margins were modified to ensure the PTV was included in the 80% isodose surface. The dose-volume histogram analysis was used to assess the PTV and normal lung volume. Results: The median dose covering 95% of the PTV was 50.27 Gy (range, 46.14-52.67), essentially consistent with the prescribed dose. The median homogeneity and conformity index was 1.41 (range, 1.31-1.53) and 1.73 (range, 1.41-2.21), respectively. The median volume of lung receiving {>=}20 Gy (V{sub 20}) was 4.2% (range, 1.4-10.2%). A linear correlation was found between the tumor diameter and V{sub 20}, and an even stronger correlation was found between the PTV/(normal lung volume) and V{sub 20}. The estimated V{sub 20} was 7.1% (range, 3.9-10.4%) for a 5-cm-diameter tumor, assumed to be the maximal size limitation for SBRT. Conclusion: SBRT with DCMAT achieved high conformity and delivered adequate doses within the PTV. The median dose covering 95% of the PTV was consistent with the prescribed dose. V{sub 20} can be estimated using the tumor diameter and normal lung volume. DCMAT was thus both a feasible and a reproducible method of SBRT delivery.

  7. Comparison of effects of dose on image quality in digital breast tomosynthesis across multiple vendors

    NASA Astrophysics Data System (ADS)

    Zhao, Amy; Santana, Maira; Samei, Ehsan; Lo, Joseph

    2017-03-01

    In traditional radiography and computed tomography (CT), contrast is an important measure of image quality that, in theory, does not vary with dose. While increasing dose may increase the overall contrast-to-noise ratio (CNR), the contrast in an image should be primarily dependent on variation in tissue density and attenuation. We investigated the behavior of all three currently FDA-approved vendors' 3D DBT systems (Siemens, Hologic, and General Electric (GE)) using the Computerized Imaging Reference Systems (CIRS) Model 011A Breast Phantom and found that for both Siemens and Hologic systems, contrast increased with dose across multiple repeated trials. For these two systems, experimental CNR also appeared to increase above the expected CNR, which suggests that these systems seem to have introduced post-processing by manipulation of contrast, and thus DBT data cannot be used to reliably quantify tissue characteristics. Additional experimentation with both 2D mammography and 3D DBT systems from GE in addition to the previously mentioned vendors, however, suggested that this relationship is not true for all systems. An initial comparison of contrast vs. dose showed no relationship between contrast and dose for 2D mammography, with the contrast remaining relatively constant in the dose range of 33% of the automatic exposure control setting (AEC) to 300% AEC for all three vendors. The GE DBT system also did not exhibit increased contrast with increased dose, suggesting that the behavior of 3D DBT systems is vendor-specific.

  8. Cancer risk estimation of genotoxic chemicals based on target dose and a multiplicative model

    SciTech Connect

    Granath, F.N. . Dept. of Mathematical Statistics Karolinska Inst., Stockholm . Dept. of Medical Epidemiology); Vaca, C.E. . Dept. of Radiobiology Casco Products AB, Stockholm ); Ehrenberg, L.G.; Toernqvist, M.A. )

    1999-04-01

    A mechanistic model and associated procedures are proposed for cancer risk assessment of genotoxic chemicals. As previously shown for ionizing radiation, a linear multiplicative model was found to be compatible with published experimental data for ethylene oxide, acrylamide, and butadiene. Concurrent analysis led to rejection of an additive model. A reanalysis of data for radiogenic cancer in mouse, dog and man shows that the relative risk coefficient is approximately the same for tumors induced in the three species. Doses in vivo, defined as the time-integrated concentrations of ultimate mutagens, expressed in millimol x kg[sup [minus]1] x h (mMh) are, like radiation doses given in Gy or rad, proportional to frequencies of potentially mutagenic events. The radiation dose equivalents of chemical doses are, calculated by multiplying chemical doses (in mMh) with the relative genotoxic potencies determined in vitro. In this way the relative cancer incidence increments in rats and mice exposed to ethylene oxide were shown to be about 0.4% per rad-equivalent, in agreement with the data for radiogenic cancer. The analyses suggest that values of the relative risk coefficients for genotoxic chemicals are independent of species and that relative cancer risks determined in animal tests apply also to humans. If reliable animal test data are not available, cancer risks may be estimated by the relative potency. In both cases exposure dose/target dose relationships, the latter via macromolecule adducts, should be determined.

  9. Evaluating Critical Brain Radiation Doses in the Treatment of Multiple Brain Lesions with Gamma Knife Radiosurgery.

    PubMed

    Hatiboglu, Mustafa Aziz; Akdur, Kerime

    2017-01-01

    Treatment of patients with multiple brain metastases has shifted to stereotactic radiosurgery, withholding whole-brain (WB) radiation therapy. However, radiation toxicity to the brain is a concern when treating multiple brain lesions with single-fraction stereotactic radiosurgery. The purpose of this study was to determine the changes in brain radiation doses when treating various numbers of targets and lesion volumes. We simulated different treatment plans with different combinations of varying tumor volumes including 0.1, 0.5, 1, 2, and 5 cm3, and tumor numbers including 1, 3, 5, 10, 15, 20, and 25. Treatment planning was performed for all combinations in a computerized tomography of the head of a patient, using Leksell GammaPlan version 10.1.1 (Elekta AB, Stockholm, Sweden). Two different dosing strategies were used. In the lower-prescription dosing schedule, a marginal dose was given to the 50% isodose line, and 20 Gy were used when the number of lesions was less than 15 and 18 Gy were applied when the number of lesions was equal to or more than 15. In the higher-prescription dosing schedule, a marginal dose of 24 Gy was used for lesions of less than 5 cm3 and 20 Gy were applied for lesions equal to 5cm3. The mean WB dose, the WB integral dose, and the volume of brain receiving 12 Gy (V12 Gy) were calculated for each scenario. Also, the beam-on time of the Gamma Knife 4C unit was reported for all treatment scenarios. Regression analysis showed that the total tumor volume was a more significant predictor of V12 Gy than the number of lesions, and a linear correlation between the total tumor volume and V12 Gy was found. We also found that the total tumor volume was a more significant predictor of the mean WB dose and the WB integral dose compared to the number of lesions. Our results suggest that multiple small to mid-sized lesions could be safely treated with a single-fraction gamma knife. © 2017 S. Karger AG, Basel.

  10. Single- and multiple-dose pharmacokinetics of inhaled indacaterol in healthy Chinese volunteers.

    PubMed

    Jiang, Ji; Li, Lilly; Yin, Hequn; Woessner, Ralph; Emotte, Corinne; Li, Ruobing; Khindri, Sanjeev; Pei, Hu

    2015-06-01

    Indacaterol is an inhaled, ultra-long-acting β2-agonist that provides 24-h bronchodilation with once-daily dosing in patients with chronic obstructive pulmonary disorder. This study evaluated the pharmacokinetics, safety, and tolerability of multiple daily inhaled doses of indacaterol 150 or 300 μg once daily in healthy Chinese volunteers. This was a single-center, randomized, double-blind, multiple-dose, parallel-group study, placebo-controlled trial including two doses of indacaterol: 150 and 300 μg. Serum indacaterol was quantified using high-performance liquid chromatography-mass spectrometry with a lower limit of quantification of 0.01 ng/mL. The pharmacokinetic parameters were analyzed using non-compartmental analysis and included C max, T max, and AUC0-24h on Day 1 and AUC0-24h,ss, C max,ss, C min,ss, C av,ss, T max,ss, T 1/2, T 1/2,acc, CL/F, V z/F, and R acc on Day 14 (after repeated once-daily doses). Safety analyses were recorded using physical examination, biochemical tests, and ECG. Indacaterol steady state was achieved after 12-14 days of daily dosing. The mean effective half-life of indacaterol (based on drug accumulation at steady state) was 33.9 and 35.8 h for 150 and 300 μg, respectively. Systemic exposure to indacaterol increased 1.27 and 1.34-fold between the 150- and 300-μg doses on Day 1 (first dose) and Day 14 (repeated dose), respectively. Indacaterol 150 and 300 μg were safe and well tolerated in these volunteers. The pharmacokinetics of multiple inhaled doses of indacaterol 150 and 300 μg (for 14 days) were consistent with moderate systemic accumulation at steady state after repeated once-daily inhalation in healthy Chinese volunteers.

  11. Multiple-Dose Pharmacokinetics and Tolerability of Gemifloxacin Administered Orally to Healthy Volunteers

    PubMed Central

    Allen, Ann; Bygate, Elizabeth; Vousden, Marika; Oliver, Stuart; Johnson, Martin; Ward, Christopher; Cheon, Ae-Jin; Choo, Youn Sung; Kim, In-Chull

    2001-01-01

    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 AUC0–τ on day 7 were 4.92 ± 1.08, 9.06 ± 2.20, 12.2 ± 3.69, and 20.1 ± 3.67 μg·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 aminotransferase not

  12. High-Dose Intravenous Vitamin C Combined with Cytotoxic Chemotherapy in Patients with Advanced Cancer: A Phase I-II Clinical Trial

    PubMed Central

    Hoffer, L. John; Robitaille, Line; Zakarian, Robert; Melnychuk, David; Kavan, Petr; Agulnik, Jason; Cohen, Victor; Small, David; Miller, Wilson H.

    2015-01-01

    Background Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail. Methods and Findings We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement. Conclusions Despite IVC’s biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC’s value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify

  13. Intravenous myocardial contrast echocardiography predicts regional and global left ventricular remodelling after acute myocardial infarction: comparison with low dose dobutamine stress echocardiography

    PubMed Central

    Abe, Y; Muro, T; Sakanoue, Y; Komatsu, R; Otsuka, M; Naruko, T; Itoh, A; Yoshiyama, M; Haze, K; Yoshikawa, J

    2005-01-01

    Objective: To assess the role of intravenous myocardial contrast echocardiography (MCE) in predicting functional recovery and regional or global left ventricular (LV) remodelling after acute myocardial infarction (AMI) compared with low dose dobutamine stress echocardiography (LDSE). Methods: 21 patients with anterior AMI and successful primary angioplasty underwent MCE and LDSE during the subacute stage (2–4 weeks after AMI). Myocardial perfusion and contractile reserve were assessed in each segment (12 segment model) with MCE and LDSE. The 118 dyssynergic segments in the subacute stage were classified as recovered, unchanged, or remodelled according to wall motion at six months’ follow up. Percentage increase in LV end diastolic volume (%ΔEDV) was also calculated. Results: The presence of perfusion was less accurate than the presence of contractile reserve in predicting regional recovery (55% v 81%, p < 0.0001). However, the absence of perfusion was more accurate than the absence of contractile reserve in predicting regional remodelling (83% v 48%, p < 0.0001). The number of segments without perfusion was an independent predictor of %ΔEDV, whereas the number of segments without contractile reserve was not. The area under the receiver operating characteristic curve showed that the number of segments without perfusion predicted substantial LV dilatation (%ΔEDV > 20%) more accurately than did the number of segments without contractile reserve (0.88 v 0.72). Conclusion: In successfully revascularised patients with AMI, myocardial perfusion assessed by MCE is predictive of regional and global LV remodelling rather than of functional recovery, whereas contractile reserve assessed by LDSE is predictive of functional recovery rather than of LV remodelling. PMID:15797931

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

    PubMed

    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.

  15. HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat

    PubMed Central

    Archin, Nancy M.; Bateson, Rosalie; Tripathy, Manoj K.; Crooks, Amanda M.; Yang, Kuo-Hsiung; Dahl, Noelle P.; Kearney, Mary F.; Anderson, Elizabeth M.; Coffin, John M.; Strain, Matthew C.; Richman, Douglas D.; Robertson, Kevin R.; Kashuba, Angela D.; Bosch, Ronald J.; Hazuda, Daria J.; Kuruc, Joann D.; Eron, Joseph J.; Margolis, David M.

    2014-01-01

    Background. A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4+ T cells of treated, aviremic human immunodeficiency virus (HIV)–positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge. Methods. Five participants in whom resting CD4+ T-cell–associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4+ T cells were assayed. Results. VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged. Conclusions. Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥24 hours. The optimal schedule for VOR administration is still to be defined. PMID:24620025

  16. Pharmacokinetic Profile of Tigecycline in Serum and Skin Blister Fluid of Healthy Subjects after Multiple Intravenous Administrations

    PubMed Central

    Sun, Heather K.; Ong, Christine T.; Umer, Ambreen; Harper, Dawn; Troy, Steven; Nightingale, Charles H.; Nicolau, David P.

    2005-01-01

    The pharmacokinetics of tigecycline, when given as a 100-mg loading dose followed by 50 mg every 12 h, were determined in serum and blister fluid. The peak tigecycline concentration and half-life in serum were greater than those in blister fluid. Tigecycline penetrates into blister fluid well, with a mean penetration rate of 74%. PMID:15793157

  17. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease.

    PubMed

    Salloway, S; Sperling, R; Gilman, S; Fox, N C; Blennow, K; Raskind, M; Sabbagh, M; Honig, L S; Doody, R; van Dyck, C H; Mulnard, R; Barakos, J; Gregg, K M; Liu, E; Lieberburg, I; Schenk, D; Black, R; Grundman, M

    2009-12-15

    Bapineuzumab, a humanized anti-amyloid-beta (Abeta) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study in mild to moderate AD. The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale-Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline. No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study "completers" and APOE epsilon4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms. Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE epsilon4 carrier status. Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.

  18. Intravenous immunoglobulin protects neurons against amyloid beta-peptide toxicity and ischemic stroke by attenuating multiple cell death pathways.

    PubMed

    Widiapradja, Alexander; Vegh, Viktor; Lok, Ker Zhing; Manzanero, Silvia; Thundyil, John; Gelderblom, Mathias; Cheng, Yi-Lin; Pavlovski, Dale; Tang, Sung-Chun; Jo, Dong-Gyu; Magnus, Tim; Chan, Sic L; Sobey, Christopher G; Reutens, David; Basta, Milan; Mattson, Mark P; Arumugam, Thiruma V

    2012-07-01

    Intravenous immunoglobulin (IVIg) preparations obtained by fractionating blood plasma, are increasingly being used increasingly as an effective therapeutic agent in treatment of several inflammatory diseases. Its use as a potential therapeutic agent for treatment of stroke and Alzheimer's disease has been proposed, but little is known about the neuroprotective mechanisms of IVIg. In this study, we investigated the effect of IVIg on downstream signaling pathways that are involved in neuronal cell death in experimental models of stroke and Alzheimer's disease. Treatment of cultured neurons with IVIg reduced simulated ischemia- and amyloid βpeptide (Aβ)-induced caspase 3 cleavage, and phosphorylation of the cell death-associated kinases p38MAPK, c-Jun NH2 -terminal kinase and p65, in vitro. Additionally, Aβ-induced accumulation of the lipid peroxidation product 4-hydroxynonenal was attenuated in neurons treated with IVIg. IVIg treatment also up-regulated the anti-apoptotic protein, Bcl2 in cortical neurons under ischemia-like conditions and exposure to Aβ. Treatment of mice with IVIg reduced neuronal cell loss, apoptosis and infarct size, and improved functional outcome in a model of focal ischemic stroke. Together, these results indicate that IVIg acts directly on neurons to protect them against ischemic stroke and Aβ-induced neuronal apoptosis by inhibiting cell death pathways and by elevating levels of the anti-apoptotic protein Bcl2.

  19. Application of Bayes theorem to aminoglycoside-associated nephrotoxicity: comparison of extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing.

    PubMed

    Kim, Myong-Jin; Bertino, Joseph S; Erb, Tara A; Jenkins, Paul L; Nafziger, Anne N

    2004-07-01

    The objective of this study was to examine the incidence of aminoglycoside-associated nephrotoxicity related to extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing by applying Bayes theorem. An electronic literature search of MEDLINE (1966-2003) and a manual search of references from published meta-analyses and review articles were performed. Studies using extended-interval dosing, individualized pharmacokinetic monitoring, or multiple-daily dosing and reported aminoglycoside-associated nephrotoxicity for patients > or = 16 years of age were included. Quality scores were assigned based on the rigor of definition of aminoglycoside-associated nephrotoxicity, duration of therapy, and length of follow-up of renal function after completion of therapy. Inclusion criteria were then based on these quality scores. Quantitative data on the incidence of aminoglycoside-associated nephrotoxicity were abstracted. Twelve extended-interval dosing studies (n = 916), 10 individualized pharmacokinetic monitoring studies (n = 2066), and 27 multiple-daily dosing studies (n = 4251) met the inclusion criteria. Prior probabilities of aminoglycoside-associated nephrotoxicity were derived from a combination of a review of published studies and expert judgment. The maximum densities for the final posterior probabilities of aminoglycoside-associated nephrotoxicity for extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing were located at 12% to 13%, 10% to 11%, and 13% to 14%, respectively. Application of Bayes theorem demonstrates that aminoglycoside dosing by individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity than extended-interval dosing or multiple-daily dosing.

  20. 21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Guidelines on the design of a multiple-dose in... Guidelines on the design of a multiple-dose in vivo bioavailability study. (a) Basic principles. (1) In... therapeutic moiety in the body. (2) The test product and the reference material should be administered to...

  1. The Addition of Low-dose Thalidomide to Bortezomib and Dexamethasone for Refractory Multiple Myeloma

    PubMed Central

    Hashimoto, Shigeo; Kuroha, Takashi; Yano, Toshio; Sato, Naoko; Furukawa, Tatsuo

    2016-01-01

    Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted. Peripheral neuropathy did not increase after thalidomide addition. Adding low-dose thalidomide may safely improve the responses for multiple myeloma refractory to bortezomib and dexamethasone. PMID:27746443

  2. HIGH-DOSE BIOTIN TREATMENT FOR SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS MAY INTERFERE WITH THYROID ASSAYS

    PubMed Central

    Minkovsky, Alissa; Lee, Mark N.; Dowlatshahi, Mitra; Angell, Trevor E.; Mahrokhian, Lilian S.; Petrides, Athena K.; Melanson, Stacy E.F.; Marqusee, Ellen; Woodmansee, Whitney W.

    2016-01-01

    Objective To review cases and increase awareness in clinicians treating patients who may be taking biotin. Methods We describe the presentation and workup of a woman with secondary progressive multiple sclerosis on high dose biotin with laboratory studies suggestive of thyrotoxicosis. Results Plasma samples showed laboratory evidence of elevated thyroid hormone levels with elevated free thyroxine >7.8 ng/dl (reference interval (RI) 0.9-1.7 ng/dl) and decreased thyroid stimulating hormone <0.02 uIU/ml (RI 0.50-5.70 uIU/ml). Laboratory values normalized when biotin was withheld prior to repeat testing. Conclusions Our case report demonstrates that ingestion of high dose biotin in multiple sclerosis patients can cause interference with laboratory assessment of thyroid function. This interference causes laboratory values suggestive of thyrotoxicosis and can lead to unnecessary evaluation. Clinicians should be aware of the risk of laboratory interference in this patient demographic. PMID:27917400

  3. HIGH-DOSE BIOTIN TREATMENT FOR SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS MAY INTERFERE WITH THYROID ASSAYS.

    PubMed

    Minkovsky, Alissa; Lee, Mark N; Dowlatshahi, Mitra; Angell, Trevor E; Mahrokhian, Lilian S; Petrides, Athena K; Melanson, Stacy E F; Marqusee, Ellen; Woodmansee, Whitney W

    2016-01-01

    To review cases and increase awareness in clinicians treating patients who may be taking biotin. We describe the presentation and workup of a woman with secondary progressive multiple sclerosis on high dose biotin with laboratory studies suggestive of thyrotoxicosis. Plasma samples showed laboratory evidence of elevated thyroid hormone levels with elevated free thyroxine >7.8 ng/dl (reference interval (RI) 0.9-1.7 ng/dl) and decreased thyroid stimulating hormone <0.02 uIU/ml (RI 0.50-5.70 uIU/ml). Laboratory values normalized when biotin was withheld prior to repeat testing. Our case report demonstrates that ingestion of high dose biotin in multiple sclerosis patients can cause interference with laboratory assessment of thyroid function. This interference causes laboratory values suggestive of thyrotoxicosis and can lead to unnecessary evaluation. Clinicians should be aware of the risk of laboratory interference in this patient demographic.

  4. The pharmacokinetics of three multiple dose regimens of chloroquine: implications for malaria chemoprophylaxis.

    PubMed Central

    Wetsteyn, J C; De Vries, P J; Oosterhuis, B; Van Boxtel, C J

    1995-01-01

    The pharmacokinetics of chloroquine were studied in healthy volunteers who received one of three different multiple-dose regimens for 3 weeks: once weekly 300 mg, twice weekly 200 mg and once daily 50 mg chloroquine. Plasma concentrations of chloroquine and metabolites were determined by h.p.l.c. with fluorescence detection. The concentration-time course was fitted to a multiple-dose pharmacokinetic model. Volume of distribution, elimination half-life and clearance were not different for the three regimens, ranging from 250-302 l kg-1, 374-479 h and 0.44-0.58 l h-1 kg-1 respectively. After the first week of all dosage regimens, peak and trough concentrations of chloroquine were above 16 micrograms l-1, sufficiently suppressive for chloroquine-sensitive P. falciparum strains. These data suggest that once daily chloroquine could be combined with proguanil in a single tablet and should improve compliance when given for malaria chemoprophylaxis. PMID:7654492

  5. The Addition of Low-dose Thalidomide to Bortezomib and Dexamethasone for Refractory Multiple Myeloma.

    PubMed

    Hashimoto, Shigeo; Kuroha, Takashi; Yano, Toshio; Sato, Naoko; Furukawa, Tatsuo

    Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted. Peripheral neuropathy did not increase after thalidomide addition. Adding low-dose thalidomide may safely improve the responses for multiple myeloma refractory to bortezomib and dexamethasone.

  6. Once versus individualized multiple daily dosing of aminoglycosides in critically ill patients.

    PubMed

    Abdel-Bari, A; Mokhtar, M Sherif; Sabry, Nagwa Ali; El-Shafi, Sanaa Abd; Bazan, Naglaa Samir

    2011-01-01

    The purpose of this study was to evaluate the once daily dosing (ODD) program in critically ill Egyptian patients compared to individualized multiple daily dosing (MDD) in terms of clinical and bacteriological efficacy. In addition, the incidence of nephrotoxicity associated with both regimens in this specific group of patients was assessed. Fifty-two patients with suspected or confirmed bacterial infections admitted to the Critical Care Medicine Department, Kasr El-Aini-Cairo University Hospitals comprised the study population. The amikacin group (30 patients) was sub-divided into 14 patients receiving amikacin ODD (1 g i.v.) and 16 patients receiving amikacin in MDD (500 mg i.v./dose). The gentamicin group (22 patients) was sub-divided into 10 patients receiving the drug ODD (240 mg i.v.) and 12 patients receiving gentamicin MDD (80 mg i.v./dose). Amikacin or gentamicin serum levels were determined by the enzyme multiplied immunoassay technique using Emit 2000. MDD regimen was adjusted based on the individual pharmacokinetic parameters using the Sawchuk-Zaske method. There was no significant difference between the two dosing regimens with regard to clinical and antibacterial efficacy or incidence of nephrotoxicity of both gentamicin and amikacin groups. In the ODD regimen, duration of treatment had no effect on increasing incidence of nephrotoxicity unlike the individualized MDD regimen. No dose adjustments were needed in the once daily dosing regimen since trough concentrations have never been above toxic level. The study showed that the ODD regimen is preferred in critically ill patients to individualized MDD as shown by comparable efficacy, nephrotoxicity and lesser need for therapeutic drug monitoring and frequent dose adjustments required in the individualized MDD regimen.

  7. Applicability of convex hull in multiple detector response space for neutron dose measurements.

    PubMed

    Hashimoto, Makoto; Iimoto, Takeshi; Kosako, Toshiso

    2009-08-01

    A novel neutron dose measurement method that flexibly responds to variations in the neutron field is being developed by Japan Atomic Energy Agency. This is an implementation of the multi-detector method (first introduced in 1960s) for neutron dose evaluation using a convex hull in the response space defined for multiple detectors. The convex hull provides a range of possible neutron dose corresponding to the incident neutron spectrum. Feasibility of the method was studied using a simulated response of mixed gas proportional counter. Monochromatic neutrons are shown to be fundamentally suitable for mapping the convex. The convex hull can be further reduced taking into consideration a priori information about physically possible incident neutron spectra, for example, theoretically derived moderated neutron spectra originated from a fission neutron source.

  8. Magnetic fields with photon beams: dose calculation using electron multiple-scattering theory.

    PubMed

    Jette, D

    2000-08-01

    Strong transverse magnetic fields can produce large dose enhancements and reductions in localized regions of a patient under irradiation by a photon beam. We have developed a new equation of motion for the transport of charged particles in an arbitrary magnetic field, incorporating both energy loss and multiple scattering. Key to modeling the latter process is a new concept, that of "typical scattered particles." The formulas which we have arrived at are particularly applicable to the transport of, and deposition of energy by, Compton electrons and pair-production electrons and positrons generated within a medium by a photon beam, and we have shown qualitatively how large dose enhancements and reductions can occur. A companion article examines this dose modification effect through systematic Monte Carlo simulations.

  9. Intravitreal bevacizumab: safety of multiple doses from a single vial for consecutive patients.

    PubMed

    Ng, Danny S; Kwok, Alvin K H; Chan, Clement W; Li, Walton W T

    2012-12-01

    To report the incidence of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor and the safety profile of multiple doses of bevacizumab from the same vial reused for multiple patients. Case series. A private hospital in Hong Kong. A systematic retrospective review of consecutive intravitreal anti-vascular endothelial growth factor injections between 5 June 2006 and 17 December 2010 at a single institute was conducted. Patients were identified from prospectively designed audit forms, and each patient's medical record was reviewed for any documented complications. Bevacizumab 1.25 mg/0.05 mL to 2.50 mg/0.1 mL was aspirated from the designated vial, with a maximum of 10 consecutive injections being aspirated from the same vial. The opened vial was then discarded without overnight storage. Ranibizumab was aspirated from the commercially available 1 mg/0.1 mL single-use vial. A total of 1655 intravitreal anti-vascular endothelial growth factor injections into 392 eyes of 383 patients were evaluated during the study period. There were 1184 bevacizumab injections and 471 ranibizumab injections. There was one case of suspected endophthalmitis after ranibizumab injection, though culture of the vitreous tap was negative. The point prevalence of endophthalmitis was 0.06% (1/1655) for the total number of injections: 0.21% (1/471) after ranibizumab, and 0% after bevacizumab. Although many centres aliquot multiple syringes from a single vial to be kept in a refrigerator for use, the current study shows that so long as proper sterile techniques are implemented, there were no cases of endophthalmitis from using the same vial, which was reused for a maximum of 10 consecutive injections. For intravitreal injection, bevacizumab costs approximately US$50 to US$100 per dose, as opposed to US$2000 per dose for ranibizumab. Sharing multiple doses of bevacizumab from a single vial can substantially reduce the cost of treatment.

  10. Multiple Sclerosis Symptom Recrudescence at the End of the Natalizumab Dosing Cycle

    PubMed Central

    Brock-Simmons, Regina; Augsburger, Amanda; Steele, Sonya U.; Mohn, Kristie; Rhone, Mandi; Bo, Jinyan; Costello, Kathleen

    2014-01-01

    Background: This study was undertaken to determine how frequently patients receiving natalizumab for multiple sclerosis (MS) experience recrudescence of their MS symptoms at the end of the dosing cycle. Methods: One hundred consecutive MS patients receiving natalizumab completed a survey evaluating changes in symptoms during the natalizumab dosing cycle. Ninety-one patients also completed questionnaires at two time points: the first week after natalizumab infusion and the last week of the dosing cycle. These included the Multiple Sclerosis Quality of Life–54 (MSQOL-54), Fatigue Visual Analog Scale (VAS), Fatigue Severity Scale (FSS), and Beck Depression Inventory–II (BDI-II). Results: End of dosing interval (EDI) symptoms were reported as currently being experienced by 57% of respondents. An additional 10% reported that they previously experienced that phenomenon, but not currently, and 33% reported never experiencing this. In those with EDI symptoms, they began to occur a median of 21 days after infusion and improved again a median of 1 day after infusion. The most common symptoms reported were fatigue, weakness, walking impairment, and cognitive difficulties. No specific demographic or disease characteristics were associated with this phenomenon. In the subgroup with EDI symptoms, the MSQOL-54, Fatigue VAS, FSS, and BDI-II scores were all significantly worse in the last week of the dosing cycle when compared with the first week. No difference was seen in these scores between first and last week in the subgroup not experiencing symptom recrudescence. Conclusions: Recrudescence of fatigue, weakness, walking impairment, or cognitive difficulties at the end of the dosing cycle occurs in about two-thirds of MS patients receiving natalizumab. PMID:25061433

  11. Single and multiple dose pharmacokinetics and tolerability of HX-1171, a novel antioxidant, in healthy volunteers

    PubMed Central

    Kim, Yo Han; Choi, Hee Youn; Lee, Shi Hyang; Lim, Hyeong-Seok; Miki, Tokutaro; Kang, Jong-Koo; Han, Kyoung-Goo; Bae, Kyun-Seop

    2015-01-01

    Background HX-1171 (1-O-hexyl-2,3,5-trimethylhydroquinone) is a promising antioxidant with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the tolerability and pharmacokinetics of HX-1171 in healthy volunteers. Methods A randomized, single-blind, placebo-controlled, dose escalation study was conducted in 83 subjects. In the single ascending dose study, 20, 40, 80, 160, 300, 600, 1,200, 1,500 or 2,000 mg of HX-1171 was administered to 67 subjects. In the multiple ascending dose study, 500 or 1,000 mg was administered to 16 subjects for 14 days. The plasma and urine concentrations of HX-1171 were determined by using a validated liquid chromatography-mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. Results Adverse events reported in the study were all mild in intensity and resolved without any sequelae. HX-1171 was rapidly and minimally absorbed with a median time at maximal concentration of 0.63–1.50 hours and slowly eliminated with a terminal half-life of 21.12–40.96 hours. Accumulation index ranged from 2.0 to 2.2 after repeated dosing for 14 days. For both the single and multiple doses administrations, urinary concentrations indicated that less than 0.01% of the HX-1171 administered was excreted in urine. Conclusion HX-1171 was well tolerated and minimally absorbed in healthy volunteers. The pharmacokinetic profile of HX-1171 was consistent with once-a-day dosing. PMID:25848210

  12. Single dose ivabradine versus intravenous metoprolol for heart rate reduction before coronary computed tomography angiography (CCTA) in patients receiving long-term calcium channel-blocker therapy.

    PubMed

    Celik, O; Atasoy, M M; Ertürk, M; Yalçın, A A; Aksu, H U; Diker, M; Aktürk, I F; Atasoy, I

    2014-07-01

    In patients with contraindication for beta-blockers who are also under long-term calcium channel-blocker therapy for any reason, ivabradine may be used as an alternative treatment to achieve the target heart rate. To assess whether single dose oral ivabradine in patients referred for coronary computed tomography angiography (CCTA) is safe and can significantly decrease heart rate compared to intravenous (i.v.) metoprolol in patients receiving long-term calcium channel-blocker therapy. One-hundred and twenty patients who were under calcium channel-blocker therapy referred for CCTA were randomized to premedication with single dose (15 mg) ivabradine (n = 63) or i.v. metoprolol (5-10 mg) (n = 62). Hearth rate (HR) was assessed at admission (HR1), prescan (HR2), and during CCTA scan (HR3) for all patients. Blood pressure (BP) was measured before medication (BP1) and immediately before CCTA scan (BP2). Although the HR averages of two groups were not significantly different before medication (HRIv1 = 80 ± 7 bpm vs. HRβ1 = 81 ± 7 bpm; P = 0.42), significant HR reduction was observed in the ivabradine group (HRIv3 = 62 ± 7 bpm) when compared to the metoprolol group (HRβ3 = 66 ± 6 bpm; P = 0.001). Decreases in HR forivabradine (18 ± 6 bpm) was significantly higher than for metoprolol (15 ± 4 bpm; P = 0.003) without relevant side-effects. Ivabradine showed no significant effect on either systolic BP or diastolic BP (siBPIv1, 139 ± 10; siBPIv2, 138 ± 10; P = 0.260; diBPIv1, 81 ± 7; diBPIv2, 81 ± 6; P = 0.59). Nevertheless, metoprolol group demonstrated significant reduction in both SiBP and DiBP (siBPβ1, 136 ± 11; siBPβ2 130 ± 11; P < 0.001; diBPβ1, 81 ± 6; diBPβ2, 78 ± 6; P < 0.001). Single dose ivabradine is safe and significantly more effective than i.v. metoprolol in decreasing HR in patients under calcium channel-blocker therapy

  13. Development of a Monte Carlo multiple source model for inclusion in a dose calculation auditing tool.

    PubMed

    Faught, Austin M; Davidson, Scott E; Fontenot, Jonas; Kry, Stephen F; Etzel, Carol; Ibbott, Geoffrey S; Followill, David S

    2017-09-01

    The Imaging and Radiation Oncology Core Houston (IROC-H) (formerly the Radiological Physics Center) has reported varying levels of agreement in their anthropomorphic phantom audits. There is reason to believe one source of error in this observed disagreement is the accuracy of the dose calculation algorithms and heterogeneity corrections used. To audit this component of the radiotherapy treatment process, an independent dose calculation tool is needed. Monte Carlo multiple source models for Elekta 6 MV and 10 MV therapeutic x-ray beams were commissioned based on measurement of central axis depth dose data for a 10 × 10 cm(2) field size and dose profiles for a 40 × 40 cm(2) field size. The models were validated against open field measurements consisting of depth dose data and dose profiles for field sizes ranging from 3 × 3 cm(2) to 30 × 30 cm(2) . The models were then benchmarked against measurements in IROC-H's anthropomorphic head and neck and lung phantoms. Validation results showed 97.9% and 96.8% of depth dose data passed a ±2% Van Dyk criterion for 6 MV and 10 MV models respectively. Dose profile comparisons showed an average agreement using a ±2%/2 mm criterion of 98.0% and 99.0% for 6 MV and 10 MV models respectively. Phantom plan comparisons were evaluated using ±3%/2 mm gamma criterion, and averaged passing rates between Monte Carlo and measurements were 87.4% and 89.9% for 6 MV and 10 MV models respectively. Accurate multiple source models for Elekta 6 MV and 10 MV x-ray beams have been developed for inclusion in an independent dose calculation tool for use in clinical trial audits. © 2017 American Association of Physicists in Medicine.

  14. Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease

    PubMed Central

    2010-01-01

    Background Purified intravenous immunoglobulin (IVIG) obtained from the plasma of healthy humans is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. IVIG contains naturally occurring auto-antibodies, including antibodies (Abs) against β-amyloid (Aβ) peptides accumulating in the brains of Alzheimer's disease (AD) patients. IVIG has been shown to alleviate AD pathology when studied with mildly affected AD patients. Although its mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain Aβ deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses. Methods We first determined the effect of IVIG on Aβ toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of Aβ burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed Aβ deposits from brain sections of APP/PS1 mice or promotes Aβ removal by primary glial cells. We determined the role of lysosomal degradation pathway and Aβ Abs in the IVIG-promoted reduction of Aβ. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human Aβ in a mouse model of AD in vivo. Results IVIG was protective against Aβ toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Aβ1-42 but did not solubilize natively formed brain Aβ deposits ex vivo. IVIG enhanced microglia-mediated Aβ clearance ex vivo, with a mechanism linked to Aβ Abs and lysosomal degradation. The IVIG-enhanced Aβ clearance appears specific for microglia since IVIG did not affect Aβ clearance by astrocytes. The cellular mechanisms of Aβ clearance we observed have potential relevance in vivo since after peripheral administration IVIG penetrated to mouse brain tissue reaching highest concentrations in the

  15. Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening.

    PubMed

    Park, Yoon-Dong; Sun, Wei; Salas, Antonio; Antia, Avan; Carvajal, Cindy; Wang, Amy; Xu, Xin; Meng, Zhaojin; Zhou, Ming; Tawa, Gregory J; Dehdashti, Jean; Zheng, Wei; Henderson, Christina M; Zelazny, Adrian M; Williamson, Peter R

    2016-08-02

    Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD-dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. Cryptococcosis is a neglected fungal meningitis that causes approximately half a million deaths annually. The most effective antifungal agent, amphotericin B, was developed in the 1950s, and no effective medicine has been developed for this disease since that time. A key aspect of amphotericin B's effectiveness is thought to be because of its ability to kill the fungus (fungicidal activity), rather than just stop or slow its growth. The present study utilized a recently identified fungicidal agent, bithionol, to identify potential fungicidal drug targets that can be used in developing modern fungicidal agents. A combined protein and genetic analysis approach was used to identify a class of enzymes, dehydrogenases, that the fungus uses to maintain homeostasis with regard to sugar nutrients. Similarities in the drug target site were found that resulted in simultaneous inhibition and killing of the fungus by bithionol. These studies thus

  16. Shot sequencing based on biological equivalent dose considerations for multiple isocenter Gamma Knife radiosurgery.

    PubMed

    Ma, Lijun; Lee, Letitia; Barani, Igor; Hwang, Andrew; Fogh, Shannon; Nakamura, Jean; McDermott, Michael; Sneed, Penny; Larson, David A; Sahgal, Arjun

    2011-11-21

    Rapid delivery of multiple shots or isocenters is one of the hallmarks of Gamma Knife radiosurgery. In this study, we investigated whether the temporal order of shots delivered with Gamma Knife Perfexion would significantly influence the biological equivalent dose for complex multi-isocenter treatments. Twenty single-target cases were selected for analysis. For each case, 3D dose matrices of individual shots were extracted and single-fraction equivalent uniform dose (sEUD) values were determined for all possible shot delivery sequences, corresponding to different patterns of temporal dose delivery within the target. We found significant variations in the sEUD values among these sequences exceeding 15% for certain cases. However, the sequences for the actual treatment delivery were found to agree (<3%) and to correlate (R² = 0.98) excellently with the sequences yielding the maximum sEUD values for all studied cases. This result is applicable for both fast and slow growing tumors with α/β values of 2 to 20 according to the linear-quadratic model. In conclusion, despite large potential variations in different shot sequences for multi-isocenter Gamma Knife treatments, current clinical delivery sequences exhibited consistent biological target dosing that approached that maximally achievable for all studied cases.

  17. Very low-dose lenalidomide therapy for elderly multiple myeloma patients.

    PubMed

    Minagawa, Kentaro; Kawano, Hiroki; Suzuki, Takuma; Inagaki, Tadahiro; Kishi, Minoru; Hirata, Tamaki; Kimura, Sachiko; Takechi, Miho; Koide, Toru; Iwai, Masahide; Katayama, Yoshio; Matsui, Toshimitsu

    2013-05-01

    Lenalidomide treatment for refractory or relapsed multiple myeloma in elderly patients may be feasible in an outpatient setting. However, difficulties have been associated with the management of adverse effects. Therefore, a dose reduction in lenalidomide has been recommended in some cases. In this report, we encountered the successful treatment of myeloma in 6 elderly patients (aged above 70 years) with very low-dose lenalidomide (5 mg daily). Four patients exhibited more than a partial response with an 8.6 months median follow-up period, which was comparable with previous findings. The major adverse effect observed was infection, which occurred during the first several cycles. Others were less toxic, especially the absence of grade 3/4 toxicities for hematological adverse effects.Although a dose reduction in lenalidomide therapy for elderly patients is controversial, a very low dose could be safe and effective. Our group is currently conducting a multi-center prospective trial to evaluate the efficacy of low-dose lenalidomide therapy.

  18. Rate of expulsion of Trichuris trichiura with multiple and single dose regimens of albendazole.

    PubMed

    Bundy, D A; Thompson, D E; Cooper, E S; Blanchard, J

    1985-01-01

    The efficacy of multiple and single dose regimens of albendazole on Trichuris trichiura infection was evaluated by counting the number of worms expelled/day from two pair-matched groups of children, for nine days following therapy. The temporal patterns of worm expulsion were similar whether the children received a single 400 mg dose or two consecutive doses: no worms were passed before the second day, or after the sixth day, after intervention, and the maximum worm expulsion rate was attained on the fourth day. A second treatment six days after the first expelled no more worms. The results obtained here resemble those obtained previously with a three-day (600 mg) regimen of mebendazole in a study of heavily infected children. We conclude: that irrespective of dose, benzimidazole carbamates require the gut transit time plus 48 hours to immobilize T. trichiura; and that a single dose of albendazole is effective against light infections of T. trichiura but requires further evaluation with high intensity infections.

  19. Shot sequencing based on biological equivalent dose considerations for multiple isocenter Gamma Knife radiosurgery

    NASA Astrophysics Data System (ADS)

    Ma, Lijun; Lee, Letitia; Barani, Igor; Hwang, Andrew; Fogh, Shannon; Nakamura, Jean; McDermott, Michael; Sneed, Penny; Larson, David A.; Sahgal, Arjun

    2011-11-01

    Rapid delivery of multiple shots or isocenters is one of the hallmarks of Gamma Knife radiosurgery. In this study, we investigated whether the temporal order of shots delivered with Gamma Knife Perfexion would significantly influence the biological equivalent dose for complex multi-isocenter treatments. Twenty single-target cases were selected for analysis. For each case, 3D dose matrices of individual shots were extracted and single-fraction equivalent uniform dose (sEUD) values were determined for all possible shot delivery sequences, corresponding to different patterns of temporal dose delivery within the target. We found significant variations in the sEUD values among these sequences exceeding 15% for certain cases. However, the sequences for the actual treatment delivery were found to agree (<3%) and to correlate (R2 = 0.98) excellently with the sequences yielding the maximum sEUD values for all studied cases. This result is applicable for both fast and slow growing tumors with α/β values of 2 to 20 according to the linear-quadratic model. In conclusion, despite large potential variations in different shot sequences for multi-isocenter Gamma Knife treatments, current clinical delivery sequences exhibited consistent biological target dosing that approached that maximally achievable for all studied cases.

  20. A Study on the Efficacy of the Addition of Low Dose Dexmedetomidine as an Adjuvant to Lignocaine in Intravenous Regional Anaesthesia (IVRA)

    PubMed Central

    Menezes, Yvonne; D’souza, Shirley Ann

    2016-01-01

    Introduction Intravenous Regional Anaesthesia (IVRA) is a simple, effective method of providing anaesthesia for short duration surgical procedures on the extremities, its chief drawbacks are tourniquet pain, short duration of block and absence of post-operative analgesia. Dexmedetomidine is known to reduce anaesthetic requirements and also provide analgesia to the patient. Aim To evaluate the efficacy of dex