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Sample records for multiple intravenous doses

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

    PubMed

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

    2014-02-01

    A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration. PMID:23859819

  2. 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.

  3. Venous thrombosis in multiple sclerosis patients after high-dose intravenous methylprednisolone: the preventive effect of enoxaparin.

    PubMed

    Kalanie, Hossein; Harandi, Ali Amini; Alidaei, Shapoor; Heidari, Daryoosh; Shahbeigi, Saeed; Ghorbani, Mehdi

    2011-01-01

    Aim. This study was designed to examine the possible role of high-dose intravenous methylprednisolone (IVMP) in the development of venous thrombosis (VT). The cerebral one anecdotally had been reported in patients with relapsing remitting multiple sclerosis (RRMS) in acute attacks and the possible preventive role of enoxaparin. Material and Methods. From a pool of 520 patients, 388 patients with definite RRMS who fulfilled entry characteristics were selected and randomly received either a 5-day course of daily 1 gr IVMP or the aforementioned plus 5 days of daily subcutaneous 40 units of enoxaparin according to a predefined protocol. Results. Mean age, gender ratio, mean relapse rate, and EDSS were similar in both groups of patients (P > 0.05). Finally, 366 patients remained in the study. Of 188 patients treated with IVMP with 855 relapses, 5 developed VT (0.37% per patient per year and 0.58% per each course of IVMP) within 3 to 15 days of starting therapy. None of the 178 patients who experienced 809 relapses who received IVMP plus enoxaparin developed such complications. Conclusion. The study implies that high-dose IVMP in MS exacerbation may increase the risk of VT and prophylactic anticoagulant treatment in this setting is warranted. PMID:22242201

  4. Venous Thrombosis in Multiple Sclerosis Patients after High-Dose Intravenous Methylprednisolone: The Preventive Effect of Enoxaparin

    PubMed Central

    Kalanie, Hossein; Harandi, Ali Amini; Alidaei, Shapoor; Heidari, Daryoosh; Shahbeigi, Saeed; Ghorbani, Mehdi

    2011-01-01

    Aim. This study was designed to examine the possible role of high-dose intravenous methylprednisolone (IVMP) in the development of venous thrombosis (VT). The cerebral one anecdotally had been reported in patients with relapsing remitting multiple sclerosis (RRMS) in acute attacks and the possible preventive role of enoxaparin. Material and Methods. From a pool of 520 patients, 388 patients with definite RRMS who fulfilled entry characteristics were selected and randomly received either a 5-day course of daily 1 gr IVMP or the aforementioned plus 5 days of daily subcutaneous 40 units of enoxaparin according to a predefined protocol. Results. Mean age, gender ratio, mean relapse rate, and EDSS were similar in both groups of patients (P > 0.05). Finally, 366 patients remained in the study. Of 188 patients treated with IVMP with 855 relapses, 5 developed VT (0.37% per patient per year and 0.58% per each course of IVMP) within 3 to 15 days of starting therapy. None of the 178 patients who experienced 809 relapses who received IVMP plus enoxaparin developed such complications. Conclusion. The study implies that high-dose IVMP in MS exacerbation may increase the risk of VT and prophylactic anticoagulant treatment in this setting is warranted. PMID:22242201

  5. 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.

  6. Automated administration of intermittent intravenous doses.

    PubMed

    Lutomski, D M; Schwartz-Fulton, J; Rivera, J O

    1985-11-01

    The cost difference of administering cimetidine 300 mg via intravenous piggyback (IVPB) every six hours by a conventional separate container system versus using an automated intermittent i.v. administration system was evaluated. The study was conducted in two phases. Phase 1 documented the amount of drug waste with the two systems, and phase 2 examined the practical use of the IVAC Multi Dose System. Nurses who administered the medication using the multiple-dose system completed a questionnaire on its operation. A materials cost analysis was performed to compare the two methods. The two systems were found to have approximately equivalent amounts of drug waste over the 30-day evaluation period of phase 1. The mean percentage of doses wasted was 12.2% with the conventional single-dose minibag method and 12.7% with the automated multiple-dose method. The multiple-dose system had a lower cost per dose of cimetidine ($2.25 versus $3.47). These savings appear to outweigh the cost of the additional equipment necessary for the automated system. The majority of nurses preferred the multiple-dose system. Potential problems encountered in accurately delivering doses with the multiple-dose automated system were identified, and possible solutions are suggested. The use of an automated multiple-dose i.v. administration system can potentially decrease the materials cost portion of drug administration. The total impact on hospital costs needs to be evaluated, and other comparisons with alternative administration systems need to be performed.

  7. Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study

    PubMed Central

    2012-01-01

    Background Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Research (WRAIR) has been developing a novel good manufacturing practice (GMP) injection of AS, which was approved by the US FDA for investigational drug use and distribution by the CDC. Methods Tolerability and pharmacokinetics of current GMP intravenous AS, as an anti-malarial agent, were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusion in 24 healthy subjects (divided into three groups) in the Phase 1 clinical trial study. Results Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment. After intravenous injection, parent drug rapidly declined and was converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15-0.23 hr for AS and 1.23-1.63 hr for DHA, but the peak concentration (Cmax) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and Cmax values of AS and DHA were increased proportionally to the AS climbing multiple doses. Discussion The safety of injectable AS, even at the highest dose of 8 mg/kg increases the probability of therapeutic success of the drug even in patients with large variability of parasitaemia. PMID:22853818

  8. Bacterial Contamination of Single- and Multiple-Dose Vials after Multiple Use and Intravenous Admixtures in Three Different Hospitals in Iran

    PubMed Central

    Khalili, Hossein; Sheikhbabayi, Mehdi; Samadi, Nasser; Jamalifar, Hossein; Dalili, Dina; Samadi, Nasrin

    2013-01-01

    There is possibility of microbial contamination of any single-dose vials (SDVs), multiple-dose vials (MDVs) and admixtures (ADXs) during the preparation and injection to the patients that could be resulted in bloodstream infection. The goal of this study was to investigate the microbial contamination of MDVs and SDVs after multiple use and ADXs prepared by nursing staff in the treatment room versus those prepared by the hospital pharmacist in the clean room. The sterility of 43 opened MDVs and SDVs, 92 prepared ADXs in treatment room and 17 prepared ADXs in clean room were studied by membrane filtration method. Only one of 92 ADXs prepared in treatment room was contaminated with Bacillus subtilis (%1.1) and none of the ADXs prepared in clean room, MDVs and SDVs had microbial contamination. Although good sanitization practices and training of nurses could reduce the risk of microbial contamination in traditional units, using clean room for preparation of parenteral products could be the best strategy. PMID:24250590

  9. 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. PMID:27272956

  10. 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.

  11. 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

  12. 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

  13. Drug Utilization, Dosing, and Costs After Implementation of Intravenous Acetaminophen Guidelines for Pediatric Patients

    PubMed Central

    Fusco, Nicholas M.; Parbuoni, Kristine; Morgan, Jill A.

    2014-01-01

    OBJECTIVES The objectives of this evaluation of medication use were to characterize the use of intravenous acetaminophen at our institution and to determine if acetaminophen was prescribed at age-appropriate dosages per institutional guidelines, as well as to evaluate compliance with restrictions for use. Total acquisition costs associated with intravenous acetaminophen usage is described as well. METHODS This retrospective study evaluated the use of acetaminophen in pediatric patients younger than 18 years of age, admitted to a tertiary care hospital, who received at least 1 dose of intravenous acet-aminophen between August 1, 2011, and January 31, 2012. RESULTS A total of 52 doses of intravenous acetaminophen were administered to 31 patients during the 6-month study period. Most patients were admitted to the otorhinolaryngology service (55%), and the majority of doses were administered either in the operating room (46%) or in the intensive care unit (46%). Nineteen doses (37%) of intravenous acetaminophen were administered to patients who did not meet institutional guidelines' eligibility criteria. Three patients received single doses of intravenous acetaminophen that were greater than the dose recommended for their age. One patient during the study period received more than the recommended 24-hour maximum cumulative dose for acetaminophen. Total acquisition cost of intravenous acetaminophen therapy over the 6-month study period was $530.40. CONCLUSIONS Intravenous acetaminophen was used most frequently among pediatric patients admitted to the otorhinolaryngology service during the perioperative period. Nineteen doses (37%) were administered to patients who did not meet the institutional guidelines' eligibility criteria. Our data support reinforcing the availability of institutional guidelines to promote cost-effective use of intravenous acetaminophen while minimizing the prescription of inappropriate doses. PMID:24782690

  14. 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.

  15. 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.

  16. 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

  17. 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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  19. Pharmacokinetics of eltoprazine in healthy male subjects after single dose oral and intravenous administration.

    PubMed Central

    Raghoebar, M; Mak, M; Cournot, A; Pistorius, M C; Van Harten, J; Roseboom, H

    1990-01-01

    The kinetics, safety and tolerability of eltoprazine hydrochloride were studied in an open, cross-over, partially randomised design after single oral (8 mg) and intravenous (3 and 8 mg) doses to 12 healthy male subjects. After intravenous administration, the mean t1/2 ranged from 7 to 9 h, the MRT was 11 h, CL was 487 +/- 148 (3 mg dose) and 471 +/- 56 (8 mg dose) ml kg-1 h-1, while CLR was 226 +/- 124 (3 mg dose) and 189 +/- 38 (8 mg dose) ml kg-1 h-1. The Vss was 3.3 +/- 0.7 (3 mg dose) and 3.8 +/- 0.5 (8 mg dose) 1 kg-1. Cumulative renal excretion was 40%. The AUC and the cumulative urinary excretion were directly proportional to dose within the range of 3-8 mg. Values of tmax varied from 1 to 4 h after oral administration. The mean Cmax value was 24 ng ml-1 after an oral dose of 8 mg. The plasma elimination half-life after oral administration was 9.8 +/- 3.9 h. Absolute oral bioavailability was 110 +/- 32%. Dose-dependent somnolence was observed. PMID:2288834

  20. 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

  1. Disposition of 2-hydroxy-4-methoxybenzophenone in rats dosed orally, intravenously, or topically.

    PubMed

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

    1986-01-01

    Administration to rats of oral doses of [14C]-2-hydroxy-4-methoxybenzophenone (HMB) in the range of 3.01-2570 mg/kg revealed that a dose-dependent elimination process was operative at the highest dose. Urinary excretion (63.9-72.9% of the dose in 72 h) was the major route for elimination of radioactivity. An intravenous dose (4.63 mg/kg) distributed rapidly throughout the body of rats and appeared in the urine in an amount (67.4%) similar to those for the oral doses. Rats absorbed large portions of doses of [14C]HMB administered topically, either as an ethanolic solution (50, 200, or 800 micrograms/rat) or formulated in a lotion (50 micrograms/rat). For rats with biliary cannulas, 36.6% of the radioactivity of an intravenous dose (4.46 mg/kg) appeared in the bile in 4 h; the initial half-life for biliary elimination was 40 min. In the bile, at least five radioactive components, none of which was intact HMB, were present. The two major components were glucuronides of HMB and demethylated HMB, and a third was probably a sulfate ester of hydroxylated HMB. In urine, there were nine radioactive components, two of which were unchanged HMB and its glucuronide.

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

    PubMed Central

    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

    2015-01-01

    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. PMID:25840597

  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. 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

  5. Intravenous immunoglobulin and mitoxantrone stop the progression of secondary progressive multiple sclerosis in a patient with interferon intolerance.

    PubMed

    Rodríguez Orozco, Alain R

    2004-01-01

    A 36 year-old female patient with secondary progressive multiple sclerosis accompanied by neuropsychiatric depression and history of intolerance to beta-interferon was treated with mitoxantrone (MX) and intravenous immunoglobulin (IVIG) for 2 years. Both clinical response and magnetic resonance imaging were performed at the end. With a combination of MX and IVIG long-term treatment, her disabilities improved as measured by the Expanded Disability Status Scale (EDSS). The combination therapy was well-tolerated. It represents an alternative to treat patients who do not respond well to cytostatics alone, or in those in whom intolerance to interferons may also occur. Immunomodulation with intravenous immunoglobulin stopped the progression of the disease and avoided subsequent exacerbations during 24 months. The role of high doses of immunoglobulins in the treatment of patients with secondary progressive MS deserves clinical trials to evaluate the stopping of progression of the disease in comparison to remissions induced by cytostatics, interferons and steroids.

  6. Disposition of decabromobiphenyl ether in rats dosed intravenously or by feeding

    SciTech Connect

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

    1987-01-01

    The disposition of /sup 14/C-labeled decabromobiphenyl ether (DBBE) in male Fischer rats dosed by feeding (0.025-5.0% of the diet) or intravenously (1 mg/kg) was determined. For rats dosed by feeding, intestinal absorption of DBBE was evident in that the intact compound was present in extracts of liver. For these rats, the size of the liver increased with increasing concentration of DBBE in the diet. Liver contained a maximum of 0.449% of the administered radioactivity at 24 h after feeding rats a diet containing 0.0277% (/sup 14/C)DBBE; no other organ or tissue contained more than 0.26%. The total amount of radioactivity found in tissues was less than 1% of the dose. Of the radioactivity recovered in the feeding experiments, more than 99% was in the feces and gut contents at 72 h; a maximum of 0.012% of the dose was in the urine. In the feces of rats fed (/sup 14/C)DBBE, there were three metabolites, which together comprised 1.5-27.9% of the radioactivity. Since absorption was minimal, most of the metabolism of (/sup 14/C)DBBE apparently took place in the gastrointestinal tract. The metabolites increased in percent of total radioactivity with the content of DBBE in the diet, an indication that enzyme induction in intestinal bacteria may have occurred at the higher doses. More extensive metabolism of (/sup 14/C)DBBE occurred after intravenous administration; only 37% of the radioactivity in the feces was unchanged DBBE. At 72 h after dosing, fecal excretion accounted for 70% of the dose; only 0.129% appeared in the urine. Muscle retained 12.9% and skin 7.25% of the radioactivity administered. In 4 h, rats with biliary cannulas excreted in the bile 7.17% of the intravenously administered radioactivity; less than 1% was excreted as intact DBBE. Biliary excretion was apparently the major route for elimination of the intravenously administered compound.

  7. Intravenous leiomyomatosis with inferior vena cava or intracardiac extension and concurrent bilateral multiple pulmonary nodules

    PubMed Central

    Zhang, Guorui; Yu, Xin; Lang, Jinghe

    2016-01-01

    Abstract Background: Intravenous leiomyomatosis is a special type of uterine leiomyoma and features formation and growth of benign leiomyoma tissue within vascular wall. Benign metastatic leiomyoma refers to benign leiomyoma metastasizing to extra-uterine sites, dominantly lung. Solitary or multiple small nodules in the lung can be seen in image scans. Methods: We report 2 cases of intravenous leiomyomatosis with inferior vena cava or intracardiac extension and concurrent multiple nodules in bilateral lungs. Results: Case 1 was a 40-year-old woman with a large mass in pelvic cavity, masses in heart chambers, and disseminates pulmonary nodules detected at preoperative image scans. Masses in pelvic cavity and heart were resected in a 2-stage surgery. Histology examination confirmed the diagnosis of intravenous leiomyomatosis. Pulmonary nodules stayed stable during follow-up. Case 2 was a 37-year-old woman with 3 times of uterine-related surgeries. A pelvic mass appeared again and filling defect was observed in left ovarian vein, right renal vein, right common iliac vein, and inferior vena cava. Tumors in pelvic cavity and within vessels were removed in a 1-stage surgery. Histology examination confirmed the diagnosis of intravenous leiomyomatosis. Pulmonary nodules remained stable during follow-up. Conclusion: The incidence of benign metastatic leiomyoma in patients with intravenous leiomyomatosis might be relatively high. Metastasis of intravenous leiomyomatosis lesions was a possible source of benign metastatic leiomyoma in these cases. PMID:27583911

  8. 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.

  9. Multiple anatomy optimization of accumulated dose

    PubMed Central

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

    2014-01-01

    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. PMID:25370619

  10. 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. PMID:27331303

  11. Single-dose intravenous gammaglobulin can stabilize neutrophil Mac-1 activation in sickle cell pain crisis

    PubMed Central

    Manwani, Deepa; Chen, Grace; Carullo, Veronica; Serban, Stelian; Olowokure, Olugbenga; Jang, Jungeun; Huggins, Matthew; Cohen, Hillel W.; Billett, Henny; Atweh, George F.; Frenette, Paul S.; Shi, Patricia A.

    2015-01-01

    Intravenous immunoglobulin (IVIG) decreases neutrophil adhesion to endothelium and red blood cell-neutrophil interactions in sickle cell mice undergoing vaso-occlusion. In this Phase I clinical trial of sickle cell anemia (SCA) patients admitted with pain crisis, we evaluated the status of adhesion molecules on neutrophils in control and IVIG-treated subjects pre- and post-infusion up to 800 mg/kg, the same dose used in murine studies. Mac-1 function significantly decreased from baseline in the low-dose IVIG (200–400 mg/kg) cohorts. IVIG-related adverse events may have occurred in the high-dose (600–800 mg/kg) cohorts. There were no significant increases in neutrophil and leukocyte counts, suggesting that IVIG may more selectively inhibit Mac-1 function as opposed to neutrophil adhesion. This study provides the first in-human validation of pre-clinical murine studies that IVIG can decrease Mac-1 function. PMID:25616042

  12. Preliminary pharmacokinetics of morphine and its major metabolites following intravenous administration of four doses to horses.

    PubMed

    Knych, H K; Steffey, E P; McKemie, D S

    2014-08-01

    The objective of the current study was to describe the pharmacokinetics of morphine and its metabolites following intravenous administration to the horse. A total of eight horses (two per dose group) received a single intravenous dose of 0.05, 0.1, 0.2, or 0.5 mg/kg morphine. Blood samples were collected up to 72 h postdrug administration, analyzed using LC-MS/MS and pharmacokinetic parameters determined. Behavior, step counts, and gastrointestinal activity were also assessed. The beta and gamma half-life for morphine ranged from 0.675 to 2.09 and 6.70 to 18.1 h, respectively, following administration of the four different IV doses. The volume of distribution at steady-state and systemic clearance ranged from 6.95 to 15.8 L/kg and 28.3 to 35.7 mL · min/kg, respectively. The only metabolites identified in blood samples were the primary metabolites identified in other species, 3-morphine-glucuronide and 6-morphine-glucuronide. Muscle fasciculations were observed at 0.2 and 0.5 mg/kg and ataxia noted at 0.5 mg/kg. Gastrointestinal activity was decreased in all dose groups (for up to 8 h in 7/8 horses and 24 h in one horse). This study extends previous studies and is the first report describing the metabolites of morphine in the horse. Plasma concentrations of morphine-3-glucuronide, a metabolite with demonstrated neuro-excitatory activity in mice, far exceeded that of morphine-6-glucuronide. Further study is warranted to assess whether the high levels of the morphine-3-glucuronide contribute to the dose-dependent excitation observed at high morphine doses.

  13. Pharmacokinetics of a single intravenous dose of marbofloxacin in adult donkeys.

    PubMed

    González, F; Rodríguez, C; De Lucas, J J; Waxman, S; San Andrés, M D; Serres, C; Nieto, J; San Andrés, M I

    2007-07-28

    Six donkeys each received 2 mg/kg marbofloxacin as a 10 per cent aqueous solution administered intravenously. Principal pharmacokinetic parameters were determined and two efficacy indices were computed by using pharmacokinetic parameters and selected mic90 values of marbofloxacin against pathogenic equine strains to predict the efficacy of the drug at this dose. The pharmacokinetics of marbofloxacin in donkeys was characterised by a large mean volume of distribution at a steady state (1.15 [0.09] l/kg) and a long mean (sd) elimination half-life of 9.24 (1.96) hours. It was also characterised by a relatively slow total body clearance of 0.10 (0.02) l/kg/hour, slower than in horses. Using mic90 values of marbofloxacin against pathogenic equine strains with a daily dose of 2 mg/kg, appropriate values of efficacy indicators were obtained only for Enterobacteriaceae. Daily intravenous doses of 0.33, 2.62 and 20 mg/kg were calculated for evaluation in clinical trials of infections due to Enterobacteriaceae, Staphylococcus aureus and Streptococci, respectively.

  14. Dose Ranging, Expanded Acute Toxicity and Safety Pharmacology Studies for Intravenously Administered Functionalized Graphene Nanoparticle Formulations

    PubMed Central

    Kanakia, Shruti; Toussaint, Jimmy; Chowdhury, Sayan Mullick; Tembulkar, Tanuf; Lee, Stephen; Jiang, Ya-Ping; Lin, Richard Z.; Shroyer, Kenneth R.; Moore, William; Sitharaman, Balaji

    2014-01-01

    Graphene nanoparticles dispersions show immense potential as multifunctional agents for in vivo biomedical applications. Herein, we follow regulatory guidelines for pharmaceuticals that recommend safety pharmacology assessment at least 10 – 100 times higher than the projected therapeutic dose, and present comprehensive single dose response, expanded acute toxicology, toxicokinetics, and respiratory/cardiovascular safety pharmacology results for intravenously administered dextran-coated graphene oxide nanoplatelet (GNP-Dex) formulations to rats at doses between 1–500 mg/kg. Our results indicate that the maximum tolerable dose (MTD) of GNP-Dex is between 50 mg/kg ≤ MTD < 125 mg/kg, blood half-life < 30 minutes, and majority of nanoparticles excreted within 24 hours through feces. Histopathology changes were noted at ≥ 250 mg/kg in the heart, liver, lung, spleen, and kidney; we found no changes in the brain and no GNP-Dex related effects in the cardiovascular parameters or hematological factors (blood, lipid, and metabolic panels) at doses < 125 mg/kg. The results open avenues for pivotal preclinical single and repeat dose safety studies following good laboratory practices (GLP) as required by regulatory agencies for investigational new drug (IND) application. PMID:24854092

  15. 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]. PMID:19192939

  16. 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.

  17. Disposition of marbofloxacin in vulture (Gyps fulvus) after intravenous administration of a single dose.

    PubMed

    Garcia-Montijano, Marino; Waxman, Samanta; de Lucas, J Julio; Luaces, I; de San Andrés, María Dolores; Rodríguez, Casilda

    2011-04-01

    The pharmacokinetics properties of marbofloxacin were studied in adult Eurassian Griffon vulture after single-dose intravenous (IV) administration of 2mg/kg. Drug concentration in plasma was determined by high-performance liquid chromatography and the data obtained were subjected to compartmental and non-compartmental kinetic analysis. Marbofloxacin presented a volume of distribution at steady-state (Vdss) of 1.51±0.22L and total plasma clearance (Cl) of 0.109±0.023L/hkg. The permanence of this drug was long in vultures (T(1/2)(λ)=12.51±2.52h; MRT(∞)=13.54±2.29h). The optimal dose of marbofloxacin estimated is 2.73mg/kg per day for the treatment of infections in vultures with MIC(90)=0.2μg/mL.

  18. 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

  19. Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses.

    PubMed Central

    Bernareggi, A; Danese, A; Cavenaghi, L

    1988-01-01

    A40926 is a new glycopeptide antibiotic with unique activity against Neisseria gonorrhoeae and high and prolonged levels in mouse blood (B. P. Goldstein, E. Selva, L. Gastaldo, M. Berti, R. Pallanza, F. Ripamonti, P. Ferrari, M. Denaro, V. Arioli, and G. Cassani, Antimicrob. Agents Chemother., 31:1961-1966, 1987). We studied the pharmacokinetics of A40926 in rats after single intravenous and subcutaneous 10-mg/kg (body weight) doses. Concentrations in plasma and urine were determined by microbiological assay. After intravenous administration, high concentrations of A40926, ranging from 132 mg/liter at 3 min to 0.7 mg/liter at 96 h, were found in plasma. Concentrations declined with a three-exponential decay correlated with a prolonged, biphasic distribution and a slow elimination (terminal half-life, 61.22 h). After completion of the distribution, the compound was widely distributed to the extravascular space. The rate-limiting step in the elimination of A40926 from the body appears to be the slow return from the deep compartment into the central one. A40926 was rapidly absorbed from the injection site after subcutaneous administration, and its availability was close to 90%. The percentage of the dose excreted in urine in 120 h was 35.9%. PMID:3364946

  20. 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

  1. 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

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

    PubMed

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

    2015-02-20

    Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox-Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1 mg/kg body weight (bw), 5 mg/kg bw, and 20 mg/kg bw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450 g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography-mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13 h, depending on route of administration--intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01 ± 3.80 ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52 ± 39.45 ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1 mg/kg bw and 5 mg/kg bw was 0.89 ± 0.09 μg/ml and 3.188 ± 0.71 μg/ml, respectively. The median (range) time to reach maximum plasma concentration (t(max)) was 4 (2-8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514 ± 0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC(0-t)) of 0.441 ± 0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio. PMID:25530452

  3. Marbofloxacin disposition after intravenous administration of a single dose in wild mallard ducks (Anas platyrhynchos).

    PubMed

    Garcia-Montijano, Marino; de Lucas, J Julio; Rodríguez, Casilda; González, Fernando; San Andrés, Manuel Ignacio; Waxman, Samanta

    2012-03-01

    Marbofloxacin, a fluoroquinolone developed specifically for veterinary use, has demonstrated considerable pharmokinetic variation among avian species. The goal of this study was to determine the disposition kinetics of marbofloxacin in mallard ducks (Anas platyrhynchos) after a single intravenous injection. Six wild mallard ducks were used in the study. Marbofloxacin was injected at a dose of 2 mg/kg into the basilic vein, and blood was subsequently collected at regular intervals from each bird. Plasma marbofloxacin concentrations were determined by using high-performance liquid chromatography. The volume of distribution at steady state was 1.78 +/- 0.37 L/kg, and the total plasma clearance was 0.59 +/- 0.08 L/kg per hour. Marbofloxacin had a relatively short permanence, with a elimination half-life of 2.81 +/- 1.20 hours, a terminal half-life of 2.43 +/- 0.61 hours, and a mean residence time of 2.99 +/- 0.52 hour. The maximum observed concentration (Cmax) and area under the curve (AUC) were 1.34 +/- 0.27 microg/mL and 3.75 +/- 0.56 microg x h/mL, respectively. Values of minimum inhibitory concentration (MIC), Cmax, and AUC have been used to predict the clinical efficacy of a drug in treating bacterial infections, with a Cmax: MIC value of 10 and an AUC: MIC ratio of 125-250 associated with optimal bactericidal effects. By using the study data and MIC breakpoints of 0.125 microg/mL or 0.2 microg/mL, values derived for Cmax: MIC were 9.37 +/- 0.99 and 5.85 +/- 0.62, respectively, and for AUC: MIC were 29.99 +/- 4.51 and 18.74 +/- 2.82, respectively. By using MIC values of 0.125 and 0.2 microg/mL and a target AUC: MIC = 125, the calculated optimal daily marbofloxacin dosages for mallard ducks were 9.24 and 14.78 mg/kg, respectively. These results suggest that, primarily because of the high total plasma clearance observed, the marbofloxacin dose for treatment of bacterial diseases in mallard ducks should be increased after intravenous administration. Intravenous doses

  4. Pharmacokinetics of repeated doses of intravenous cocaine across the menstrual cycle in rhesus monkeys.

    PubMed

    Evans, Suzette M; Foltin, Richard W

    2006-01-01

    Numerous studies in rodents suggest that there are sex differences in response to cocaine that are related to fluctuations in the ovarian hormones of females. Given that female rhesus monkeys have menstrual cycles that are remarkably similar to those of humans, they provide an ideal laboratory animal model for assessing the effects of cocaine across the menstrual cycle. The present study assessed the effects of 4 injections of intravenous (i.v.) cocaine (0.00, 0.25 or 0.50 mg/kg), spaced 15 min apart, in 4 female rhesus monkeys. Each monkey was tested with each dose during 4 phases of the menstrual cycle: menses, midfollicular, periovulatory and midluteal. Estradiol and progesterone levels were measured each session before cocaine administration to verify phase of the menstrual cycle. Cocaine and cocaine metabolite levels were measured 5 min after each cocaine dose and 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Similarly, levels of luteinizing hormone (LH) and prolactin levels were measured before, 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Cocaine and metabolite levels increased as a function of dose, but there were minimal differences across the menstrual cycle following repeated injections of cocaine. With a few exceptions, LH levels decreased as a function of time within the session, with no differences as a function of cocaine dose. Cocaine produced transient increases in LH levels during the luteal phase, with maximal levels occurring after the second cocaine injection. Lastly, cocaine substantially decreased prolactin levels across all menstrual cycle phases. Taken together, these data indicate that any behavioral differences observed either across the menstrual cycle or between males and females, are probably not related to alterations in the pharmacokinetics of cocaine across the menstrual cycle. PMID:16426669

  5. A Convenient Method for Measuring Blood Ascorbate Concentrations in Patients Receiving High-Dose Intravenous Ascorbate

    PubMed Central

    Ma, Yan; Sullivan, Garrett G; Schrick, Elizabeth; Choi, In-Young; He, Zhuoya; Lierman, JoAnn; Lee, Phil; Drisko, Jeanne A; Chen, Qi

    2013-01-01

    Objective A simple method of using fingerstick blood glucose monitors (FSBG) to estimate blood ascorbate values after high-dose intravenous (IV) ascorbate infusion is evaluated as a substitution for HPLC measurement. Methods In 33 participants, readings from FSBG were taken before and after IV ascorbate infusions at various time points, with the post-infusion FSBG readings subtracted by the baseline glucose readings. The results of the subtractions (AAFSBG) were correlated with ascorbate concentrations detected by HPLC (AAHPLC). Results A linear regression was found between ascorbate concentrations detected by the fingersitck method (AAFSBG) and by HPLC (AAHPLC). The linear correlations were identical in healthy subjects, diabetic subjects and cancer patients. ANOVA analysis obtained an AAFSBG/AAHPLC ratio of 0.90, with 90% confidence interval of (0.69, 1.20). The corrections of AAFSBG improved similarity to AAHPLC, but did not significantly differ from the un-corrected values. Conclusion The FSBG method can be used as an approximate estimation of high blood ascorbate concentration after IV ascorbate (>50 mg/dL, or 2.8 mM) without correction. However this measurement is not accurate in detecting lower or baseline blood ascorbate. It is also important to highlight that in regard to glucose monitoring, FSBG readings will be erroneously elevated following intravenous ascorbate use and insulin should not be administered to patients based on these readings. PMID:23885992

  6. High Dose Intraveneous Vitamin C and Chikungunya Fever: A Case Report

    PubMed Central

    Gonzalez, Michael J.; Miranda-Massari, Jorge R.; Berdiel, Miguel J.; Duconge, Jorge; Rodríguez-López, Joshua L.; Hunninghake, Ron; Cobas-Rosario, Vicente J.

    2015-01-01

    The Chikungunya (CHIKV) fever is a viral disease produced by a single-stranded RNA Alphavirus from the Togaviridae genus. Its transmission occurs only through mosquito vectors, principally Aedes aegypti. It requires a human-mosquito-human transmission cycle. It is associated with severe arthritis/arthralgias, myalgias, high fever, headache, and maculopapular rash. Joint ache appears to be symmetrical. The virus has an incubation period of 2 to 7 days, where the high fever is typically presented. It is followed by arthralgias and myalgias, and rashes, which last for 3 to 5 days. However, the arthralgias can persist for months after the infection, which can contribute to severe arthritis. As of now, no vaccine exists for the virus and no official treatment has been developed aside from standard procedures of the use of acetaminophen (paracetamol), and non-steroidal anti-inflammatory drugs. This is a case report of a 54-year old Hispanic individual that reported left shoulder pain, left knee pain and fever. The symptoms started on a Saturday in September 2014 in middle of the night. The patient was treated with high doses of intravenous vitamin C over two days. The symptoms resolved after the infusions without any side effects. Based on the positive outcome in this case, we propose that intravenous vitamin C should be studied further as a potential treatment for acute viral infections. PMID:25705076

  7. Focal and segmental glomerulosclerosis following a single intravenous dose of puromycin aminonucleoside.

    PubMed Central

    Diamond, J. R.; Karnovsky, M. J.

    1986-01-01

    Focal and segmental glomerulosclerosis (FSGS) represents a final pathologic pattern of a number of human renal disorders. Among laboratory models, repeated intraperitoneal injections of the aminonucleoside of puromycin (PA) produces a histologic pattern not unlike the human process. A single intravenous dose of this drug usually results in glomerular morphologic changes in rats resembling those in human nephrotic syndrome with minimal changes. This report describes acute and chronic glomerular injury that begins as early as 8 days after a single central administration of PA and progresses to FSGS within an 18-week period. It seems likely that minimal change disease and FSGS are two pathologic processes in the same continuum of disease. In this model, the severity and persistence of the glomerular lesion may represent irreversible glomerular epithelial cell (GEC) injury secondary to the toxic effects of PA. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:3953770

  8. Scleromyxoedema: treatment of cutaneous and systemic manifestations with high-dose intravenous immunoglobulin.

    PubMed

    Kulczycki, A; Nelson, M; Eisen, A; Heffernan, M

    2003-12-01

    Scleromyxoedema is a rare disease characterized by cutaneous sclerosis, mucin deposition and paraproteinaemia. Internal disease is common, particularly musculoskeletal, gastrointestinal and central nervous system involvement. We report a series of three consecutive patients with scleromyxoedema treated with high-dose intravenous immunoglobulin (hdIVIg). Each of the three patients had relatively low levels of a highly basic IgG-lambda paraprotein, and each has demonstrated a sustained response of both their cutaneous and extracutaneous disease to hdIVIg. As all patients had perioral skin involvement and microstomia, one measure of cutaneous improvement was the increase in intraincisor distance. Extracutaneous manifestations of scleromyxoedema that improved included ureteral stricture, vocal strength and dysphagia.

  9. 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.

  10. 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

  11. Non-ST Elevation Myocardial Infraction after High Dose Intravenous Immunoglobulin Infusion

    PubMed Central

    Mizrahi, Meir; Adar, Tomer; Orenbuch-Harroch, Efrat; Elitzur, Yair

    2009-01-01

    Intravenous immunoglobulins (IVIgs) are used for several indications, including autoimmune conditions. IVIg treatment is associated with several possible adverse reactions including induction of a hypercoagulable state. We report a 76-year-old woman treated with IVIg for myasthenia gravis, which developed chest pain and weakness following IVIg infusion. The symptoms were associated with ST segment depression in V4–6 and elevated troponin levels. The patient was diagnosed with non-ST elevation myocardial infarction (NSTEMI). The patient had no significant risk factor besides age and a cardiac perfusion scan was interpreted as normal (the patient refused to undergo cardiac catheterization). This case is compatible with IVIg-induced hypercoagulability resulting in NSTEMI. Cardiac evaluation should therefore be considered prior to initiation of IVIg treatment especially in patients with multiple cardiovascular risks. PMID:20182639

  12. Pharmacokinetic profile of cefbuperazone in healthy Chinese volunteers after single and multiple drip intravenous infusion by HPLC-MS/MS.

    PubMed

    Liu, Dongbo; Geng, Taohua; Wang, Yiya; Ding, Li

    2016-09-10

    A selective and reproducible HPLC-MS/MS method was developed and fully validated for the determination of cefbuperazone in human plasma and urine. Samples were prepared using protein precipitation and separated on a Zorbax Eclipse Plus C18 column (2.1×50mm, 3.5μm). The API-4000 mass spectrometer was operated under multiple reaction monitoring mode (MRM) using the electrospray ionization technique. Linearity was achieved from 0.250 to 250μg/mL in plasma and 20.0-5000μg/mL in urine. The method was successfully applied to a pharmacokinetic study of cefbuperazone in healthy Chinese volunteers after drip intravenous infusion of 0.5, 1.0, 2.0g cefbuperazone sodium injection. Cefbuperazone reached a maximum concentration (Cmax) of 44.7±8.1μg/mL, 86.7±12.7μg/mL and 168±14μg/mL in 0.5, 1.0 and 2.0g dose groups respectively, at 60min after the start of infusion. The half-life (t1/2) was between 1.8-1.9h, and the elimination constant (kel) was between 0.36-0.39h(-1). The results proved that cefbuperazone showed linear pharmacokinetic profile in the dose range of 0.5-2.0g without gender difference. Drug accumulation was not observed. Cefbuperazone reached the maximum excretion rate in urine 2h after the start of infusion. About 60.0% of the administered drug was excreted via urine as unchanged form within 12h. The cumulative excretion of cefbuperazone after single drip intravenous infusion was proportional to the administered dose within the range from 0.5g to 2.0g. PMID:27394175

  13. Disposition of chloroquine in man after single intravenous and oral doses.

    PubMed

    Gustafsson, L L; Walker, O; Alván, G; Beermann, B; Estevez, F; Gleisner, L; Lindström, B; Sjöqvist, F

    1983-04-01

    1 Chloroquine was given in 300 mg single doses as an i.v. infusion, an oral solution and as tablets at intervals of at least 56 days to 11 healthy volunteers. Concentrations of chloroquine and its metabolite desethylchloroquine were measured in plasma, erythrocytes and urine using h.p.l.c. 2 Chloroquine was detectable in all plasma samples up to 23 days and occasionally up to 52 days after dosage. Urinary concentrations were monitored up to 119 days. The disposition pattern was multiexponential reflecting extensive tissue binding of the drug. 3 After i.v. dosing the volume of distribution ranged from 116 to 285 l/kg and the apparent terminal half-life from 146 to 333 h. Total plasma clearance +/- s.d. was 712 +/- 166 ml/min and renal clearance 412 +/- 139 ml/min. The mean estimated urinary recovery of chloroquine was 47%, 42% and 46% after i.v., oral solution and tablets indicating nearly complete bioavailability. The corresponding figures for the metabolite were 7%, 10% and 12%. 4 The disposition of chloroquine in erythrocytes was parallel to that in plasma. The concentrations in erythrocytes were consistently 2 to 5 times higher than in plasma. 5 Subjective side effects like difficulties with swallowing and accommodation, diplopia and fatigue occurred during intravenous infusion and were closely related to plasma concentrations. No effect was seen on the electrocardiogram, mean arterial blood pressure and pulse rate. No adverse reactions were observed after the oral doses. High frequency audiometry did not reveal any significant hearing impairment for the group as a whole.

  14. Multiple intravenous infusions of bone marrow mesenchymal stem cells reverse hyperglycemia in experimental type 2 diabetes rats.

    PubMed

    Hao, Haojie; Liu, Jiejie; Shen, Jing; Zhao, Yali; Liu, Huilin; Hou, Qian; Tong, Chuan; Ti, Dongdong; Dong, Liang; Cheng, Yu; Mu, Yiming; Liu, Jianping; Fu, Xiaobing; Han, Weidong

    2013-07-01

    The worldwide rapid increase in diabetes poses a significant challenge to current therapeutic approaches. Single-dose mesenchymal stem cell (MSC) infusion ameliorates hyperglycemia but fails to restore normoglycemia in diabetic animals. We therefore hypothesized that multiple intravenous MSC infusions may reverse hyperglycemia in type 2 diabetes (T2D) rats. We administered serial allogenous bone-marrow derived MSC infusions (1 × 10(6)cells/infusion) via the tail vein once every 2 weeks to T2D rats, induced by high-fat diet and streptozocin (STZ) administration. Hyperglycemia decreased only transiently after a single infusion in early-phase (1 week) T2D rats, but approximated normal levels after at least three-time infusions. This normal blood level was maintained for at least 9 weeks. Serum concentrations of both insulin and C-peptide were dramatically increased after serial MSC infusions. Oral glucose tolerance tests revealed that glucose metabolism was significantly ameliorated. Immunofluorescence analysis of insulin/glucagon staining revealed the restoration of islet structure and number after multiple MSC treatments. When multiple-MSC treatment was initiated in late-phase (5 week) T2D rats, the results were slightly different. The results of this study suggested that a multiple-MSC infusion strategy offers a viable clinical option for T2D patients.

  15. Neonatal administration of high-dose intravenous immunoglobulin in rhesus hemolytic disease.

    PubMed

    Voto, L S; Sexer, H; Ferreiro, G; Tavosnanska, J; Orti, J; Mathet, E R; Margulies, M; Margulies, M

    1995-01-01

    Our aim was to assess the effectiveness of neonatal treatment of Rh hemolytic disease with high-dose intravenous immunoglobulin (HDIVIG), in reducing neonatal hemolysis. A total of 40 neonates born to isoimmunized Rh negative women were studied. The population was randomized into 2 groups: Group 1 received IVIG 800 mg/kg/day for 3 days, plus phototherapy; and Group 2 received only phototherapy. No significant difference was observed between the groups in the severity of either the antenatal and neonatal disease, mode of delivery, mean birthweight, gestational age at delivery, proportion of preterm deliveries, 1 minute Apgar Score, days of phototherapy, and presence of neonatal cholestasis. Group 1 babies showed a significantly decreased duration of hospitalization, less hemolysis, and a less marked increase in bilirubin levels on the first day of life than Group 2 newborns. Therefore, Group 1 neonates received less treatment with transfusions (exchange-transfusions and/or simple blood treatment with transfusions) than those in Group 2. Our data suggest that the frequency of transfusional therapy can be reduced by combining conventional phototherapy with HDIVIG. Further studies are needed to determine the optimum timing and dosages of neonatal HDIVIG treatment.

  16. High-dose intravenous immunoglobulin in inflammatory myopathies: experience based on controlled clinical trials.

    PubMed

    Dalakas, M C

    2003-10-01

    Controlled clinical trials with high-dose intravenous immunoglobulin (IVIg) have been conducted in patients with DM and IBM, but not PM. A double-blind placebo-controlled study in DM patients, resistant or partially responsive to conventional therapies, showed that IVIg is very effective in improving both the muscle strength and the skin rash. The clinical benefit, which was impressive in patients with early disease, was associated with improvement in the muscle cytoarchitecture. Quantitative histological studies in repeated muscle biopsies showed a statistically significant increased in the size of muscle fibers and the number of capillaries with normalization of the capillary diameter. Resolution of the aberrant immunopathological parameters including interception of complement activation products and downregulation of T cells, ICAM-I, VCAM, TGF-beta and MHC-I molecules was also noted. In IBM, IVIg showed marginal, and non statistically significant, improvements in muscle strength. Up to 20% of patients however, demonstrated clinical improvement with increased activities of daily living while certain muscle groups, such as the muscles of swallowing, showed significant improvements compared to placebo implying mild regional benefits. In PM, small uncontrolled series have shown improvements in muscle strength in up to 70% of the IVIg-treated patients. Because PM, as a stand-alone clinical entity, is a very rare disease, completion of controlled trials will be very difficult.

  17. The Positive Effects of One-Hour Intravenous Administration of Bortezomib on Peripheral Neuropathy in Multiple Myeloma Patients

    PubMed Central

    Jung, Joo Young; Kim, Ho Young; Han, Boram; Choi, Dae Ro; Zang, Dae Young; Kim, Hyo Jung

    2014-01-01

    Bortezomib-induced peripheral neuropathy (BiPN) in multiple myeloma (MM) patients is a common and serious side effect. Currently, it has been reported that subcutaneous (SC) administration of bortezomib decreases the incidence of BiPN as compared to standard intravenous (IV) bolus injection without any differences in efficacy. However, there are reports of severe injection site reaction following SC administration of bortezomib. The aim of this study was to evaluate the response rate and incidence of BiPN following one-hour IV infusion of bortezomib. The data was retrospectively collected from MM patients who had been treated with IV administration of bortezomib for one hour. Twenty-three patients were evaluated (median age 72 years, 13 males). The median number of treatment cycles was 5 (range 2–10). The cumulative bortezomib dose was 26.0 mg/m2 (14.3–66.3) and percent of actual per expected cumulative dose was 90% (50–100). The overall response (complete response plus partial response) rate was 65%. The incidence of BiPN was 57% (n = 13) and incidence of severe neuropathy was 4% (n = 1). One-hour IV infusion of bortezomib was an effective regimen for MM with reduced incidence of severe BiPN. This route of administration of bortezomib could be an alternative mode of delivery for patients with severe injection site reactions following SC administration. PMID:24995276

  18. High-Dose Vitamin C Promotes Regression of Multiple Pulmonary Metastases Originating from Hepatocellular Carcinoma

    PubMed Central

    Seo, Min-Seok; Kim, Ja-Kyung

    2015-01-01

    We report a case of regression of multiple pulmonary metastases, which originated from hepatocellular carcinoma after treatment with intravenous administration of high-dose vitamin C. A 74-year-old woman presented to the clinic for her cancer-related symptoms such as general weakness and anorexia. After undergoing initial transarterial chemoembolization (TACE), local recurrence with multiple pulmonary metastases was found. She refused further conventional therapy, including sorafenib tosylate (Nexavar). She did receive high doses of vitamin C (70 g), which were administered into a peripheral vein twice a week for 10 months, and multiple pulmonary metastases were observed to have completely regressed. She then underwent subsequent TACE, resulting in remission of her primary hepatocellular carcinoma. PMID:26256994

  19. Effectiveness of low-dose intravenous ketamine to attenuate stress response in patients undergoing emergency cesarean section with spinal anesthesia

    PubMed Central

    Senapathi, Tjokorda Gde Agung; Widnyana, I Made Gede; Wiryana, Made; Aribawa, I Gusti Ngurah Mahaalit; Aryabiantara, I Wayan; Hartawan, I Gusti Agung Gede Utara; Sinardja, I Ketut; Suarjaya, I Putu Pramana; Nada, I Ketut Wibawa; Jaya, AA Gde Putra Semara

    2016-01-01

    Purpose Cesarean section is a surgical procedure. Surgical procedures will induce stress responses, which may have negative impact on postoperative recovery. Ketamine plays a role in the homeostatic regulation of inflammatory response in order to attenuate stress response. We tried to determine the effectiveness of low-dose intravenous ketamine to attenuate stress response in patients undergoing emergency cesarean section with spinal anesthesia. Patients and methods Thirty-six pregnant women undergoing emergency cesarean section with spinal anesthesia were randomly divided into two groups (n=18). Ketamine 0.3 mg/kg (KET group) or NaCl 0.9% (NS group) was administered intravenously before the administration of spinal anesthesia. C-reactive protein (CRP) and neutrophil levels were measured preoperatively and postoperatively. Results Elevation of CRP stress response was lower in the KET group and significantly different (P≤0.05) from that in the NS group. Neutrophil level was elevated in both the groups and hence not significantly different from each other (P>0.05). Postoperative visual analog scale pain score was not significantly different between the two groups (P>0.05), but there was a statistically significant (P≤0.05) positive and weak correlation between visual analog scale and CRP level postoperatively. Conclusion Low-dose intravenous ketamine effectively attenuates the CRP stress response in patients undergoing emergency cesarean section with spinal anesthesia. PMID:27703393

  20. Having Multiple Sexual Partners among Iranian Intra-Venous Drug Users

    PubMed Central

    Assari, Shervin; Yarmohamadivasel, Mosaieb; Moghani Lankarani, Maryam; Sehat, Mahmood; Narenjiha, Hooman; Rafiey, Hassan; Noori, Roya; Shirinbayan, Peymaneh; Ahmadi, Khodabakhsh

    2013-01-01

    Background: Transmission of HIV from intra-venous drug users (IDUs) to the community occurs predominantly through high-risk sexual behaviors. Limited information exists regarding the high-risk sexual behaviors of IDUs in Iran. Aim: The aim of this study was to determine the prevalence and factors associated with having multiple sexual partners among Iranian IDUs. Methods: This is a national survey on drug-dependent adults. Participants were sampled from medical centers, prisons, and streets of capitals of 29 provinces in Iran between May 2007 and February 2008. We analyzed data of 1416 current IDUs. Socio-demographics and drug use characteristics were entered into a binary logistic regression model to determine predictors of having multiple sexual partners. Results: Having multiple sexual partners in the past or at the time of survey was reported by 56.4% of Iranian IDUs. Multivariate analysis showed that the likelihood of having multiple sexual partners in IDUs decreased by being married [odds ratio (OR), 0.38; P < 0.001] and increased by female gender (OR, 13.44; P = 0.02), having illegal income (OR, 1.72; P = 0.003), higher monthly family income (OR, 1.01; P = 0.003), pleasure, curiosity, and recreation as cause of first drug use (OR, 1.37; P = 0.04), ruins as usual place for injection (OR, 1.89; P = 0.001) and history of syringe sharing (OR, 1.50; P = 0.02). Conclusion: Having multiple sexual partners was reported by majority of Iranian IDUs, and this was linked to socio-demographics, initiation data, and other risk behaviors. This information should be considered in prevention efforts to reduce sexual transmission of HIV infection in Iran. PMID:25346698

  1. Dose-dependent effects of intravenous lorazepam on cardiovascular activity, plasma catecholamines and psychological function during rest and mental stress.

    PubMed

    Tulen, J H; Moleman, P; Boomsma, F; van Steenis, H G; van den Heuij, V J

    1991-01-01

    Dose-dependent effects of intravenously administered lorazepam on psychophysiological activity during rest and mental stress were studied in order to examine differential responses to doses which may induce anxiolysis or sedation. In a double-blind randomized cross-over study, nine male volunteers participated in a placebo and a lorazepam session, during which the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.6, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). Heart rate showed a dose-dependent decrease during rest with an ED50 of 0.13 mg lorazepam, while lorazepam had no effect on the cardiovascular and plasma catecholamine response magnitudes to the CWT. Subjective fatigue and reaction time increased significantly after 0.94 mg lorazepam, while at the same dose vigor decreased; state anxiety after the CWT was not influenced by lorazepam. These data show differential effects of lorazepam on cardiovascular, biochemical and psychological function. While heart rate was suppressed at low doses during rest and reaction time and subjective fatigue increased at doses which induced sedation, state anxiety and physiological response patterns to the CWT were not influenced by lorazepam.

  2. 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

  3. Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose.

    PubMed

    Viscardi, Rose M; Othman, Ahmed A; Hassan, Hazem E; Eddington, Natalie D; Abebe, Elias; Terrin, Michael L; Kaufman, David A; Waites, Ken B

    2013-05-01

    Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial

  4. 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

  5. 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

  6. Dose evaluation from multiple detector outputs using convex optimisation.

    PubMed

    Hashimoto, Makoto; Iimoto, Takeshi; Kosako, Toshiso

    2011-07-01

    A dose evaluation using multiple radiation detectors can be improved by the convex optimisation method. It enables flexible dose evaluation corresponding to the actual radiation energy spectrum. An application to the neutron ambient dose equivalent evaluation is investigated using a mixed-gas proportional counter. The convex derives the certain neutron ambient dose with certain width corresponding to the true neutron energy spectrum. The range of the evaluated dose is comparable to the error of conventional neutron dose measurement equipments. An application to the neutron individual dose equivalent measurement is also investigated. Convexes of particular dosemeter combinations evaluate the individual dose equivalent better than the dose evaluation of a single dosemeter. The combinations of dosemeters with high orthogonality of their response characteristics tend to provide a good suitability for dose evaluation.

  7. Single- and Multiple-Dose Pharmacokinetics and Absolute Bioavailability of Tedizolid

    PubMed Central

    Flanagan, Shawn; Fang, Edward; Muñoz, Kelly A; Minassian, Sonia L; Prokocimer, Philippe G

    2014-01-01

    Objectives Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate. Design Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. Setting Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. Participants Ninety healthy volunteers. Intervention Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100–400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days. Measurements and Main Results A dose-dependent increase was observed in the maximum plasma concentration (1.2–5.1 μg/ml) and the area under the concentration-time curve (17.4–58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100–400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores. Conclusion These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the

  8. The Role of Postpartum Intravenous Corticosteroids in the Prevention of Relapses in Multiple Sclerosis

    PubMed Central

    Avila, Mirla; Stosic, Milena; Robles, Liliana; Prieto, Pilar Guillermo; Hutton, George J.; Rivera, Victor M.

    2011-01-01

    Multiple sclerosis (MS) is most prevalent in women of childbearing age. It is well established that the relapse rate decreases during pregnancy but increases significantly during the first postpartum trimester. The objective of this retrospective study was to evaluate the effectiveness of the administration of 1 g of intravenous methylprednisolone (IVMP) after delivery in the prevention of MS relapses. The study involved 47 women with one or more documented pregnancies; each pregnancy was treated as a separate case. There were 50 cases with relapsing-remitting MS and 2 with secondary progressive MS. The cases were divided into two groups: the IVMP group (those who received 1 g of IVMP after delivery) and the no-IVMP group (those who did not receive IVMP after delivery). There were 39 cases in the IVMP group and 13 in the no-IVMP group. During the first postpartum trimester, relapses occurred in 17.9% of the IVMP group, compared with 46.2% of the no-IVMP group (P = .0448). The difference in relapse percentage between the two groups during the second and third postpartum trimesters was not statistically significant. Our study shows a statistically significant benefit of postpartum IVMP administration in reducing MS relapses. PMID:24453710

  9. The Preventive Role of Low-Dose Intravenous Ketamine on Postoperative Shivering in Children: A Placebo Randomized Controlled Trial

    PubMed Central

    Sanie, Mohammad Sadegh; Kalani, Navid; Ghobadifar, Mohamed Amin; Zabetian, Hassan; Hosseini, Mehdi

    2016-01-01

    Background Postoperative shivering is a major problem in children undergoing general anesthesia. Objectives The aim of the present study was to investigate the role of low-dose intravenous ketamine for prevention of shivering after induction of general anesthesia in children who had undergone tonsillectomy. Patients and Methods This was a randomized, double-blinded, placebo-controlled trial including 80 children, of American society of anesthesiologists (ASA) physical status I or II, scheduled for tonsillectomy under general anesthesia who were randomly assigned to an intravenous ketamine (0.5 mg/kg, n = 40; group K) group or matched dose placebo (n = 40; group N) group. Surgical and demographic data, unexpected side effects, and the occurrence of shivering for each child were assessed by a blinded observer at the following time points: T0, in the recovery room; T10, at 10 minutes; T20, at 20 minutes; T30, and at 30 minutes. Results With regards to the demographic and surgical data, no significant differences between the two study groups were observed (P ≥ 0.05). Shivering intensity in children who had received ketamine was significantly lower than children who had not received ketamine, at T0, T10, T20, and T30 after arrival (P < 0.05). There were no significant differences in hallucination, nausea, vomiting, hemodynamic dysfunction, blurred vision, and seizure in the K group compared with the N group (P ≥ 0.05). Conclusions Administration of intravenous ketamine at a dosage of 0.5 mg/kg immediately after anesthesia induction had a preventive effect on shivering intensity without hemodynamic alterations in children undergoing general anesthesia for tonsillectomy. PMID:27635389

  10. 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

  11. Comparison of intravenous and subcutaneous exposure supporting dose selection of subcutaneous belimumab systemic lupus erythematosus Phase 3 program

    PubMed Central

    Yapa, S Wickramaratne Senarath; Roth, D; Gordon, D

    2016-01-01

    Background Belimumab is a recombinant, human, IgG1λ monoclonal antibody that targets B-lymphocyte stimulator. The intravenous formulation is indicated for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Belimumab has been formulated for subcutaneous (SC) administration to improve patient convenience. This post-hoc modeling and simulation analysis characterizes the population pharmacokinetics (PK) of SC belimumab, and compares the exposure profiles of the approved belimumab IV dose—10 mg/kg every four weeks—to the 200 mg SC weekly dose in SLE patients, highlighting key pharmacological differences relevant for clinicians. Methods Data from two Phase 1 studies in US American and Japanese healthy subjects were analyzed with a non-linear mixed effects modeling approach. The resulting SC population PK model and a previously developed IV population PK model were used to conduct simulation trials in a Phase 3 IV belimumab SLE patient population, comparing chronic exposure profiles and exposure ranges stratified by body weight tertiles for IV vs SC dosing. Results The PK of belimumab following SC administration was best described by a linear two-comment model. The estimates for clearance, steady-state volume of distribution, and bioavailability were 208 mL/day, 5250 mL, and 76%, respectively. After four weeks of SC dosing, simulated belimumab concentrations exceeded the steady-state trough concentrations of the IV dosing regimen. At steady state simulated serum profiles demonstrated comparable average belimumab concentrations (Cavg,ss) after IV and SC dosing. Simulated belimumab exposures demonstrated largely overlapping concentration ranges following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing. Discussion The predicted Cavg,ss of belimumab in SLE patients was comparable following 200 mg SC weekly and 10 mg/kg IV every four weeks dosing. The simulated belimumab accumulation following SC weekly dosing

  12. Biological dose optimization with multiple ion fields

    NASA Astrophysics Data System (ADS)

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

    2008-12-01

    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.

  13. Absorption and disposition of florfenicol after intravenous, intramuscular and subcutaneous dosing in alpacas.

    PubMed

    Pentecost, Rebecca L; Niehaus, Andrew J; Werle, Nicholas; Lakritz, Jeffrey

    2015-04-01

    The objectives of this study were to define disposition and systemic availability of florfenicol in alpacas. Administration of 20 mg/kg doses to 8 male alpacas by i.v., i.m. and s.c. routes was performed by randomized, 3-way crossover design. Clearance and steady state volumes (Vdss) after i.v. injection were 5 ml/min/kg and 775 ml/kg respectively. Mean residence time (MRT) and terminal phase half-life (T1/2λz) were 2.8 h and 2 h respectively. Maximum serum concentrations (Cmax) after i.m. were higher than s.c. administration (p = 0.034). After s.c. dosing, T1/2λz and MRT were greater than after i.m. injection (p < 0.001; p = 0.006 respectively). Mean absorption time (MAT) after s.c. dosing was also prolonged (p = 0.006). Fractional absorption of florfenicol after i.m. and s.c. was not different (p > 0.05). Serum florfenicol concentrations remained >1.0 µg/ml for 20 h after i.m. dosing. Differences in rate and extent of florfenicol absorption after extravascular dosing could influence therapeutic outcomes.

  14. Comparative evaluation of prophylactic single-dose intravenous antibiotic with postoperative antibiotics in elective urologic surgery

    PubMed Central

    Moslemi, Mohammad K; Movahed, Seyed M Moosavi; Heidari, Akram; Saghafi, Hossein; Abedinzadeh, Mehdi

    2010-01-01

    Background Unrestricted antibiotic use is very common in Iran. As a result, emergence of resistant organisms is commonplace. Antibiotic prophylaxis in surgery consists of a short antibiotic course given immediately before the procedure in order to prevent development of a surgical site infection. The basic principle of prophylaxis is to maintain effective concentrations of an antibiotic active against the commonest pathogens during the entire surgery. Materials and methods We prospectively investigated 427 urologic surgery cases in our department between August 2008 and September 2009 (Group1). As reference cases, we retrospectively reviewed 966 patients who underwent urologic surgery between May 2004 and May 2008 (Group 2) who were administered antibiotics without any restriction. Prophylactic antibiotics such as cefazolin were administered intravenously according to our protocol. Postoperative body temperature, peripheral white blood cell counts, urinalysis, and urine culture were checked. Results To judge perioperative infections, wound condition and general condition were evaluated in terms of surgical site infection, as well as remote infection and urinary tract infection, up to postoperative day 30. Surgical site infection was defined as the presence of swelling, tenderness, redness, or drainage of pus from the wound, superficially or deeply. Remote infection was defined as occurrence of pneumonia, sepsis, or urinary tract infection. Perioperative infection rates (for surgical site and remote infection) in Group 1 and Group 2 were nine of 427 (2.6%) and 24 of 966 (2.5%), respectively. Surgical site infection rates of categories A and B in Group 1 were 0 and two (0.86%), respectively, while those in Group 2 were 0 and five (0.92%), respectively. There was no significant difference in infection rates in terms of remote infection and surgical site infection between Group 1 and Group 2 (P = 0.670). The amounts, as well as the prices, for intravenously

  15. Comparing Two Different Doses of Intravenous Midazolam in Pediatric Sedation and Analgesia

    PubMed Central

    Barzegari, Hassan; Masoumi, Kambiz; Motamed, Hassan; Zohrevandi, Behzad; Zeynadini Meymand, Shima

    2016-01-01

    Introduction: Midazolam has turned into a common drug for pediatric procedural sedation and analgesia. However, there is not much data regarding its proper dose and potential side effects in the Iranian children population. Therefore, the present study was done to compare 2 doses of IV midazolam in this regard. Methods: The present clinical trial was performed to compare 0.1 and 0.3 mg/kg doses of IV midazolam in induction of sedation for head trauma infant patients in need of brain computed tomography (CT) scan. Conscious infants under 2 years old, with stable hemodynamics were included. Onset and duration of action as well as probable side effects were compared between the two groups using SPSS version 22. Results: 110 infants with the mean age of 14.0 ± 5.9 months (range: 4 - 24) and mean weight of 9.7 ± 2 kg (range: 5 - 15) were randomly allocated to one of the 2 study groups (54.6% female). Success rate in 0.1 and 0.3 mg/kg groups were 38.2% (21 patients) and 60% (33 patients), respectively (p = 0.018). Overall, 56 (50.9%) patients did not reach proper sedation and were sedated receiving ketamine (22 patients) or another dose of midazolam (34 patients, mean additional dose needed was 2.1 ± 1.1 mg). Conclusion: The results of the present study demonstrated the higher success rate and longer duration of action for 0.3 mg/kg midazolam compared to 0.1 mg/kg. The groups were equal regarding onset of action, effect on vital signs and probable side effects. PMID:27800539

  16. Implementation of dose superimposition to introduce multiple doses for a mathematical absorption model (transit compartment model).

    PubMed

    Shen, Jun; Boeckmann, Alison; Vick, Andrew

    2012-06-01

    A mathematical absorption model (e.g. transit compartment model) is useful to describe complex absorption process. However, in such a model, an assumption has to be made to introduce multiple doses that a prior dose has been absorbed nearly completely when the next dose is administered. This is because the drug input cannot be determined from drug depot compartment through integration of the differential equation system and has to be analytically calculated. We propose a method of dose superimposition to introduce multiple doses; thereby eliminating the assumption. The code for implementing the dose superimposition in WinNonlin and NONMEM was provided. For implementation in NONMEM, we discussed a special case (SC) and a general case (GC). In a SC, dose superimposition was implemented solely using NM-TRAN abbreviated code and the maximum number of the doses that can be administered for any subject must be pre-defined. In a GC, a user-supplied function (FUNCA) in FORTRAN code was defined to perform dose superimposition to remove the restriction that the maximum number of doses must be pre-defined. PMID:22555854

  17. Penetration of Linezolid into Soft Tissues of Healthy Volunteers after Single and Multiple Doses

    PubMed Central

    Dehghanyar, Pejman; Bürger, Cornelia; Zeitlinger, Markus; Islinger, Florian; Kovar, Florian; Müller, Markus; Kloft, Charlotte; Joukhadar, Christian

    2005-01-01

    The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously. All following doses were self-administered orally. The tissue penetration of linezolid was assessed by use of in vivo microdialysis. In the single-dose experiments the ratios of the area under the concentration-time curve from 0 to 8 h (AUC0-8) for tissue to the AUC0-8 for free plasma were 1.4 ± 0.3 (mean ± standard deviation) and 1.3 ± 0.4 for subcutaneous adipose and muscle tissue, respectively. After multiple doses, the corresponding mean ratios were 0.9 ± 0.2 and 1.0 ± 0.5, respectively. The ratios of the AUC from 0 to 24 h (AUC0-24) for free linezolid in tissues to the MIC were between 50 and 100 for target pathogens with MICs between 2 and 4 mg/liter. In conclusion, the present study showed that linezolid penetrates rapidly into the interstitial space fluid of subcutaneous adipose and skeletal muscle tissues in healthy volunteers. On the basis of pharmacokinetic-pharmacodynamic calculations, we suggest that linezolid concentrations in soft tissues can be considered sufficient to inhibit the growth of many clinically relevant bacteria. PMID:15917535

  18. 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.

  19. Disposition of 2-mercaptobenzothiazole and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally, and topically and in guinea pigs dosed topically

    SciTech Connect

    el Dareer, S.M.; Kalin, J.R.; Tillery, K.F.; Hill, D.L.; Barnett, J.W. Jr. )

    1989-01-01

    To determine the metabolic disposition of (14C)-2-mercaptobenzothiazole (MBT) and (14C)-2-mercaptobenzothiazole disulfide (MBTS), male and female rats were dosed topically. Topical doses were 36.1 micrograms/animal for (14C)MBT and 33.6 micrograms/animal for (14C)MBTS. Although more MBT passed through the skin than MBTS and although, relative to rats, guinea pigs absorbed a greater percentage of the dose (33.4% compared to 16.1-17.5% of the MBT and 12.2% compared to 5.94-7.87% for MBTS), the disposition of radioactivity derived from the two compounds was similar. Washing of the skin removed more of the radioactivity from guinea pigs than from rats. For both sexes of rats dosed intravenously with (14C)MBT or (14C)MBTS, disposition of the compounds was similar. In 72 h, 90.9-101% of the dose appeared in the urine and 3.79-15.1% in the feces. At this time, a small portion of the administered radioactivity remained associated with erythrocytes. Oral dosing of rats for 14 d with unlabeled MBT prior to a single dose of (14C)MBT or with unlabeled MBTS prior to a single dose of (14C)MBTS (0.730 mg/kg). For both sexes, disposition of the compounds was similar. At 96 h after dosing, a small portion of the administered radioactivity remained associated with erythrocytes, most of which was bound to the membranes. For both compounds and sexes, 60.8-101% of the radioactivity administered appeared in the urine and 3.46-9.99% in the feces in 96 h. At the time, only trace amounts of radioactivity remained in tissues other than blood. Of these tissues, thyroid contained the highest concentration. In the urine, there was a detectable MBT or MBTS, but there were two metabolites, one of which was identified as a thioglucuronide derivative of MBT. The other was possibly a sulfonic acid derivative of MBT.

  20. 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

  1. Pharmacokinetics of marbofloxacin in loggerhead sea turtles (Caretta caretta) after single intravenous and intramuscular doses.

    PubMed

    Lai, Olimpia R; Marín, Pedro; Laricchiuta, Pietro; Marzano, Giacomo; Crescenzo, Giuseppe; Escudero, Elisa

    2009-09-01

    The disposition kinetics of marbofloxacin at a single dose of 2 mg/kg bodyweight were determined in a crossover trial with five clinically healthy loggerhead sea turtles (Caretta caretta) after i.v. and i.m. administration. Marbofloxacin plasma concentrations were determined by high-performance liquid chromatography (LOD/LOQ 0.05 microg/ml). Data were subjected to noncompartmental analysis. The integrated pharmacokinetic/pharmacodynamic variables showed that optimal area under the curve (AUC(0-24 h)): minimal inhibitory concentration (MIC) (>125) and Cmax: MIC (>8) ratios, as reported for concentration-dependent bactericidal antimicrobials (e.g., fluoroquinolones), were achievable with both a once daily i.v. or i.m. dose for microorganisms with MIC < or = 0.5 microg/ml, while a Cmax: MIC > 8 for MIC > or = 1 microg/ml was achievable only after the i.v. administration. The absence of adverse reactions in the animals after i.v. or i.m. administration of marbofloxacin and the favorable pharmacokinetic/pharmacodynamic properties after a single dose of 2 mg/kg suggest the possibility of its safe and effective clinical use in loggerhead sea turtles.

  2. Short and long-term effects of high-dose intravenous methylprednisolone pulse therapy on thyroid-associated ophthalmopathy

    PubMed Central

    Liu, Xiaomei; Wang, Shu; Qin, Li; Qiang, Wei; Dahal, Mahesh; Fan, Ping; Gao, Shan; Shi, Bingyin

    2016-01-01

    The majority of previous studies on high-dose intravenous methylprednisolone pulse (IVMP) therapy have observed the clinical conditions of patients prior to and following treatment without any long-term follow-up, and these studies have predominantly focused on combined treatment. The present prospective clinical study aimed to assess the long-term effects and safety of high-dose IVMP therapy in thyroid-associated ophthalmopathy (TAO), as well as the significance of thyrotropin receptor antibody (TRAb) and soluble intercellular adhesion molecule-l (sICAM-1) during IVMP therapy. A total of 58 patients with TAO were treated with high-dose IVMP therapy, and their clinical characteristics and indices were recorded before, during and after therapy, with a 12–57 month (mean, 28.4 months) follow-up. Before treatment and on the second day after each IVMP therapy, serum TRAb and sICAM-1 levels were evaluated in 23 patients with TAO via a competitive radioimmunoassay and enzyme-linked immunosorbent assay, respectively. The results of the present study demonstrated that the symptoms of eyelid swelling, ophthalmodynia, photophobia, lacrimation and diplopia, and visual acuity, ocular motility, proptosis and clinical activity score (CAS) indices were all significantly improved after IVMP therapy. In addition, analysis of covariance demonstrated that alterations in the levels of serum TRAb during the course of treatment were associated with CAS of TAO, whereas the change in serum sICAM-1 was not. In conclusion, high-dose IVMP therapy is an effective, safe, stable and well-tolerated treatment for TAO, which is associated with rare, minor adverse effects. Furthermore, serum TRAb levels are correlated with the CAS of TAO and may serve as a predictor of the response to methylprednisolone therapy. PMID:27446294

  3. 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

  4. The acute effect of high-dose intravenous vitamin C and other nutrients on blood pressure: a cohort study

    PubMed Central

    Travica, Nikolaj; Sali, Avni

    2016-01-01

    Background Regular intake of vitamin C/ascorbate reduces blood pressure (BP) in hypertensives. High-dose intravenous vitamin C (IVC) achieves higher plasma levels; however, there is a paucity of research on acute BP effects. Our study is the first to investigate the effect of high-dose IVC, with or without concomitant i.v. nutrients, on BP during i.v. treatment. Methods A cohort of adult patients scheduled to receive IVC treatment for infection, cancer or fatigue, as prescribed by their treating doctor, participated at a Melbourne clinic, Australia. Ambulatory BP was assessed every 10 min over 90 min during i.v. treatment. Patients received 15–100 g of IVC alone or in addition to i.v. vitamin B, glutathione, magnesium or zinc. BP change over time adjusted for baseline BP, IVC dosage, i.v. treatment and BMI was analysed. Results A total of 77 mostly normotensive patients participated, with a third receiving IVC alone (42±20 g), and two-thirds also received other i.v. nutrients. IVC alone (>30 g) reduced the mean BP up to 8–9 mmHg in prehypertensive patients. In contrast, concomitant intravenous vitamin B12 (IVB12) significantly increased the mean BP by 11–13 mmHg. Comparison of BP change during IVC versus IVC+IVB12 indicated a highly significant difference [systolic blood pressure: mean difference (SD)=16.6 (17.8) mmHg, P<0.001; diastolic blood pressure: mean difference (SD)=12.5 (16.7) mmHg, P=0.003]. Conclusion Our study suggests an acute BP-reducing effect of high-dose IVC, particularly with dosages above 30 g, and in patients with prehypertension and normal BMI. Furthermore, our study indicated a marked and clinically relevant hypertensive effect of IVB12, suggesting routine BP monitoring during i.v. therapy in clinical practice. PMID:26910646

  5. 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.

  6. Effect on postoperative analgesia of small-dose lysine acetylsalicylate added to prilocaine during intravenous regional anesthesia.

    PubMed

    Corpataux, J B; Van Gessel, E F; Donald, F A; Forster, A; Gamulin, Z

    1997-05-01

    Nonsteroidal antiinflammatory drugs act largely peripherally by blocking the local synthesis of prostaglandins. The aim of this study was to evaluate whether the addition of a small dose of lysine acetylsalicylate (LA) to the prilocaine used for intravenous regional anesthesia (IVRA) would improve the quality of postoperative analgesia. Sixty patients undergoing lower extremity IVRA for foot or ankle surgery were randomly assigned to three double-blind groups: LA-IVRA where 90 mg of LA was mixed with prilocaine 0.5% for IVRA and 1 mL of 0.9% NaCl administered intravenously (IV) through the forearm catheter after tourniquet inflation; LA-IV where 1 mL of 0.9% NaCl was mixed with prilocaine and 90 mg of LA administered IV; and placebo where 1 mL of 0.9% NaCl was administered both with prilocaine for the IVRA and IV. Duration of analgesia (time elapsed between tourniquet release and first injection of morphine, expressed as mean +/- SD) was significantly longer (P < 0.05) in LA-IVRA (387 +/- 216 min) when compared with LA-IV (175 +/- 264 min) and placebo (126 +/- 201 min). Analgesic requirements remained significantly lower in LA-IVRA when compared with placebo only during the first six postoperative hours, LA-IV being in an intermediate position. Pain scores were significantly lower in LA-IVRA during the first postoperative hour when compared with LA-IV and during the first 3 postoperative hours when compared with placebo. We conclude that 90 mg of LA (corresponding to 50 mg of acetylsalicylic acid) added to prilocaine 0.5% during IVRA improves the quality of postoperative analgesia in the early postoperative period.

  7. Multiple-dose pharmacokinetics of ceftazidime in cancer patients.

    PubMed Central

    Garcia, I; Fainstein, V; Smith, R G; Bodey, G P

    1983-01-01

    The pharmacokinetic parameters of ceftazidime were determined in 25 patients with neoplastic diseases. A group of 13 patients each received 1 g of ceftazidime over 15 min as a single intravenous dose. The mean peak drug concentration in serum was 77.4 micrograms/ml, and the serum half-life was 144 min. Urinary excretion at 12 h was 64.5%. These 13 patients also received 2 g of ceftazidime over 15 min at 8-h intervals for 7 or 8 days. The mean peak drug concentrations in serum were 103.6 micrograms/ml on day 1 and 87 micrograms/ml on day 7 or 8. A second group of 12 patients received 1 g of ceftazidime over 30 min, followed by 1 g over 2 h and every 4 h thereafter. The mean peak drug concentration in serum at 30 min was 57.5 micrograms/ml. Average peak and trough levels obtained on day 2 or 3 were 65 and 34.8 micrograms/ml, respectively, and remained in this range thereafter. The above-mentioned dose schedules produced high and adequate ceftazidime concentrations in serum. Images PMID:6357067

  8. Pharmacokinetics of enrofloxacin after single dose oral and intravenous administration in the African penguin (Spheniscus demersus).

    PubMed

    Wack, Allison N; KuKanich, Butch; Bronson, Ellen; Denver, Mary

    2012-06-01

    The pharmacokinetics of a single dose of enrofloxacin administered orally, both pilled and in fish, and i.v. to African penguins (Spheniscus demersus) at 15 mg/kg were determined. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were measured via high-pressure liquid chromatography with mass spectrometry. An i.v. administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 7.86 microg/ml at time zero. Plasma volume of distribution for i.v. administration was 3.00 L/kg, with a mean elimination half-life of 13.67 hr and a mean total body clearance rate of 3.03 ml/min/kg. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of4.38 microg/ml at 4.8 hr after administration when pilled, whereas mean maximum plasma concentration was 4.77 microg/ml at 1.59 hr after administration when given in fish. Mean terminal elimination half-life was 13.79 hr pilled and 11.93 hr when given in fish. Low concentrations of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration. Enrofloxacin administered to African penguins at 15 mg/kg p.o.q. 24 hr, whether in fish or pilled, is expected to achieve the surrogate markers of efficacy for bacteria with a minimum inhibitory concentration of 0.5 microg/ml or less; however, clinical studies are needed to determine efficacy.

  9. Pharmacokinetics of enrofloxacin after single dose oral and intravenous administration in the African penguin (Spheniscus demersus).

    PubMed

    Wack, Allison N; KuKanich, Butch; Bronson, Ellen; Denver, Mary

    2012-06-01

    The pharmacokinetics of a single dose of enrofloxacin administered orally, both pilled and in fish, and i.v. to African penguins (Spheniscus demersus) at 15 mg/kg were determined. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were measured via high-pressure liquid chromatography with mass spectrometry. An i.v. administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 7.86 microg/ml at time zero. Plasma volume of distribution for i.v. administration was 3.00 L/kg, with a mean elimination half-life of 13.67 hr and a mean total body clearance rate of 3.03 ml/min/kg. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of4.38 microg/ml at 4.8 hr after administration when pilled, whereas mean maximum plasma concentration was 4.77 microg/ml at 1.59 hr after administration when given in fish. Mean terminal elimination half-life was 13.79 hr pilled and 11.93 hr when given in fish. Low concentrations of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration. Enrofloxacin administered to African penguins at 15 mg/kg p.o.q. 24 hr, whether in fish or pilled, is expected to achieve the surrogate markers of efficacy for bacteria with a minimum inhibitory concentration of 0.5 microg/ml or less; however, clinical studies are needed to determine efficacy. PMID:22779234

  10. 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.

  11. Pharmacokinetics and Safety of a Single Intravenous Dose of myo-Inositol in Preterm Infants of 23 to 29 weeks

    PubMed Central

    Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Watterberg, Kristi L.; Laptook, Abbot R.; Wrage, Lisa A.; Nolen, Tracy L.; Fennell, Timothy R.; Ehrenkranz, Richard A.; Poindexter, Brenda B.; Cotten, C. Michael; Hallman, Mikko K.; Frantz, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; O’Shea, T. Michael; Lacy, Conra Backstrom; Walsh, Michele C.; Shankaran, Seetha; Sánchez, Pablo J.; Bell, Edward F.; Higgins, Rosemary D.

    2014-01-01

    Background Myo-inositol given to preterm infants with respiratory distress has reduced death, increased survival without bronchopulmonary dysplasia (BPD) and reduced severe retinopathy of prematurity (ROP) in 2 randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed prior to efficacy trials. Methods Infants of 23–29 weeks gestation were randomized to a single intravenous (IV) dose of inositol at 60 or 120 mg/kg or placebo. Over 96 h, serum levels (sparse sampling population PK) and urine inositol excretion were determined. Population PK models were fit using a nonlinear mixed effects approach. Safety outcomes were recorded. Results A 1-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age (GA) strata and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance 0.0679 l/kg/h, endogenous production 2.67 mg/kg/h and the half life 5.22 h when modeled without the covariates. During the first 12 h renal inositol excretion quadrupled in the 120 mg/kg group, returning to near baseline after 48 h. There was no diuretic side-effect. No significant differences in adverse events occurred between the 3 groups (p > 0.05). Conclusions A single compartment model accounting for endogenous production satisfactorily described the PK of IV inositol. PMID:24067395

  12. Controlled studies with high-dose intravenous immunoglobulin in the treatment of dermatomyositis, inclusion body myositis, and polymyositis.

    PubMed

    Dalakas, M C

    1998-12-01

    There are three major subsets of the inflammatory myopathies: polymyositis (PM), dermatomyositis (DM), and inclusion-body myositis (IBM). High-dose intravenous immunoglobulin (IVIg) has been tried in controlled clinical trials in patients with DM and IBM but not with PM. In patients with DM that is resistant or partially responsive to conventional therapies, IVIg was very effective. The treated patients experienced dramatic improvement not only in muscle strength but also of their skin rash. Repeated muscle biopsies with quantitative histologic studies showed the IVIg-treated patients had a statistically significant improvement of the muscle cytoarchitecture, with resolution of the aberrant immunopathologic parameters. In two controlled clinical trials conducted in IBM patients, IVIg showed marginal improvements in muscle strength which were nonsignificant. However, a few IBM patients had a definite clinical improvement with increased activities of daily living, but when analyzed within the entire IVIg-treated group, their total gains in muscle strength did not reach statistical significance compared to the placebo-treated group. Of interest is that certain muscle groups in the IVIg-treated patients, such as the muscles of swallowing, showed significant improvement compared to those of the placebo-treated patients, implying mild regional effects. In PM, uncontrolled trials have shown improvements in muscle strength, but the controlled clinical trial is still ongoing.

  13. 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.

  14. Effect of antiarrhythmic therapy with intravenous loading dose of amiodarone: evidence for an altered response in diabetic patients.

    PubMed

    Iervasi, G; Clerico, A; Bonini, R; Nannipieri, M; Manfredi, C; Sabatino, L; Biagini, A; Donato, L

    1998-01-01

    Amiodarone, a potent class III antiarrhythmic agent with adrenergic antagonism properties, is administered increasingly to diabetic patients with cardiac arrhythmias refractory to all other available forms of therapy. Because a large percentage of diabetic patients show a perturbed autonomic regulation of the cardiovascular system, including a pertubed regulation of heart rate, we studied the antiarrhythmic response as well as the early effects (within 5 days) on heart rate of an intravenous amiodarone loading dose in diabetic patients. Seven type II (noninsulin-dependent) diabetic patients (age 64.7 +/- 9.7 years), affected by uncontrolled atrial fibrilation or atrial flutter, were enrolled for the study and a group of 12 well-matched (for age, sex and arrhythmia) nondiabetic patients served as a control group. It was found that before amiodarone administration, nondiabetic patients showed significantly wider variations in the circadian rhythm of heart rate values than diabetic patients (p = 0.0062, unpaired t-test). In all patients but one (who was nondiabetic), amiodarone treatment resulted in a cardioversion to sinus rhythm. After amiodarone administration, nondiabetic patients showed a significantly greater decrease (p = 0.0011) in heart rate values in comparison with the diabetic group (-35% vs. -20% on average, at the end of the study). Furthermore, in nondiabetic patients there was also an earlier significant fall (within the first 4 h after the start of treatment with amiodarone, p < 0.001) in the heart rate values in comparison with diabetic patients, in whom a significant decrease (p < 0.001) was found only at the 4th day. A significant (p = 0.0004), more rapid onset of the antiarrhythmic response to the drug was found in nondiabetic patients (6.8 +/- 6.0 h) in comparison with diabetic patients (98.0 +/- 14.8 h). Our findings suggest that the antiarrhythmic effects of amiodarone in diabetic patients with uncontrolled atrial fibrilation or atrial flutter

  15. 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

  16. Dose-escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma.

    PubMed

    Iida, Shinsuke; Ogiya, Daisuke; Abe, Yasunobu; Taniwaki, Masafumi; Asou, Hiroya; Maeda, Kaijiro; Uenaka, Kazunori; Nagaoka, Soshi; Ishiki, Tsuyoshi; Conti, Ilaria; Tobinai, Kensei

    2016-09-01

    B-cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti-BAFF monoclonal antibody. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m(2) . All patients had treatment-emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose-limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438). PMID:27350068

  17. Metabolism of small multiple doses of (14C) nicotine in the cat

    PubMed Central

    Turner, D. M.

    1971-01-01

    1. The distribution and metabolism of (2′-14C) nicotine given as a series of small intravenous injections (4 μg/kg every 60 s for 20 min) have been studied in the cat. 2. Blood concentrations of (14C) nicotine reached a maximum of 100 ng/ml at 20 min whereas blood concentrations of cotinine were maximal shortly afterwards. 3. The maximum concentration of nicotine in the blood was greater than that obtained by giving the same total dose as a continuous infusion ((4 μg/kg)/min for 20 min). 4. Urinary excretion accounted for 90% of the total multiple dose in 72 hours. After 24 h, however, only 2·5% of the radioactivity as (14C) nicotine and 0·05% as (14C) cotinine was excreted. 5. Gastric juice after 2 h contained significant amounts of activity which was almost entirely composed of (14C) nicotine and (14C) cotinine. 6. There were significant regional differences in the concentration of (14C) nicotine in the brain; amounts were greatest in cerebral hemispheres and smallest in the spinal cord. The hypothalamus and thalamus contained significantly higher concentrations of (14C) nicotine than the whole mid brain. (14C) Cotinine concentrations were highest in the cerebellum. PMID:5576257

  18. Intravenous non-high-dose pantoprazole is equally effective as high-dose pantoprazole in preventing rebleeding among low risk patients with a bleeding peptic ulcer after initial endoscopic hemostasis

    PubMed Central

    2012-01-01

    Background Many studies have shown that high-dose proton-pumps inhibitors (PPI) do not further reduce the rate of rebleeding compared to non-high-dose PPIs but we do not know whether intravenous non-high-dose PPIs reduce rebleeding rates among patients at low risk (Rockall score < 6) or among those at high risk, both compared to high-dose PPIs. This retrospective case-controlled study aimed to identify the subgroups of these patients that might benefit from treatment with non-high-dose PPIs. Methods Subjects who received high dose and non-high-dose pantoprazole for confirmed acute PU bleeding at a tertiary referral hospital were enrolled (n = 413). They were divided into sustained hemostasis (n = 324) and rebleeding groups (n = 89). The greedy method was applied to allow treatment-control random matching (1:1). Patients were randomly selected from the non-high-dose and high-dose PPI groups who had a high risk peptic ulcer bleeding (n = 104 in each group), and these were then subdivided to two subgroups (Rockall score ≥ 6 vs. < 6, n = 77 vs. 27). Results An initial low hemoglobin level, serum creatinine level, and Rockall score were independent factors associated with rebleeding. After case-control matching, the significant variables between the non-high-dose and high-dose PPI groups for a Rockall score ≥ 6 were the rebleeding rate, and the amount of blood transfused. Case-controlled matching for the subgroup with a Rockall score < 6 showed that the rebleeding rate was similar for both groups (11.1% in each group). Conclusion Intravenous non-high-dose pantoprazole is equally effective as high-dose pantoprazole when treating low risk patients with a Rockall sore were < 6 who have bleeding ulcers and high-risk stigmata after endoscopic hemostasis. PMID:22455511

  19. 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).

  20. 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

  1. Solution of the multiple dosing problem using linear programming.

    PubMed

    Hacisalihzade, S S; Mansour, M

    1985-07-01

    A system theoretical approach to drug concentration-time data analysis is introduced after the discussion of some relevant concepts as they are used in system theory. The merits of this approach are demonstrated in multiple dosing problem. It is shown that dosage minimization without stringent constraints does not result in the desired therapeutic effect. In a different optimization the discrepancy between the actual and the desired time-histories of the relevant substance's plasma concentration is minimized. It is shown that both of these optimizations can be reduced to linear programming problems which are easily solvable with today's computers. These methods are demonstrated in a case study of dopaminergic substitution in Parkinson's disease where computer simulations show them to yield excellent results. Finally, the limits of this approach are also discussed.

  2. XG-102 administered to healthy male volunteers as a single intravenous infusion: a randomized, double-blind, placebo-controlled, dose-escalating study

    PubMed Central

    Deloche, Catherine; Lopez-Lazaro, Luis; Mouz, Sébastien; Perino, Julien; Abadie, Claire; Combette, Jean-Marc

    2014-01-01

    The aim of the study is to evaluate the safety, tolerability and pharmacokinetics (PK) of the JNK inhibitor XG-102 in a randomized, double blind, placebo controlled, sequential ascending dose parallel group Phase 1 Study. Three groups of male subjects received as randomly assigned ascending single XG-102 doses (10, 40, and 80 μg/kg; 6 subjects per dose) or placebo (2 subjects per dose) as an intravenous (IV) infusion over 60 min. Safety and tolerability were assessed by physical examination, vital signs, electrocardiography, eye examination, clinical laboratory tests and adverse events (AEs). PK was analyzed using noncompartmental methods. All reported AEs were mild to moderate and neither their number nor their distribution by System Organ Class suggest a dose relationship. Only headache and fatigue were considered probably or possibly study drug related. Headache frequency was similar for active and placebo, consequently this was not considered to be drug related but probably to study conditions. The other examinations did not show clinically relevant deviations or trends suggesting a XG-102 relationship. Geometric mean half-life was similar among doses, ranging from 0.36 to 0.65 h. Geometric mean XG-102 AUC0–last increased more than linearly with dose, 90% confidence intervals (CIs) did not overlap for the two highest doses. Geometric mean dose normalized Cmax values suggest a more than linear increase with dose but 90% CIs overlap. It may be concluded that XG-102 single IV doses of 10–80 μg/kg administered over 1 h to healthy male subjects were safe and well tolerated. PMID:25505576

  3. 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

  4. 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.

  5. Efficacy, safety, and dose response of intravenous anti-D immune globulin (WinRho SDF) for the treatment of idiopathic thrombocytopenic purpura in children.

    PubMed

    Freiberg, A; Mauger, D

    1998-01-01

    We analyzed data from 20 children treated for acute or chronic idiopathic (immune) thrombocytopenic purpura (ITP) at a single institution to determine the relationship between dose of intravenous anti-D immune globulin (WinRho SDF; Nabi, Boca Raton, FL), increase in platelet count, and decrease in hemoglobin in the therapy of ITP. Higher doses of anti-D were clearly associated with a greater therapeutic response in the platelet count, with no increase in hemolysis for both acute and chronic ITP. A significant correlation was found between dose and peak increase in platelet count measured in the 14 days following administration. This effect was present for both acute ITP (17 infusions, P = .0001) and chronic ITP (30 infusions, P = .038). Although hemolysis was seen in nearly all infusions, with a median hemoglobin fall of 1.9 g/dL (range, 0 to 4.2), the decrease in hemoglobin was greater than 2.5 for only three infusions, and the largest fall in hemoglobin (4.2) was in a child with an underlying hemolytic anemia. Furthermore, for both acute and chronic ITP there was no relationship between the decrease in hemoglobin and the dose given (P = .22), nor between the increase in platelet count and fall in hemoglobin (P = .27). This analysis supports the use of higher doses of anti-D for the treatment of ITP, and demonstrates the need for a trial of high-dose anti-D (>100 microg/kg) in acute and chronic ITP.

  6. Phase II trial of high-dose topotecan, melphalan and CY with autologous stem cell support for multiple myeloma

    PubMed Central

    Kazmi, SMA; Saliba, RM; Donato, M; Wang, M; Hosing, C; Qureshi, S; Anderlini, P; Popat, U; Champlin, RE; Giralt, SA; Qazilbash, MH

    2014-01-01

    In spite of high-dose chemotherapy followed by autologous hematopoietic SCT multiple myeloma (MM) eventually recurs, highlighting the need for more effective treatment approaches. Patients received topotecan 3.5 mg/m2 intravenously on days −6 to −2, melphalan 70 mg/m2 intravenously on days −3 and −2 and CY 1 g/m2 intravenously on days −6, −5 and −4. Overall response rate (ORR) consisting of complete response and partial response (CR + PR, PFS, OS and toxicity are reported. Between August 2002 to March 2004, 60 patients (34 men and 26 women) with a median age of 61 years (range 45–72) were enrolled. Forty-one patients were treated for consolidation of first remission, while 19 patients had relapsed/refractory disease. ORR was 85% (CR 12%, very good PR 43% and PR 30%). Median time to neutrophil (ANC>0.5 × 109/L) and plt engraftment (>20 × 109/L) was 10 (range 7–12 days) and 9 days (range 6–79 days), respectively. A majority of the common adverse events were grade 1–3 mucositis/stomatitis (65%), grade 1 or 2 nausea (59%) and grade 1 or 2 diarrhea (41%). Median PFS was 18.5 months and median OS has yet not been reached. In conclusion, topotecan, melphalan and CY is a safe and active conditioning regimen for auto hematopoietic SCT in MM. The ORR and PFS were comparable to high-dose melphalan. PMID:20581887

  7. A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma.

    PubMed

    Dunn, Tamara J; Dinner, Shira; Price, Elizabeth; Coutré, Steven E; Gotlib, Jason; Hao, Ying; Berube, Caroline; Medeiros, Bruno C; Liedtke, Michaela

    2016-04-01

    Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

  8. 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.

  9. 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...

  10. Prediction of nonresponsiveness to medium-dose intravenous immunoglobulin (1 g/kg) treatment: an effective and safe schedule of acute treatment for Kawasaki disease

    PubMed Central

    Moon, Kyung Pil; Kim, Beom Joon; Lee, Kyu Jin; Oh, Jin Hee; Han, Ji Whan; Lee, Kyung Yil

    2016-01-01

    Purpose Medium-dose (1 g/kg) intravenous immunoglobulin (IVIG) is effective in the majority of patients with Kawasaki disease (KD) but some patients who do not respond to medium-dose IVIG are at high risk for the development of coronary artery lesions (CALs). The purpose of this study was to identify the clinical predictors associated with unresponsiveness to medium-dose IVIG and the development of CALs. Methods A retrospective study was performed in 91 children with KD who were treated with medium-dose IVIG at our institution from January 2004 to December 2013. We classified the patients into responders (group 1; n=68) and nonresponders (group 2; n=23). We compared demographic, laboratory, and echocardiographic data between the 2 groups. Results Multivariate logistic regression analysis identified 6 variables as predictors for resistance to medium-dose IVIG. We generated a predictive scoring system assigning 1 point each for percentage of neutrophils ≥65%, C-reactive protein≥100 mg/L, aspartate aminotransferase≥100 IU/L, and alanine aminotransferase≥100 IU/L, as well as 2 points for less than 5 days of illness, and serum sodium level≤136 mmol/L. Using a cutoff point of ≥4 with this scoring system, we could predict nonresponsiveness to medium-dose IVIG with 74% sensitivity and 71% specificity. Conclusion If a patient has a low-risk score in this system, medium-dose IVIG can be recommended as the initial treatment. Through this process, we can minimize the adverse effects of high-dose IVIG and incidence of CALs. PMID:27186228

  11. 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

  12. Monotherapy with Intravenous Followed by Oral High-Dose Ciprofloxacin versus Combination Therapy with Ceftazidime plus Amikacin as Initial Empiric Therapy for Granulocytopenic Patients with Fever

    PubMed Central

    Giamarellou, Helen; Bassaris, Harry P.; Petrikkos, George; Busch, Wilhelm; Voulgarelis, Michel; Antoniadou, Anastasia; Grouzi, Elisabeth; Zoumbos, Nikolaos

    2000-01-01

    The aim of the present study was to obtain clinical experience with the use of high-dose ciprofloxacin as monotherapy for the treatment of febrile neutropenia episodes (granulocyte count, <500/mm3) compared to a standard regimen and to clarify whether ciprofloxacin administration may be switched to the oral route. In a prospective randomized study ciprofloxacin was given at 400 mg three times a day (t.i.d.) for at least 72 h followed by oral administration at 750 mg twice a day (b.i.d). That regimen was compared with ceftazidime given intravenously at 2 g t.i.d. plus amikacin given intravenously at 500 mg b.i.d. The frequency of successful clinical response without modification at the end of therapy was almost identical for ciprofloxacin (50% [62 of 124 patients]) compared with that for ceftazidime plus amikacin (50.8% [62 of 122 patients]) in an intent-to-treat analysis; the frequencies were 48.3% (57 of 118 patients) versus 49.6% (56 of 113 patients), respectively, in a per-protocol analysis (P values for one-sided equivalence, 0.0485 and 0.0516, respectively; δ = 10%), with no significant differences among patients with bacteremia and other microbiologically or clinically documented infections and fever of unknown origin. For 82 (66.1%) patients, it was possible to switch from parenteral ciprofloxacin to the oral ciprofloxacin, and the response was successful for 61 (74.4%) patients. The efficacies of the regimens against streptococcal bacteremias were 16.6% (one of six patients) for the ciprofloxacin group and 33.3% (one of three patients) for the combination group (it was not statistically significant), with one breakthrough streptococcal bacteremia observed among the ciprofloxacin-treated patients. Adverse events were mostly self-limited and were observed in 27 (20.6%) ciprofloxacin-treated patients and 26 (19.7%) patients who were receiving the combination. This study demonstrates that high-dose ciprofloxacin given intravenously for at least 3 days and then

  13. 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

  14. 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

  15. On the mechanism of high-dose intravenous immunoglobulin treatment of patients with chronic inflammatory demyelinating polyneuropathy.

    PubMed

    van Doorn, P A; Rossi, F; Brand, A; van Lint, M; Vermeulen, M; Kazatchkine, M D

    1990-01-01

    A proportion of patients with a chronic inflammatory demyelinating polyneuropathy (CIDP) improves after polyvalent intravenous immunoglobulin (IVIg) treatment. When anti-neuroblastoma cell line (NBL) antibodies are present, they decrease or disappear after IVIg treatment. Purified IgM anti-NBL antibodies from a CIDP patient were inhibited by F(ab')2 of IVIg and by F(ab')2 of a patient recovered from Guillain-Barré syndrome (GBS). Inhibition of anti-NBL antibodies was also found among sera from normal individuals. This suggests that the self-limiting character of GBS and the therapeutic effect of IVIg in CIDP are dependent on suppression of auto-antibodies. This suppression may be mediated by anti-idiotypes present in recovered GBS patients and in the normal donor population contributing to IVIg.

  16. Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma

    PubMed Central

    Sullivan, Dan; Lonial, Sagar; Mohrbacher, Ann F.; Chatta, Gurkamal; Shustik, Chaim; Burris, Howard; Venkatakrishnan, Karthik; Neuwirth, Rachel; Riordan, William J.; Karol, Michael; von Moltke, Lisa L.; Acharya, Milin; Zannikos, Peter; Stewart, A. Keith

    2014-01-01

    Purpose Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses. Methods Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m2, days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected. Results Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102–112 L/h for first dose; 15–32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m2 group. Conclusions Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m2 doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen. PMID:20306195

  17. Pharmacokinetics of R 82913 in AIDS patients: a phase I dose-finding study of oral administration compared with intravenous infusion.

    PubMed Central

    De Wit, S; Hermans, P; Sommereijns, B; O'Doherty, E; Westenborghs, R; van de Velde, V; Cauwenbergh, G F; Clumeck, N

    1992-01-01

    The pharmacokinetics of oral administration of R 82913, or tetrahydroimidazol [4,5,1-jk]-benzodiazepin-2(1H)-one or -thione (TIBO), was compared with those of intravenous administration in five AIDS patients. TIBO was administered as a single daily 1-h infusion of 100 mg for 29 days and orally as a single daily dose for 14 days with three consecutive regimens of 100, 200, and 100 mg with probenecid (1 g) daily. Each cycle was followed by a wash-out period. Oral bioavailability of TIBO appears to be low and is not improved by the adjunction of probenecid. Trough levels obtained with oral administration systematically remained far below the 90% inhibitory concentration of TIBO against human immunodeficiency virus type 1 (HIV-1). Tolerance of TIBO was excellent. No clinical efficacy could be demonstrated. p24 antigenemia decreased significantly in one patient under intravenous therapy. TIBO derivatives are promising anti-HIV-1 agents in vitro, but improvement of oral bioavailability is needed before implementation of long-term efficacy and tolerability studies. Moreover, rapid emergence of resistance, which has been recently documented, constitutes a major problem with most nonnucleoside reverse transcriptase inhibitors. PMID:1482134

  18. Effects of Rate of Infusion and Probenecid on Serum Levels, Renal Excretion, and Tolerance of Intravenous Doses of Cefoxitin in Humans: Comparison with Cephalothin

    PubMed Central

    Goodwin, C. Stewart; Raftery, E. B.; Goldberg, A. D.; Skeggs, H.; Till, A. E.; Martin, C. M.

    1974-01-01

    Using a randomized crossover design, 1-g intravenous doses of cephalothin and cefoxitin, a cephalosporinase-resistant cephamycin, were infused into 12 normal adult males over periods of 120, 30, and 3 min, the last with and without prior intravenous infusions of probenecid (1 g). Mean peak serum concentrations of antibiotic activity after cephalothin infusions were 23, 56, 103, and 102 μg/ml, respectively, and after cefoxitin infusions they were 27, 74, 115, and 125 μg/ml, respectively. Probenecid treatment prolonged the terminal serum half-life of cephalothin-like activity from 0.52 to 1.0 h, and of cefoxitin from 0.68 to 1.4 h. In contrast to cephalothin, which was found to be metabolized about 25% to the less active desacetyl form, cefoxitin was metabolized less than 2% to the virtually inactive descarbamyl form, as judged from urinary recoveries. Neither antibiotic displayed detectable organ toxicity. Of 300 recent clinical isolates of gram-negative bacilli other than Pseudomonas spp., 83% were susceptible to cephalothin but 95% were susceptible to cefoxitin. Organisms resistant to cephalothin but susceptible to cefoxitin included strains of Escherichia coli, Proteus vulgaris, Klebsiella spp., Serratia marcescens, Enterobacter spp., and Bacteroides spp. PMID:15830485

  19. High-dose intravenous immunoglobulin therapy for rapidly progressive interstitial pneumonitis accompanied by anti-melanoma differentiation-associated gene 5 antibody-positive amyopathic dermatomyositis

    PubMed Central

    Hamada-Ode, Kazu; Taniguchi, Yoshinori; Kimata, Takahito; Kawaguchi, Yasushi; Shimamura, Yoshiko; Kuwana, Masataka; Fujimoto, Shimpei; Terada, Yoshio

    2015-01-01

    Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive amyopathic dermatomyositis (ADM) associated with rapidly progressive interstitial pneumonitis (RPIP) frequently has a poor prognosis and optimal treatment is not well defined. Here, we report a 62-year-old Japanese man with anti-MDA5 antibody-positive ADM associated with RPIP presented with progressive shortness of breath, Heliotrope rash, Gottron’s papules, arthralgia, and fatigue but no sign of muscle weakness. Laboratory investigation revealed serum levels of the following biomarkers: ferritin, 1393 ng/mL; Krebs von der Lungen-6, 1880 U/mL; and creatine kinase, 85 U/L. Computed tomography (CT) images showed diffuse ground-glass opacity in both lung fields. Because anti-MDA5 was positive, we made a diagnosis of ADM associated with RPIP and initiated treatment. Following five courses of combination therapy with prednisolone, cyclosporine A, and intravenous cyclophosphamide (IVCY), IVCY treatment was switched to high-dose intravenous immunoglobulin therapy (IVIg) because of the reactivation of interstitial pneumonia with an increased serum ferritin level. Additional treatment with IVIg improved RPIP, with normalization of anti-ADM antibody levels. Therefore, IVIg mayt be a new candidate treatment for anti-MDA5 antibody-positive ADM associated with RPIP. PMID:27708934

  20. 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

  1. 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.

  2. 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. PMID:25721486

  3. 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.

  4. 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. PMID:24344511

  5. 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.

  6. 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.

  7. Bortezomib in combination with low-dose oral melphalan, dexamethasone and thalidomide for relapsed elderly patients with multiple myeloma

    PubMed Central

    Azarm, Taleb; Akbari, Mojtaba; Azarm, Arezo; Mohager, Hamid

    2012-01-01

    BACKGROUND: The aim of the study was to assess the effects of combination of bortezomib moderate dose and continuous oral low dose melphalan and thalidomide and dexamethasone (BMTD regimen) in elderly patients aged ≥ 65 years with relapsed multiple myeloma (MM). METHODS: Twenty four patients with advanced MM were enrolled to receive eight 3-week treatment cycles with bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 followed by three 5-week cycles with bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22. Within all cycles, dexamethasone 24 mg/d was given intravenously on the day of bortezomib injection and the day thereafter. In addition, patients received oral treatment of melphalan at a dose of 5 mg/d continuously for twenty days for every cycle. RESULTS: Mean age of study patients was 72.8 ± 6.4 years. All patients that completed at least one treatment cycle were evaluated for response. Complete, partial, and minor responses occurred in 19%, 65% and 6% of patients, respectively. Overall response rate was 90% (efficacy analysis). CONCLUSIONS: This study demonstrated potent in vivo activity of combination therapy with BMTD regimen in patients with relapsed MM, with an acceptable safety profile and high overall response rate. PMID:23248651

  8. 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.

  9. Intravenous therapy

    PubMed Central

    Waitt, C; Waitt, P; Pirmohamed, M

    2004-01-01

    Intravenous administration of fluids, drugs, and nutrition is very common in hospitals. Although insertion of peripheral and central cannulae and subsequent intravenous therapy are usually well tolerated, complications that prolong hospitalisation, and in some cases cause death, can arise on occasions. Additionally, many cannulae are inserted unnecessarily. This article seeks to review this area and to outline good medical practice. PMID:14760169

  10. 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…

  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. 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.

  13. Effect of intravenous clonidine premedication for the bloodless surgical field in patients undergoing middle ear or nasal surgery: A comparison of three different doses

    PubMed Central

    Ramchandani, Sarita; Lakra, Anand Masih; Shah, Pratibha Jain; Lalwani, Jaya; Sahare, Kamal Kishore

    2015-01-01

    Aim: To evaluate the effect of intravenous (IV) clonidine premedication for the bloodless surgical field in patients undergoing middle ear or nasal surgery comparing three different doses. Subjects and Methods: This prospective randomized, clinical trial was performed on 90 normotensive patients belonging to American Society of Anesthesiologists grade I/II, aged 18–60 years, of either sex, undergoing routine middle ear or nasal surgery. These patients were divided into three Groups A, B, and C with 30 patients in each according to the dose of IV clonidine used as premedicant that is 3, 4, and 5 µg/kg, respectively. The hypotensive period commenced 10 min after the start of surgery till the surgeon's request for no hypotension required any longer. The target mean blood pressure for producing bloodless surgical field was 60–70 mmHg. During the hypotensive period, the surgeons were asked to rate the bleeding severity score on a six-point scale from 0 (no bleeding) to 5 (severe bleeding). Statistical Analysis Used: ANOVA, Chi-square test, Z-test, standard deviation and P value. Results: IV clonidine premedication in a dose of 4 and 5 µg/kg reduces bleeding and provides a clear field for surgery. It also reduces the requirement of isoflurane, fentanyl, and metoprolol for controlled hypotension. However, clonidine 5 µg/kg was not more effective than clonidine 4 µg/kg in producing these effects rather was associated with some side effects. Conclusion: IV clonidine premedication in a dose of 4 µg/kg is safe and effective for producing a bloodless surgical field in the middle ear and nasal surgery. PMID:26712981

  14. The cost of treating immune thrombocytopenic purpura using intravenous Rh immune globulin versus intravenous immune globulin.

    PubMed

    Sandler, S G; Novak, S C; Roland, B

    2000-03-01

    Multiple factors, including efficacy, toxicity and cost, may influence the decision to treat immune thrombocytopenic purpura (ITP) with intravenous immune globulin (IVIG) or intravenous Rho (D) immune globulin (IV RhIG). We conducted a survey of 50 hospitals in 31 states to determine the costs for treating ITP using conventional doses for IVIG or IV RhIG, based on package insert recommendations. The average cost for a dose of IVIG ($2,771) was 71.7% ($1,157) more than that for a dose of IV RhIG ($1,614). In the absence of clearly defined differences in clinical outcomes when treating ITP with IVIG or IV RhIG, the difference in cost may be an important factor in selecting the treatment.

  15. Effects of intravenous benzo[a]pyrene dose administration on levels of exposure biomarkers, DNA adducts, and gene expression in rats.

    PubMed

    Moreau, Marjory; Ouellet, Nathalie; Ayotte, Pierre; Bouchard, Michèle

    2015-01-01

    The effects of benzo[a]pyrene (BaP) administration on biomarkers of exposure and early effects were studied in male Sprague-Dawley rats intravenously injected with doses of 0.4, 4, 10, or 40 μmol BaP/kg . Blood, tissues, and excreta were collected 8 and 24 h posttreatment. BaP and several of its metabolites were simultaneously measured in blood, tissues and excreta by ultra-high-performance liquid chromatography (UHPLC)/fluorescence. DNA adducts of BaP diol epoxide (BaPDE) in lungs were quantified using an ultrasensitive immunoassay with chemiluminescence detection. Expression of selected genes in lungs of treated rats (lung RNA) compared to control rats was also assessed by quantitative real-time polymerase chain reaction. There was a dose-dependent increase in blood, tissue, and excreted levels of BaP metabolites. At 8 and 24 h postinjection, BaP and hydroxyBaP were found in higher concentrations in blood and tissues compared to other analytes. However, diolBaP were excreted in greater amounts in urine and apparently more rapidly than hydroxyBaP. Mean percentages (± SD) of injected dose excreted in urine as 4,5-diolBaP during the 0-8 h and 0-24 h period posttreatment were 0.16 ± 0.027% and 0.14 ± 0.083%, respectively. Corresponding values for 3-OHBaP were 0.0045 ± 0.0009% and 0.026 ± 0.014%. BaP-diones were not detectable in blood, tissues, and excreta; 7,8-diolBaP and BaPtetrol were found to be minor metabolites. There was also a dose-dependent increase in DNA adduct formation in lung. Analysis of gene expression further showed a modulation of Cyp1a1, Cyp1b1, Nqo1, Nrf2, Fos, and Ahr expression at 10- and 40-μmol/kg doses, but not at the lower doses. This study provided a better assessment of the influence of absorbed BaP doses on biological levels of diolBaP and OHBaP exposure biomarkers and association of the latter with early biological alterations, such as DNA adducts and gene expression. PMID:25506633

  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. [Effects of intravenous nicardipine on blood pressure, hemorheology platelet function in arterial hypertension. Dose-effect relations].

    PubMed

    Zannad, F; Voisin, P; Sadoul, N; Marchal, C; Donetti, C; Stoltz, J F; Gilgenkrantz, J M

    1987-06-01

    In arterial hypertension, hyperviscosity with hemorheological disturbances and platelet dysfunction may play a role in the prognosis and complications of the disease. We studied the effects of Nicardipine (NIC) on these blood disturbances in a group of 21 untreated patients with essential hypertension, aged 25 to 70 years (SBP/DBP = 185 +/- 28/105 +/- 17 mmHg). During one hour before and 4 hours after the IV injection of single doses of 5, 7.5 or 10 mg NIC over 5 min, blood pressure was recorded automatically (Dinamap). Hemorheological variables and platelet function were studied before and 30 min, 3 h and 24 hours after the injection. NIC lowered blood pressure and increased heart rate significantly (At 5 min, SBP = -24 mmHg; DBP = -18 mmHg; HR = +22 b/min). These effects were dose-dependent with rapid onset and short duration (less than 2 hrs). NIC decreased plasma viscosity from 1.36 +/- 0.08 to 1.30 +/- 0.07 Cst; p less than 0.01, whole blood viscosity from 22.4 +/- 2.8 to 20.7 +/- 1.5 mPas; p less than 0.05 for gamma = 0.512 s-1, and erythrocyte filterability with the Ca++ ionophore A 23187 from 16.3 +/- 3.8 to 13.5 +/- 3.1; p less than 0.01. Platelet aggregation with ADP was unchanged, but aggregation with A 23187 decreased from 46.9 +/- 21.2 to 31.3 +/- 25.6; p less than 0.05, as well as plasma levels of beta-thromboglobulin (71.2 +/- 29.8 to 55.4 +/- 24.3 ng/ml; p less than 0.02) and platelet generated malonaldehyde (7.2 +/- 1.8 to 6.7 +/- 1.4 nM/10(9) platelets; NS).(ABSTRACT TRUNCATED AT 250 WORDS)

  18. 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

  19. Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice

    PubMed Central

    2011-01-01

    Background The clinical use of mefloquine (MQ) has declined due to dose-related neurological events. Next generation quinoline methanols (NGQMs) that do not accumulate in the central nervous system (CNS) to the same extent may have utility. In this study, CNS levels of NGQMs relative to MQ were measured and an early lead chemotype was identified for further optimization. Experimental design The plasma and brain levels of MQ and twenty five, 4-position modified NGQMs were determined using LCMS/MS at 5 min, 1, 6 and 24 h after IV administration (5 mg/kg) to male FVB mice. Fraction unbound in brain tissue homogenate was assessed in vitro using equilibrium dialysis and this was then used to calculate brain-unbound concentration from the measured brain total concentration. A five-fold reduction CNS levels relative to mefloquine was considered acceptable. Additional pharmacological properties such as permeability and potency were determined. Results The maximum brain (whole/free) concentrations of MQ were 1807/4.9 ng/g. Maximum whole brain concentrations of NGQMs were 23 - 21546 ng/g. Maximum free brain concentrations were 0.5 to 267 ng/g. Seven (28%) and two (8%) compounds exhibited acceptable whole and free brain concentrations, respectively. Optimization of maximum free brain levels, IC90s (as a measure or potency) and residual plasma concentrations at 24 h (as a surrogate for half-life) in the same molecule may be feasible since they were not correlated. Diamine quinoline methanols were the most promising lead compounds. Conclusion Reduction of CNS levels of NGQMs relative to mefloquine may be feasible. Optimization of this property together with potency and long half-life may be feasible amongst diamine quinoline methanols. PMID:21645370

  20. The pharmacokinetics of DPH after the administration of a single intravenous or intramuscular dose in healthy dogs.

    PubMed

    Sanchez, A; Valverde, A; Sinclair, M; Mosley, C; Singh, A; Mutsaers, A J; Hanna, B; Gu, Y; Johnson, R

    2016-10-01

    The objective of this study was to determine the pharmacokinetics of diphenhydramine (DPH) in healthy dogs following a single i.v. or i.m. dose. Dogs were randomly allocated in two treatment groups and received DPH at 1 mg/kg, i.v., or 2 mg/kg, i.m. Blood samples were collected serially over 24 h. Plasma concentrations of DPH were determined by high-performance liquid chromatography, and noncompartmental pharmacokinetic analysis was performed with the commercially available software. Cardio-respiratory parameters, rectal temperature and effects on behaviour, such as sedation or excitement, were recorded. Diphenhydramine Clarea , Vdarea and T1/2 were 20.7 ± 2.9 mL/kg/min, 7.6 ± 0.7 L/kg and 4.2 ± 0.5 h for the i.v. route, respectively, and Clarea /F, Vdarea /F and T1/2 20.8 ± 2.7 mL/kg/min, 12.3 ± 1.2 L/kg and 6.8 ± 0.7 h for the i.m. route, respectively. Bioavailability was 88% after i.m. administration. No significant differences were found in physiological parameters between groups or within dogs of the same group, and values remained within normal limits. No adverse effects or changes in mental status were observed after the administration of DPH. Both routes of administration resulted in DPH plasma concentrations which exceeded levels considered therapeutic in humans.

  1. Repair in mouse lung between multiple small doses of X rays

    SciTech Connect

    Travis, E.L.; Parkins, C.S.; Down, J.D.; Fowler, J.F.; Thames, H.D.

    1983-05-01

    Multiple fraction experiments have been carried out to determine the response of mouse lung to repeated small doses of 240 kV X rays down to 150 rad/fraction using breathing rate and lethality to assess damage. Two experimental approaches were used to measure the effect of small doses in vivo: (1) multiple equal doses and (2) multiple priming doses followed by a large test dose. Analysis was performed using the multitarget two-component model and the linear test dose. The amount of repair was calculated as a function of either dose per fraction (F/sub R/) or total dose (F/sub rec/). Both F/sub R/ and F/sub rec/ increased with decreasing dose per fraction but the change in F/sub R/ was small. The advantage of F/sub rec/ was that it varied more rapidly with dose per fraction than F/sub R/, so that possible differences between tissue repair capabilities are more visible on plots of repair as a function of dose per fraction. F/sub R/ and F/sub rec/ both decreased with the level of single-dose isoeffect injury; thus neither parameter is acceptable for comparing repair capability of different normal tissues with widely differing single-dose end point levels. Beta/alpha values were calculated and found to be a more acceptable index of repair capability than either F/sub R/ or F/sub rec/ because unlike those two parameters, ..beta../..cap alpha.. varied little with level of damage. Beta/alpha values of 1.7 to 4.2 krad/sup -1/ were obtained for both lung death and increased breathing rate and are clearly intermediate between the lower ..beta../..cap alpha.. ratios for acute reactions, i.e., skin and intestine, and the higher values for late reactions in kidney and spinal cord.

  2. High-dose intravenous immunoglobulin and splenectomy for the treatment of HIV-related immune thrombocytopenia in patients with severe haemophilia.

    PubMed

    Beard, J; Savidge, G F

    1988-03-01

    Four patients with severe haemophilia A and one patient with severe Christmas disease developed severe immune thrombocytopenia (platelet count less than 20 x 10(9)/l). All five patients were HIV-antibody positive and one was HIV-antigen positive. Four patients were treated initially with prednisolone, but with only a transient platelet response in three and no response in the fourth. All patients were treated with high dose intravenous immunoglobulin (0.4 g/kg daily for 5 d) resulting in a rise in platelet count in all cases (range 138-300 x 10(9)/l) and then proceeded to splenectomy. Three remain in complete remission after 6-14 months, and one showed a good response with platelet counts ranging from 103 to 187 x 10(9)/l. The fifth patients achieved a normal platelet count for 3 months post-splenectomy, but suffered a relapse with platelet counts ranging from 25 to 108 x 10(9)/l over the next 3 years. However, following a severe Varicella infection 10 months ago, during which he developed a marked transient thrombocytosis, he has also maintained a normal platelet count.

  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. 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

  5. Evaluation of Oral and IntravenousRoute Pharmacokinetics, Plasma Protein Binding and Uterine Tissue Dose Metrics of Bisphenol A: A Physiologically Based Pharmacokinetic Approach

    SciTech Connect

    Teeguarden, Justin G.; Waechter, John M.; Clewell, III, H. J.; Covington, Tammie R.; Barton, H. A.

    2005-06-01

    Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastic and epoxy resins, both of which are used in food contact and other applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed to provide a physiological context in which the processes controlling BPA pharmacokinetics (e.g. plasma protein binding, enterohepatic recirculation of the glucuronide (BPAG)) could be incorporated. A uterine tissue compartment was included to allow the correlation of simulated ER binding of BPA with increases in uterine wet weight (UWW) in rats. Intravenous and oral-route blood kinetics of BPA in rats and oral-route plasma and urinary elimination kinetics in humans were well described by the model. Simulations of rat oral-route BPAG pharmacokinetics were less exact, most likely the result of oversimplification of the GI tract compartment. Comparison of metabolic clearance rates derived from fitting rat i.v. and oral-route data implied that intestinal glucuronidation of BPA is significant. In rats but not humans, terminal elimination rates were strongly influenced by enterohepatic recirculation. In the absence of BPA binding to plasma proteins, simulations showed high ER occupancy at doses without uterine effects. Restricting free BPA to the measured unbound amount demonstrated the importance of including plasma binding in BPA kinetic models: the modeled relationship between ER occupancy and UWW increases was consistent with expectations for a receptor mediated response with low ER occupancy at doses with no response and increasing occupancy with larger increases in UWW.

  6. 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

  7. 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.

  8. 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.

  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. 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

  12. Before and After Study of Pharmacists’ and Students’ Knowledge of Two Novel Antidotes: High-Dose Insulin Euglycemia and Intravenous Fatty Acid Emulsion 20%

    PubMed Central

    Tolento, Amanda; Howland, Mary Ann

    2015-01-01

    Purpose: To assess pharmacists’ and students’ knowledge of high-dose insulin euglycemia (HIE) and intravenous fatty acid emulsion 20% (IFE) and to see whether it improved after an educational intervention. Methods: A survey to assess the knowledge about the use of HIE and IFE as antidotes was e-mailed to practicing pharmacists, pharmacy residents, and students prior to and following an educational intervention. Fact sheets on the antidotes were developed in conjunction with the New York City Poison Control Center and were used as the educational intervention in this study. The impact of exposure to the intervention was measured by comparing the number of correct responses per question on the pre- and posttests and the mean pre- and posttest scores using chi-square and t tests, respectively. Results: Most respondents felt either not at all or only somewhat comfortable with managing a toxicologic emergency. There was a statistically significant difference in mean scores on the pretest and posttest (2.9 vs 5.45; P = .001) and for the number of participants giving correct responses for each question before and after education: 52.4% of respondents answered “I don’t know” to the questions prior to education versus 21.2% after education (P < .001). Fewer respondents felt not at all comfortable managing a toxicologic emergency after the educational intervention (42.4 vs 50.3%; P < .001). Conclusion: Pharmacists and students reported little comfort in managing toxicological emergencies in general and have limited baseline knowledge about these agents. Educational interventions can significantly improve knowledge. Prior familiarity with these newer antidotes should reduce delays in their administration in an emergency. PMID:26448670

  13. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments.

    PubMed Central

    Basta, M; Dalakas, M C

    1994-01-01

    In patients with dermatomyositis (DM) the earliest lesion is microvasculopathy mediated by deposition of C5b-C9 membranolytic attack complex (MAC) on intramuscular capillaries. This leads sequentially to muscle ischemia, necrosis of muscle fibers, and muscle weakness. High-dose intravenous immunoglobulin (IVIG), which can modulate complement-dependent tissue damage in animal models, has been shown to be effective in the treatment of patients with DM. We used an in vitro C3 uptake assay to examine 55 coded sera from 13 patients with DM and 5 patients with other non-complement-mediated neuromuscular diseases, before and after treatment with IVIG or placebo. Patients with active DM had a significantly higher baseline C3 uptake compared with the others (geometric mean 12,190 vs 3,090 cpm). Post-IVIG but not post-placebo sera inhibited the C3 uptake, without depleting the complement components, by 70.6-93.4%. The maximum inhibition of C3 uptake occurred within hours after IVIG infusion, started to rebound 2 d later, and reached pretreatment levels after 30 d. The serum levels of SC5b-9 complex production were high at baseline but normalized after IVIG therapy. Repeat biopsies from muscles of improved patients showed disappearance of C3b NEO and MAC deposits from the endomysial capillaries and restoration of the capillary network. We conclude that IVIG exerts its beneficial clinical effect by intercepting the assembly and deposition of MAC on the endomysial capillaries through the formation of complexes between the infused immunoglobulins and C3b, thereby preventing the incorporation of activated C3 molecules into C5 convertase. These findings provide the first serological and in situ evidence that IVIG modulates complement attack in a human disease. Images PMID:7962520

  14. [Two cases of long-term home parenteral nutrition in which increased doses of intravenous selenium were administered and the serum and hair selenium concentration was measured].

    PubMed

    Washizawa, Naohiro; Kozono, Koki; Naganuma, Hirokazu; Kimura, Yuki; Sato, Yukihiko; Sakai, Masahiro; Chino, Kenichi; Shimoda, Masato; Suzuki, Takashi; Oshima, Yoko; Kaneko, Hiromasa

    2013-12-01

    Care should be taken regarding the intravenous administration of selenium (Se), an essential element, which is known to be associated with toxemia. The concentration of Se in the serum and hair of 2 patients (patient A and B) with short bowel syndrome, undergoing long-term home parenteral nutrition (HPN), was measured. As nutritional management, commercial total parenteral nutrition infusion was used without restricting oral intake. The patients received sodium selenite (Na2O3Se x 5H2O), a hospital preparation, at the Toho University Omori Medical Center. The dosage was gradually increased from 40 microg/ week to 120 micog/week over 17 months, and the Se concentration in serum and hair was measured bimonthly using inductively coupled plasma mass spectrometry (ICP-MS). The serum concentration of Se increased from 2.0 to 5.3 microg/dL and from 9.0 to 9.7 microg/dL in the case of patient A and B, respectively; however, it did not reach the average value that was observed in healthy volunteers (11.8 microg/dL). In contrast, the concentration of Se in hair gradually approached the reference value (reference range, 405-784 ppb at color correction criteria range 217-520 ppb) in the case of patient A (change from 189 to 278 ppb) and B (change from 291 to 200 ppb). Therefore, we were able to safely manage these cases without any deficiency and poisoning symptoms, by gradually increasing the administration doses.

  15. 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

  16. Infused vincristine and adriamycin with high dose methylprednisolone (VAMP) in advanced previously treated multiple myeloma patients.

    PubMed Central

    Forgeson, G. V.; Selby, P.; Lakhani, S.; Zulian, G.; Viner, C.; Maitland, J.; McElwain, T. J.

    1988-01-01

    Forty-five patients with relapsed or refractory multiple myeloma received continuous infusions of vincristine (0.4 mg total dose daily for 4 days) and adriamycin (9 mg m-2 daily for 4 days) with a high dose of methylprednisolone (1 g m-2 i.v. or p.o. daily by 1 h infusion), the VAMP regimen. Sixteen (36%) responded, with a median duration of remission of 11 months and median survival of 20 months. Major toxicities encountered were infective and cardiovascular. Two smaller groups of myeloma patients were treated with high dose methylprednisolone (HDMP) alone, or VAMP plus weekly low dose cyclophosphamide (Cyclo-VAMP). HDMP produced short responses in 25% of patients with less toxicity than VAMP. Cyclo-VAMP was used in a highly selected group of patients who had previously responded to high dose melphalan. It was well tolerated and produced responses in 61% of this group. PMID:3207601

  17. Pharmacokinetics of Unbound Linezolid in Plasma and Tissue Interstitium of Critically Ill Patients after Multiple Dosing Using Microdialysis

    PubMed Central

    Buerger, Cornelia; Plock, Nele; Dehghanyar, Pejman; Joukhadar, Christian; Kloft, Charlotte

    2006-01-01

    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. PMID:16801426

  18. Visual P2-N2 complex and arousal at the time of encoding predict the time domain characteristics of amnesia for multiple intravenous anesthetic drugs in humans

    PubMed Central

    Pryor, Kane O.; Reinsel, Ruth A.; Mehta, Meghana; Li, Yuelin; Wixted, John T.; Veselis, Robert A.

    2010-01-01

    Background Intravenous anesthetics have marked effects on memory function, even at subclinical concentrations. Fundamental questions remain in characterizing anesthetic amnesia and identifying affected systems-level processes. We applied a mathematical model to evaluate time-domain components of anesthetic amnesia in human subjects. Methods 61 volunteers were randomized to receive propofol (n = 12), thiopental (13), midazolam (12), dexmedetomidine (12), or placebo (12). With drug present, subjects encoded pictures into memory using a 375-item continuous recognition task, with subsequent recognition later probed with drug absent. Memory function was sampled at up to 163 time points, and modeled over the time domain using a two-parameter, first-order negative power function. The parietal event-related P2-N2 complex was derived from electroencephalography, and arousal repeatedly sampled. Each drug was evaluated at two concentrations. Results The negative power function consistently described the course of amnesia (mean R2 = 0.854), but there were marked differences between drugs in the modulation of individual components (P < 0.0001). Initial memory strength was a function of arousal (P = 0.005), while subsequent decay was related to reaction time (P < 0.0001) and the P2-N2 complex (P = 0.007/0.002 for discrete components). Conclusions In humans, the amnesia caused by multiple intravenous anesthetic drugs is characterized by arousal-related effects on initial trace strength, and a subsequent decay predicted by attenuation of the P2-N2 complex at encoding. We propose that failure of normal memory consolidation follows drug-induced disruption of interregional synchrony critical for neuronal plasticity, and discuss our findings in the framework of memory systems theory. PMID:20613477

  19. Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and Patch Administration in Rats.

    PubMed

    Lee, Soo-Han; Kim, Seung-Hyun; Noh, Yook-Hwan; Choi, Byung-Moon; Noh, Gyu-Jeong; Park, Woo-Dae; Kim, Eun-Jung; Cho, Ik-Hyun; Bae, Chun-Sik

    2016-02-01

    Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation.

  20. Estimation of radiation risk in presence of classical additive and Berkson multiplicative errors in exposure doses.

    PubMed

    Masiuk, S V; Shklyar, S V; Kukush, A G; Carroll, R J; Kovgan, L N; Likhtarov, I A

    2016-07-01

    In this paper, the influence of measurement errors in exposure doses in a regression model with binary response is studied. Recently, it has been recognized that uncertainty in exposure dose is characterized by errors of two types: classical additive errors and Berkson multiplicative errors. The combination of classical additive and Berkson multiplicative errors has not been considered in the literature previously. In a simulation study based on data from radio-epidemiological research of thyroid cancer in Ukraine caused by the Chornobyl accident, it is shown that ignoring measurement errors in doses leads to overestimation of background prevalence and underestimation of excess relative risk. In the work, several methods to reduce these biases are proposed. They are new regression calibration, an additive version of efficient SIMEX, and novel corrected score methods.

  1. Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers.

    PubMed

    Lasseter, K; Dilzer, S; Jansat, J M; Garcia Gil, E; Caracta, C F; Ortiz, S

    2012-04-01

    Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction and increased cholinergic tone. The global initiative for chronic obstructive lung disease (GOLD) guidelines recommend long-acting anticholinergics for COPD maintenance treatment. Aclidinium bromide is a novel, long-acting muscarinic antagonist developed for the treatment of COPD. A phase I, randomized, single-blind, multiple-dose clinical trial was conducted to assess the safety and pharmacokinetics (PK) of multiple doses of twice-daily (BID) aclidinium in healthy subjects. Thirty healthy male and female subjects received aclidinium 200 μg, 400 μg, 800 μg, or placebo twice daily for 7 days. Subjects were randomized to 1 of 3 cohorts and 10 subjects in each cohort were randomized (8:2) to either aclidinium or placebo groups. Safety was assessed via adverse events (AEs), laboratory evaluations, vital signs, and ECGs. Plasma samples were obtained at multiple time points throughout the study and analyzed for aclidinium and its inactive acid and alcohol metabolites using a fully validated method of liquid chromatography coupled with tandem mass spectrometry. A total of 9 treatment-emergent AEs were reported (1, placebo; 3, aclidinium 400 μg; 5, aclidinium 800 μg), all of which were mild in severity. No serious AEs were reported. There were no clinically meaningful changes in laboratory parameters or vital signs. PK parameters on Day 7 following BID dosing of aclidinium showed that steady state was achieved for aclidinium and its metabolites. On Days 1 and 7, maximum plasma concentrations (Cmax) of aclidinium were generally observed at the first PK time point (5 min postdose) and rapidly declined, with plasma concentrations generally less than 10% of Cmax by 6 h postdose in all aclidinium groups. Mean effective t(½) after the evening dose on Day 7 ranged from 4.6 to 7.0 h for aclidinium 400 μg and 800 μg, similar to the terminal t(½) observed on Day 1 (4.5-5.9 h

  2. Effect of computer-generated prompts on physician prescribing of multiple daily doses.

    PubMed

    Atkinson, V; Andrews, J D

    1987-06-01

    Cost containment of health care costs and computerization of pharmacy services are two trends that have become evident in recent years. The work described here was an attempt to reduce the prescribing of multiple daily doses of medications that could be prescribed once or twice daily by utilizing a pharmacy computer system. Ten drugs were identified as being prescribed more than 30% of the time in more frequent dosing schedules than recommended in the literature. Five of the drugs were randomly assigned to an experimental group and five to a control group. The computer system included a reminder with all experimental drug group orders for drugs effective given once or twice daily for maintenance therapy. This reminder was printed on both the physician's active medication profile and the nurse's medication administration record. The control period was designated as being the four month period prior to the initiation of the study. The experimental period was identified as the following four months where reminders were included with the drugs. No information concerning the study was circulated to the physicians or nursing staff. The results revealed no trend of fewer orders for multiple doses in the experimental group. In fact, all drugs in both the experimental and control groups showed random fluctuations in the number of orders for multiple doses. Possible reasons for the failure of this project include the impact of the reminders on the physicians, the timing of the study, and the medical condition of the patients. PMID:10282583

  3. 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

  4. Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis.

    PubMed

    McNicol, E D; Tzortzopoulou, A; Cepeda, M S; Francia, M B D; Farhat, T; Schumann, R

    2011-06-01

    Paracetamol is the most commonly prescribed analgesic for the treatment of acute pain. The efficacy and safety of i.v. formulations of paracetamol is unclear. We performed a systematic search (multiple databases, bibliographies, any language, to May 2010) for single-dose, randomized, controlled clinical trials of propacetamol or i.v. paracetamol for acute postoperative pain in adults or children. Thirty-six studies involving 3896 patients were included. For the primary outcome, 37% of patients (240/367) receiving propacetamol or i.v. paracetamol experienced at least 50% pain relief over 4 h compared with 16% (68/527) receiving placebo (number needed to treat=4.0; 95% confidence interval, 3.5-4.8). The proportion of patients in propacetamol or i.v. paracetamol groups experiencing at least 50% pain relief diminished over 6 h. Patients receiving propacetamol or paracetamol required 30% less opioid over 4 h and 16% less opioid over 6 h than those receiving placebo. However, this did not translate to a reduction in opioid-induced adverse events (AEs). Similar comparisons between propacetamol or i.v. paracetamol and active comparators were either not statistically significant, not clinically significant, or both. AEs occurred at similar rates with propacetamol or i.v. paracetamol and placebo. However, pain on infusion occurred more frequently in those receiving propacetamol compared with placebo (23% vs 1%). A single dose of either propacetamol or i.v. paracetamol provides around 4 h of effective analgesia for about 37% of patients with acute postoperative pain. Both formulations are associated with few AEs, although patients receiving propacetamol have a higher incidence of pain on infusion. PMID:21558067

  5. Phage therapy dosing: The problem(s) with multiplicity of infection (MOI)

    PubMed Central

    Abedon, Stephen T.

    2016-01-01

    ABSTRACT The concept of bacteriophage multiplicity of infection (MOI) – ratios of phages to bacteria – historically has been less easily applied than many phage workers would prefer or, perhaps, may be aware. Here, toward clarification of the concept, I discuss multiplicity of infection in terms of semantics, history, mathematics, pharmacology, and actual practice. For phage therapy and other biocontrol purposes it is desirable, especially, not to solely employ MOI to describe what phage quantities have been applied during dosing. Why? Bacterial densities can change between bacterial challenge and phage application, may not be easily determined immediately prior to phage dosing, and/or target bacterial populations may not be homogeneous with regard to phage access and thereby inconsistent in terms of what MOI individual bacteria experience. Toward experiment reproducibility and as practiced generally for antibacterial application, phage dosing instead should be described in terms of concentrations of formulations (phage titers) as well as volumes applied and, in many cases, absolute numbers of phages delivered. Such an approach typically will be far more desirable from a pharmacological perspective than solely indicating ratios of agents to bacteria. This essay was adapted, with permission, from an appendix of the 2011 monograph, Bacteriophages and Biofilms, Nova Science Publishers.

  6. Dose rate effect on micronuclei induction in human blood lymphocytes exposed to single pulse and multiple pulses of electrons.

    PubMed

    Acharya, Santhosh; Bhat, N N; Joseph, Praveen; Sanjeev, Ganesh; Sreedevi, B; Narayana, Y

    2011-05-01

    The effects of single pulses and multiple pulses of 7 MV electrons on micronuclei (MN) induction in cytokinesis-blocked human peripheral blood lymphocytes (PBLs) were investigated over a wide range of dose rates per pulse (instantaneous dose rate). PBLs were exposed to graded doses of 2, 3, 4, 6, and 8 Gy of single electron pulses of varying pulse widths at different dose rates per pulse, ranging from 1 × 10(6) Gy s(-1) to 3.2 × 10(8) Gy s(-1). Different dose rates per pulse were achieved by changing the dose per electron pulse by adjusting the beam current and pulse width. MN yields per unit absorbed dose after irradiation with single electron pulses were compared with those of multiple pulses of electrons. A significant decrease in the MN yield with increasing dose rates per pulse was observed, when dose was delivered by a single electron pulse. However, no reduction in the MN yield was observed when dose was delivered by multiple pulses of electrons. The decrease in the yield at high dose rates per pulse suggests possible radical recombination, which leads to decreased biological damage. Cellular response to the presence of very large numbers of chromosomal breaks may also alter the damage.

  7. Safety and Efficacy of Single Dose versus Multiple Doses of AmBisome® for Treatment of Visceral Leishmaniasis in Eastern Africa: A Randomised Trial

    PubMed Central

    Khalil, Eltahir A. G.; Weldegebreal, Teklu; Younis, Brima M.; Omollo, Raymond; Musa, Ahmed M.; Hailu, Workagegnehu; Abuzaid, Abuzaid A.; Dorlo, Thomas P. C.; Hurissa, Zewdu; Yifru, Sisay; Haleke, William; Smith, Peter G.; Ellis, Sally; Balasegaram, Manica; EL-Hassan, Ahmed M.; Schoone, Gerard J.; Wasunna, Monique; Kimutai, Robert; Edwards, Tansy; Hailu, Asrat

    2014-01-01

    Background Anti-leishmanial drug regimens that include a single dose AmBisome® could be suitable for eastern African patients with symptomatic visceral leishmaniasis (VL) but the appropriate single dose is unknown. Methodology A multi-centre, open-label, non-inferiority, randomized controlled trial with an adaptive design, was conducted to compare the efficacy and safety of a single dose and multiple doses of AmBisome® for the treatment of VL in eastern Africa. The primary efficacy endpoint was definitive cure (DC) at 6 months. Symptomatic patients with parasitologically-confirmed, non-severe VL, received a single dose of AmBisome® 7.5 mg/kg body weight or multiple doses, 7 times 3 mg/kg on days 1–5, 14, and 21. If interim analyses, evaluated 30 days after the start of treatment following 40 or 80 patients, showed the single dose gave significantly poorer parasite clearance than multiple doses at the 5% significance level, the single dose was increased by 2·5 mg/kg. In a sub-set of patients, parasite clearance was measured by quantitative reverse transcriptase (qRT) PCR. Principal Findings The trial was terminated after the third interim analysis because of low efficacy of both regimens. Based on the intention-to-treat population, DC was 85% (95%CI 73–93%), 40% (95%CI 19–64%), and 58% (95%CI 41–73%) in patients treated with multiple doses (n = 63), and single doses of 7·5 (n = 21) or 10 mg/kg (n = 40), respectively. qRT-PCR suggested superior parasite clearance with multiple doses as early as day 3. Safety data accorded with the drug label. Conclusions The tested AmBisome® regimens would not be suitable for VL treatment across eastern Africa. An optimal single dose regimen was not identified. Trials Registration www.clinicaltrials.gov NCT00832208 PMID:24454970

  8. Arteether toxicokinetics and pharmacokinetics in rats after 25 mg/kg/day single and multiple doses.

    PubMed

    Li, Q G; Brueckner, R P; Peggins, J O; Trotman, K M; Brewer, T G

    1999-01-01

    Multiple doses of arteether (ARTE) at 25 mg/kg cause CNS and anorectic toxicities in rats. The same dose of ARTE was used to study the toxicokinetics (TK) after multiple injections and the pharmacokinetics (PK) following single administration. Animals were administered ARTE in sesame oil for 7 days, blood samples were collected using destructive sampling for up to 192 h after dosing and assayed by HPLC-ECD. Two other groups of rats were administered either a single 25 mg/kg i.v. or i.m. dose. In addition, the drug remaining in the i.m. injection site was measured. During the 7 day treatments, anorectic toxicity of ARTE was observed, and that caused significant reductions in food consumption and body weight after day 2. TK data on days 2-7 revealed marked changes compared to the PK parameters estimated on day 1. AUC (4367 ng x h/ml) on day 7 was 5-fold higher than AUC (905 ng x h/ml) on day 1. The volume of distribution at steady state (V(SS)) on day 7 (41.8 l) was 40% of the day 1 value of the V(SS) (104.3 l). Clearance (CL) was increased by 89% of the day 1 value, from 0.98 l/h to 1.85 l/h on day 7. The elimination t(1/2) of ARTE was also prolonged from 13.7 h (day 1) to 31.2 h (day 7). These data suggest that ARTE may have altered its distribution and elimination in rats as a result of the systemic toxicity. Analysis of the injection sites showed that 38% and 91% of the total amount of ARTE single dose remained in the muscles at 24 h (after first injection) and 168 h (at 24 h after 7 daily multiple doses), respectively. Fast and slow absorption phases from muscle were seen with t(1/2) of 0.97 h and 26.3 h, respectively. The apparent elimination t(1/2) of ARTE after i.m. injection (13.7 h) was much longer than that after i.v. dosing (0.67 h) due to the prolonged muscle absorption phase. Acute toxicity data of artemisinin drugs demonstrated that animals receiving a high single ARTE dose in sesame oil died between days 5-11, similar to artemether. When animals

  9. Familial and multiple gastrointestinal stromal tumors with fair response to a half-dose of imatinib.

    PubMed

    Bamba, Shigeki; Hirota, Seiichi; Inatomi, Osamu; Ban, Hiromitsu; Nishimura, Takashi; Shioya, Makoto; Imaeda, Hirotsugu; Nishida, Atsushi; Sasaki, Masaya; Murata, Satoshi; Andoh, Akira

    2015-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Since our first report in 1998, approximately 30 families with multiple GISTs due to a germline gain-of-function mutation of c-kit have been reported. We herein present a case of a family with multiple GISTs that have a germline c-kit mutation in exon 11 (Del-Val560) in two siblings. One of the patients showed a fair response to treatment with a half-dose of imatinib (200 mg/day). There are few reports describing the response to imatinib in familial GISTs and this drug appears to be a promising therapeutic option.

  10. Pharmacokinetics of Single- and Multiple-Dose Oral Clarithromycin in Soft Tissues Determined by Microdialysis▿

    PubMed Central

    Traunmüller, Friederike; Zeitlinger, Markus; Zeleny, Petra; Müller, Markus; Joukhadar, Christian

    2007-01-01

    The antimicrobial spectrum of clarithromycin renders this antibiotic a frequently used option in the treatment of skin and soft-tissue infections. In most cases, these infections are caused by extracellularly proliferating microorganisms. Thus, clarithromycin concentrations achieved in the interstitial space are considered particularly important for clinical efficacy. In the present study, clarithromycin concentrations in plasma and interstitial-space fluid of subcutaneous adipose tissue and skeletal muscle of six healthy male volunteers were assessed by means of the microdialysis technique after oral single-dose administration of 250 mg and multiple doses of 500 mg of clarithromycin twice a day (b.i.d.). The ratios of the area under the concentration-time curve of free clarithromycin from 0 to 24 h calculated for a single dose of 250 mg (fAUC0-24) in interstitial-space fluid to the fAUC0-24 in plasma were 0.29 ± 0.17 and 0.42 ± 0.18 for subcutis and skeletal muscle, respectively. For 500 mg of clarithromycin at the steady state (3 to 5 days of intake twice daily), the fAUC0-24(b.i.d.) ratios at the steady state were 0.39 ± 0.04 and 0.41 ± 0.19 for subcutis and skeletal muscle, respectively. The half-life was around 2 h after a single dose but increased to approximately 4 h in plasma and tissues after repetitive clarithromycin administration. Based on subsequently performed pharmacokinetic-pharmacodynamic calculations, a dosing regimen of 500 mg b.i.d. may be ineffective in the treatment of soft-tissue infections caused by pathogens with a drug MIC higher than 0.125 mg/liter. PMID:17606673

  11. Pharmacokinetics of single- and multiple-dose oral clarithromycin in soft tissues determined by microdialysis.

    PubMed

    Traunmüller, Friederike; Zeitlinger, Markus; Zeleny, Petra; Müller, Markus; Joukhadar, Christian

    2007-09-01

    The antimicrobial spectrum of clarithromycin renders this antibiotic a frequently used option in the treatment of skin and soft-tissue infections. In most cases, these infections are caused by extracellularly proliferating microorganisms. Thus, clarithromycin concentrations achieved in the interstitial space are considered particularly important for clinical efficacy. In the present study, clarithromycin concentrations in plasma and interstitial-space fluid of subcutaneous adipose tissue and skeletal muscle of six healthy male volunteers were assessed by means of the microdialysis technique after oral single-dose administration of 250 mg and multiple doses of 500 mg of clarithromycin twice a day (b.i.d.). The ratios of the area under the concentration-time curve of free clarithromycin from 0 to 24 h calculated for a single dose of 250 mg (fAUC(0-24)) in interstitial-space fluid to the fAUC(0-24) in plasma were 0.29 +/- 0.17 and 0.42 +/- 0.18 for subcutis and skeletal muscle, respectively. For 500 mg of clarithromycin at the steady state (3 to 5 days of intake twice daily), the fAUC(0-24(b.i.d.)) ratios at the steady state were 0.39 +/- 0.04 and 0.41 +/- 0.19 for subcutis and skeletal muscle, respectively. The half-life was around 2 h after a single dose but increased to approximately 4 h in plasma and tissues after repetitive clarithromycin administration. Based on subsequently performed pharmacokinetic-pharmacodynamic calculations, a dosing regimen of 500 mg b.i.d. may be ineffective in the treatment of soft-tissue infections caused by pathogens with a drug MIC higher than 0.125 mg/liter. PMID:17606673

  12. Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

    PubMed Central

    Weisel, Katja C.; Dimopoulos, Meletios A.; Moreau, Philippe; Lacy, Martha Q.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Banos, Anne; Oriol, Albert; Alegre, Adrian; Chen, Christine; Cavo, Michele; Garderet, Laurent; Ivanova, Valentina; Martinez-Lopez, Joaquin; Knop, Stefan; Yu, Xin; Hong, Kevin; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Miguel, Jesus San

    2016-01-01

    Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 − < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 − < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30. PMID:27081177

  13. Pharmacokinetics of guaifenesin following administration of multiple doses to exercised Thoroughbred horses.

    PubMed

    Knych, H K; Stanley, S D; Benson, D; Arthur, R M

    2016-08-01

    Guaifenesin is an expectorant commonly used in performance horses to aid in the clearance of mucus from the airways. Guaifenesin is also a centrally acting skeletal muscle relaxant and as such is a prohibited drug with withdrawal necessary prior to competition. To the authors' knowledge, there are no reports in the literature describing single or multiple oral administrations of guaifenesin in the horse to determine a regulatory threshold and related withdrawal time. Therefore, the objective of the current study was to describe the pharmacokinetics of guaifenesin following oral administration in order to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 2 g of guaifenesin orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum guaifenesin concentrations were determined and pharmacokinetic parameters calculated. Guaifenesin was rapidly absorbed (Tmax of 15 min) following oral administration. The Cmax was 681.3 ± 323.8 ng/mL and 1080 ± 732.8 following the first and last dose, respectively. The serum elimination half-life was 2.62 ± 1.24 h. Average serum guaifenesin concentrations remained above the LOQ of the assay (0.5 ng/mL) by 48 h postadministration of the final dose in 3 of 9 horses. PMID:26763117

  14. Multiple toxic doses of methamphetamine alter neurotensin concentrations in various region of the rat brain

    SciTech Connect

    Hanson, G.R.; Merchant, K.; Gibb, J.W.; Letter, A.A.

    1986-03-05

    The authors have previously reported that multiple high doses of methamphetamine (METH) alter neuronal monoamine metabolism and release. Recently, Hokfelt et al. showed that neurotensin, a tridecapeptide, has neurotransmitter properties which may be involved with DA neuronal activity. In the present study they investigated the possible effects of METH on the CNS neurotensin system. Five doses of METH (15 mg/kg) were administered every 6 h; control and treated rats were sacrificed 18 h after the last dose and concentrations of neurotensin-like immuno-reactivity (NTLI) were measured by radioimmunoassay. NTLI was elevated 200-300% in the nucleus accumbens, neostriatum, and substantia nigra; 30-40% increases in NTLI were measured in the hippocampus and hypothalamus. No change was observed in amygdala, A-10 or periaqueductal gray. In contrast to the above measured areas, the frontal lobe and olfactory bulb showed decreases of 25-35%. These findings demonstrate that METH treatment alters the activities of several CNS neurotensin systems, possibly due to the influence of this drug on DA pathways. The variability in the type and magnitude of these responses suggests that DA and neurotensin systems interact by more than one mechanism.

  15. High-dose therapy and innovative approaches to treatment of multiple myeloma.

    PubMed

    Barlogie, B

    2001-04-01

    High-dose therapy in multiple myeloma (MM) appears to be superior in terms of event-free survival and overall survival compared with conventional therapy. Melphalan-based high-dose therapy increases complete remission rates from 5% to 50% and extends event-free survival beyond 3 years and overall survival beyond 6 years. Critical disease features associated with durable complete remission, event-free survival, and overall survival include the absence of chromosome 13 deletion, low beta(2)-microglobulin, and low C-reactive protein levels. Data on 1,000 patients enrolled in tandem high-dose trials show that chromosome 13 deletion is an important prognostic feature. The timely application of a second cycle of high-dose therapy extends event-free survival and overall survival markedly in MM patients with low beta(2)-microglobulin levels. Long-term results of the total therapy trial indicate that patients who do not have chromosome 13 deletions and present with low C-reactive protein and beta(2)-microglobulin levels have longer complete remissions than patients lacking these prognostic factors. Thalidomide shows clear evidence of antitumor activity possibly because of its antiangiogenic activity. Magnetic resonance imaging (MRI) indicates that bone marrow lesions become smaller or disappear while patients receive dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation chemotherapy and that patients who have a compete remission after diagnostic MRI have a superior event-free and overall survival than those who still have persistent MRI lesions. Prospective trials are underway to evaluate the effectiveness of consolidation therapy (total therapy II).

  16. Dose response of multiple parameters for calyculin A-induced premature chromosome condensation in human peripheral blood lymphocytes exposed to high doses of cobalt-60 gamma-rays.

    PubMed

    Lu, Xue; Zhao, Hua; Feng, Jiang-Bin; Zhao, Xiao-Tao; Chen, De-Qing; Liu, Qing-Jie

    2016-09-01

    Many studies have investigated exposure biomarkers for high dose radiation. However, no systematic study on which biomarkers can be used in dose estimation through premature chromosome condensation (PCC) analysis has been conducted. The present study aims to screen the high-dose radiation exposure indicator in calyculin A-induced PCC. The dose response of multiple biological endpoints, including G2/A-PCC (G2/M and M/A-PCC) index, PCC ring (PCC-R), ratio of the longest/shortest length (L/L ratio), and length and width ratio of the longest chromosome (L/B ratio), were investigated in calyculin A-induced G2/A-PCC spreads in human peripheral blood lymphocytes exposed to 0-20Gy (dose-rate of 1Gy/min) cobalt-60 gamma-rays. The G2/A-PCC index was decreased with enhanced absorbed doses of 4-20Gy gamma-rays. The G2/A PCC-R at 0-12Gy gamma-rays conformed to Poisson distribution. Three types of PCC-R were scored according to their shape and their solidity or hollowness. The frequencies of hollow PCC-R and PCC-R including or excluding solid ring in G2/A-PCC spreads were enhanced with increased doses. The length and width of the longest chromosome, as well as the length of the shortest chromosome in each G2/M-PCC or M/A-PCC spread, were measured. All L/L or L/B ratios in G2/M-PCC or M/A-PCC spread increased with enhanced doses. A blind test with two new irradiated doses was conducted to validate which biomarker could be used in dose estimation. Results showed that hollow PCC-R and PCC-R including solid ring can be utilized for accurate dose estimation, and that hollow PCC-R was optimal for practical application.

  17. Pharmacokinetics and tissue penetration of a single dose of ceftriaxone (1,000 milligrams intravenously) for antibiotic prophylaxis in thoracic surgery.

    PubMed Central

    Martin, C; Ragni, J; Lokiec, F; Guillen, J C; Auge, A; Pecking, M; Gouin, F

    1992-01-01

    The pharmacokinetics and tissue penetration of ceftriaxone after a single intravenous injection of 1,000 mg to 17 patients for antibiotic prophylaxis in thoracic surgery were studied. The patients were scheduled for elective noncardiac thoracic surgery. Adequate levels in serum (higher than or equal to the MIC for 90% of isolates of Staphylococcus aureus, Streptococcus spp., Escherichia coli, Haemophilus influenzae, and Klebsiella pneumoniae) were found for all patients throughout the surgical procedures. Mean maximal (5-min) and final (24-h) ceftriaxone levels in serum were 157 +/- 42 and 8.6 +/- 4.5 mg/liter, respectively. The beta-phase elimination half-life was 8.6 +/- 3 h, the plasma clearance was 18.4 +/- 6.25 ml/min, and the apparent volume of distribution at steady state was 0.21 +/- 0.07 liters/kg. At the time of the thoracotomy, the ceftriaxone concentrations were 13.5 +/- 7.8 micrograms/g in thoracic wall fat and 27 +/- 9 micrograms/g in lung tissue. At the time of closure, the ceftriaxone concentration was 15 +/- 9 micrograms/g in thoracic wall fat. During the different steps of the surgical procedures, 100% of patients had adequate levels in tissue (higher than or equal to the MIC for 90% of isolates of Streptococcus spp., E. coli, H. influenzae, and K. pneumoniae). For S. aureus, 90 to 100% of patients had adequate tissue ceftriaxone levels. PMID:1482149

  18. Downregulation of TGF-beta1 mRNA and protein in the muscles of patients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin.

    PubMed

    Amemiya, K; Semino-Mora, C; Granger, R P; Dalakas, M C

    2000-02-01

    We used reverse transcription-polymerase chain reaction to study the level of TGF-beta1 mRNA expression and immunocytochemistry to examine the immunoreactive TGF-beta1 in muscle biopsy specimens from five patients with dermatomyositis (DM) and five patients with inclusion body myositis (IBM) obtained before and after 3 months treatment with intravenous immunoglobulin (IVIg). At baseline, the mRNA expression of TGF-beta1 was increased up to fivefold in the muscles of DM patients compared to that of IBM patients. After IVIg, TGF-beta1 was downregulated and the TGF-beta1 mRNA decreased twofold in the muscles of patients with DM who had successfully responded to therapy, but remained unchanged in the muscles of patients with IBM who did not respond. The downregulation of TGF-beta1 in DM was associated with improvement of the muscle cytoarchitecture and reduction of the endomysial inflammation and connective tissue, suggesting that in DM the excess of TGF-beta1 may be involved in the pathogenesis of chronic inflammation, fibrosis, and accumulation of extracellular matrix proteins.

  19. Absence of multiple local minima effects in intensity modulated optimization with dose-volume constraints

    NASA Astrophysics Data System (ADS)

    Llacer, Jorge; Deasy, Joseph O.; Bortfeld, Thomas R.; Solberg, Timothy D.; Promberger, Claus

    2003-01-01

    This paper reports on the analysis of intensity modulated radiation treatment optimization problems in the presence of non-convex feasible parameter spaces caused by the specification of dose-volume constraints for the organs-at-risk (OARs). The main aim was to determine whether the presence of those non-convex spaces affects the optimization of clinical cases in any significant way. This was done in two phases: (1) Using a carefully designed two-dimensional mathematical phantom that exhibits two controllable minima and with randomly initialized beamlet weights, we developed a methodology for exploring the nature of the convergence characteristics of quadratic cost function optimizations (deterministic or stochastic). The methodology is based on observing the statistical behaviour of the residual cost at the end of optimizations in which the stopping criterion is progressively more demanding and carrying out those optimizations to very small error changes per iteration. (2) Seven clinical cases were then analysed with dose-volume constraints that are stronger than originally used in the clinic. The clinical cases are two prostate cases differently posed, a meningioma case, two head-and-neck cases, a spleen case and a spine case. Of the 14 different sets of optimizations (with and without the specification of maximum doses allowed for the OARs), 12 fail to show any effect due to the existence of non-convex feasible spaces. The remaining two sets of optimizations show evidence of multiple minima in the solutions, but those minima are very close to each other in cost and the resulting treatment plans are practically identical, as measured by the quality of the dose-volume histograms (DVHs). We discuss the differences between fluence maps resulting from those similar treatment plans. We provide a possible reason for the observed results and conclude that, although the study is necessarily limited, the annealing characteristics of a simulated annealing method may not be

  20. Pharmacokinetics of enoxacin and its oxometabolite after multiple oral dosing and penetration into prostatic tissue.

    PubMed

    Hamel, B; Mottet, N; Audran, M; Costa, P; Bressolle, F

    2000-12-01

    The objective of this study was to determine the concentrations of enoxacin and its oxo-metabolite in human prostatic tissue after multiple oral doses (400 mg bd) in 13 patients. On the first day of treatment, elimination half-lives were 6.8 h for enoxacin and 7.1 h for its metabolite; they were increased on day 4 (10.3 and 13.2 h, respectively). The ratios of drug concentration in prostatic tissue and plasma averaged 2.2 for enoxacin and 1.4 for its metabolite. In conclusion, concentrations of enoxacin achieved within the prostatic tissue were higher than plasma concentrations suggesting that there was an active transport mechanism.

  1. Peripheral intravenous line (image)

    MedlinePlus

    A peripheral intravenous line is a small, short plastic catheter that is placed through the skin into a vein, ... or foot, but occasionally in the head. A peripheral intravenous line is used to give fluids and ...

  2. Different doses of intravenous Magnesium sulfate on cardiovascular changes following the laryngoscopy and tracheal intubation: A double-blind randomized controlled trial

    PubMed Central

    Honarmand, Azim; Safavi, Mohammadreza; Badiei, Sajad; Daftari-Fard, Neda

    2015-01-01

    Objective: Laryngoscopy and intratracheal intubation may cause acute hemodynamic instabilities due to catecholamine release. Magnesium sulfate (MgSO4) prevents catecholamine release and results in bradycardia and vasodilatation, so can be used to diminish complications of laryngoscopy and intubation in doses > 50 mg/kg. The aim of this study was to compare the different doses of MgSO4 used to improve cardiovascular instabilities due to laryngoscopy and intratracheal intubation. Methods: In this double-blind randomized controlled trial, 120 patients undergoing elective surgery were divided equally into four groups (n = 30) and received different doses of MgSO4 as case groups (Group I: 30 mg/kg, Group II: 40 mg/kg, Group III: 50 mg/kg) or the equal volume of normal saline as a control group. The patients’ hemodynamic status was recorded at baseline, before laryngoscopy and in 1, 3, 5, and 10 minutes after laryngoscopy. Bradycardia, tachycardia, hypertension, hypotension, ST-T changes, arrhythmias, and duration of extubation and laryngoscopy were also recorded. Findings: There was no significant difference in heart rate between four groups (Pbaseline = 0.46, Ppreoperation = 0.55, P1 min = 0.86, P3 min = 0.30, P5 min = 0.63, P10 min = 0.74). Systolic, diastolic and mean arterial pressures were statistically significant less at 1, 3, and 5 minutes after intubation in comparison with other times of following-up in the three groups received MgSO4 than the control group. Conclusion: The use of MgSO4 in doses less than 50 mg/kg can be effective to reduce cardiovascular instability related to laryngoscopy and tracheal intubation. PMID:25984545

  3. Effect of a single dose of dexamethasone on glucose homeostasis in healthy horses by using the combined intravenous glucose and insulin test.

    PubMed

    Haffner, J C; Eiler, H; Hoffman, R M; Fecteau, K A; Oliver, J W

    2009-01-01

    Sustained dexamethasone administration to horses results in insulin resistance, which may predispose them to laminitis. A single dose of dexamethasone is commonly used as a diagnostic aid, yet the effect of a single dose of dexamethasone on glucose homeostasis in horses is not well defined. The objective of this study was to characterize the change in glucose dynamics over time in response to a single dose of dexamethasone. A combined glucose-insulin tolerance test (CGIT) was performed on 6 adult geldings before and at 2, 24, and 72 h postdexamethasone (40 microg/kg of BW, i.v.); a minimum of 1 wk of rest was allowed between treatments. Before any treatment, the CGIT resulted in a hyperglycemic phase followed by a hypoglycemic phase. Dexamethasone affected glucose dynamics in 3 ways: 1) at 2 h, dexamethasone shortened the ascending branch of the negative phase (P < 0.001) of the test, indicating moderate insulin resistance; 2) at 24 h, dexamethasone impaired glucose clearance by extending the positive phase and eliminating the negative phase while insulin was elevated before the CGIT, indicating a decreased response to insulin; and 3) at 72 h, dexamethasone caused a deeper nadir value (P < 0.001) compared with predexamethasone, indicating an increased response to insulin. It was concluded that dexamethasone decreased the response to insulin as early as 2 h and maximally at 24 h. At 72 h, dexamethasone caused an increased response to insulin, which was unexpected.

  4. Continuous infusion cyclophosphamide and low-dose total body irradiation is a safe and effective conditioning regimen for autologous transplant in multiple myeloma.

    PubMed

    Byrne, M; Wingard, J R; Moreb, J S

    2013-11-01

    We present the results of a novel conditioning regimen in multiple myeloma (MM) patients undergoing tandem autologous stem cell transplant (ASCT). MM patients were enrolled in a prospective phase II clinical trial. After initial ASCT, disease response was assessed by day +100. Patients achieving very good partial remission (VGPR) were offered maintenance therapy. If patients achieved VGPR, they were offered a second ASCT using continuous intravenous cyclophosphamide (CICy) 6 g/m(2) over 4 days and low-dose total body irradiation (ldTBI) 600 rads over 2 days. Total body irradiation was replaced by melphalan 140 mg/m(2) if patients had received prior radiation. Twenty-one patients received tandem ASCT. Three patients received CICy and melphalan. Median duration of neutropenia with CICy/ldTBI was 11 days. Fifteen patients (71.4%) developed febrile neutropenia while grade 1 to 2 diarrhea was the next most common adverse event (42.9%). There was no treatment-related mortality. Four patients had entered complete remission (19%) and 6 achieved VGPR (28.6%). In conclusion, this conditioning regimen is safe and effective and may be useful in patients who do not benefit from first ASCT using more traditional conditioning regimen.

  5. An Automated Dosing Method for a HIFU Device Containing Multiple Phased Arrays

    NASA Astrophysics Data System (ADS)

    Zeng, Xiaozheng Jenny; Barnes, Steve; Sekins, K. Michael

    2010-03-01

    A device containing multiple 2D therapeutic and imaging ultrasound phased arrays is proposed for acoustic hemostasis applications. An automated dosing algorithm selects the optimal combination of therapeutic phased arrays and calculates the acoustic power required of each array. Simulations demonstrate that therapeutic temperatures (70° Cdosing times. The spatial-peak-time-averaged intensity in the target focal zone was ≈600 W/cm2, below the inertial cavitation threshold for these conditions. Simulations showed that the proposed ultrasound device yielded a relatively uniform temperature distribution in the target volume.

  6. Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple sclerosis.

    PubMed Central

    Filippi, M; Campi, A; Martinelli, V; Colombo, B; Yousry, T; Canal, N; Scotti, G; Comi, G

    1995-01-01

    This study was performed to evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) increases the sensitivity of brain MRI for detecting enhancing lesions in patients with primary progressive multiple sclerosis (PPMS). T1 weighted brain MRI was obtained for 10 patients with PPMS in two sessions. In the first session, one scan was obtained five to seven minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, one scan before and two scans five to seven minutes and one hour after the injection of 0.3 mmol/kg Gd-DTPA (triple dose) were obtained. Four enhancing lesions were detected in two patients when the standard dose of Gd-DTPA was used. The numbers of enhancing lesions increased to 13 and the numbers of patients with such lesions to five when the triple dose of Gd-DTPA was used and to 14 and six in the one hour delayed scans. The mean contrast ratio for enhancing lesions detected with the triple dose of Gd-DTPA was higher than those for lesions present in both the standard dose (P < 0.0009) and the one hour delayed scans (P = 0.04). These data indicate that with a triple dose of Gd-DTPA many more enhancing lesions can be detected in patients with PPMS. This is important both for planning clinical trials and for detecting the presence of inflammation in vivo in the lesions of such patients. Images PMID:8530944

  7. A new multiple dose powder inhaler, (Turbuhaler), compared with a pressurized inhaler in a study of terbutaline in asthmatics.

    PubMed

    Persson, G; Gruvstad, E; Ståhl, E

    1988-08-01

    Twelve adult asthmatic patients participated in an open, randomized, cross-over comparison between cumulatively increasing doses of terbutaline sulphate administered via the multiple dose powder inhaler (Turbuhaler) or via a pressurized inhaler. Turbuhaler and the pressurized inhaler showed equipotency both with respect to bronchodilatation and side effects. Both treatments produced a significant increase in pulmonary function measurements, forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). No increase in pulse rate was seen with either treatment but there was an increase in tremor at higher doses with both treatments. Inhalation of beta-agonists via Turbuhaler seems to be an effective way of treating asthma. PMID:3234516

  8. Dose response of multiple parameters for calyculin A-induced premature chromosome condensation in human peripheral blood lymphocytes exposed to high doses of cobalt-60 gamma-rays.

    PubMed

    Lu, Xue; Zhao, Hua; Feng, Jiang-Bin; Zhao, Xiao-Tao; Chen, De-Qing; Liu, Qing-Jie

    2016-09-01

    Many studies have investigated exposure biomarkers for high dose radiation. However, no systematic study on which biomarkers can be used in dose estimation through premature chromosome condensation (PCC) analysis has been conducted. The present study aims to screen the high-dose radiation exposure indicator in calyculin A-induced PCC. The dose response of multiple biological endpoints, including G2/A-PCC (G2/M and M/A-PCC) index, PCC ring (PCC-R), ratio of the longest/shortest length (L/L ratio), and length and width ratio of the longest chromosome (L/B ratio), were investigated in calyculin A-induced G2/A-PCC spreads in human peripheral blood lymphocytes exposed to 0-20Gy (dose-rate of 1Gy/min) cobalt-60 gamma-rays. The G2/A-PCC index was decreased with enhanced absorbed doses of 4-20Gy gamma-rays. The G2/A PCC-R at 0-12Gy gamma-rays conformed to Poisson distribution. Three types of PCC-R were scored according to their shape and their solidity or hollowness. The frequencies of hollow PCC-R and PCC-R including or excluding solid ring in G2/A-PCC spreads were enhanced with increased doses. The length and width of the longest chromosome, as well as the length of the shortest chromosome in each G2/M-PCC or M/A-PCC spread, were measured. All L/L or L/B ratios in G2/M-PCC or M/A-PCC spread increased with enhanced doses. A blind test with two new irradiated doses was conducted to validate which biomarker could be used in dose estimation. Results showed that hollow PCC-R and PCC-R including solid ring can be utilized for accurate dose estimation, and that hollow PCC-R was optimal for practical application. PMID:27542714

  9. Anesthetic management of a patient with multiple sclerosis undergoing cesarean section with low dose epidural bupivacaine

    PubMed Central

    Sethi, Sameer; Kapil, Sonia

    2014-01-01

    A 32-year-old Indian female 38 weeks pregnant, with a history of multiple sclerosis since 2008 was admitted in obstetric ward for safe confinement. She had a history of diminution of vision in both eyes and limb weakness, relapsing – remitting type with movement-induced muscle spasms, in all the four limbs. Her symptoms were usually diplopia, difficulty in vision and ataxic gait. Sh was then treated with methylprednisolone. She was on oral dimethyl fumarate trial, which was stopped at the beginning of pregnancy. Presently, she was completely asymptomatic. Epidural anesthesia with an indwelling catheter was administered with 15 ml of 0.25% bupivacaine in 5 ml increments. A total of 3 mg of epidural morphine was given for post-operative analgesia. The surgery evolved without any intercurrences and patient was discharged from the hospital 72 h after surgery without worsening of her symptoms. We report a safe anesthetic management of a patient with MS undergoing cesarean section with low dose epidural bupivacaine with the addition of morphine for post-operative analgesia. PMID:25191198

  10. An open multiple dose study of Optrex Eye Lotion in eye irritation due to hayfever.

    PubMed

    Clark, M J; Chapman, N D; Noyelle, R M; Lancaster, L

    1989-10-01

    Twenty-four patients consulting their general practitioner with eye irritation due to hayfever entered a seven-day open, multiple dose study of a newly formulated Optrex Eye Lotion. Patients self-administered Optrex by irrigation into their left eye three times daily for seven days, with an option to use the same preparation in their right eye if they thought this to be of benefit. Assessment was by means of daily diary cards completed by the patient each evening for the seven-day period. Following the first instillation, the treated eye felt significantly better at 20 seconds and at four minutes when compared with the untreated eye. Differences between the eyes for degree of redness, comfort and clearness of vision were not significant, but 15 patients (63 per cent) optionally used Optrex in their right eye. Seventeen patients (71 per cent) reported that they derived overall benefit from the use of Optrex Eye Lotion during the study period. Two patients reported side effects during the study but, in each case, the investigator did not consider the event to be therapy related. One patient withdrew on Day 7 of the trial due to worsening of their allergic conjunctivitis. It can be concluded that some subjective benefit was gained by the majority of patients in that a considerable number of them chose to treat both eyes for the duration of the study.

  11. Growth and development of larval green frogs (Rana clamitans) exposed to multiple doses of an insecticide

    USGS Publications Warehouse

    Boone, M.D.; Bridges, C.M.; Rothermel, B.B.

    2001-01-01

    Our objective was to determine how green frogs (Rana clamitans) are affected by multiple exposures to a sublethal level of the carbamate insecticide, carbaryl, in outdoor ponds. Tadpoles were added to 1,000-1 ponds at a low or high density which were exposed to carbaryl 0, 1, 2, or 3 times. Length of the larval period, mass, developmental stage, tadpole survival, and proportion metamorphosed were used to determine treatment effects. The frequency of dosing affected the proportion of green frogs that reached metamorphosis and the developmental stage of tadpoles. Generally, exposure to carbaryl increased rates of metamorphosis and development. The effect of the frequency of carbaryl exposure on development varied with the density treatment; the majority of metamorphs and the most developed tadpoles came from high-density ponds exposed to carbaryl 3 times. This interaction suggests that exposure to carbaryl later in the larval period stimulated metamorphosis, directly or indirectly, under high-density conditions. Our study indicates that exposure to a contaminant can lead to early initiation of metamorphosis and that natural biotic factors can mediate the effects of a contaminant in the environment.

  12. Taenia crassiceps Infection Attenuates Multiple Low-Dose Streptozotocin-Induced Diabetes

    PubMed Central

    Espinoza-Jiménez, Arlett; Rivera-Montoya, Irma; Cárdenas-Arreola, Roberto; Morán, Liborio; Terrazas, Luis I.

    2010-01-01

    Taenia crassiceps, like other helminths, can exert regulatory effects on the immune system of its host. This study investigates the effect of chronic T. crassiceps infection on the outcome of Multiple Low Dose Streptozotocin-Induced Diabetes (MLDS). Healthy or previously T. crassiceps-infected mice received MLDS and type 1 diabetes (T1D) symptoms were evaluated for 6 weeks following the induction of MLDS. T. crassiceps-infected mice displayed lower blood glucose levels throughout the study. A significantly lower percentage of T. crassiceps-infected mice (40%) developed T1D compared to the uninfected group (100%). Insulitis was remarkably absent in T. crassiceps-infected mice, which had normal pancreatic insulin content, whereas uninfected mice showed a dramatic reduction in pancreatic insulin. Infected mice that received MLDS did not show an increase in their regulatory T cell population, however, they had a greater number of alternatively activated macrophages, higher levels of the cytokine IL-4, and lower levels of TNF-α. Therefore, infection with T. crassiceps causes an immunomodulation that modifies the incidence and development of MLDS-induced autoimmune diabetes. PMID:20069130

  13. Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice

    SciTech Connect

    Amirshahrokhi, K.; Dehpour, A.R.; Hadjati, J.; Sotoudeh, M.; Ghazi-Khansari, M.

    2008-10-01

    Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of {beta} cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a {mu}-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1{beta}, tumor necrosis factor-{alpha} and interferon-{gamma}] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of {beta} cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of {beta} cells and insulitis in the MLDS model of type 1 diabetes.

  14. Prophylactic activity of increasing doses of intravenous histamine in refractory migraine: Retrospective observations of a series of patients with migraine without aura

    PubMed Central

    Pietrini, Umberto; De Luca, Massimo; Del Bene, Enrico; De Cesaris, Francesco; Bertinotti, Luca; Colangelo, Nicola; Moggi Pignone, Alberto

    2004-01-01

    Background: Histamine is thought to play a pivotal role in the modulation of peripheral and central pain. The administration of increasing doses of histamine may lead to desensitization of receptors of histamine types 1 and 2, causing meningeal vasodilation, and to depletion of neuropeptides in the trigeminal ganglion, thus inhibiting the initiation of migraine. Objective: In this study, the efficacy and tolerability of increasing doses of IV histamine in migraine prophylaxis were investigated. Methods: This single-center, open-label, retrospective, controlled study was conducted at the Headache Center (Department of Internal Medicine, University of Florence, Villa Monna Tessa, Italy). Patients included in the study had 3 to 6 migraines without aura per month that were refractory to common symptomatic and prophylactic agents in the 6 months preceding the study. Patients were treated with IV histamine hydrochloride for 21 days starting with a dosage of 0.5 mg/d and increasing to 4.0 mg/d. To assess the efficacy of the treatment, these patients were matched for age; sex; and frequency, duration, and severity of attacks with untreated migraineurs. Clinical benefit was defined as ⩽ 1 migraine of mild intensity per month. Tolerability was assessed during the hospitalization period, and patients were instructed to contact the Headache Center to report any adverse effects after hospital discharge. Results: The histamine group comprised 47 patients (40 women, 7 men; mean [SD] age, 42.0 [8.6] years) and the control group comprised 23 patients (20 women, 3 men; mean [SD] age, 38.8 [8.4] years). The histamine-treated patients showed a clinical benefit lasting for a mean of 10.4 (4.2) months, while the patients in the control group showed a clinical benefit of 3.8 (1.9) months. The difference in the duration of the clinical benefit between the 2 groups was 6.6 months (95% CI, 5.15-7.99). Adverse effects consisted of flushing, heat sensation during infusion, headache, and

  15. Intravenous magnetic nanoparticle cancer hyperthermia

    PubMed Central

    Huang, Hui S; Hainfeld, James F

    2013-01-01

    Magnetic nanoparticles heated by an alternating magnetic field could be used to treat cancers, either alone or in combination with radiotherapy or chemotherapy. However, direct intratumoral injections suffer from tumor incongruence and invasiveness, typically leaving undertreated regions, which lead to cancer regrowth. Intravenous injection more faithfully loads tumors, but, so far, it has been difficult achieving the necessary concentration in tumors before systemic toxicity occurs. Here, we describe use of a magnetic nanoparticle that, with a well-tolerated intravenous dose, achieved a tumor concentration of 1.9 mg Fe/g tumor in a subcutaneous squamous cell carcinoma mouse model, with a tumor to non-tumor ratio > 16. With an applied field of 38 kA/m at 980 kHz, tumors could be heated to 60°C in 2 minutes, durably ablating them with millimeter (mm) precision, leaving surrounding tissue intact. PMID:23901270

  16. Intravenous bisphosphonates for postmenopausal osteoporosis

    PubMed Central

    Mottaghi, Peyman

    2010-01-01

    Numerous clinical studies have shown bisphoshonates (BPs) to be useful and cost-effective options for the fractures prevention and postmenopausal bone loss. The use of oral bisphoshonates is an established option for managment of osteoporosis in postmenopausal women, but many of them complaint from gastrointestinal side effect or frequently dosed oral regimens. To improve upon the suboptimal therapeutic compliance in postmenopausal women, newer, longer-acting intravenous formulations of BPs has been approved for intermittent administration in postmenopausal women. These preparations would become an option for patients who can not tolerate oral BPs or it was ineffective in increasing their bone density. This article proposed to review effectiveness and tolerability of intravenous BPs in postmenopausal women with osteoporosis. PMID:21526078

  17. Dose-response studies on tolerance to multiple doses of secobarbital and methaqualone in a polydrug abuse population.

    PubMed

    Faulkner, T P; Hayden, J H; Mehta, C M; Olson, D A; Comstock, E G

    1979-01-01

    Patients from a polydrug abuse treatment program were titrated with either secobarbital or methaqualone, their primary drug of abuse, to a state of mild intoxication, consisting of lateral and vertical nystagmus, ataxia, slurred speech, and drownsiness. The mean dose required to produce each sign was compared to that determined in a similarly treated control group. Tolerance to secobarbital was more easily demonstrated than tolerance to methaqualone, and nystagmus was the least sensitive indicator of patient tolerance. The individual signs were also cumulated into a graded rating scale of central nervous system depression which would be related to the dose administered. Tolerence was easily demonstrated at the higher stages of toxicity for secobarbital in the overall patient population, but tolerance to methaqualone was only unequivocal in the subjects indicating a relatively high frequency of abuse. Tolerance to methaqualone occurred at the lower stages of toxicity, suggesting that there is a difference between tolerance to secobarbital and tolerance to methaqualone. There was no indication that patients who also abuse alcohol are more tolerant than their patient counterparts. The patients who also had a history of amphetamine abuse, however, were less tolerant than the nonusers of these drugs.

  18. Phase I study of high-dose continuous intravenous infusion of VP-16 in combination with high-dose melphalan followed by autologous bone marrow transplantation in children with stage IV neuroblastoma.

    PubMed

    Valteau-Couanet, D; Vassal, G; Pondarré, C; Bonnay, M; Benhamou, E; Couanet, D; Plantaz, D; Hartmann, O

    1996-04-01

    The purpose of the study was to determine the maximum tolerated dose of continuous infusion of high-dose VP-16 in combination with high-dose melphalan (HDM) for conditioning before autologous bone marrow transplantation (ABMT). Thirteen children (median age 27 months) with stage IV neuroblastoma were treated with high-dose VP-16 and HDM followed by ABMT as consolidation treatment. All had previously received conventional chemotherapy with a mean number of six drugs. Surgery of the primary tumor had been performed in 12/13. We performed a dose-escalating study of VP-16 from 1800 mg/m2/72 h with 300 mg/m2/72 h dose increments according to toxicity. VP-16 was administered as a 72-h i.v. infusion. Melphalan (140 mg/m2/day) was administered once as an i.v. push. VP-16 pharmacokinetics were analyzed in 12 patients. Five children received 1800 mg/m2/72 h of VP-16, five received 2100 mg/m2/72 h and three, 2400 mg/m2/72 h. The mean duration of granulocytopenia (< 0.5 x 10(9)/1) was 24 days and thrombocytopenia (< 50 x 10(9)/1) was 36 days. No major infectious complications occurred. Gastrointestinal (GI) toxicity was the dose-limiting toxicity. Five severe manifestations of GI toxicity in three patients led us to consider 2400 mg/m2/72 h as the MTD. The mean VP-16 clearance rate was 17.3 ml/min/m2 with continuous infusion. A mean steady-state plasma concentration of 24.2 micrograms/ml (s.d. = 2) and 28.3 micrograms/ml (s.d. = 1.9) was achieved at the 1800 mg/ml and 2100 mg/m2 dose levels, respectively, GI toxicity is dose limiting when VP-16 at 2400 mg/m2/72 h, is associated with HDM. When given as a continuous i.v. infusion, at 2100 mg/m2/72 h, VP-16 associated with HDM is well tolerated before ABMT in young heavily pre-treated children.

  19. Whole Brain Irradiation With Hippocampal Sparing and Dose Escalation on Multiple Brain Metastases: A Planning Study on Treatment Concepts

    SciTech Connect

    Prokic, Vesna; Wiedenmann, Nicole; Fels, Franziska; Schmucker, Marianne; Nieder, Carsten; Grosu, Anca-Ligia

    2013-01-01

    Purpose: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). Methods and Materials: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. Results: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55 {+-} 0.62 Gy and 6.29 {+-} 0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8 {+-} 1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2 {+-} 0.7 Gy and 32.7 {+-} 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23 {+-} 1.42 Gy in SC. Conclusions: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.

  20. 21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Guidelines on the design of a multiple-dose in vivo bioavailability study. 320.27 Section 320.27 Food and Drugs FOOD AND DRUG ADMINISTRATION... subjects in the fasting or nonfasting state, depending upon the conditions reflected in the...

  1. 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 vivo bioavailability study. 320.27 Section 320.27 Food and Drugs FOOD AND DRUG ADMINISTRATION... subjects in the fasting or nonfasting state, depending upon the conditions reflected in the...

  2. 21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Guidelines on the design of a multiple-dose in vivo bioavailability study. 320.27 Section 320.27 Food and Drugs FOOD AND DRUG ADMINISTRATION... subjects in the fasting or nonfasting state, depending upon the conditions reflected in the...

  3. 21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Guidelines on the design of a multiple-dose in vivo bioavailability study. 320.27 Section 320.27 Food and Drugs FOOD AND DRUG ADMINISTRATION... subjects in the fasting or nonfasting state, depending upon the conditions reflected in the...

  4. Treatment of advanced head and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal treatment approach.

    PubMed

    Nissenbaum, M; Browde, S; Bezwoda, W R; de Moor, N G; Derman, D P

    1984-01-01

    Fifty-eight patients with advanced head and neck cancer were entered into a randomised trial comparing chemotherapy (DDP + bleomycin) alone, multiple daily fractionated radiation therapy, and multimodality therapy consisting of chemotherapy plus multiple fractionated radiation therapy. Multimodal therapy gave a significantly higher response rate (69%) than either single-treatment modality. The use of a multiple daily dose fractionation allowed radiation therapy to be completed over 10 treatment days, and the addition of chemotherapy to the radiation treatment did not significantly increase toxicity. Patients receiving multimodal therapy also survived significantly longer (median 50 weeks) than those receiving single-modality therapy (median 24 weeks).

  5. Multiple myeloma among atomic bomb survivors in Hiroshima and Nagasaki, 1950-76: relationship to radiation dose absorbed by marrow

    SciTech Connect

    Ichimaru, M.; Ishimaru, T.; Mikami, M.; Matsunaga, M.

    1982-08-01

    The relationship between atomic bomb exposure and the incidence of multiple myeloma has been examined in a fixed cohort of atomic bomb survivors and controls in the life-span study sample for Hiroshima and Nagasaki. From October 1950 to December 1976, 29 cases of multiple myeloma were confirmed in this sample. Our analysis shows that the standardized relative risk (RR) adjusted for city, sex, and age at the time of bombings (ATB) increased with marrow-absorbed radiation dose. The increased RR does not appear to differ between cities or sexes and is demonstrable only for those survivors whose age ATB was between 20 and 59 years. The estimated risk in these individuals is approximately 0.48 cases/million person-years/rad for bone marrow total dose. This excess risk did not become apparent in individuals receiving 50 rad or more in marrow total dose until 20 years or more after exposure.

  6. Multiple myeloma among atomic bomb survivors in Hiroshima and Nagasaki, 1950-76: relationship to radiation dose absorbed by marrow

    SciTech Connect

    Ichimaru, M.; Ishimaru, T.; Mikami, M.; Matsunaga, M.

    1982-08-01

    The relationship between atomic bomb exposure and the incidence of multiple myeloma has been examined in a fixed cohort of atomic bomb survivors and controls in the life-span study sample for Hiroshima and Nagasaki. From October 1950 to December 1976, 29 cases of multiple myeloma were confirmed in this sample. Our analysis shows that the standardized relative risk (RR) adjusted for city, sex, and age at the time of bombings (ATB) increased with marrow-absorbed radiation dose. The increased RR does not appear to differ between cities or sexes and is demonstrable only for those survivors whose age ATB was between 20 and 59 years. The estimaged risk in these individuals is approximately 0.48 cases/million person-years/rad for bone marrow total dose. This excess risk did not become apparent in individuals receiving 50 rad or more in marrow total dose until 20 years or more after exposure.

  7. A Pharmacokinetic and Dosing Study of Intravenous Insulin-Like Growth Factor-I and IGF-Binding Protein-3 Complex to Preterm Infants

    PubMed Central

    Löfqvist, Chatarina; Niklasson, Aimon; Engström, Eva; Friberg, Lena E.; Camacho-hübner, Cecilia; Ley, David; Borg, Jan; Smith, Lois E. H.; Hellström, Ann

    2015-01-01

    In preterm infants, low levels of Insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of i.v. administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 d chronological age, an i.v. 3 h infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiologic safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 µg/kg. The study was conducted at Queen Silvia Children’s Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3 F) with mean (range) post menstrual age 27 wk (26–29) and birth weight 1022 g (810 –1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12–28) and 771 (651–1047) ng/mL, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25–59) and 838 (754 –1182) ng/mL, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59 –1.42) and 0.87 (0.85– 0.94) hours, respectively. Blood glucose, insulin, sodium, potassium, and physiologic safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated. PMID:19190540

  8. Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers.

    PubMed

    Pope, Laura E; Khalil, M H; Berg, James E; Stiles, Mark; Yakatan, Gerald J; Sellers, Edward M

    2004-10-01

    Dextromethorphan (DM) pharmacological properties predict that the widely used cough suppressant could be used to treat several neuronal disorders, but it is rapidly metabolized after oral dosing. To find out whether quinidine (Q), a CYP2D6 inhibitor, could elevate and prolong DM plasma profiles, 2 multiple-dose studies identified the lowest oral dose of Q that could be used in a fixed combination with 3 doses of DM. A multiple-dose study in healthy subjects with an extensive or a poor enzyme metabolizer phenotype evaluated the safety and pharmacokinetic profile of a selected fixed-dose combination (AVP-923). Study 1 randomized 46 healthy subjects, who were extensive CYP2D6 metabolizers, to receive 0, 2.5, 10, 25, 50, or 75 mg Q twice daily in combination with 30 mg DM for 7 days. Plasma and urine samples were collected after the first and last doses for the assay of DM, dextrorphan (DX), and Q. Study 2 randomized 65 healthy extensive CYP2D6 metabolizers to 8 groups given twice-daily 45- or 60-mg DM doses combined with 0, 30, 45, or 60 mg Q for 7 days. The effects of increasing Q were not different with doses greater than 25 mg, whereas lower doses showed a dose-related increase in plasma DM concentrations. Urinary ratios of DM/DX showed a Q dose- and time-related increase in the number of subjects converted to the poor metabolizer phenotype that reached 100% on day 3 of dosing with 25 mg Q. Results from both studies indicated that 25 to 30 mg Q is adequate to maximally suppress O-demethylation of DM. Study 3 evaluated 7 extensive metabolizers and 2 poor metabolizers given an oral capsule every 12 hours containing 30 mg Q combined with 30 mg DM. DM plasma AUC values increased in both groups of subjects during the 8-day study. The mean urinary metabolic ratio (DM/DX) increased at least 27-fold in extensive metabolizers by day 8. There was no effect of Q on urinary metabolic ratios in poor metabolizers. Safety evaluations, including electrocardiograms, indicated that

  9. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis

    PubMed Central

    Nash, Richard A.; Bowen, James D.; McSweeney, Peter A.; Pavletic, Steven Z.; Maravilla, Kenneth R.; Park, Man-soo; Storek, Jan; Sullivan, Keith M.; Al-Omaishi, Jinan; Corboy, John R.; DiPersio, John; Georges, George E.; Gooley, Theodore A.; Holmberg, Leona A.; LeMaistre, C. Fred; Ryan, Kate; Openshaw, Harry; Sunderhaus, Julie; Storb, Rainer; Zunt, Joseph; Kraft, George H.

    2010-01-01

    There were 26 patients enrolled in a pilot study of high-dose immunosuppressive therapy (HDIT) for severe multiple sclerosis (MS). Median baseline expanded disability status scale (EDSS) was 7.0 (range, 5.0–8.0). HDIT consisted of total body irradiation, cyclophosphamide, and antithymocyte globulin (ATG) and was followed by transplantation of autologous, granulocyte colony-stimulating factor (G-CSF)-mobilized CD34-selected stem cells. Regimen-related toxicities were mild. Because of bladder dysfunction, there were 8 infectious events of the lower urinary tract. One patient died from Epstein-Barr virus (ESV)-related posttransplantation lymphoproliferative disorder (PTLD) associated with a change from horse-derived to rabbit-derived ATG in the HDIT regimen. An engraftment syndrome characterized by noninfectious fever with or without rash developed in 13 of the first 18 patients and was associated in some cases with transient worsening of neurologic symptoms. There were 2 significant adverse neurologic events that occurred, including a flare of MS during mobilization and an episode of irreversible neurologic deterioration after HDIT associated with fever. With a median follow-up of 24 (range, 3–36) months, the Kaplan-Meier estimate of progression (≥ 1.0 point EDSS) at 3 years was 27%. Of 12 patients who had oligoclonal bands in the cerebrospinal fluid at baseline, 9 had persistence after HDIT. After HDIT, 4 patients developed new enhancing lesions on magnetic resonance imaging of the brain. The estimate of survival at 3 years was 91%. Important clinical issues in the use of HDIT and stem cell transplantation for MS were identified; however, modifications of the initial approaches appear to reduce treatment risks. This was a heterogeneous high-risk group, and a phase 3 study is planned to fully assess efficacy. PMID:12763935

  10. A novel CRTH2 antagonist: Single- and multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-453859 in healthy subjects.

    PubMed

    Géhin, Martine; Strasser, Daniel S; Zisowsky, Jochen; Farine, Hervé; Groenen, Peter M A; Dingemanse, Jasper; Sidharta, Patricia N

    2015-07-01

    The chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 , a key mediator in inflammatory disorders. In this randomized, double-blind, placebo-controlled study we investigated the single- and multiple-dose tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) up to a dose of 800 mg once a day of ACT-453859, a potent and selective CRTH2 antagonist. ACT-453859 was moderately rapidly absorbed and followed a biphasic elimination pattern, with an elimination half-life between 11 and 20 hours. Steady-state conditions were reached after 1 day, and ACT-453859 did not accumulate. Urinary excretion of unchanged ACT-453859 did not exceed 1.4% of the administered dose. Administration of ACT-453859 resulted in a dose-dependent blockadeof CRTH2 on the surface of eosinophils. The maximum PD effect of ACT-453859 was reached about 2.0 hours after dosing, which corresponded to the highest concentration at which PD were assessed. At steady state, 100 and 800 mg ACT-453859 once a day resulted in blockade of CRTH2 over 24 hours. In this entry-into-humans study, ACT-453859 showed good tolerability at all doses and a PK and PD profile compatible with once-daily dosing.

  11. Comparison of doses received by the hippocampus in patients treated with single isocenter- vs multiple isocenter-based stereotactic radiation therapy to the brain for multiple brain metastases.

    PubMed

    Algan, Ozer; Giem, Jared; Young, Julie; Ali, Imad; Ahmad, Salahuddin; Hossain, Sabbir

    2015-01-01

    To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiation therapy using a single isocenter (SI)-based or multiple isocenter (MI)-based treatment planning in patients with less than 4 brain metastases. In total, 10 patients with magnetic resonance imaging (MRI) demonstrating 2-3 brain metastases were included in this retrospective study, and 2 sets of stereotactic intensity-modulated radiation therapy (IMRT) treatment plans (SI vs MI) were generated. The hippocampus was contoured on SPGR sequences, and doses received by the hippocampus and the brain were calculated and compared between the 2 treatment techniques. A total of 23 lesions in 10 patients were evaluated. The median tumor volume, the right hippocampus volume, and the left hippocampus volume were 3.15, 3.24, and 2.63mL, respectively. In comparing the 2 treatment plans, there was no difference in the planning target volume (PTV) coverage except in the tail for the dose-volume histogram (DVH) curve. The only statistically significant dosimetric parameter was the V100. All of the other measured dosimetric parameters including the V95, V99, and D100 were not significantly different between the 2 treatment planning techniques. None of the dosimetric parameters evaluated for the hippocampus revealed any statistically significant difference between the MI and SI plans. The total brain doses were slightly higher in the SI plans, especially in the lower dose region, although this difference was not statistically different. The use of SI-based treatment plan resulted in a 35% reduction in beam-on time. The use of SI treatments for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain when compared with MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.

  12. Fingolimod first-dose effects in patients with relapsing multiple sclerosis concomitantly receiving selective serotonin-reuptake inhibitors.

    PubMed

    Bermel, R A; Hashmonay, R; Meng, X; Randhawa, S; von Rosenstiel, P; Sfikas, N; Kantor, D

    2015-05-01

    Selective serotonin-reuptake inhibitors (SSRIs), commonly administered for depression and anxiety in patients with multiple sclerosis, are associated with QT interval prolongation. Fingolimod (FTY720; Gilenya(®), Novartis Pharma AG) is a first-in-class sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis. Fingolimod first-dose administration is associated with a transient, generally asymptomatic, slowing of heart rate, which may also prolong QT interval. This posthoc analysis compared cardiac outcomes in over 3300 patients with relapsing multiple sclerosis who were or were not receiving SSRIs during fingolimod treatment initiation, including a subset of patients receiving citalopram or escitalopram. Vital signs were recorded hourly for 6h, and electrocardiograms were obtained pre-dose and 6 h post-dose. Changes in mean hourly heart rate from baseline (pre-dose) to 6 h post-dose were similar among patients not receiving SSRIs (fingolimod 0.5 mg, -7.5 bpm; placebo, 0.0 bpm) and those receiving SSRIs (fingolimod 0.5 mg, -6.6 bpm; placebo, 0.3 bpm). In patients treated with fingolimod 0.5 mg, the mean change in corrected QT interval from baseline to 6 h after treatment initiation was under 10 ms, and few patients had absolute corrected QT intervals of over 450 ms (men) or 470 ms (women), calculated according to Bazett׳s or Fridericia׳s correction methods, irrespective of whether or not they were receiving an SSRI; similar findings were reported in the placebo group. Co-administration of SSRIs and fingolimod was not associated with an increased incidence of any electrocardiogram findings compared with fingolimod therapy alone, and the majority of patients receiving fingolimod (83-86%) were discharged from first-dose monitoring at 6 h irrespective of whether they were also receiving SSRIs. These analyses provide reassurance that concomitant use of SSRIs does not affect cardiac outcomes associated with fingolimod treatment

  13. Distribution of R- and S-methadone into human milk during multiple, medium to high oral dosing

    PubMed Central

    Begg, Evan J; Malpas, Timothy J; Hackett, L Peter; Ilett, Kenneth F

    2001-01-01

    Aims To measure the interdose milk to plasma ratio (M/P) of R- and S-methadone during multiple dosing in lactating mothers taking medium to high doses of methadone (> 40 mg daily), and to assess likely infant exposure. Methods Eight mother/child pairs were studied, initially during their postpartum hospital stay (immature milk), and where possible again after 15 days (mature milk). The women were on a methadone maintenance programme with daily doses of ≥40 mg day−1. Venous blood was collected at 0, 1, 2, 4, 6, 8, 12, and 24 h and milk was collected from both breasts at 0–4, 4–8, 8–12, 12–16, 16–20, and 20–24 h after dose. R- and S-methadone were quantified by h.p.l.c. The areas under the plasma and milk concentration-time curves (AUC) were estimated and M/PAUC was calculated. The relative infant dose of both enantiomers was estimated as the product of drug concentration in milk and an average daily milk intake of 0.15 l kg−1. Results For immature milk (n = 8) the M/PAUC for R-methadone was 0.68 (95% CI 0.48, 0.89) and for S-methadone 0.38 (0.26, 0.50). For mature milk (n = 2) the M/PAUCs for R-methadone were 0.39 and 0.54 and for S-methadone 0.24 and 0.30, respectively. The estimated doses of R- and S-methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R- plus S-methadone together was 2.8% (1.7, 3.9%). Conclusions Breastfeeding during medium to high dose methadone appears to be ‘safe’ according to conventional criteria because the dosage is < 10%. However because the absolute dose received by the infant is dependent on the maternal dose rate, the risk-benefit ratio should be considered for each individual case. The doses of methadone received via milk are unlikely to be sufficient to prevent the neonatal abstinence syndrome. PMID:11736879

  14. Organ dose measurements from multiple-detector computed tomography using a commercial dosimetry system and tomographic, physical phantoms

    NASA Astrophysics Data System (ADS)

    Lavoie, Lindsey K.

    The technology of computed tomography (CT) imaging has soared over the last decade with the use of multi-detector CT (MDCT) scanners that are capable of performing studies in a matter of seconds. While the diagnostic information obtained from MDCT imaging is extremely valuable, it is important to ensure that the radiation doses resulting from these studies are at acceptably safe levels. This research project focused on the measurement of organ doses resulting from modern MDCT scanners. A commercially-available dosimetry system was used to measure organ doses. Small dosimeters made of optically-stimulated luminescent (OSL) material were analyzed with a portable OSL reader. Detailed verification of this system was performed. Characteristics studied include energy, scatter, and angular responses; dose linearity, ability to erase the exposed dose and ability to reuse dosimeters multiple times. The results of this verification process were positive. While small correction factors needed to be applied to the dose reported by the OSL reader, these factors were small and expected. Physical, tomographic pediatric and adult phantoms were used to measure organ doses. These phantoms were developed from CT images and are composed of tissue-equivalent materials. Because the adult phantom is comprised of numerous segments, dosimeters were placed in the phantom at several organ locations, and doses to select organs were measured using three clinical protocols: pediatric craniosynostosis, adult brain perfusion and adult cardiac CT angiography (CTA). A wide-beam, 320-slice, volumetric CT scanner and a 64-slice, MDCT scanner were used for organ dose measurements. Doses ranged from 1 to 26 mGy for the pediatric protocol, 1 to 1241 mGy for the brain perfusion protocol, and 2-100 mGy for the cardiac protocol. In most cases, the doses measured on the 64-slice scanner were higher than those on the 320-slice scanner. A methodology to measure organ doses with OSL dosimeters received from CT

  15. Multiple-dose lorazepam kinetics: shuttling of lorazepam glucuronide between the circulation and the gut during day- and night-time dosing intervals in response to feeding.

    PubMed

    Chaudhary, A; Lane, R A; Woo, D; Herman, R J

    1993-12-01

    Lorazepam kinetics were examined in seven healthy males age 18 to 30 years after single- and multiple-dose lorazepam administration and in the presence and absence of neomycin and cholestyramine to block the enterohepatic circulation of the drug. Methods used a simultaneous i.v./p.o. dosing regimen with provision to measure lorazepam clearance during day- and night-time dosing intervals. The day-time steady-state clearance of free lorazepam measured 7.55 +/- 1.95 ml/min/kg (mean +/- S.D.) and was identical to that observed after single-dose administration (7.68 +/- 3.19 ml/min/kg). Neomycin and cholestyramine increased lorazepam clearances 5 to 45% (P < or = .05) as would be expected for interruption of an enterohepatic circulation and in keeping with previous observations under nonsteady-state conditions. Lorazepam clearances were the same during the day as during the night, except in the presence of neomycin and cholestyramine, where night-time clearances were significantly greater (10.16 +/- 3.52 vs. 8.77 +/- 2.43 ml/min/kg, P < or = .05). Urinary recoveries of lorazepam glucuronide, on the other hand, were greater during the day than during the night (114 +/- 11 vs. 77 +/- 15%, P < or = .05) and in all cases were greater than 100% of the administered dose for that interval. Thus, there is a diurnal variation in lorazepam elimination consistent with a fasting-induced increase in hepatic glucuronidation during the night. This, combined with the relative inactivity of the gut during this period, serves to trap the glucuronide and delay its transfer back to the systemic circulation and urine.

  16. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma

    PubMed Central

    Martin, Tom; Bensinger, William; Alsina, Melissa; Siegel, David S.; Kavalerchik, Edward; Huang, Mei; Orlowski, Robert Z.; Niesvizky, Ruben

    2013-01-01

    We previously reported a phase 1b dose-escalation study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in relapsed or progressive multiple myeloma where the maximum planned dose (MPD) was carfilzomib 20 mg/m2 days 1 and 2 of cycle 1 and 27 mg/m2 days 8, 9, 15, 16, and thereafter; lenalidomide 25 mg days 1 to 21; and dexamethasone 40 mg once weekly on 28-day cycles. Herein, we present results from the phase 2 dose expansion at the MPD, focusing on the 52 patients enrolled in the MPD cohort. Median follow-up was 24.4 months. In the MPD cohort, overall response rate (ORR) was 76.9% with median time to response of 0.95 month (range, 0.5-4.6) and duration of response (DOR) of 22.1 months. Median progression-free survival was 15.4 months. ORR was 69.2% in bortezomib-refractory patients and 69.6% in lenalidomide-refractory patients with median DOR of 22.1 and 10.8 months, respectively. A median of 9.5 (range, 1-45) carfilzomib cycles were started with 7.7% of patients requiring carfilzomib dose reductions and 19.2% discontinuing CRd due to adverse events (AEs). Grade 3/4 AEs included lymphopenia (48.1%), neutropenia (32.7%), thrombocytopenia (19.2%), and anemia (19.2%). CRd at the MPD was well tolerated with robust, rapid, and durable responses. This trial was registered at clinicaltrials.gov as #NCT00603447. PMID:24014245

  17. Voriconazole Disposition After Single and Multiple, Oral Doses in Healthy, Adult Red-tailed Hawks ( Buteo jamaicensis ).

    PubMed

    Gentry, Jordan; Montgerard, Christy; Crandall, Elizabeth; Cruz-Espindola, Crisanta; Boothe, Dawn; Bellah, Jamie

    2014-09-01

    Voriconazole is effective for treatment of aspergillosis, a common disease in captive red-tailed hawks ( Buteo jamaicensis ). To determine the disposition and safety of voriconazole after single and multiple, oral doses, 12 adult red-tailed hawks were studied in 2 phases. In phase 1, each bird received a single dose of voriconazole solution (10 mg/kg) by gavage. Blood samples were collected at 0, 0.5, 1, 3, 6, 9, 12, 16, 24, and 36 hours after treatment. In phase 2, each of 8 birds received voriconazole oral solution at 10 mg/kg PO q12h for 14 days. Plasma samples were collected on days 0, 5, and 10 and after the final dose and were processed as in phase 1. Plasma samples were submitted for analysis of voriconazole levels by high-performance liquid chromatography and ultraviolet spectrophotometry and for measurement of selected plasma biochemical parameters. After single dosing, voriconazole concentrations reached a (mean ± SD) peak (Cmax) of 4.7 ± 1.3 μg/mL at 2.0 ± 1.2 hours. The disappearance half-life (t1/2) was 2.8 ± 0.7 hours, and the mean residence time (MRT) was 4.6 ± 0.9 hours. After the last dose at 14 days, the mean Cmax of voriconazole was 4.5 ± 2.7 μg/mL at 2.4 ± 1.1 hours. The t1/2 was 2.1 ± 0.8 hours, and the MRT was 3.5 ± 1.1 hours. Although concentrations of several plasma biochemical parameters were significantly different at study end compared with prestudy concentrations, only plasma creatine kinase activity was outside the reference range. No adverse reactions were observed in any of the birds. After both single and multiple dosing at 10 mg/kg, voriconazole concentrations exceeded the minimum inhibitory concentration to inhibit 90% (MIC90) of Aspergillus species (1 μg/mL) by at least fourfold and remained above the MIC90 for 8.8 ± 1.1 hours after single dosing versus 6.5 ± 1.5 hours after multiple dosing (P = .003). This difference suggests that more frequent dosing (eg, up to q8h) may be necessary to maintain target

  18. Prediction of drug terminal half-life and terminal volume of distribution after intravenous dosing based on drug clearance, steady-state volume of distribution, and physiological parameters of the body.

    PubMed

    Berezhkovskiy, Leonid M

    2013-02-01

    The steady state, V(ss), terminal volume of distribution, V(β), and the terminal half-life, t(1/2), are commonly obtained from the drug plasma concentration-time profile, C(p)(t), following intravenous dosing. Unlike V(ss) that can be calculated based on the physicochemical properties of drugs considering the equilibrium partitioning between plasma and organ tissues, t(1/2) and V(β) cannot be calculated that way because they depend on the rates of drug transfer between blood and tissues. Considering the physiological pharmacokinetic model pertinent to the terminal phase of drug elimination, a novel equation that calculates t(1/2) (and consequently V(β)) was derived. It turns out that V(ss), the total body clearance, Cl, equilibrium blood-plasma concentration ratio, r; and the physiological parameters of the body such as cardiac output, and blood and tissue volumes are sufficient for determination of terminal kinetics. Calculation of t(1/2) by the obtained equation appears to be in good agreement with the experimentally observed vales of this parameter in pharmacokinetic studies in rat, monkey, dog, and human. The equation for the determination of the pre-exponent of the terminal phase of C(p)(t) is also found. The obtained equation allows to predict t(1/2) in human assuming that V(ss) and Cl were either obtained by allometric scaling or, respectively, calculated in silico or based on in vitro drug stability measurements. For compounds that have high clearance, the derived equation may be applied to calculate r just using the routine data on Cl, V(ss), and t(1/2), rather than doing the in vitro assay to measure this parameter.

  19. Influence of Al³⁺ addition on the flocculation and sedimentation of activated sludge: comparison of single and multiple dosing patterns.

    PubMed

    Wen, Yue; Zheng, Wanlin; Yang, Yundi; Cao, Asheng; Zhou, Qi

    2015-05-15

    In this study, the flocculation and sedimentation performance of activated sludge (AS) with single and multiple dosing of trivalent aluminum (Al(3+)) were studied. The AS samples were cultivated in sequencing batch reactors at 22 °C. The dosages of Al(3+) were 0.00, 0.125, 0.5, 1.0, and 1.5 meq/L for single dosing, and 0.1 meq/L for multiple dosing. Under single dosing conditions, as Al(3+) dosage increased, the zeta potential, total interaction energy, and effluent turbidity decreased, whereas the sludge volume index (SVI) increased, indicating that single Al(3+) dosing could enhance sludge flocculation, but deteriorate sedimentation. By comparison, adding an equal amount of Al(3+) through multiple dosing achieved a similar reduction in turbidity, but the zeta potential was higher, while the loosely bound extracellular polymeric substances (LB-EPS) content and SVI remarkably declined. Although the difference in the flocculation performances between the two dosing patterns was not significant, the underlying mechanisms were quite distinct: the interaction energy played a more important role under single dosing conditions, whereas multiple dosing was more effective in reducing the EPS content. Multiple dosing, which allows sufficient time for sludge restructuring and floc aggregation, could simultaneously optimize sludge flocculation and sedimentation.

  20. Disposition of intravenous radioactive acyclovir

    SciTech Connect

    de Miranda, P.; Good, S.S.; Laskin, O.L.; Krasny, H.C.; Connor, J.D.; Lietman, P.S.

    1981-11-01

    The kinetic and metabolic disposition of (8-14C)acyclovir (ACV) was investigated in five subjects with advanced malignancy. The drug was administered by 1-hr intravenous infusion at doses of 0.5 and 2.5 mg/kg. Plasma and blood radioactivity-time, and plasma concentration-time data were defined by a two-compartment open kinetic model. There was nearly equivalent distribution of radioactivity in blood and plasma. The overall mean plasma half-life and total body clearance +/- SD of ACV were 2.1 +/- 0.5 hr and 297 +/- 53 ml/min/1.73 m2. Binding of ACV to plasma proteins was 15.4 +/- 4.4%. Most of the radioactive dose excreted was recovered in the urine (71% to 99%) with less than 2% excretion in the feces and only trace amounts in the expired Co2. Analyses by reverse-phase high-performance liquid chromatography indicated that 9-(carboxymethoxymethyl)guanine was the only significant urinary metabolite of ACV, accounting for 8.5% to 14.1% of the dose. A minor metabolite (less than 0.2% of dose) had the retention time of 8-hydroxy-9-((2-hydroxyethoxy)methyl)guanine. Unchanged urinary ACV ranged from 62% to 91% of the dose. There was no indication of ACV cleavage to guanine. Renal clearance of ACV was approximately three times the corresponding creatinine clearances.

  1. Multiple Introduction and Naturally Occuring Drug Resistance of HCV among HIV-Infected Intravenous Drug Users in Yunnan: An Origin of China’s HIV/HCV Epidemics

    PubMed Central

    Chen, Min; Ma, Yanling; Chen, Huichao; Luo, Hongbing; Dai, Jie; Song, Lijun; Yang, Chaojun; Mei, Jingyuan; Yang, Li; Dong, Lijuan; Jia, Manhong; Lu, Lin

    2015-01-01

    Background The human immunodeficiency virus 1 (HIV-1) epidemic in China historically stemmed from intravenous drug users (IDUs) in Yunnan. Due to a shared transmission route, hepatitis C virus (HCV)/HIV-1 co-infection is common. Here, we investigated HCV genetic characteristics and baseline drug resistance among HIV-infected IDUs in Yunnan. Methods Blood samples of 432 HIV-1/HCV co-infected IDUs were collected from January to June 2014 in six prefectures of Yunnan Province. Partial E1E2 and NS5B genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed. Results Among the 293 specimens successfully genotyped, seven subtypes were identified, including subtypes 3b (37.9%, 111/293), 3a (21.8%, 64/293), 6n (14.0%, 41/293), 1b (10.6%, 31/293), 1a (8.2%, 24/293), 6a (5.1%, 15/293) and 6u (2.4%, 7/293). The distribution of HCV subtypes was mostly related to geographic location. Subtypes 3b, 3a, and 6n were detected in all six prefectures, however, the other four subtypes were detected only in parts of the six prefectures. Phylogeographic analyses indicated that 6n, 1a and 6u originated in the western prefecture (Dehong) and spread eastward and showed genetic relatedness with those detected in Burmese. However, 6a originated in the southeast prefectures (Honghe and Wenshan) bordering Vietnam and was transmitted westward. These subtypes exhibited different evolutionary rates (between 4.35×10−4 and 2.38×10−3 substitutions site-1 year-1) and times of most recent common ancestor (tMRCA, between 1790.3 and 1994.6), suggesting that HCV was multiply introduced into Yunnan. Naturally occurring resistance-associated mutations (C316N, A421V, C445F, I482L, V494A, and V499A) to NS5B polymerase inhibitors were detected in direct-acting antivirals (DAAs)-naïve IDUs. Conclusion This work reveals the temporal-spatial distribution of HCV subtypes and baseline HCV drug resistance among HIV-infected IDUs in Yunnan. The findings enhance our

  2. A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis

    PubMed Central

    2013-01-01

    Introduction The aim of this study was to evaluate the safety, pharmacokinetics, and clinical response of brodalumab (AMG 827), a human, anti-IL-17 receptor A (IL-17RA) monoclonal antibody in subjects with moderate-to-severe rheumatoid arthritis (RA). Methods This phase Ib, randomized, placebo-controlled, double-blind multiple ascending dose study enrolled subjects with moderate to severe RA (≥6/66 swollen and ≥8/68 tender joints). Subjects were randomized 3:1 to receive brodalumab (50 mg, 140 mg, or 210 mg subcutaneously every two weeks for 6 doses per group; or 420 mg or 700 mg intravenously every 4 weeks for two doses per group) or placebo. Endpoints included incidence of adverse events (AEs) and pharmacokinetics. Exploratory endpoints included pharmacodynamics, and improvements in RA clinical metrics. Results Forty subjects were randomized to investigational product; one subject discontinued due to worsening of RA (placebo). The study was not designed to assess efficacy. AEs were reported by 70% (7/10) of placebo subjects and 77% (22/30) of brodalumab subjects. Three serious AEs were reported in two subjects; there were no opportunistic infections. Brodalumab treatment resulted in inhibition of IL-17 receptor signaling and receptor occupancy on circulating leukocytes. No treatment effects were observed with individual measures of RA disease activity. On day 85 (week 13) 37% (11/30) of brodalumab subjects and 22% (2/9) of placebo subjects achieved ACR20; 7% (2/30) brodalumab subjects and 11% (1/9) of placebo subjects achieved ACR50; and 0% (0/30) brodalumab subjects and 0% (0/9) of placebo subjects achieved ACR70. Conclusions Multiple dose administration of brodalumab was tolerated in subjects with active RA. There was no evidence of a clinical response to brodalumab in subjects with RA. Trial registration ClinicalTrials.gov, NCT00771030 PMID:24286136

  3. Peripheral intravenous line - infants

    MedlinePlus

    PIV - infants; Peripheral IV - infants; Peripheral line - infants; Peripheral line - neonatal ... A peripheral intravenous line (PIV) is a small, short, plastic tube, called a catheter. A health care provider puts ...

  4. Intravenous cannula site management.

    PubMed

    Brooks, Nicola

    2016-08-24

    Intravenous cannulation is becoming one of the most common procedures in healthcare as increasing numbers of patients are treated for acute and chronic illnesses. The use of an intravenous cannula is not without risk, so it is essential that the healthcare practitioner can justify why the patient requires cannulation, as well as being able to safely manage and provide ongoing care for patients with the device. This article provides an overview of intravenous cannulation, including the selection of appropriate cannulation sites, identification of the different types and sizes of cannula used, and cannula maintenance. Specific complications related to intravenous cannulation are discussed and guidance is given on how to recognise and avoid potential complications to ensure that practice is safe and effective. PMID:27641593

  5. Cocktail-Dosing Microdialysis Study to Simultaneously Assess Delivery of Multiple Organic-Cationic Drugs to the Brain.

    PubMed

    Kitamura, Atsushi; Okura, Takashi; Higuchi, Kei; Deguchi, Yoshiharu

    2016-02-01

    Brain microdialysis is a powerful tool to estimate brain-to-plasma unbound concentration ratio at the steady state (Kp,uu) of compounds by direct measurement of the unbound concentration in brain interstitial fluid. Here, we evaluated a method to estimate Kp,uu values of multiple organic-cationic drugs simultaneously, by means of brain microdialysis combined with cocktail dosing. Five cationic drugs (diphenhydramine, memantine, oxycodone, pyrilamine, and tramadol), substrates of the proton-coupled organic cation antiport system, were selected as model drugs, and compared under single-dosing and cocktail-dosing conditions. We selected doses of the drugs at which no significant drug-drug interaction occurs at the proton-coupled organic cation antiport system in the blood-brain barrier (BBB). This was confirmed by uptake studies in hCMEC/D3 cells, an in vitro BBB model. The Kp,uu values after cocktail administration were in the range of 1.8-5.2, and were in good agreement with those after single administration. These results suggest that the microdialysis method with cocktail dosing is suitable to estimate Kp,uu values of several cationic drugs simultaneously, if there is no drug-drug interaction during BBB transport. The method could be useful for evaluating drug candidates with high Kp,uu values at an early stage in the development of central nervous system-acting drugs.

  6. Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids

    PubMed Central

    Cunningham, Colin S.; McMahon, Lance R.

    2013-01-01

    Rationale Receptor mechanisms underlying the behavioral effects of clinically used nicotinic acetylcholine receptor agonists have not been fully established. Objective Drug discrimination was used to compare receptor mechanisms underlying the effects of smoking cessation aids. Methods Separate groups of male C57BL/6J mice discriminated 0.56, 1, or 1.78 mg/kg of nicotine base. Nicotine, varenicline, and cytisine were administered alone, in combination with each other, and in combination with mecamylamine and dihydro-β-erythroidine (DHβE). Midazolam and morphine were tested to examine sensitivity to non-nicotinics. Results The ED50 value of nicotine to produce discriminative stimulus effects systematically increased as training dose increased. Varenicline and cytisine did not fully substitute for nicotine and, as compared with nicotine, their ED50 values varied less systematically as a function of nicotine training dose. Morphine did not substitute for nicotine, whereas midazolam substituted for the low and not the higher training doses of nicotine. As training dose increased, the dose of mecamylamine needed to produce a significant rightward shift in the nicotine dose-effect function also increased. DHβE antagonized nicotine in animals discriminating the smallest dose of nicotine. Varenicline did not antagonize the effects of nicotine, whereas cytisine produced a modest though significant antagonism of nicotine. Conclusions These results suggest that differences in pharmacologic mechanism between nicotine, varenicline, and cytisine include not only differences in efficacy at a common subtype of nicotinic acetylcholine receptor, but also differential affinity and/or efficacy at multiple receptor subtypes. PMID:23494230

  7. Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling-defined high-risk multiple myeloma.

    PubMed

    Jethava, Y; Mitchell, A; Zangari, M; Waheed, S; Schinke, C; Thanendrarajan, S; Sawyer, J; Alapat, D; Tian, E; Stein, C; Khan, R; Heuck, C J; Petty, N; Avery, D; Steward, D; Smith, R; Bailey, C; Epstein, J; Yaccoby, S; Hoering, A; Crowley, J; Morgan, G; Barlogie, B; van Rhee, F

    2016-01-01

    Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance. PMID:27471869

  8. Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling-defined high-risk multiple myeloma

    PubMed Central

    Jethava, Y; Mitchell, A; Zangari, M; Waheed, S; Schinke, C; Thanendrarajan, S; Sawyer, J; Alapat, D; Tian, E; Stein, C; Khan, R; Heuck, C J; Petty, N; Avery, D; Steward, D; Smith, R; Bailey, C; Epstein, J; Yaccoby, S; Hoering, A; Crowley, J; Morgan, G; Barlogie, B; van Rhee, F

    2016-01-01

    Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance. PMID:27471869

  9. Pomalidomide Plus Low-Dose Dexamethasone Improves Survival for Patients with Multiple Myeloma

    MedlinePlus

    ... Patients with Multiple Myeloma Summary Results from a randomized phase III trial show that the combination of ... condition of accelerated approval for the drug. That randomized phase III clinical trial ( CC-4047-MM-007 ) ...

  10. Rizatriptan, a novel 5-HT1B/1D agonist for migraine: single- and multiple-dose tolerability and pharmacokinetics in healthy subjects.

    PubMed

    Goldberg, M R; Lee, Y; Vyas, K P; Slaughter, D E; Panebianco, D; Ermlich, S J; Shadle, C R; Brucker, M J; McLoughlin, D A; Olah, T V

    2000-01-01

    Rizatriptan is a novel 5-HT1D/1B agonist for relief of migraine headache. The pharmacokinetics, metabolite profiles, and tolerability of rizatriptan were examined in a multiple-dose study in healthy subjects. Rizatriptan (N = 24) (or placebo, N = 12) was administered as a single 10 mg dose, followed 48 hours later by administration of one 10 mg dose every 2 hours for three doses on 4 consecutive days, corresponding to the maximum daily dose for a migraine attack. The AUC of rizatriptan and its active N-monodesmethyl metabolite after three 10 mg doses was approximately threefold greater than the plasma concentrations following a single 10 mg dose. Metabolite profiles were similar after single and multiple doses. Adverse events during rizatriptan were mild and transient; similar events occurred during placebo, with a somewhat reduced incidence. Diastolic blood pressure tended to increase compared with placebo (approximately 5 mmHg), particularly on the first multiple-dose day (p < .01 vs. placebo). In conclusion, rizatriptan is well tolerated by healthy subjects during multiple-dose administration, with no unexpected accumulation of drug in plasma. PMID:10631625

  11. Addendum to brachytherapy dose-volume histogram commissioning with multiple planning systems.

    PubMed

    Gossman, Michael S

    2016-01-01

    The process for validating dose-volume histogram data in brachytherapy software is presented as a supplement to a previously published article. Included is the DVH accuracy evaluation of the Best NOMOS treatment planning system called "Best TPS VolumePlan." As done previously in other software, a rectangular cuboid was contoured in the treatment planning system. A single radioactive 125I source was positioned coplanar and concentric with one end. Calculations were performed to estimate dose deposition in partial volumes of the cuboid structure, using the brachytherapy dosimetry formalism defined in AAPM Task Group 43. Hand-calculated, dose-volume results were compared to TPS-generated, point-source-approximated dose-volume histogram data to establish acceptance. The required QA for commissioning was satisfied for the DVH as conducted previously for other software, using the criterion that the DVH %VolTPS "actual variance" calculations should differ by no more than 5% at any specific radial distance with respect to %VolTG-43, and the "average variance" DVH %VolTPS calculations should differ by no more than 2% over all radial distances with respect to %VolTG-43. The average disagreement observed between hand calculations and treatment planning system DVH was less than 0.5% on average for this treatment planning system and less than 1.1% maximally for 1 ≤ r ≤ 5 cm. PMID:27167288

  12. Multiple-dose pharmacokinetics and safety of rufloxacin in normal volunteers.

    PubMed Central

    Kisicki, J C; Griess, R S; Ott, C L; Cohen, G M; McCormack, R J; Troetel, W M; Imbimbo, B P

    1992-01-01

    The pharmacokinetics and safety of rufloxacin were evaluated in a double-blind, placebo-controlled study. Two groups of 16 healthy volunteers were given a single oral loading dose of 400 or 600 mg of rufloxacin on day 1 of the study. A single daily maintenance dose of 200 or 300 mg was then administered for a further 9 days; in addition, four subjects in each group received placebos. Rufloxacin levels in plasma and urine were determined by high-performance liquid chromatography. Following the initial dose, the mean (+/- standard error of the mean) peak concentrations of rufloxacin in plasma were 3.35 +/- 0.12 micrograms/ml in the 400-mg group and 4.54 +/- 0.19 micrograms/ml in the 600-mg group. They were generally reached 2 to 3 h after dosing. At the end of treatment, maximum levels in plasma rose to 4.51 +/- 0.15 and 7.20 +/- 0.25 micrograms/ml in the 400-mg and 600-mg groups, with a mean extent of accumulation (fold) of 3.1 +/- 0.1 and 3.3 +/- 0.1. For the 400-mg and 600-mg groups, the elimination half-lives were 40.0 +/- 1.5 and 44.0 +/- 1.3 h, mean residence times were 57.8 +/- 2.2 and 63.7 +/- 1.8 h, apparent volumes of distribution were 132 +/- 4 and 139 +/- 5 liters, and apparent total body clearance were 39 +/- 1 and 44 +/- 4 ml/min, assuming complete bioavailability. Of the total dose administered, the percentages excreted in urine were 49.6 +/- 1.3 and 51.1 +/-2.1%, with renal clearances of 21 +/- 1 and 22 +/- 2 ml/min, for the 400-mg and 600-mg groups. On the whole, the treatments were well tolerated, but some minor adverse events (mainly headache, insomnia, or abdominal discomfort) were reported for 7 subjects on abnormalities were detected in the laboratory examinations or in ocular function tests. This study shows that a 200-mg daily oral dose of rufloxacin preceded by a loading dose of 400 mg are well tolerated and produce steady-state concentrations in plasma above the MIC for most susceptible pathogens. PMID:1329618

  13. Effects of multiple exposures of small doses of Pembina Cardium crude oil and diesel in rats.

    PubMed

    Khan, A A; Coppock, R W; Schuler, M M

    2001-04-01

    In lands used for agricultural purposes, petroleum- or diesel-contaminated wastes and accidental spills of crude oil at some drilling sites pose exposure risks for occupational public, livestock, and wildlife. This study has assessed the effects of an Alberta crude oil, Pembina Cardium crude oil (PCCO), and a commercial diesel fuel #2 (CDF-2) in Sprague-Dawley rats after repeated exposures at small dose levels. Rats were given by gavage on day 1, 3, 5, and 8 specified dosages of either the control vehicle, methylcellulose (MC) (1.25 ml/kg), or PCCO (0.25-1.25 ml/kg), or CDF-2 (1.25 ml/kg). Exposure of rats to these dose levels of the test substances caused no overt symptoms of intoxication. A small but statistically significant increase in liver somatic index was observed in rats exposed to 1.25 ml/kg doses of PCCO and CDF-2; however, kidney somatic index was not significantly affected by these treatments. Blood analyses for hematological and clinical indicators of systemic impairments did not show any significant changes (p > 0.05) between the control and PCCO- or CDF-2-exposed rats. Biochemical assessment of liver and kidney tissues showed that compared to the control group, the PCCO- and CDF-2-exposed groups had a marked and significant increase (p < 0.05) in the hepatic activity of ethoxyresorufin-O-deethylase (EROD, a cytochrome P-450 [CYP] 1A1/A2-linked enzyme). In PCCO-exposed rats, the induction of EROD was dose-dependent. Exposure of rats with PCCO and CDF-2 also caused dose-related increases from the unexposed (control) or MC dosed rats in (1) hepatic activities of aryl hydrocarbon hydroxylase (AHH, a CYP 1A1-linked enzyme), ethoxycoumarin-O-deethylase (ECOD, a CYP 2B/1A-linked enzyme), glutathione transferase (GT), and NADPH-catalyzed microsomal lipid peroxidation; and (ii) ECOD activity in kidneys. The induction of hepatic CYP-linked enzymatic activities by PCCO and CDF-2 could be due to de novo synthesis of selected isoforms, as evidenced by the

  14. A multiple dose powder inhaler (Turbuhaler) compared with a conventional aerosol. An acceptance study in asthmatics.

    PubMed

    Osterman, K; Norborg, A M; Stähl, E

    1989-05-01

    Nineteen patients with asthma completed an open, randomized, crossover study in which 0.5 mg terbutaline sulphate was administered either via Turbuhaler or via the metered dose inhaler (MDI) for 2-week periods. The clinical effect of the two treatment forms was comparable; both provided adequate bronchodilator therapy. Patients also considered Turbuhaler and MDI equally effective, with a small preference for the MDI. Turbuhaler seems to be a valuable alternative to bronchodilator MDI therapy. PMID:2735519

  15. USING DOSE ADDITION TO ESTIMATE CUMULATIVE RISKS FROM EXPOSURES TO MULTIPLE CHEMICALS

    EPA Science Inventory

    The Food Quality Protection Act (FQPA) of 1996 requires the EPA to consider the cumulative risk from exposure to multiple chemicals that have a common mechanism of toxicity. Three methods, hazard index (HI), point-of-departure index (PODI), and toxicity equivalence factor (TEF), ...

  16. Intravenous regional analgesia using bupivacaine.

    PubMed

    Ware, R J

    1975-11-01

    Intravenous regional analgesia using bupivacaine (Marcain) was employed as the anaesthetic technique in a series of 50 cases undergoing a variety of surgical procedures on the upper limb. A short pilot study was undertaken to determine the optimal dosage and concentration of bupivacaine. This was found to be 1-5 mg/kg in 0-2% concentration and proved suitable for all patients regardless of age or physical condition. The use of bupivacaine produced highly successful results in 98% of cases. Onset of analgesia was very rapid (3-5 minutes) and profound muscular relaxation occurred in approximately half of the cases. The degree of muscle relaxation was, however, always adequate for the successful reduction of fractures. Only one patient exhibited an adverse reaction to the dose of bupivacaine used and this was limited to a brief period of slight drowsiness. The results of this series suggest that bupivacaine may provide advantages over previously used local analgesic agents for intravenous regional analgesia and that it may be the agent of choice for this useful technique.

  17. Impact of cytogenetic classification on outcomes following early high-dose therapy in multiple myeloma.

    PubMed

    Kaufman, G P; Gertz, M A; Dispenzieri, A; Lacy, M Q; Buadi, F K; Dingli, D; Hayman, S R; Kapoor, P; Lust, J A; Russell, S; Go, R S; Hwa, Y L; Kyle, R A; Rajkumar, S V; Kumar, S K

    2016-03-01

    Early high-dose therapy (HDT), consisting of high-dose melphalan and autologous stem cell transplantation following doublet or triplet novel agent induction, is a preferred management strategy for transplant-eligible myeloma patients. We set out to examine the utility of the current fluorescence in situ hybridization (FISH)-based risk stratification in a homogenously treated population of transplant-eligible myeloma patients receiving novel induction regimens and early HDT with or without posttransplant maintenance therapy. FISH was available in 409 patients at the time of diagnosis for patients receiving HDT within 12 months of diagnosis. We present comprehensive outcomes for chromosome 14 translocations and 17p abnormalities that both support and refute current risk stratification models. In contrast to its current classification as a marker of 'standard risk' (SR), t(11;14) was associated with inferior overall survival (OS) when compared with the classical SR cohort. The use of novel agent maintenance therapy (bortezomib or lenalidomide) following early HDT ameliorates the negative prognostic value of high-risk (HR) cytogenetic markers. HR patients who received maintenance following early HDT had similar OS compared with the SR cohort at 5 years. PMID:26487275

  18. Safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC by intranasal administration of multiple escalating dose in healthy male subjects.

    PubMed

    Thennati, Rajamannar; Khanna, Aman; Khanna, Mallika; Sonaiya, Tushar; Mehta, Tejas; Mehta, Kalpana; Shahi, Pradeep; Patel, Jigneshkumar

    2014-11-01

    A novel corticosteroid compound (short form of IUPAC name: SFDAC) has been discovered by Sun Pharma Advanced Research Company (SPARC) Ltd. A randomized, observer-blind, active-controlled, parallel-groups, intranasal multiple escalating dose study was conducted in healthy male subjects to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC formulated as an aqueous suspension for intranasal administration. Intranasal sprays of SFDAC, active control fluticasone propionate (FP) and placebo were administered once in a day for 14 days as per randomization. Various clinical evaluations including 24-hour serum cortisol and urinary free cortisol (UFC) profiles were carried out. Blood samples were collected at pre-defined time-points and analyzed using a validated chromatographic method for estimation of SFDAC and its metabolite. The results of the study indicate that multiple dose of SFDAC intranasal spray upto 3,200 µg is safe and tolerated. Clinically significant suppression of hypothalamic pituitary adrenal (HPA) axis was not observed. The plasma concentration of SFDAC was found to be below the lower limit of quantification (LLQ) at most time-points for all subjects. SFDAC M1 metabolite was detected only at picogram level in plasma. The safety and pharmacokinetic characteristics of SFDAC observed in this study support further clinical development of the SFDAC nasal spray.

  19. Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

    PubMed Central

    2009-01-01

    Background The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food. Methods Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates. Results A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1

  20. Lack of effect of multiple doses of vortioxetine on the pharmacokinetics and pharmacodynamics of aspirin and warfarin.

    PubMed

    Chen, Grace; Zhang, Wencan; Serenko, Michael

    2015-06-01

    Vortioxetine is an antidepressant with multimodal activity approved for the treatment of major depressive disorder. Two separate randomized, placebo-controlled trials evaluated the effects of multiple doses of vortioxetine (10 mg/day) on the pharmacokinetics and pharmacodynamics of aspirin and warfarin in healthy volunteers. In the aspirin study, subjects received vortioxetine 10 mg or placebo once daily for 14 days, followed by coadministration with aspirin 150 mg once daily for 6 days, in 2 periods with a crossover design. In the warfarin study, subjects were randomized after reaching target international normalized ratio (INR) values on warfarin to receive vortioxetine 10 mg or matching placebo once daily for 14 days, with all subjects receiving a maintenance dose of warfarin (1-10 mg). Vortioxetine had no effect on the steady-state pharmacokinetic parameters of aspirin or its metabolite salicylic acid, and no statistically significant effect on the inhibition of arachidonic acid-, adenosine-5'-diphosphate-, or collagen-induced platelet aggregation at any time points. Coadministration of vortioxetine did not alter the pharmacokinetics of (R)- and (S)-warfarin enantiomers, or the mean coagulation parameters of warfarin treatment alone. Coadministration of vortioxetine doses in healthy volunteers had no effect on aspirin or warfarin pharmacokinetics or pharmacodynamics. Vortioxetine was well tolerated when coadministered with aspirin or warfarin. PMID:25641606

  1. The Aurora-A inhibitor MLN8237 affects multiple mitotic processes and induces dose-dependent mitotic abnormalities and aneuploidy

    PubMed Central

    Asteriti, Italia Anna; Cesare, Erica Di; Mattia, Fabiola De; Hilsenstein, Volker; Neumann, Beate; Cundari, Enrico; Lavia, Patrizia; Guarguaglini, Giulia

    2014-01-01

    Inhibition of Aurora kinase activity by small molecules is being actively investigated as a potential anti-cancer strategy. A successful therapeutic use of Aurora inhibitors relies on a comprehensive understanding of the effects of inactivating Aurora kinases on cell division, a challenging aim given the pleiotropic roles of those kinases during mitosis. Here we have used the Aurora-A inhibitor MLN8237, currently under phase-I/III clinical trials, in dose-response assays in U2OS human cancer cells synchronously proceeding towards mitosis. By following the behaviour and fate of single Aurora-inhibited cells in mitosis by live microscopy, we show that MLN8237 treatment affects multiple processes that are differentially sensitive to the loss of Aurora-A function. A role of Aurora-A in controlling the orientation of cell division emerges. MLN8237 treatment, even in high doses, fails to induce efficient elimination of dividing cells, or of their progeny, while inducing significant aneuploidy in daughter cells. The results of single-cell analyses show a complex cellular response to MLN8237 and evidence that its effects are strongly dose-dependent: these issues deserve consideration in the light of the design of strategies to kill cancer cells via inhibition of Aurora kinases. PMID:25153724

  2. Evaluation of the effect of multiple doses of rifampin on the pharmacokinetics and safety of ponatinib in healthy subjects.

    PubMed

    Narasimhan, Narayana I; Dorer, David J; Davis, Jeffrey; Turner, Christopher D; Sonnichsen, Daryl

    2015-09-01

    Ponatinib, an oral tyrosine kinase inhibitor with significant activity in heavily pretreated patients with chronic myeloid leukemia, is a CYP3A4 substrate. This open-label, nonrandomized, fixed-order crossover study evaluated the effect of multiple oral doses of rifampin, a strong CYP3A4 inducer, on the pharmacokinetics of ponatinib (45 mg, single dose). Twenty healthy adults received ponatinib on day 1, rifampin 600 mg alone on days 8-13, 15, and 16, and rifampin 600 mg with ponatinib on day 14. Rifampin decreased maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUC0-t ) and from time zero to infinity (AUC0-∞ ) of ponatinib by 42%, 59%, and 63%, respectively, with no effect on time to Cmax . The limits of the 90% confidence intervals of the estimated geometric mean ratios of ponatinib Cmax , AUC0-t , and AUC0-∞ did not fall within the 80-125% margins for equivalence, suggesting a statistically significant interaction. Coadministration of ponatinib with strong CYP3A4 inducers should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure, because the safety of ponatinib dose increases has not been studied in this context. PMID:27137144

  3. Acyclovir kinetics after intravenous infusion.

    PubMed

    de Miranda, P; Whitley, R J; Blum, M R; Keeney, R E; Barton, N; Cocchetto, D M; Good, S; Hemstreet, G P; Kirk, L E; Page, D A; Elion, G B

    1979-12-01

    The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1-hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (+/- SEM), determined by radioimmunoassay, were 6.4 +/- 0.7, 12.1 +/- 2.3, 14.9 +/- 2.7, and 33.7 +/- 7.1 microM. The plasma concentration-time profiles could be described by a biexponential equation. The half-life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose-independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse-phase high-performance liquid chromatography revealed the presence of the metabolite 9-carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.

  4. Multiple impairments of cutaneous nociceptor function induced by cardiotoxic doses of Adriamycin in the rat.

    PubMed

    Boros, Krisztina; Jancsó, Gábor; Dux, Mária; Fekécs, Zoltán; Bencsik, Péter; Oszlács, Orsolya; Katona, Márta; Ferdinandy, Péter; Nógrádi, Antal; Sántha, Péter

    2016-09-01

    Besides their deleterious action on cardiac muscle, anthracycline-type cytostatic agents exert significant neurotoxic effects on primary sensory neurons. Since cardiac sensory nerves confer protective effects on heart muscle and share common traits with cutaneous chemosensitive nerves, this study examined the effects of cardiotoxic doses of adriamycin on the function and morphology of epidermal nerves. Sensory neurogenic vasodilatation, plasma extravasation, and the neural CGRP release evoked by TRPV1 and TRPA1 agonists in vitro were examined by using laser Doppler flowmetry, the Evans blue technique, and ELISA, respectively. Carrageenan-induced hyperalgesia was assessed with the Hargreaves method. Immunohistochemistry was utilized to study cutaneous innervation. Adriamycin treatment resulted in profound reductions in the cutaneous neurogenic sensory vasodilatation and plasma extravasation evoked by the TRPV1 and TRPA1 agonists capsaicin and mustard oil, respectively. The in vitro capsaicin-, but not high potassium-evoked neural release of the major sensory neuropeptide, CGRP, was markedly attenuated after adriamycin treatment. Carrageenan-induced inflammatory hyperalgesia was largely abolished following the administration of adriamycin. Immunohistochemistry revealed a substantial loss of epidermal TRPV1-expressing nociceptive nerves and a marked thinning of the epidermis. These findings indicate impairments in the functions of TRPV1 and TRPA1 receptors expressed on cutaneous chemosensitive nociceptive nerves and the loss of epidermal axons following the administration of cardiotoxic doses of adriamycin. Monitoring of the cutaneous nociceptor function in the course of adriamycin therapy may well be of predictive value for early detection of the deterioration of cardiac nerves which confer protection against the deleterious effects of the drug. PMID:27342418

  5. The Role of Intravenous Immunoglobulin Preparations in the Treatment of Systemic Sclerosis

    PubMed Central

    Baleva, Marta; Nikolov, Krasimir

    2011-01-01

    Scleroderma is progressive autoimmune disease associated with severe disability. The major underlying pathological process in scleroderma is progressive development of fibrous tissue and obliteration of the microvasculature. Currently, there are no medical products for the treatment of scleroderma that provide both sufficient immunosuppression and low-risk side safety profile with negligible side effects. There are a large number of experimental data showing that intravenous immunoglobulin (IVIG) has multiple clinical and morphological effects. On the other hand, some authors report good effect of intravenous immune globulins in patients with scleroderma. The less frequent side effects of IVIG in doses below or equal to 2 g/kg/month divided in 5 consecutive days make IVIG a promising treatment of choice in scleroderma. PMID:22121376

  6. Multiple-dose chronic inhalation toxicity study of size-separated kaolin refractory ceramic fiber in male Fischer 344 rats.

    PubMed

    Mast, R W; McConnell, E E; Hesterberg, T W; Chevalier, J; Kotin, P; Thevenaz, P; Bernstein, D M; Glass, L R; Miiller, W; Anderson, R

    1995-01-01

    Abstract Refractory ceramic fibers (RCF) are man-made vitreous fibers used primarily in industrial high-temperature applications, especially for insulation of furnaces and kilns. Because of their increasing use and potential for human exposure an in an effort to define the dose-response, as a follow up to a maximum tolerated dose [30 mg/m(3)] study in rats (Mast et al., 1995), a multiple dose chronic toxicity/carcinogenicity inhalation study was conducted in Fischer 344 (F344) rats. Four groups of 140 weanling male F344 rats were exposed via noseonly inhalation to either HEPA-filtered air (chamber controls) or 3, 9, or 16 mg/m(3)(approximately 36, 91, and 162 fibers/cm(3)) of kaolin-based "size-selected" RCF fibers (approximately 1 µm in diameter and approximately 20 µm in length) for 6 h/day, 5 days/wk for 24 mo. They were then held unexposed until approximately 20% survival and sacrificed (30 mo). Croups of 3-6 animals were sacrificed at 3, 6, 12, 18, and 24 mo to follow the progression of pulmonary lesions and to determine fiber lung burdens. Additional groups of 3-6 rats were removed from exposure at 3, 6, 12, and 18 mo and were held until sacrificed at 24 mo (recovery groups) for similar determinations. A dose-related increase in fiber lung burden was observed. Lung burdens at 24 mo ranged from 5.6 × 10(4) to 27.8 × 10(4) fibers/mg dry lung tissue. Significant increases in lung weights and lung to body weight ratios were seen in the high-dose group. Treatment-related lesions were restricted to the lungs. To some extent, all doses of RCF resulted in minimal to mild macrophage infiltration, bronchiolization of proximal alveoli, and microgranuloma formation by 12 mo of exposure. Interstitial fibrosis was observed at 12 mo in the 9 and 16 mg/m(3) groups but not in the low-dose group at any time point. A minimal amount of focal pleural fibrosis was first observed at 12 mo in the 9 and 76 mg/m(3) dose groups and progressed to a mild severity in the high-dose

  7. Pharmacokinetics, Pharmacodynamics, Safety, and Clinical Activity of Multiple Doses of RCT-18 in Chinese Patients With Systemic Lupus Erythematosus.

    PubMed

    Zhao, Qian; Chen, Xia; Hou, Yong; Jiang, Ji; Zhong, Wen; Yao, Xuejing; Wang, Wenxiang; Li, Lin; Fang, Jianmin; Zhang, Fengchun; Hu, Pei

    2016-08-01

    RCT-18 is a novel recombinant fusion protein that blocks the activity of a B-lymphocyte stimulator and a proliferation-inducing ligand. This was a randomized, single-blind, and placebo-controlled phase 1 study in 12 patients with systemic lupus erythematosus. Eligible patients were randomized 3:1 to receive multiple subcutaneous doses of RCT-18 for 4 weeks (180 mg, once weekly) or placebo and monitored over an 84-day observation period for pharmacokinetics, pharmacodynamics, immunogenicity, safety, and clinical activity. After multiple-dose RCT-18, the maximal serum concentration (Cmax ) of total and free RCT-18 was reached within 1 to 2 days. Mean elimination half-life for total RCT-18 and free RCT-18 was 11.4 to 26.4 days and 2.4 to 26.5 days, respectively. Slight accumulation was found after multiple subcutaneous administrations. The average accumulation ratios of AUC and Cmax after the fourth administration of RCT-18 were 2.0 and 1.7 for total RCT-18, and 1.8 and 1.6 for free RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to Cmax of 14 to 46 days. Pharmacokinetic characteristics of RCT-18 in SLE patients were similar to those in patients with rheumatoid arthritis. No positive reaction was detected in the immunogenicity assessments. RCT-18 was biologically active, according to serum immunoglobulin and B-cell levels. Treatment-related IgM and IgA reduction was found during this study. CD19(+) , IgD(+) , and CD27(+) B-cell counts were increased after administration and decreased subsequently. SLE patients treated with RCT-18 were more prone to infections, including moderate and severe infections. Lower dosages of RCT-18 should be considered in further clinical development.

  8. Computer simulations to estimate organ doses from clinically validated cardiac, neuro, and pediatric protocols for multiple detector computed tomography scanners

    NASA Astrophysics Data System (ADS)

    Ghita, Monica

    Recent advances in Computed Tomography (CT) technology, particularly that of multiple detector CT (MDCT) scanning, have provided increased utilization and more diverse clinical applications including more advanced vascular and cardiac exams, perfusion imaging, and screening exams. Notwithstanding the benefits to the patient undergoing a CT study, the fundamental concern in radiation protection is the minimization of the radiation exposure delivered as well as the implementation of structures to prevent inappropriate ordering and clinical use of these advanced studies. This research work developed a computational methodology for routine clinical use to assess patient organ doses from MDCT scanners. To support the methodology, a computer code (DXS-Diagnostic X-ray Spectra) was developed to accurately and conveniently generate x-ray spectra in the diagnostic energy range (45-140 keV). The two accepted standard radiation transport calculation methods namely, deterministic and Monte Carlo, have been preliminarily investigated for their capability and readiness to support the proposed goal of the work. Thorough tests demonstrated that the lack of appropriate discrete photon interaction coefficients in the aforementioned diagnostic energy range impedes the applicability of the deterministic approach to routine clinical use; improvements in the multigroup treatment may make it more viable. Thus, the open source Monte Carlo code, MCNP5, was adapted to appropriately model an MDCT scan. For this, a new method, entirely based on routine clinical CT measurements, was developed and validated to generate an "equivalent source and filtration" model that obviates the need of proprietary information for a given CT scanner. Computer simulations employing the Monte Carlo methodology and UF's tomographic human phantoms were performed to assess, compare, and optimize pediatric, cardiac and neuro-imaging protocols for the new 320-slice scanner at Shands/UF based on dose considerations

  9. Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate.

    PubMed

    Coelho, Deise Riba; Miranda, Elaine Silva; Saint'Pierre, Tatiana Dillenburg; Paumgartten, Francisco José Roma

    2014-07-01

    Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 > 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen > bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies.

  10. Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate.

    PubMed

    Coelho, Deise Riba; Miranda, Elaine Silva; Saint'Pierre, Tatiana Dillenburg; Paumgartten, Francisco José Roma

    2014-07-01

    Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 > 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen > bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies. PMID:25075781

  11. Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate

    PubMed Central

    Coelho, Deise Riba; Miranda, Elaine Silva; Saint’Pierre, Tatiana Dillenburg; Paumgartten, Francisco José Roma

    2014-01-01

    Meglumine antimoniate (MA) and sodium stibogluconate are pentavalent antimony (SbV) drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous). Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h) and a slow (t1/2 >> 24 h) elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen >> bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain). The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies. PMID:25075781

  12. An acute dose of gamma-hydroxybutyric acid alters gene expression in multiple mouse brain regions.

    PubMed

    Schnackenberg, B J; Saini, U T; Robinson, B L; Ali, S F; Patterson, T A

    2010-10-13

    Gamma-hydroxybutyric acid (GHB) is normally found in the brain in low concentrations and may function as a neurotransmitter, although the mechanism of action has not been completely elucidated. GHB has been used as a general anesthetic and is currently used to treat narcolepsy and alcoholism. Recreational use of GHB is primarily as a "club drug" and a "date rape drug," due to its amnesic effects. For this study, the hypothesis was that behavioral and neurochemical alterations may parallel gene expression changes in the brain after GHB administration. Adult male C57/B6N mice (n=5/group) were administered a single dose of 500 mg/kg GHB (i.p.) and were sacrificed 1, 2 and 4 h after treatment. Control mice were administered saline. Brains were removed and regionally dissected on ice. Total RNA from the hippocampus, cortex and striatum was extracted, amplified and labeled. Gene expression was evaluated using Agilent whole mouse genome 4x44K oligonucleotide microarrays. Microarray data were analyzed by ArrayTrack and differentially expressed genes (DEGs) were identified using P < or = 0.01 and a fold change > or = 1.7 as the criteria for significance. Principal component analysis (PCA) and Hierarchical Cluster Analysis (HCA) showed that samples from each time point clustered into distinct treatment groups with respect to sacrifice time. Ingenuity pathways analysis (IPA) was used to identify involved pathways. The results show that GHB induces gene expression alterations in hundreds of genes in the hippocampus, cortex and striatum, and the number of affected genes increases throughout a 4-h time course. Many of these DEGs are involved in neurological disease, apoptosis, and oxidative stress.

  13. Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

    NASA Astrophysics Data System (ADS)

    Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

    2014-02-01

    Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

  14. Multiple dosing of ephedra-free dietary supplements: hemodynamic, electrocardiographic, and bacterial contamination effects.

    PubMed

    Foster, L; Allan, M C; Khan, A; Moore, P; Williams, D K; Hubbard, M; Dixon, L; Gurley, B J

    2013-03-01

    Four popular ephedra-free dietary supplements were evaluated for their effects on heart rate (HR), blood pressure (BP), and electrocardiographic (ECG) parameters. Twelve healthy men participated in a study randomized for product sequence, with a 21-day washout period between supplement-administration phases. Throughout the study, Holter monitors were used to assess ECG and HR activity. BP was assessed automatically on multiple occasions. The supplements were ingested three times daily for 3 days. Caffeine content, microbial load, and serum caffeine concentrations were determined. Mean systolic (SBP) and diastolic BP (DBP) readings showed significant increases relative to baseline (10.8 ± 2.5 and 5.3 ± 3.1 mm Hg, respectively; P < 0.05). All supplements significantly increased HR and decreased bradycardia runs; abnormal atrial/ventricular events were frequently noted. Gastrointestinal and sympathomimetic symptoms were also common. Two supplements were heavily contaminated with Bacillus species. In light of these findings, the use of ephedra-free dietary supplements should be discouraged in individuals with hypertension, diabetes, or other cardiovascular diseases. PMID:23361101

  15. Paracetamol serum concentrations in preterm infants treated with paracetamol intravenously: a case series

    PubMed Central

    2012-01-01

    Introduction Until now, studies on paracetamol given intravenously have mainly been performed with the pro-drug propacetamol or with paracetamol in preterm babies above 32 weeks of gestation. Studies in these babies indicate that intravenous paracetamol is tolerated well, however studies on the efficacy of intravenous paracetamol are lacking. There are no pharmacokinetic data on the administration of multiple doses of paracetamol in preterm babies with a gestational age below 32 weeks. Case presentation We present a case series of nine Caucasian preterm babies, six boys and three girls, with a mean gestational age of 28.6 weeks (range 25.9 to 31.6 weeks). Case one, a girl with a gestational age of 25 weeks and six days, presented with necrotizing enterocolitis. In the second case, a female baby with a gestational age of 26 weeks and two days presented with hematoma. In case three, a female baby with a gestation of 26 weeks and one day developed intraventricular hemorrhage. In case four, a male baby with a gestational age of 31 weeks and four days presented with pain after vacuum delivery. Case five, a female baby born after a gestation of 29 weeks and six days presented with hematoma. In case six, a male baby with a gestation of 30 weeks and six days presented with hematoma. In case seven, a male baby, born with a gestational age of 30 weeks and six days, presented with caput succedaneum and hematoma. In case eight, a male baby, born after a gestation of 28 weeks and four days, developed abdominal distention. Case nine, a female baby, born with a gestational age of 27 weeks and three days presented with hematoma. These babies were treated with intravenous paracetamol 15 mg/kg every six hours. Serum concentrations and aspartate transaminase were determined after prolonged administration. Pain scores were assessed using the Premature Infant Pain Profile. Conclusion Paracetamol serum concentrations ranged from 8 to 64 mg/L after eight to 12 doses of intravenous

  16. Characterization of a Mouse Model of Emphysema Induced by Multiple Instillations of Low-Dose Elastase

    PubMed Central

    Oliveira, Milena V.; Abreu, Soraia C.; Padilha, Gisele A.; Rocha, Nazareth N.; Maia, Lígia A.; Takiya, Christina M.; Xisto, Debora G.; Suki, Bela; Silva, Pedro L.; Rocco, Patricia R. M.

    2016-01-01

    Many experimental models have been proposed to study the pathophysiological features of emphysema, as well as to search for new therapeutic approaches for acute or chronically injured lung parenchyma. We aimed to characterize an emphysema model induced by multiple instillations of elastase by tracking changes in inflammation, remodeling, and cardiac function after each instillation. Forty-eight C57BL/6 mice were randomly assigned across two groups. Emphysema (ELA) animals received 1, 2, 3, or 4 intratracheal instillations of pancreatic porcine elastase (PPE, 0.2 IU) with a 1-week interval between them. Controls (C) received saline following the same protocol. Before and after implementation of the protocol, animals underwent echocardiographic analysis. After the first instillation of PPE, the percentage of mononuclear cells in the lung parenchyma increased compared to C (p = 0.0001). The second instillation resulted in hyperinflated alveoli, increased mean linear intercept, and reduced elastic fiber content in lung parenchyma compared to C (p = 0.0197). Following the third instillation, neutrophils and collagen fiber content in alveolar septa and airways increased, whereas static lung elastance was reduced compared to C (p = 0.0094). After the fourth instillation, the percentage of M1 macrophages in lungs; levels of interleukin-1β (IL-1β), keratinocyte-derived chemokine, hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF); and collagen fiber content in the pulmonary vessel wall were increased compared to C (p = 0.0096). At this time point, pulmonary arterial hypertension was apparent, with increased diastolic right ventricular wall thickness. In conclusion, the initial phase of emphysema was characterized by lung inflammation with predominance of mononuclear cells, whereas at the late stage, impairment of pulmonary and cardiovascular functions was observed. This model enables analysis of therapies at different time points during

  17. Schedule Dependence in Cancer Therapy: Intravenous Vitamin C and the Systemic Saturation Hypothesis

    PubMed Central

    Miranda Massari, Jorge R.; Duconge, Jorge; Riordan, Neil H.; Ichim, Thomas

    2013-01-01

    Despite the significant number of in vitro and in vivo studies to assess vitamin C effects on cancer following the application of large doses and its extensive use by alternative medicine practitioners in the USA; the precise schedule for successful cancer therapy is still unknown. Based on interpretation of the available data, we postulate that the relationship between Vitamin C doses and plasma concentration x time, the capability of tissue stores upon distribution, and the saturable mechanism of urinary excretion are all important determinants to understand the physiology of high intravenous vitamin C dose administration and its effect on cancer. Practitioners should pay more attention to the cumulative vitamin C effect instead of the vitamin C concentrations to account for observed discrepancy in antitumor response. We suggest that multiple, intermittent, short-term intravenous infusions of vitamin C over a longer time period will correlate with greater antitumor effects than do single continuous IV doses of the same total exposure. This approach would be expected to minimize saturation of renal reabsorption, providing a continuous “dynamic flow” of vitamin C in the body for optimal systemic exposure and clinical outcomes. This prevents the “systemic saturation” phenomena, which may recycle vitamin C and render it less effective as an anticancer agent. Nonetheless, more pharmacokinetic and pharmacodynamic studies are needed to fully understand this schedule-dependence phenomenon. PMID:24860238

  18. Alcohol drinking and multiple myeloma risk--a systematic review and meta-analysis of the dose-risk relationship.

    PubMed

    Rota, Matteo; Porta, Lorenzo; Pelucchi, Claudio; Negri, Eva; Bagnardi, Vincenzo; Bellocco, Rino; Corrao, Giovanni; Boffetta, Paolo; La Vecchia, Carlo

    2014-03-01

    The role of alcohol intake in the risk for multiple myeloma (MM) is unclear, although some recent findings suggest an inverse relationship. To summarize the information on the topic, we carried out a systematic review and a dose-risk meta-analysis of published data. Through the literature search until August 2013, we identified 18 studies, eight case-control and 10 cohort studies, carried out in a total of 5694 MM patients. We derived pooled meta-analytic estimates using random-effects models, taking into account the correlation between estimates, and we carried out a dose-risk analysis using a class of nonlinear random-effects meta-regression models. The relative risk for alcohol drinkers versus non/occasional drinkers was 0.97 [95% confidence interval (CI), 0.85-1.10] overall, 0.96 (95% CI, 0.74-1.24) among case-control studies, and 1.00 (95% CI, 0.89-1.13) among cohort studies. Compared with nondrinkers, the pooled relative risks were 0.96 (95% CI, 0.81-1.13) for light (i.e. ≤ 1 drink/day) and 0.89 (95% CI, 0.74-1.07) for moderate-to-heavy (i.e. >1 drink/day) alcohol drinkers. The dose-risk analysis revealed a model-based MM risk reduction of about 15% at two to four drinks/day (i.e. 25-50 g of ethanol). The present meta-analysis of published data found no strong association between alcohol drinking and MM risk, although a modest favorable effect emerged for moderate-to-heavy alcohol drinkers.

  19. High-dose therapy improves the bone remodelling compartment canopy coverage and bone formation in multiple myeloma.

    PubMed

    Hinge, Maja; Delaisse, Jean-Marie; Plesner, Torben; Clasen-Linde, Erik; Salomo, Morten; Andersen, Thomas Levin

    2015-11-01

    Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling. Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed that a good response to anti-myeloma treatment increased the extent of formative bone surfaces with canopy, and reduced the extent of eroded surfaces without canopy, reverting the uncoupled bone remodelling, while improving canopy coverage. The association between improved coupling and the canopy coverage supports the notion that canopies are critical for the coupling of bone formation to resorption. Furthermore, this study supports the observation that systemic bone disease in MM can be reversed in MM patients responding to anti-myeloma treatment.

  20. Intravenous Rh immune globulin for treating immune thrombocytopenic purpura.

    PubMed

    Sandler, S G

    2001-11-01

    Intravenous Rh [corrected] immune globulin was licensed by the U. S. Food and Drug administration in 1995 for the treatment of acute and chronic immune thrombocytopenic purpura in children and chronic immune thrombocytopenic purpura in adults. In 1996, the American Society of Hematology published a practice guideline for immune thrombocytopenic purpura, but treatment recommendations of necessity were formulated using only results of early clinical trials with intravenous Rh immune globulin. To date, there are no published results of large-scale clinical trials comparing conventional doses of intravenous immune globulin with the most promising dose range for intravenous Rh immune globulin (50-75 microg/kg). However, clinical experience is accumulating to indicate that intravenous Rh immune globulin is as effective, probably safer, and easier to administer than intravenous immune globulin. Acute intravascular hemolysis after infusions of intravenous Rh immune globulin for immune thrombocytopenic purpura has been reported with an estimated incidence of 1 in 1,115 patients. The risk factors for this adverse event have not been defined.

  1. Intravenous iron therapy: how far have we come?

    PubMed Central

    Cançado, Rodolfo Delfini; Muñoz, Manuel

    2011-01-01

    Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia (IDA) because of its effectiveness and low cost. But unfortunately in many iron deficient conditions, oral iron is a less than the ideal treatment mainly because of adverse events related to the gastrointestinal tract as well as the long course required to treat anemia and replenish body iron stores. The first iron product for intravenous use was high-molecular-weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to prescribe intravenous iron in the treatment of iron deficiency anemia for many years. In 1999 and 2001, two new intravenous iron preparations (ferric gluconate and iron sucrose) were introduced into the market as safer alternatives to iron dextran. Over the last five years, three new intravenous iron dextran-free preparations have been developed and have better safety profiles than the more traditional intravenous compounds, as none require test doses and all these products are promising in respect to a more rapid replacement of body iron stores (15-60 minutes/infusion) as they can be given at higher doses (from 500 mg to more than 1000 mg/infusion). The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, safety profile and toxicity of intravenous iron for the treatment of iron deficiency anemia. PMID:23049364

  2. Whole-body CT-based imaging algorithm for multiple trauma patients: radiation dose and time to diagnosis

    PubMed Central

    Gordic, S; Hodel, S; Simmen, H-P; Brueesch, M; Frauenfelder, T; Wanner, G; Sprengel, K

    2015-01-01

    Objective: To determine the number of imaging examinations, radiation dose and the time to complete trauma-related imaging in multiple trauma patients before and after introduction of whole-body CT (WBCT) into early trauma care. Methods: 120 consecutive patients before and 120 patients after introduction of WBCT into the trauma algorithm of the University Hospital Zurich were compared regarding the number and type of CT, radiography, focused assessment with sonography for trauma (FAST), additional CT examinations (defined as CT of the same body regions after radiography and/or FAST) and the time to complete trauma-related imaging. Results: In the WBCT cohort, significantly more patients underwent CT of the head, neck, chest and abdomen (p < 0.001) than in the non-WBCT cohort, whereas the number of radiographic examinations of the cervical spine, chest and pelvis and of FAST examinations were significantly lower (p < 0.001). There were no significant differences between cohorts regarding the number of radiographic examinations of the upper (p = 0.56) and lower extremities (p = 0.30). We found significantly higher effective doses in the WBCT (29.5 mSv) than in the non-WBCT cohort (15.9 mSv; p < 0.001), but fewer additional CT examinations for completing the work-up were needed in the WBCT cohort (p < 0.001). The time to complete trauma-related imaging was significantly shorter in the WBCT (12 min) than in the non-WBCT cohort (75 min; p < 0.001). Conclusion: Including WBCT in the initial work-up of trauma patients results in higher radiation doses, but fewer additional CT examinations are needed, and the time for completing trauma-related imaging is shorter. Advances in knowledge: WBCT in trauma patients is associated with a high radiation dose of 29.5 mSv. PMID:25594105

  3. The efficacy and safety of multiple doses of vortioxetine for generalized anxiety disorder: a meta-analysis

    PubMed Central

    Fu, Jie; Peng, Lilei; Li, Xiaogang

    2016-01-01

    Objective Vortioxetine is a novel antidepressant approved for the treatment of major depressive disorder by the US Food and Drug Administration in September 2013. This meta-analysis assessed the efficacy and safety of different doses of vortioxetine for generalized anxiety disorder of adults. Methods PubMed, Cochrane Library, PsycINFO, and Clinical Trials databases were searched from 2000 through 2015. The abstracts of the annual meetings of the American Psychiatric Association and previous reviews were searched to identify additional studies. The search was limited to individual randomized controlled trials (RCTs), and there was no language restriction. Four RCTs met the selection criteria. These studies included 1,843 adult patients. Results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). The data were pooled with a random-effects or fixed-effects model. Results The results showed that multiple doses (2.5, 5, and 10 mg/d) of vortioxetine did not significantly improve the generalized anxiety disorder symptoms compared to placebo (OR=1.16, 95% CI=0.84–1.60, Z=0.89, P=0.38; OR=1.41, 95% CI=0.82–2.41, Z=1.25, P=0.21; OR=1.05, 95% CI=0.76–1.46, Z=0.32, P=0.75, respectively). We measured the efficacy of 2.5 mg/d vortioxetine compared to 10 mg/d, and no significant differences were observed. The common adverse effects included nausea and headache. With increased dose, nausea was found to be more frequent in the vortioxetine (5 and 10 mg/d) group (OR=2.99, 95% CI=1.31–6.84, Z=2.60, P=0.009; OR=2.80, 95% CI=1.85–4.25, Z=4.85, P<0.00001, respectively), but no significant differences were observed for headache. Conclusion The results showed no significant improvement in the treatment of generalized anxiety disorder for vortioxetine compared to placebo, and nausea was more frequent with higher doses. So the current evidences do not support using vortioxetine for the treatment of generalized anxiety disorder. Few RCTs were included in our

  4. Comparing the Efficacy of Intravenous Acetaminophen and Intravenous Meperidine in Pain Relief After Outpatient Urological Surgery

    PubMed Central

    Kolahdouzan, Khosro; Eydi, Mahmood; Mohammadipour Anvari, Hassan; Golzari, Samad EJ; Abri, Reyhaneh; Ghojazadeh, Morteza; Ojaghihaghighi, Seyed Hossein

    2014-01-01

    Background: Pain relief after surgery is an essential component of postoperative care. Objectives: The purpose of this study was to compare the efficacy of intravenous acetaminophen and intravenous meperidine in pain relief after outpatient urological surgery. Patients and Methods: In a prospective, randomized, double-blind clinical trial, 100 outpatients of urological surgery were studied in two groups of acetaminophen (A) and meperidine (M). Patients in group A received 1g of acetaminophen in 100 mL saline within 15 minutes and patients in group M received a single intravenous injection of meperidine 0.5 mg/kg, 15 minutes prior to the end of operation. Postoperative pain was recorded using visual analog scale (VAS). Vital signs, nausea, vomiting, dizziness and respiratory depressions were compared between the two groups. Results: Pain severity in patients treated with intravenous acetaminophen six hours after the operation within one-hour interval was significantly lower than meperidine group (P < 0.0001). Ninety patients in the meperidine group and five patients in the acetaminophen group required additional doses of analgesics. Nausea was significantly lower in acetaminophen group than meperidine group. Conclusions: Intravenous acetaminophen reduced pain following outpatient urological surgery more significantly than meperidine. PMID:25798377

  5. Contrast agent choice for intravenous coronary angiography

    SciTech Connect

    Zeman, H.D.; Siddons, D.P.

    1989-01-01

    The screening of the general population for coronary artery disease would be practical if a method existed for visualizing the extent of occlusion after an intravenous injection of contrast agent. Measurements performed with monochromatic synchrotron radiation x-rays and an iodine containing contrast agent at the Stanford Synchrotron Radiation Laboratory have shown that such an intravenous angiography procedure would be possible with an adequately intense monochromatic x-ray source. Because of the size and cost of synchrotron radiation facilities it would be desirable to make the most efficient use of the intensity available, while reducing as much as possible the radiation dose experienced by the patient. By choosing contrast agents containing elements with a higher atomic number than iodine, it is possible to both improve the image quality and reduce the patient radiation dose, while using the same synchrotron source. By using Si monochromator crystals with a small mosaic spread, it is possible to increase the x-ray flux available for imaging by over an order of magnitude, without any changes in the storage ring or wiggler magnet. The most critical imaging task for intravenous coronary angiography utilizing synchrotron radiation x-rays is visualizing a coronary artery through the left ventricle or aorta which also contains a contrast agent. Calculations have been made of the signal to noise ratio expected for this imaging task for various contrast agents with atomic numbers between that of iodine and bismuth.

  6. [Inhalational or intravenous anesthesia?].

    PubMed

    Dahan, A; Aarts, L P H J

    2016-01-01

    The debate continues whether there is a difference in patient outcome following inhalational versus intravenous anesthesia. A recent meta-analysis showed improved outcome following inhalational anesthesia in patients undergoing cardiac surgery but not in patients undergoing non-cardiac procedures. In this article we discuss the meta-analysis and its caveats, taking into account additional comparative studies. Our overall conclusion is that it is too early to definitively claim that one anesthesia technique results in a better outcome than the other. PMID:27650024

  7. Single- and multiple-dose pharmacokinetics of genistein capsules in healthy chinese subjects: A phase I, randomized, open-label study

    PubMed Central

    Zeng, Xing; Feng, Yi; Yang, Liu; Huang, Yu; Zhou, Dan; Sun, Jing; Liu, Yiming; Deng, Yuanhui

    2008-01-01

    Background: Genistein capsules are currently being developed to treat osteoporosis in China. Genistein is extracted from the fruit of Sophora japonica Leguminosae. Objective: The objective of this study was to assess the pharmacokinetics of genistein capsules after single and multiple oral doses in healthy Chinese subjects. Methods: This was a Phase I, randomized, open-label, single- and multiple- dose study in healthy Chinese adults (aged 19–40 years). In the single-dose study, subjects were randomly assigned in a 1:1:1 ratio to receive genistein 50, 100, or 300 mg (in 50-mg capsules). To assess the effect of food on the pharmacokinetics, subjects in the 50-mg group were equally randomized again into fasting and postprandial (genistein was administered after a high-fat breakfast) groups according to a 2-way cross-over design. A separate equal-sized group of subjects were administered genistein 50 mg on day 1 (single dose), received no treatment on days 2 and 3, and were administered genistein 50 mg QD for 6 days (days 4–9) to obtain a multiple-dose pharmacokinetic profile. Because genistein is converted so rapidly and completely to glucuronidated genistein after administration, plasma concentrations of glucuronidated genistein were determined using a validated high-performance liquid chromatography/ tandem mass spectrometry method. Drug tolerability was assessed by monitoring adverse events (AEs) and laboratory parameters. Results: The study enrolled 40 healthy subjects (24 men, 16 women; 10 each in the 50-, 100-, and 300-mg single-dose groups and 10 in the multiple-dose group). Three subjects voluntarily withdrew (2 in the 100-mg group and 1 in the 300-mg group) before study drug administration. Thirty-seven subjects (24 men, 13 women) completed the study and were included in the analysis. The mean (SD) values of the single-dose genistein 50-, 100-, and 300-mg groups were as follows: Tmax, 6.0 (2.4), 7.4 (2.4), and 5.6 (1.2) hours, respectively; tl/2, 13.0 (4

  8. [How to control postoperative pain: intravenous route].

    PubMed

    Occella, P; Vivaldi, F

    2003-12-01

    Intravenous administration of analgesic drugs is one of the most common ways to control post-operative pain. It can be used in almost all kinds of surgical interventions and particularly those of medium and high complexity. Besides, when other techniques are contraindicated because of clinical and/or managing problems, intravenous way finds its best application. Among analgesic drugs NSAID (ketorolac) and opioids (tramadol, morphine, buprenorphine) are most frequently used. As to administration techniques, elastomeric pump is, according to personal experience, a simple-to-manage, practical and precise device with lower cost respect to other administration set. Elastomeric pump is a single use reservoir that allows continuous administration of drugs with a uniform pre-set infusion speed. Finally, guide-lines, showing pre-load and infusion doses of analgesic drugs, based on pain intensity, are presented. PMID:14663417

  9. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects.

    PubMed

    Sidharta, Patricia N; van Giersbergen, Paul L M; Dingemanse, Jasper

    2013-11-01

    This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new endothelin receptor antagonist (ERA) with sustained receptor binding and enhanced tissue penetration properties compared to other ERAs. Healthy male subjects (n = 32) received once daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. Administration of macitentan was safe and well tolerated. Macitentan had no effect on bile salts, suggesting an improved liver safety profile. The multiple-dose pharmacokinetics of macitentan were dose-proportional and were characterized by a median tmax and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48 hours and accumulated approximately 8.5-fold. Compared to placebo, administration of macitentan caused a dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A small dose-dependent increase in the 6β-hydroxycortisol/cortisol urinary excretion ratio was observed, although there were no statistically significant differences between treatments including placebo. Effects of macitentan on cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET-1-dependent pathologies.

  10. The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs.

    PubMed

    Savides, M C; Pohland, R C; Wilkie, D A; Abbott, J A; Newbound, G C; Freise, K J; Clark, T P

    2012-08-01

    Previous studies have demonstrated that a single, topical application of a novel, long-acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty-four laboratory dogs were administered a single placebo or 1×, 3×, or 5× multiple of the dose of 2.6 mg/kg (50 μL/kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1× group were transient and included a low prevalence (≤ 33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3× and 5× groups, which was associated with a dose-limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher-dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1× dose and describe the outcome of an overdose of up to 5× dose in the absence of opioid reversal.

  11. Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs.

    PubMed

    Fish, Brian L; Gao, Feng; Narayanan, Jayashree; Bergom, Carmen; Jacobs, Elizabeth R; Cohen, Eric P; Moulder, John E; Orschell, Christie M; Medhora, Meetha

    2016-11-01

    The NIAID Radiation and Nuclear Countermeasures Program is developing medical agents to mitigate the acute and delayed effects of radiation that may occur from a radionuclear attack or accident. To date, most such medical countermeasures have been developed for single organ injuries. Angiotensin converting enzyme (ACE) inhibitors have been used to mitigate radiation-induced lung, skin, brain, and renal injuries in rats. ACE inhibitors have also been reported to decrease normal tissue complication in radiation oncology patients. In the current study, the authors have developed a rat partial-body irradiation (leg-out PBI) model with minimal bone marrow sparing (one leg shielded) that results in acute and late injuries to multiple organs. In this model, the ACE inhibitor lisinopril (at ~24 mg m d started orally in the drinking water at 7 d after irradiation and continued to ≥150 d) mitigated late effects in the lungs and kidneys after 12.5-Gy leg-out PBI. Also in this model, a short course of saline hydration and antibiotics mitigated acute radiation syndrome following doses as high as 13 Gy. Combining this supportive care with the lisinopril regimen mitigated overall morbidity for up to 150 d after 13-Gy leg-out PBI. Furthermore, lisinopril was an effective mitigator in the presence of the growth factor G-CSF (100 μg kg d from days 1-14), which is FDA-approved for use in a radionuclear event. In summary, by combining lisinopril (FDA-approved for other indications) with hydration and antibiotics, acute and delayed radiation injuries in multiple organs were mitigated. PMID:27682899

  12. Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs.

    PubMed

    Fish, Brian L; Gao, Feng; Narayanan, Jayashree; Bergom, Carmen; Jacobs, Elizabeth R; Cohen, Eric P; Moulder, John E; Orschell, Christie M; Medhora, Meetha

    2016-11-01

    The NIAID Radiation and Nuclear Countermeasures Program is developing medical agents to mitigate the acute and delayed effects of radiation that may occur from a radionuclear attack or accident. To date, most such medical countermeasures have been developed for single organ injuries. Angiotensin converting enzyme (ACE) inhibitors have been used to mitigate radiation-induced lung, skin, brain, and renal injuries in rats. ACE inhibitors have also been reported to decrease normal tissue complication in radiation oncology patients. In the current study, the authors have developed a rat partial-body irradiation (leg-out PBI) model with minimal bone marrow sparing (one leg shielded) that results in acute and late injuries to multiple organs. In this model, the ACE inhibitor lisinopril (at ~24 mg m d started orally in the drinking water at 7 d after irradiation and continued to ≥150 d) mitigated late effects in the lungs and kidneys after 12.5-Gy leg-out PBI. Also in this model, a short course of saline hydration and antibiotics mitigated acute radiation syndrome following doses as high as 13 Gy. Combining this supportive care with the lisinopril regimen mitigated overall morbidity for up to 150 d after 13-Gy leg-out PBI. Furthermore, lisinopril was an effective mitigator in the presence of the growth factor G-CSF (100 μg kg d from days 1-14), which is FDA-approved for use in a radionuclear event. In summary, by combining lisinopril (FDA-approved for other indications) with hydration and antibiotics, acute and delayed radiation injuries in multiple organs were mitigated.

  13. Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU.

    PubMed

    Ji, Zhiying; LeBaron, Matthew J; Schisler, Melissa R; Zhang, Fagen; Bartels, Michael J; Gollapudi, B Bhaskar; Pottenger, Lynn H

    2016-05-01

    The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P < 0.05), indicating the systemic availability of MMS; however, the N7MeG DNA adduct, a target exposure biomarker, exhibited a non-linear dose-response in blood and liver tissues. Blood reticulocyte micronuclei (MN), a genotoxic effect biomarker, exhibited a clear no-observed-genotoxic-effect-level (NOGEL) of 5 mkd as a point of departure (PoD) for MMS. Two separate dose-response models, the Lutz and Lutz model and the stepwise approach using PROC REG both supported a bilinear/threshold dose-response for MN induction. Liver gene expression, a mechanistic endpoint, also exhibited a bilinear dose-response. Similarly, in MNU-treated rats, hepatic DNA adducts, gene expression changes and MN all exhibited clear PoDs, with a NOGEL of 1 mkd for MN induction, although dose-response modeling of the MNU-induced MN data showed a better statistical fit for a linear dose-response. In summary, these results provide in vivo data that support the existence of clear non-linear dose-responses for a number of biologically significant events along the pathway for genotoxicity induced by DNA-reactive agents.

  14. Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study.

    PubMed

    Mateos, María Victoria; Richardson, Paul G; Dimopoulos, Meletios A; Palumbo, Antonio; Anderson, Kenneth C; Shi, Hongliang; Elliott, Jennifer; Dow, Edward; van de Velde, Helgi; Niculescu, Liviu; San Miguel, Jesús F

    2015-04-01

    This analysis, using data from the bortezomib-melphalan-prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant-ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m(2); this was selected as the cut-off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (≥39 mg/m(2)) versus lower (<39 mg/m(2)) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age-adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management.

  15. Response to Multiple Radiation Doses of Human Colorectal Carcinoma Cells Infected With Recombinant Adenovirus Containing Dominant-Negative Ku70 Fragment

    SciTech Connect

    Urano, Muneyasu; He Fuqiu; Minami, Akiko; Ling, C. Clifton; Li, Gloria C.

    2010-07-01

    Purpose: To investigate the effect of recombinant replication-defective adenovirus containing dominant-negative Ku70 fragment on the response of tumor cells to multiple small radiation doses. Our ultimate goal is to demonstrate the feasibility of using this virus in gene-radiotherapy to enhance the radiation response of tumor cells. Methods and Materials: Human colorectal HCT8 and HT29 carcinoma cells were plated in glass tubes, infected with virus (25 multiplicity of infection), and irradiated with a single dose or zero to five doses of 3 Gy each at 6-h intervals. Hypoxia was induced by flushing with 100% nitrogen gas. The cells were trypsinized 0 or 6 h after the final irradiation, and cell survival was determined by colony formation. The survival data were fitted to linear-quadratic model or exponential line. Results: Virus infection enhanced the radiation response of the HCT8 and HT29 cells. The virus enhancement ratio for single-dose irradiation at a surviving fraction of 0.1 was {approx}1.3 for oxic and hypoxic HCT8 and 1.4 and 1.1 for oxic and hypoxic HT29, respectively. A similar virus enhancement ratio of 1.2-1.3 was observed for both oxic and hypoxic cells irradiated with multiple doses; however, these values were smaller than the values found for dominant-negative Ku70-transfected Rat-1 cells. This difference has been discussed. The oxygen enhancement ratio for HCT8 and HT29 receiving fractionated doses was 1.2 and 2.0, respectively, and virus infection altered them slightly. Conclusion: Infection of recombinant replication-defective adenovirus containing dominant-negative Ku70 fragment enhanced the response of human colorectal cancer cells to single and multiple radiation doses.

  16. Intravenous lidocaine as a suppressant of coughing during tracheal intubation.

    PubMed

    Yukioka, H; Yoshimoto, N; Nishimura, K; Fujimori, M

    1985-12-01

    Effects of intravenously administered lidocaine on cough suppression during tracheal intubation under general anesthesia were evaluated in two studies. In study 1, 100 patients received either a placebo or 0.5, 1.0, 1.5, or 2.0 mg/kg lidocaine intravenously 1 min before tracheal intubation. All visible coughs were classified as coughing. The incidence of coughing decreased as the dose of lidocaine increased. A dose of 1 mg/kg or more of intravenous lidocaine suppressed the cough reflex significantly (P less than 0.01). Coughing was suppressed completely by 2 mg/kg of intravenous lidocaine. In study 2, 108 patients received 2 mg/kg lidocaine intravenously or a placebo 1, 3, 5, 7, 10, or 15 min before intubation. The same criteria for determining whether a patient did or did not cough during tracheal intubation were used as in study 1. The incidence of coughing decreased significantly (P less than 0.01) when 2 mg/kg of lidocaine was injected intravenously between 1 and 5 min before our attempting intubation. Cough reflex was suppressed completely by plasma concentrations of lidocaine in excess of 3 micrograms/ml. PMID:4061901

  17. Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results.

    PubMed

    Bowen, J D; Kraft, G H; Wundes, A; Guan, Q; Maravilla, K R; Gooley, T A; McSweeney, P A; Pavletic, S Z; Openshaw, H; Storb, R; Wener, M; McLaughlin, B A; Henstorf, G R; Nash, R A

    2012-07-01

    The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). TBI, CY and antithymocyte globulin were followed by transplantation of autologous, CD34-selected PBSCs. Neurological examinations, brain magnetic resonance imaging and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean Expanded Disability Status Scale (EDSS)=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥1.0 EDSS point was 0.52 (95% confidence interval, 0.30-0.75). Five patients had an EDSS at baseline of ≤6.0; four of them had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.

  18. Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results

    PubMed Central

    Bowen, James D.; Kraft, George H.; Wundes, Annette; Guan, QingYan; Maravilla, Kenneth R.; Gooley, Theodore A.; McSweeney, Peter A.; Pavletic, Steven Z.; Openshaw, Harry; Storb, Rainer; Wener, Mark; McLaughlin, Bernadette A.; Henstorf, Gretchen R.; Nash, Richard A.

    2011-01-01

    The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). Total body irradiation, cyclophosphamide, and antithymocyte globulin were followed by transplantation of autologous, CD34-selected peripheral blood stem cells (PBSC). Neurological examinations, brain MRIs and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean EDSS=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥ 1.0 EDSS point was 0.52 (95% CI, 0.30 to 0.75). Five patients had an EDSS at baseline of ≤ 6.0; four of these had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS. PMID:22056644

  19. Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action.

    PubMed

    Damal, Kavitha; Stoker, Emily; Foley, John F

    2013-01-01

    Multiple sclerosis (MS) is a debilitating neurological disorder that affects nearly 2 million adults, mostly in the prime of their youth. An environmental trigger, such as a viral infection, is hypothesized to initiate the abnormal behavior of host immune cells: to attack and damage the myelin sheath surrounding the neurons of the central nervous system. While several other pathways and disease triggers are still being investigated, it is nonetheless clear that MS is a heterogeneous disease with multifactorial etiologies that works independently or synergistically to initiate the aberrant immune responses to myelin. Although there are still no definitive markers to diagnose the disease or to cure the disease per se, research on management of MS has improved many fold over the past decade. New disease-modifying therapeutics are poised to decrease immune inflammatory responses and consequently decelerate the progression of MS disease activity, reduce the exacerbations of MS symptoms, and stabilize the physical and mental status of individuals. In this review, we describe the mechanism of action, optimal dosing, drug administration, safety, and efficacy of the disease-modifying therapeutics that are currently approved for MS therapy. We also briefly touch upon the new drugs currently under investigation, and discuss the future of MS therapeutics.

  20. Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action

    PubMed Central

    Damal, Kavitha; Stoker, Emily; Foley, John F

    2013-01-01

    Multiple sclerosis (MS) is a debilitating neurological disorder that affects nearly 2 million adults, mostly in the prime of their youth. An environmental trigger, such as a viral infection, is hypothesized to initiate the abnormal behavior of host immune cells: to attack and damage the myelin sheath surrounding the neurons of the central nervous system. While several other pathways and disease triggers are still being investigated, it is nonetheless clear that MS is a heterogeneous disease with multifactorial etiologies that works independently or synergistically to initiate the aberrant immune responses to myelin. Although there are still no definitive markers to diagnose the disease or to cure the disease per se, research on management of MS has improved many fold over the past decade. New disease-modifying therapeutics are poised to decrease immune inflammatory responses and consequently decelerate the progression of MS disease activity, reduce the exacerbations of MS symptoms, and stabilize the physical and mental status of individuals. In this review, we describe the mechanism of action, optimal dosing, drug administration, safety, and efficacy of the disease-modifying therapeutics that are currently approved for MS therapy. We also briefly touch upon the new drugs currently under investigation, and discuss the future of MS therapeutics. PMID:24324326

  1. Intravenous Fluid Generation System

    NASA Technical Reports Server (NTRS)

    McQuillen, John; McKay, Terri; Brown, Daniel; Zoldak, John

    2013-01-01

    The ability to stabilize and treat patients on exploration missions will depend on access to needed consumables. Intravenous (IV) fluids have been identified as required consumables. A review of the Space Medicine Exploration Medical Condition List (SMEMCL) lists over 400 medical conditions that could present and require treatment during ISS missions. The Intravenous Fluid Generation System (IVGEN) technology provides the scalable capability to generate IV fluids from indigenous water supplies. It meets USP (U.S. Pharmacopeia) standards. This capability was performed using potable water from the ISS; water from more extreme environments would need preconditioning. The key advantage is the ability to filter mass and volume, providing the equivalent amount of IV fluid: this is critical for remote operations or resource- poor environments. The IVGEN technology purifies drinking water, mixes it with salt, and transfers it to a suitable bag to deliver a sterile normal saline solution. Operational constraints such as mass limitations and lack of refrigeration may limit the type and volume of such fluids that can be carried onboard the spacecraft. In addition, most medical fluids have a shelf life that is shorter than some mission durations. Consequently, the objective of the IVGEN experiment was to develop, design, and validate the necessary methodology to purify spacecraft potable water into a normal saline solution, thus reducing the amount of IV fluids that are included in the launch manifest. As currently conceived, an IVGEN system for a space exploration mission would consist of an accumulator, a purifier, a mixing assembly, a salt bag, and a sterile bag. The accumulator is used to transfer a measured amount of drinking water from the spacecraft to the purifier. The purifier uses filters to separate any air bubbles that may have gotten trapped during the drinking water transfer from flowing through a high-quality deionizing cartridge that removes the impurities in

  2. Intravenous acetaminophen use in pediatrics.

    PubMed

    Shastri, Nirav

    2015-06-01

    Acetaminophen is a commonly used pediatric medication that has recently been approved for intravenous use in the United States. The purpose of this article was to review the pharmacodynamics, indications, contraindications, and precautions for the use of intravenous acetaminophen in pediatrics.

  3. Utility of the sore throat pain model in a multiple-dose assessment of the acute analgesic flurbiprofen: a randomized controlled study

    PubMed Central

    2014-01-01

    Background The sore throat pain model has been conducted by different clinical investigators to demonstrate the efficacy of acute analgesic drugs in single-dose randomized clinical trials. The model used here was designed to study the multiple-dose safety and efficacy of lozenges containing flurbiprofen at 8.75 mg. Methods Adults (n = 198) with moderate or severe acute sore throat and findings of pharyngitis on a Tonsillo-Pharyngitis Assessment (TPA) were randomly assigned to use either flurbiprofen 8.75 mg lozenges (n = 101) or matching placebo lozenges (n = 97) under double-blind conditions. Patients sucked one lozenge every three to six hours as needed, up to five lozenges per day, and rated symptoms on 100-mm scales: the Sore Throat Pain Intensity Scale (STPIS), the Difficulty Swallowing Scale (DSS), and the Swollen Throat Scale (SwoTS). Results Reductions in pain (lasting for three hours) and in difficulty swallowing and throat swelling (for four hours) were observed after a single dose of the flurbiprofen 8.75 mg lozenge (P <0.05 compared with placebo). After using multiple doses over 24 hours, flurbiprofen-treated patients experienced a 59% greater reduction in throat pain, 45% less difficulty swallowing, and 44% less throat swelling than placebo-treated patients (all P <0.01). There were no serious adverse events. Conclusions Utilizing the sore throat pain model with multiple doses over 24 hours, flurbiprofen 8.75 mg lozenges were shown to be an effective, well-tolerated treatment for sore throat pain. Other pharmacologic actions (reduced difficulty swallowing and reduced throat swelling) and overall patient satisfaction from the flurbiprofen lozenges were also demonstrated in this multiple-dose implementation of the sore throat pain model. Trial registration This trial was registered with ClinicalTrials.gov, registration number: NCT01048866, registration date: January 13, 2010. PMID:24988909

  4. Intravenous infection of mice with Naegleria fowleri.

    PubMed

    May, R G; John, D T

    1982-01-01

    Naegleria fowleri produced fatal meningoencephalitis in mice following intravenous (i.v.) inoculation. Amebae were present in the peripheral circulation for 120 minutes after i.v. inoculation with a dose of 10(7) trophozoites per mouse. Amebae were cultured from and observed in brain (days 1-21), lung (days 1-12), and liver and kidney (days 1-5). Infected mice exhibited weight loss, leukocytosis, reduced lymphocyte/neutrophil ratio, neurologic symptoms, and mortality. Histologically, the disease was characterized by an acute, hemorrhagic, necrotizing meningoencephalitis. Although amebae were detected in tissues other than brain, pathologic involvement of these tissues was minimal.

  5. Effects of high-dose and multiple-dose gonadotropin stimulation on mouse oocyte quality as assessed by preimplantation development following in vitro fertilization.

    PubMed

    Edgar, D H; Whalley, K M; Mills, J A

    1987-10-01

    The effects of increasing the level of ovarian stimulation on preimplantation embryonic development were assessed using a mouse in vitro fertilization system. When F1 hybrid (C57BL/6 X CBA/Ca) mice received a single injection of 5 IU pregnant mare's serum gonadotropin (PMSG) followed 60 hr later by 5 IU human chorionic gonadotropin (hCG) approximately 50% of the resultant postovulatory oocytes developed to the blastocyst stage following in vitro fertilization. Increasing the single dose of PMSG to 10 or 15 IU resulted in significant reductions in the frequency of development to the blastocyst stage. When one or two additional doses of 5 IU PMSG were administered 24 and 48 hr after an initial injection of 5 IU, lower frequencies of oocytes with the potential for full preimplantation development were again observed. This reduction in gamete quality was significantly greater when the final dose of PMSG was administered only 12 hr prior to hCG. The results suggest that excessive gonadotropin stimulation may compromise the quality of the preimplantation embryos obtained following in vitro fertilization and that the timing of gonadotropin administration may also be critical.

  6. Determination of hydromorphone in human plasma by a sensitive RP-HPLC-ESI-MS method and its application to a clinical pharmacokinetic study in postoperative patients after low dose intravenous administration with infusion pump.

    PubMed

    Sun, Luning; Pan, Yinbin; Ding, Li; Luo, Xuemei; Yan, Zhengyu; Liu, Cunming; Qian, Yanning; Chu, Yan

    2012-03-01

    A sensitive reverse phase high performance liquid chromatography-electrospray ionization-mass spectrometry (RP-HPLC-ESI-MS) method has been developed and validated for the determination of hydromorphone in human plasma using naloxone as the internal standard (IS). After alkalization with saturated sodium bicarbonate, the plasma samples were extracted with ethyl acetate. Chromatographic separation was performed on a C18 column with the column temperature of 50 °C and a mobile phase of 5mM ammonium acetate buffer containing 1% formic acid-methanol (88:12, v/v). Hydromorphone and the IS were detected by selected ion monitoring using the protonated molecules at m/z 286.2 for hydromorphone and m/z 328.2 for the IS. Calibration curve was linear over the range of 0.01-50 ng/mL. The lower limit of quantification was 0.01 ng/mL. The method was successfully applied to the pharmacokinetic study in postoperative patients after intravenous infusion of 1.5mg hydromorphone hydrochloride. The obtained main pharmacokinetic parameters of hydromorphone in postoperative patients were as follows: the maximum hydromorphone plasma concentration (C(max)) was (24.15 ± 12.51)ng/mL, the time to the C(max) was (10.0 ± 0.0)min, and the elimination half-life was (2.7 ± 0.8)h. PMID:22169470

  7. SU-E-T-223: Investigation of the Accuracy of Two-Dimensional Dose Distributions Measurement From High-Dose-Rate Brachytherapy Ir-192 Source Using Multiple-Diode-Array Detector (MapCheck2)

    SciTech Connect

    Taguenang, J; De La Fuente, T Herman; Ahmad, S; Ali, I

    2014-06-01

    Purpose: To investigate the dosimetric accuracy of multiple-diode-array detector (Mapcheck2) for high-dose-rate brachytherapy Ir-192 source. The two-dimensional (2D) dose distributions measured with MapCheck2 were validated with EBT2 Gafchromic film measurement and AAPM task-group- 43 (TG-43) modeling. Methods: 2D-dose distributions from Ir-192 source were measured with MapCheck2 and EBT2-films. MapCheck2 response was corrected for effects: directional dependence, diode and phantom heterogeneity. Optical density growth of the film was controlled by synchronized scanning of the film exposed to Ir-192 and calibration films exposed to 6 MV linac beams. Similarly, MapCheck2 response was calibrated to dose using 6 MV beams. An empirical model was developed for the dose distributions measured with Mapcheck2 that considered directional, diode and phantom heterogeneity corrections. The dose deposited in solid-state-detectors was modeled using a cavity theory model for the diode. This model was then validated with measurements using EBT2-films and calculations with TG-43. Results: The response of MapCheck2 has been corrected for different effects including: (a) directional dependence of 0–20% over angular range 0o–90o, (b) phantom heterogeneity (3%) and (c) diode heterogeneity (9%). The corrected dose distributions measured with MapCheck2 agreed well with the measured dose distributions from EBT2-film and with calculations using TG-43 within 5% over a wide range of dose levels and rates. The advantages of MapCheck2 include less noisy, linear and stable response compared with film. The response of MapCheck2 exposed to 192Ir-source showed no energy dependence similar to its response to MV energy beam. Detection spatial-resolution of individual diodes was 0.8×0.8 mm2, however, 2DMapCheck2 resolution is limited by distance between diodes (7.07 mm). Conclusion: The dose distribution measured with MapCheck2 agreed well within 5% with that measured using EBT2-films; and

  8. Intravenous ferric carboxymaltose for the treatment of iron deficiency anemia

    PubMed Central

    Friedrisch, João Ricardo; Cançado, Rodolfo Delfini

    2015-01-01

    Nutritional iron deficiency anemia is the most common deficiency disorder, affecting more than two billion people worldwide. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia, but in many conditions, oral iron is less than ideal mainly because of gastrointestinal adverse events and the long course needed to treat the disease and replenish body iron stores. Intravenous iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell made of polymers such as dextran, sucrose or gluconate. The first iron product for intravenous use was the high molecular weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to use intravenous iron for the treatment of iron deficiency anemia over many years. Intravenous ferric carboxymaltose is a stable complex with the advantage of being non-dextran-containing and a very low immunogenic potential and therefore not predisposed to anaphylactic reactions. Its properties permit the administration of large doses (15 mg/kg; maximum of 1000 mg/infusion) in a single and rapid session (15-minute infusion) without the requirement of a test dose. The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, and safety profile of ferric carboxymaltose in the treatment of patients with iron deficiency anemia. PMID:26670403

  9. Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for Antisense Oligonucleotides With 2′-O-(2-Methoxyethyl) Modifications

    PubMed Central

    Yu, Rosie Z; Grundy, John S; Henry, Scott P; Kim, Tae-Won; Norris, Daniel A; Burkey, Jennifer; Wang, Yanfeng; Vick, Andrew; Geary, Richard S

    2015-01-01

    Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2′-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state. PMID:25602582

  10. Predictive dose-based estimation of systemic exposure multiples in mouse and monkey relative to human for antisense oligonucleotides with 2'-o-(2-methoxyethyl) modifications.

    PubMed

    Yu, Rosie Z; Grundy, John S; Henry, Scott P; Kim, Tae-Won; Norris, Daniel A; Burkey, Jennifer; Wang, Yanfeng; Vick, Andrew; Geary, Richard S

    2015-01-20

    Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2'-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state.

  11. Single- and multiple-dose pharmacokinetics of ethambutol and rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing extended daily dialysis and ECMO treatment.

    PubMed

    Strunk, Ann-Kathrin; Ciesek, Sandra; Schmidt, Julius J; Kühn, Christian; Hoeper, Marius M; Welte, Tobias; Kielstein, Jan T

    2016-01-01

    The dosing of drugs in critically ill patients undergoing renal replacement therapy is based on limited data. We report for the first time single- and multiple-dose pharmacokinetics of ethambutol (EMB), which is cleared renally to 80%, and rifampicin (RIF), which is cleared renally to <30%, in a patient requiring both extracorporeal membrane oxygenation (ECMO) and renal replacement therapy. Extended dialysis removed a considerable amount of both EMB and RIF, with a dialyser plasma clearance ranging between 37 and 95 ml/min for EMB and between 39 and 53 ml/min for RIF. The EMB peak level (3h after a 2-h infusion) using a dose of 1000 mg/day on the first day of treatment was 2.3mg/l, which is in the low therapeutic range (2-5mg/l). Doubling the dose to 2000 mg/day resulted in peak levels slightly to markedly above the recommended range. There was no detectable effect of the ECMO membrane on the removal of both drugs. After an initial dose as for patients without renal impairment (15 mg/kg/day), therapeutic drug monitoring should be used to guide EMB dosing in patients undergoing extended daily dialysis. PMID:26518065

  12. Therapeutic Horseback Riding Outcomes of Parent-Identified Goals for Children with Autism Spectrum Disorder: An ABA' Multiple Case Design Examining Dosing and Generalization to the Home and Community

    ERIC Educational Resources Information Center

    Holm, Margo B.; Baird, Joanne M.; Kim, Young Joo; Rajora, Kuwar B.; D'Silva, Delma; Podolinsky, Lin; Mazefsky, Carla; Minshew, Nancy

    2014-01-01

    We examined whether different doses of therapeutic riding influenced parent-nominated target behaviors of children with autism spectrum disorder (ASD) (a) during the session (b) at home, and (c) in the community. We used a single subject multiple Baseline, multiple case design, with dosing of 1, 3, and 5 times/week. Three boys with ASD, 6-8 years…

  13. Intravenous alcohol self-administration in the P rat.

    PubMed

    Windisch, Kyle A; Kosobud, Ann E K; Czachowski, Cristine L

    2014-08-01

    Alcohol consumption produces a complex array of effects that can be divided into two types: the explicit pharmacological effects of ethanol (which can be temporally separate from time of intake) and the more temporally "relevant" effects (primarily olfactory and taste) that bridge the time from intake to onset of the pharmacological effects. Intravenous (IV) self-administration of ethanol limits the confounding "non-pharmacological" effects associated with oral consumption, allows for controlled and precise dosing, and bypasses first order absorption kinetics, allowing for more direct and better-controlled assessment of alcohol's effect on the brain. IV ethanol self-administration has been reliably demonstrated in mouse and human experimental models; however, models of IV self-administration have been historically problematic in the rat. An operant multiple-schedule study design was used to elucidate the role of each component of a compound IV-ethanol plus oral-sucrose reinforcer. Male alcohol-preferring P rats had free access to both food and water during all IV self-administration sessions. Animals were trained to press a lever for orally delivered 1% sucrose (1S) on a fixed ratio 4 schedule, and then surgically implanted with an indwelling jugular catheter. Animals were then trained to respond on a multiple FR4-FR4 schedule composed of alternating 2.5-min components across 30-min sessions. For the multiple schedule, two components were used: an oral 1S only and an oral 1S plus IV 20% ethanol (25 mg/kg/injection). Average total ethanol intake was 0.47 ± 0.04 g/kg. We found significantly higher earning of sucrose-only reinforcers and greater sucrose-lever error responding relative to the compound oral-sucrose plus IV-ethanol reinforcer. These response patterns suggest that sucrose, not ethanol, was responsible for driving overall responding. The work with a compound IV ethanol-oral sucrose reinforcer presented here suggests that the existing intravenous ethanol

  14. Optimization of Treatment Geometry to Reduce Normal Brain Dose in Radiosurgery of Multiple Brain Metastases with Single–Isocenter Volumetric Modulated Arc Therapy

    PubMed Central

    Wu, Qixue; Snyder, Karen Chin; Liu, Chang; Huang, Yimei; Zhao, Bo; Chetty, Indrin J.; Wen, Ning

    2016-01-01

    Treatment of patients with multiple brain metastases using a single-isocenter volumetric modulated arc therapy (VMAT) has been shown to decrease treatment time with the tradeoff of larger low dose to the normal brain tissue. We have developed an efficient Projection Summing Optimization Algorithm to optimize the treatment geometry in order to reduce dose to normal brain tissue for radiosurgery of multiple metastases with single-isocenter VMAT. The algorithm: (a) measures coordinates of outer boundary points of each lesion to be treated using the Eclipse Scripting Application Programming Interface, (b) determines the rotations of couch, collimator, and gantry using three matrices about the cardinal axes, (c) projects the outer boundary points of the lesion on to Beam Eye View projection plane, (d) optimizes couch and collimator angles by selecting the least total unblocked area for each specific treatment arc, and (e) generates a treatment plan with the optimized angles. The results showed significant reduction in the mean dose and low dose volume to normal brain, while maintaining the similar treatment plan qualities on the thirteen patients treated previously. The algorithm has the flexibility with regard to the beam arrangements and can be integrated in the treatment planning system for clinical application directly. PMID:27688047

  15. Multiple-dose therapy with bovine colostrum confers significant protection against diarrhea in a mouse model of human rotavirus-induced gastrointestinal disease.

    PubMed

    Inagaki, M; Yamamoto, M; Cairangzhuoma; Xijier; Yabe, T; Uchida, K; Kawasaki, M; Nakagomi, T; Nakagomi, O; Minamoto, N; Kanamaru, Y

    2013-02-01

    Rotavirus is the most important etiologic agent of severe gastroenteritis. Previously, we reported that skimmed and concentrated bovine late colostrum (SCBLC) obtained from normal unimmunized cows at 6 to 7d after parturition effectively prevented against human rotavirus (HRV)-induced severe gastroenteritis in vivo, when administered as a single dose 60 min before viral inoculation. In the present study, we examined the efficacy of multiple administrations of SCBLC at smaller dosages after viral inoculation in vivo. We demonstrate that multiple administrations within 24h after virus inoculation resulted in earlier recovery from diarrheal symptoms, in an administration frequency-dependent manner. Furthermore, we investigated whether isolated IgG anti-HRV activity in SCBLC was equivalent to that of IgG isolated from bovine mature milk as measured by in vitro activity assays. We found that IgG-containing fractions from SCBLC and mature milk exhibited approximately the same level of anti-HRV activity. We concluded that the SCBLC contains a high level of IgG against HRV-induced severe gastroenteritis, which will be possible to use in protective effects in immunocompromised hosts, such as children and the elderly. Multiple doses of SCBLC during the early stages of infection or lower dosage of SCBLC given as a single dose both resulted in relief of diarrheal symptoms. PMID:23200479

  16. A New Method for Synthesizing Radiation Dose-Response Data From Multiple Trials Applied to Prostate Cancer

    SciTech Connect

    Diez, Patricia; Vogelius, Ivan S.; Bentzen, Soren M.

    2010-07-15

    Purpose: A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high). Methods and Materials: Nine published prostate cancer dose escalation studies including 6,539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, {gamma}{sub 50}, is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies. Results: Nonrandomized studies produced a statistically significantly higher {gamma}{sub 50} than randomized studies for intermediate- to high-risk patients ({gamma}{sub 50} = 1.63 vs. {gamma}{sub 50} = 0.93, p = 0.03) and a borderline significantly higher ({gamma}{sub 50} = 1.78 vs. {gamma}{sub 50} = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in {gamma}{sub 50} was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of {gamma}{sub 50} = 0.84 with 95% confidence interval 0.54-1.15. Conclusions: Nonrandomized studies overestimate the steepness of the dose-response curve as compared with randomized trials. This is probably the result of stage migration, improved treatment techniques, and a shorter follow-up in higher dose patients that were typically entered more recently. This overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients.

  17. Pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720) in cynomolgus monkeys after single oral and intravenous doses.

    PubMed

    Li, Hongshan; Meno-Tetang, Guy M L; Chiba, Kenji; Arima, Noriyuki; Heining, Peter; Jusko, William J

    2002-05-01

    The pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720), a novel immunosuppressive agent, were examined in cynomolgus monkeys (three males and three females). After single doses of 0.1 mg/kg p.o. or i.v. bolus and 1 mg/kg p.o. were administered to the animals, the concentrations of FTY720, and the numbers of lymphocytes, CD20+CD2-B cells, and CD2+CD20-T cells in blood were measured over 23 days. A linear three-compartment model characterized the time course of FTY720 concentrations with a terminal half-life of about 31 h, clearance of about 0.53 l/h/kg, and bioavailability of about 38%. The dynamic responses were not area under the curve (or dose) proportional for either males or females. An indirect response model with a distribution pool captured the cell trafficking data for all doses for each cell type, where initial blood counts (R(0)) were about 7650, 2100, and 5250 cells/microl; maximum fractional inhibition (I(max)) about 0.88, 0.85, and 0.91; influx (k(in)) about 6014, 1312, and 5662 cells/microl/h; efflux (k(out)) about 0.798, 0.555, and 1.08 h(-1); intercompartmental k(cp) about 0.134, 0.192, and 0.082 h(-1); and intercompartmental k(pc) rate constants about 3.9 x 10(-4), and 0.016 and 8.9 x 10(-6) h(-1) for lymphocytes, B cells, and T cells, respectively. The inhibition concentration IC(50) was about 0.48 microg/l for all cells, which was remarkably low. The apparent distribution volumes of peripheral pool (V(p)) were markedly larger than blood volume (V(b)) for all cells. The I(max) for cell trafficking was achieved at doses smaller than that producing graft protection, indicating stronger central than peripheral effects of this drug. The profound cell trafficking effects of FTY720 can be readily captured and interpreted with an extended indirect response model. PMID:11961052

  18. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis(e–Pub ahead of print)(LOE Classification)

    PubMed Central

    Burton, J.M.; Kimball, S.; Vieth, R.; Bar-Or, A.; Dosch, H.-M.; Cheung, R.; Gagne, D.; D'Souza, C.; Ursell, M.; O'Connor, P.

    2010-01-01

    Objective: Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively. Methods: An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score. Results: Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413nmol/L, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls. Conclusions: High-dose vitamin D (∼10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects. Classification of evidence: This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation

  19. Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition.

    PubMed

    Balcarek, Joanna; Sevá Pessôa, Bruno; Bryson, Catherine; Azizi, Michel; Ménard, Joël; Garrelds, Ingrid M; McGeehan, Gerard; Reeves, Richard A; Griffith, Sue G; Danser, A H Jan; Gregg, Richard

    2014-05-01

    This study compared the pharmacodynamic/pharmacokinetic profile of the new renin inhibitor VTP-27999 in salt-depleted healthy volunteers, administered once daily (75, 150, 300, and 600 mg) for 10 days, versus placebo and 300 mg aliskiren. VTP-27999 was well tolerated with no significant safety issues. It was rapidly absorbed, attaining maximum plasma concentrations at 1 to 4 hours after dosing, with a terminal half-life of 24 to 30 hours. Plasma renin activity remained suppressed during the 24-hour dosing interval at all doses. VTP-27999 administration resulted in a dose-dependent induction of renin, increasing the concentration of plasma renin maximally 350-fold. This induction was greater than with aliskiren, indicating greater intrarenal renin inhibition. VTP-27999 decreased plasma angiotensin II and aldosterone. At 24 hours and later time points after dosing on day 10 in the 600-mg group, angiotensin II and aldosterone levels were increased, and plasma renin activity was also increased at 48 and 72 hours, compared with baseline. VTP-27999 decreased urinary aldosterone excretion versus placebo on day 1. On day 10, urinary aldosterone excretion was higher in the 300- and 600-mg VTP-27999 dose groups compared with baseline. VTP-27999 decreased blood pressure to the same degree as aliskiren. In conclusion, excessive intrarenal renin inhibition, obtained at VTP-27999 doses of 300 mg and higher, is accompanied by plasma renin rises, that after stopping drug intake, exceed the capacity of extrarenal VTP-27999 to block fully the enzymatic reaction. This results in significant rises of angiotensin II and aldosterone. Therefore, renin inhibition has an upper limit.

  20. A multicenter clinical study to determine the feasible initial dose of lenalidomide for maintenance therapy in patients with multiple myeloma following autologous peripheral blood stem-cell transplantation

    PubMed Central

    YAMAMOTO, MASAHIDE; OHASHI, KAZUTERU; KAKIHANA, KAZUHIKO; NAKAMURA, YUICHI; KOMENO, TAKUYA; KOJIMA, HIROSHI; MORITA, SATOSHI; SAKAMAKI, HISASHI

    2016-01-01

    Maintenance therapy with lenalidomide (LEN) for patients with multiple myeloma (MM) following autologous peripheral blood stem cell transplantation (auto-PBSCT) may be a promising option for preventing relapse or disease progression. However, the recommended dose of LEN has yet to be firmly established. We herein report the results of a multicenter clinical study for determining the feasible initial dose (FID) of LEN. In this trial, a total of 11 patients who achieved a very good partial response or complete response following auto-PBSCT were enrolled from five transplant centers in Japan. Three dose levels of LEN (level 0, 5 mg; level 1, 10 mg; and level 2,:15 mg) were tested in this study. FID was defined as the maximum estimated dose at which 70% of the patients could receive maintenance therapy for 12 weeks without any serious adverse events or disease progression. Using a continual reassessment method, 6 patients were assigned to level 0 and the remaining 5 patients were assigned to level 1. All 6 patients (100%) at level 0, but only 2 patients (40%) at level 1, completed 12 weeks of administration with their assigned dose of LEN. The results of our study demonstrated that, although 5 mg of LEN was acceptable in terms of safety, 7.5 mg of LEN may also be an acceptable FID. PMID:27313858

  1. Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects.

    PubMed

    Spiegelstein, Ofer; Stevens, Jasper; Van Gerven, Joop; Nathan, Pradeep J; Maynard, James P; Mayleben, David W; Hellriegel, Edward; Yang, Ronghua

    2016-10-01

    CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement. Two randomized, double-blind, placebo-controlled dose escalation studies with single (0.02 to 5 mg) or multiple administration (0.02 to 0.5 mg once daily) of CEP-26401 were conducted in healthy subjects. Plasma and urine samples were collected to investigate CEP-26401 pharmacokinetics. Pharmacodynamic endpoints included a subset of tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and nocturnal polysomnography. Population pharmacokinetic-pharmacodynamic modeling was conducted on one CANTAB and one polysomnography parameter of interest. CEP-26401 was slowly absorbed (median tmax range 3-6 hours) and the mean terminal elimination half-life ranged from 24-60 hours. Steady-state plasma concentrations were achieved within six days of dosing. CEP-26401 exhibits dose- and time-independent pharmacokinetics, and renal excretion is a major elimination pathway. CEP-26401 had a dose-dependent negative effect on sleep, with some positive effects on certain CANTAB cognitive parameters seen at lower concentrations. The derived three compartment population pharmacokinetic model, with first-order absorption and elimination, accurately described the available pharmacokinetic data. CEP-26401 was generally well tolerated up to 0.5 mg/day with most common treatment related adverse events being headache and insomnia. Further clinical studies are required to establish the potential of low-dose CEP-26401 in cognition enhancement.

  2. Repeated intravenous doxapram induces phrenic motor facilitation

    PubMed Central

    Sandhu, MS; Lee, KZ; Gonzalez-Rothi, EJ; Fuller, DD

    2013-01-01

    Doxapram is a respiratory stimulant used to treat hypoventilation. Here we investigated whether doxapram could also trigger respiratory neuroplasticity. Specifically, we hypothesized that intermittent delivery of doxapram at low doses would lead to long-lasting increases (i.e., facilitation) of phrenic motor output in anesthetized, vagotomized, and mechanically-ventilated rats. Doxapram was delivered intravenously in a single bolus (2 or 6 mg/kg) or as a series of 3 injections (2 mg/kg) at 5 min intervals. Control groups received pH-matched saline injections (vehicle) or no treatment (anesthesia time control). Doxapram evoked an immediate increase in phrenic output in all groups, but a persistent increase in burst amplitude only occurred after repeated dosing with 2 mg/kg. At 60 min following the last injection, phrenic burst amplitude was 168±24% of baseline (%BL) in the group receiving 3 injections (P < 0.05 vs. controls), but was 103±8%BL and 112±4%BL in the groups receiving a single dose of 2 or 6 mg/kg, respectively. Following bilateral section of the carotid sinus nerves, the acute phrenic response to doxapram (2 mg/kg) was reduced by 68% suggesting that at low doses the drug was acting primarily via the carotid chemoreceptors. We conclude that intermittent application of doxapram can trigger phrenic neuroplasticity, and this approach might be of use in the context of respiratory rehabilitation following neurologic injury. PMID:24013015

  3. Effect-directed analysis of contaminated sediments with partition-based dosing using green algae cell multiplication inhibition.

    PubMed

    Bandow, Nicole; Altenburger, Rolf; Streck, Georg; Brack, Werner

    2009-10-01

    Effect-directed analysis (EDA) has been frequently and successfully used to identify key toxicants in sediment extracts. However, by disregarding bioavailability this approach may lead to a biased prioritisation of fractions and toxicants with respect to hazards and risks. To overcome this problem the present EDA of sediment components from the Bílina river (Most Czech Republic), that inhibit growth of the green algae Scenedesmus vacuolatus, applies a novel partition-based dosing technique to prioritize and identify major toxic fractions and compounds in comparison to conventional solvent dosing. The novel dosing technique is based on partitioning from loaded silicone rods to the aqueous phase similar to partition processes that determine exposure in native sediment-water systems. In the present study the application of partition-based dosing had a big influence suggesting polar compounds such as triclosan as key toxicants while polycyclic aromatic hydrocarbon (PAH) fractions did not exhibit significant effects. In contrast, conventional dosing prioritized mainly PAHs in agreement with previous studies. For both approaches individual toxicants could be confirmed quantitatively based on the index of confirmation quality (ICQ), which compares the effect of fractions and artificial mixtures of identified and quantified toxicants over the full range of effect levels. PMID:19848144

  4. Helical Tomotherapy for Whole-Brain Irradiation With Integrated Boost to Multiple Brain Metastases: Evaluation of Dose Distribution Characteristics and Comparison With Alternative Techniques

    SciTech Connect

    Levegrün, Sabine; Pöttgen, Christoph; Wittig, Andrea; Lübcke, Wolfgang; Abu Jawad, Jehad; Stuschke, Martin

    2013-07-15

    Purpose: To quantitatively evaluate dose distribution characteristics achieved with helical tomotherapy (HT) for whole-brain irradiation (WBRT) with integrated boost (IB) to multiple brain metastases in comparison with alternative techniques. Methods and Materials: Dose distributions for 23 patients with 81 metastases treated with WBRT (30 Gy/10 fractions) and IB (50 Gy) were analyzed. The median number of metastases per patient (N{sub mets}) was 3 (range, 2-8). Mean values of the composite planning target volume of all metastases per patient (PTV{sub mets}) and of the individual metastasis planning target volume (PTV{sub ind} {sub met}) were 8.7 ± 8.9 cm{sup 3} (range, 1.3-35.5 cm{sup 3}) and 2.5 ± 4.5 cm{sup 3} (range, 0.19-24.7 cm{sup 3}), respectively. Dose distributions in PTV{sub mets} and PTV{sub ind} {sub met} were evaluated with respect to dose conformity (conformation number [CN], RTOG conformity index [PITV]), target coverage (TC), and homogeneity (homogeneity index [HI], ratio of maximum dose to prescription dose [MDPD]). The dependence of dose conformity on target size and N{sub mets} was investigated. The dose distribution characteristics were benchmarked against alternative irradiation techniques identified in a systematic literature review. Results: Mean ± standard deviation of dose distribution characteristics derived for PTV{sub mets} amounted to CN = 0.790 ± 0.101, PITV = 1.161 ± 0.154, TC = 0.95 ± 0.01, HI = 0.142 ± 0.022, and MDPD = 1.147 ± 0.029, respectively, demonstrating high dose conformity with acceptable homogeneity. Corresponding numbers for PTV{sub ind} {sub met} were CN = 0.708 ± 0.128, PITV = 1.174 ± 0.237, TC = 0.90 ± 0.10, HI = 0.140 ± 0.027, and MDPD = 1.129 ± 0.030, respectively. The target size had a statistically significant influence on dose conformity to PTV{sub mets} (CN = 0.737 for PTV{sub mets} ≤4.32 cm{sup 3} vs CN = 0.848 for PTV{sub mets} >4.32 cm{sup 3}, P=.006), in contrast to N{sub mets}. The achieved

  5. A novel treatment planning methodology for high dose (166)Ho-DOTMP therapy in patients with multiple myeloma

    NASA Astrophysics Data System (ADS)

    McCullough, Steven Patrick

    2000-09-01

    Bone marrow ablation, i.e., the complete sterilization of the active bone marrow, followed by bone marrow transplantation (BMT) is a comment treatment of hematological malignancies. The use of targeted bone- seeking radiopharmaceuticals to selectively deliver radiation to the adjacent bone marrow cavities while sparing normal tissues is a promising technique. Current radiopharmaceutical treatment planning methods do not properly compensate for the patient-specific variable distribution of radioactive material within the skeleton. To improve the current method of internal dosimetry, novel methods for measuring the radiopharmaceutical distribution within the skeleton were developed. 99mTc-MDP was proven as an adequate surrogate for measuring 166Ho-DOTMP skeletal uptake and biodistribution, allowing these measures to be obtained faster, safer, and with higher spatial resolution. This translates directly into better measurements of the radiation dose distribution within the bone marrow. The resulting bone marrow dose-volume histograms allow prediction of the patient disease response where conventional organ scale dosimetry failed. They indicate that complete remission is only achieved when greater than 90% of the bone marrow receives at least 30 Gy. Comprehensive treatment planning requires combining target and non-target organ dosimetry. Organs in the urinary tract were of special concern. The kidney dose is primarily dependent upon the mean transit time of 166 Ho-DOTMP through the kidney. Deconvolution analysis of renograms predicted a mean transit time of 2.6 minutes for 166Ho- DOTMP. The radiation dose to the urinary bladder wall is dependent upon numerous factors including patient hydration and void schedule. For beta-emitting isotopes such as 166Ho, reduction of the bladder wall dose is best accomplished through good patient hydration and ensuring a partially full bladder at the time of injection. Encouraging the patient to void frequently, or catheterizing the

  6. Benchmark Dose Analysis from Multiple Datasets: The Cumulative Risk Assessment for the N-Methyl Carbamate Pesticides

    EPA Science Inventory

    The US EPA’s N-Methyl Carbamate (NMC) Cumulative Risk assessment was based on the effect on acetylcholine esterase (AChE) activity of exposure to 10 NMC pesticides through dietary, drinking water, and residential exposures, assuming the effects of joint exposure to NMCs is dose-...

  7. Multiple-estimate Monte Carlo calculation of the dose rate constant for a cesium-131 interstitial brachytherapy seed

    SciTech Connect

    Wittman, Richard S.; Fisher, Darrell R.

    2007-01-03

    The purpose of this study was to calculate a more accurate dose rate constant for the Cs-131 (model CS-1, IsoRay Medical, Inc., Richland, Washington) interstitial brachytherapy seed. Previous measurements of the dose rate constant for this seed have been reported by others with incongruity. Recent direct measurements by thermoluminescence dosimetry and by gamma-ray spectroscopy were about 15 percent greater than earlier thermoluminescence dosimetry measurements. Therefore, we set about to calculate independent values by a Monte Carlo approach that combined three estimates as a consistency check, and to quantify the computational uncertainty. The calculated dose rate constant for the Cs-131 seed was 1.040 cGy h^{-1} U^{-1} for an ionization chamber model and 1.032 cGy h^{-1} U^{-1} for a circular ring model. A formal value of 2.2% uncertainty was calculated for both values. The range of our multi-estimate values were from 1.032 cGy h^{-1} U^{-1} to 1.061 cGy h^{-1} U^{-1}. We also modeled three I-125 seeds with known dose rate constants to test the accuracy of this study's approach.

  8. Orthostatic stability with intravenous levodopa.

    PubMed

    Siddiqi, Shan H; Creech, Mary L; Black, Kevin J

    2015-01-01

    Intravenous levodopa has been used in a multitude of research studies due to its more predictable pharmacokinetics compared to the oral form, which is used frequently as a treatment for Parkinson's disease (PD). Levodopa is the precursor for dopamine, and intravenous dopamine would strongly affect vascular tone, but peripheral decarboxylase inhibitors are intended to block such effects. Pulse and blood pressure, with orthostatic changes, were recorded before and after intravenous levodopa or placebo-after oral carbidopa-in 13 adults with a chronic tic disorder and 16 tic-free adult control subjects. Levodopa caused no statistically or clinically significant changes in blood pressure or pulse. These data add to previous data that support the safety of i.v. levodopa when given with adequate peripheral inhibition of DOPA decarboxylase. PMID:26336641

  9. Optimal patterns for sequentially multiple focusing in high intensity focused ultrasound and their application to thermal dose

    NASA Astrophysics Data System (ADS)

    Shim, Mun-Bo; Lee, Hyoungki; Lee, Hotaik; Park, Junho; Ahn, Minsu

    2012-11-01

    The purpose of this study is to propose a new method for multiple-focus generation to shorten overall treatment time as well as to avoid the formation of high intensity regions outside the target volume. A numerical simulation of the acoustic fields produced by a 1017-element spherical-section ultrasound phased array transducer operating at a frequency of 1.0MHz with 16 cm radius of curvature is performed for the proposed multiple-focus generation. The total foci are partitioned into the several patterns because multiple focusing generally gives rise to the grating lobes outside of the three dimensional region of interest even if applying the optimization of intensity gain in determining the phases and amplitudes of the excitation source vector. The optimization problem is repeatedly formulated in term of the focal points until the multiple-focus patterns cover all the focal points. Genetic algorithm is used for selecting the patterns without the grating lobes. The obtained set of multiple-focus patterns can sequentially be used to necrose a given volume in the short time as well as in the safe treatment. The proposed method might prove useful to improve the speed and safety of focused ultrasound thermal ablation. This strategy will also be effective for any transducers as well as for other cases of multiple-focus generation.

  10. Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates.

    PubMed

    Otten, Ron A; Adams, Debra R; Kim, Caryn N; Jackson, Eddie; Pullium, Jennifer K; Lee, Kemba; Grohskopf, Lisa A; Monsour, Michael; Butera, Sal; Folks, Thomas M

    2005-01-15

    A nonhuman-primate model of human immunodeficiency virus type 1 (HIV-1) infection that more closely emulates human heterosexual transmission by use of multiple exposures to low doses of virus is critical to better evaluate intervention strategies that include microbicides or vaccines. In this report, we describe such a system that uses female pig-tailed macaques exposed vaginally to a CCR5-using simian-human immunodeficiency virus (SHIV(SF162P3)) at weekly intervals. Results of dose-titration experiments indicated that 3 once-weekly exposures to 10 tissue culture infectious doses of SHIV(SF162P3) resulted in consistent transmission of virus and establishment of systemic infection. The efficacy of cellulose acetate phthalate (CAP) as a vaginal microbicide was evaluated by applying it to the vaginal vault of macaques (n = 4) 15 min before each weekly exposure to SHIV(SF162P3). One conclusion that can be drawn from the data derived from multiple exposures to virus is that CAP prevented infection in 12 of 13 possible chances for infection, over the course of 39 total exposures. Our findings provide a basis to refine monkey models for transmission of HIV-1, which may be relevant to preclinical evaluation for therapeutic interventions.

  11. Health-related quality-of-life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide.

    PubMed

    Delforge, Michel; Minuk, Leonard; Eisenmann, Jean-Claude; Arnulf, Bertrand; Canepa, Letizia; Fragasso, Alberto; Leyvraz, Serge; Langer, Christian; Ezaydi, Yousef; Vogl, Dan T; Giraldo-Castellano, Pilar; Yoon, Sung-Soo; Zarnitsky, Charles; Escoffre-Barbe, Martine; Lemieux, Bernard; Song, Kevin; Bahlis, Nizar Jacques; Guo, Shien; Monzini, Mara Silva; Ervin-Haynes, Annette; Houck, Vanessa; Facon, Thierry

    2015-06-01

    We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients' health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide.

  12. Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy

    PubMed Central

    Ricotti, Valeria; Spinty, Stefan; Roper, Helen; Hughes, Imelda; Tejura, Bina; Robinson, Neil; Layton, Gary; Davies, Kay

    2016-01-01

    Purpose SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration ClinicalTrials.gov NCT02383511 PMID:27055247

  13. Long-Term Efficacy of Postpartum Intravenous Iron Therapy

    PubMed Central

    Zimmermann, Roland

    2014-01-01

    Background. The potential benefits of administering a dose of intravenous iron in patients with moderate postpartum anaemia rather than oral iron alone remains unproven. Aims. To determine whether a single injection of intravenous iron followed by a 6-week course of oral iron is as effective over 6 months in restoring normal haemoglobin levels and replenishing iron stores in women with moderate postpartum anaemia as a course of oral iron alone in women with mild postpartum anaemia. Materials and Methods. Retrospective two-arm cohort study in women with mild postpartum anaemia (haemoglobin 9.6–10.5 g/dL) prescribed iron daily for 6 weeks (N = 150) and women with moderate postpartum anaemia (haemoglobin 8.5–9.5 g/dL), given a single 500 mg injection of intravenous iron followed by iron daily for 6 weeks (N = 75). Haemoglobin and ferritin were measured 6 months postpartum. Results. Haemoglobin returned to similar mean levels in both groups. Ferritin levels were statistically significantly higher in the intravenous + oral group (57.7 ± 49.3 μg/L versus 32.9 ± 20.1 μg/L). Conclusions. Despite lower baseline haemoglobin, intravenous iron carboxymaltose was superior to oral iron alone in replenishing iron stores in moderate postpartum anaemia and may prove similarly beneficial in mild postpartum anaemia. PMID:25431768

  14. Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation.

    PubMed

    Zhang, Pei; Cui, Wanchang; Hankey, Kim G; Gibbs, Allison M; Smith, Cassandra P; Taylor-Howell, Cheryl; Kearney, Sean R; MacVittie, Thomas J

    2015-11-01

    Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus, and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition, respectively, suggesting possible crosstalk between spleen and other organs. These data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs.

  15. SU-E-T-79: Comparison of Doses Received by the Hippocampus in Patients Treated with Single Vs Multiple Isocenter Based Stereotactic Radiation Therapy to the Brain for Multiple Brain Metastases

    SciTech Connect

    Algan, O; Giem, J; Young, J; Ali, I; Ahmad, S; Hossain, S

    2014-06-01

    Purpose: To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiotherapy utilizing a single isocenter (SI) versus multiple isocenter (MI) in patients with multiple intracranial metastases. Methods: Seven patients imaged with MRI including SPGR sequence and diagnosed with 2–3 brain metastases were included in this retrospective study. Two sets of stereotactic IMRT treatment plans, (MI vs SI), were generated. The hippocampus was contoured on SPGR sequences and doses received by the hippocampus and whole brain were calculated. The prescribed dose was 25Gy in 5 fractions. The two groups were compared using t-test analysis. Results: There were 17 lesions in 7 patients. The median tumor, right hippocampus, left hippocampus and brain volumes were: 3.37cc, 2.56cc, 3.28cc, and 1417cc respectively. In comparing the two treatment plans, there was no difference in the PTV coverage except in the tail of the DVH curve. All tumors had V95 > 99.5%. The only statistically significant parameter was the V100 (72% vs 45%, p=0.002, favoring MI). All other evaluated parameters including the V95 and V98 did not reveal any statistically significant differences. None of the evaluated dosimetric parameters for the hippocampus (V100, V80, V60, V40, V20, V10, D100, D90, D70, D50, D30, D10) revealed any statistically significant differences (all p-values > 0.31) between MI and SI plans. The total brain dose was slightly higher in the SI plans, especially in the lower dose regions, although this difference was not statistically significant. Utilizing brain-sub-PTV volumes did not change these results. Conclusion: The use of SI treatment planning for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain compared to MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.

  16. Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans

    PubMed Central

    Huestis, M.A.; Cone, E.J.; Pirnay, S.O.; Umbricht, A.; Preston, K.L.

    2013-01-01

    Background Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine. Methods Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography tandem mass spectrometry with limits of quantitation of 0.1 μg/L. Results Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3±1.0, 44.5±4.8, 85.2±7.7, 124.6±16.6, and 137.7±18.8 μg/L, respectively. Maximum norbuprenorphine concentrations occurred 10–15 min (3.7±0.7 μg/L) after 16 mg IV administration. Conclusions Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2–16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg. PMID:23246635

  17. [Complications caused by intravenous therapy].

    PubMed

    Quirós Luque, José María; Gago Fornells, Manuel

    2005-11-01

    Nursing professionals must know everything related to complications caused by intravenous therapy including the ways to prevent and solve these complications. We need not forget that nurses are the ones mainly responsible for the insertion, manipulation, removal and care of catheters.

  18. 21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... therapeutic moiety absorbed. (3) Other methods based on valid scientific reasons should be used to determine... analytical method. (iv) The drug product is an extended release dosage form. (b) Study design. (1) A multiple... for valid scientific reasons, and should provide for a drug elimination period if...

  19. Covariates of intravenous paracetamol pharmacokinetics in adults

    PubMed Central

    2014-01-01

    Background Pharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled. Methods This pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models. Results Paracetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (FPREG = 1.14) and decreased during abdominal surgery (FABDCL = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (FORTHOV = 0.649), while those in intensive care had increased V2 (FICV = 1.51). Conclusions Size and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored. PMID:25342929

  20. Contrast agent choice for intravenous coronary angiography

    NASA Astrophysics Data System (ADS)

    Zeman, H. D.; Siddons, D. P.

    1990-05-01

    The screening of the general population for coronary artery disease would be practical if a method existed for visualizing the extent of occlusion after an intravenous injection of contrast agent. Measurements performed with monochromatic synchrotron radiation X-rays and an iodine-containing contrast agent at the Stanford Synchrotron Radiation Laboratory have shown that such an intravenous angiography procedure would be possible with an adequately intense monochromatic X-ray source. Because of the size and cost of synchrotron radiation facilities it would be desirable to make the most efficient use of the intensity available, while reducing as much as possible the radiation dose experienced by the patient. By choosing contrast agents containing elements with a higher atomic number than iodine, it is possible to both improve the image quality and reduce the patient radiation dose, while using the same synchrotron radiation source. By using Si monochromator crystals with a small mosaic spread, it is possible to increase the X-ray flux available for imaging by over an order of magnitude, without any changes in the storage ring or wiggler magnet. The most critical imaging task for intravenous coronary angiography utilizing synchrotron radiation X-rays is visualizing a coronary artery through the left ventricle or aorta which also contain contrast agent. Calculations have been made of the signal to noise ratio expected for this imaging task for various contrast agents with atomic numbers between that of iodine and bismuth. The X-ray energy spectrum of the X-17 superconduction wiggler beam line at the National Synchrotron Light Source at Brookhaven National Laboratory has been used for these calculations. Both perfect Si crystals and Si crystals with a small mosaic spread are considered as monochromators. Contrast agents containing Gd or Yb seem to have about the optimal calculated signal to noise ratio. Gd-DTPA is already approved for use as a contrast agent for

  1. Ototoxicity of 12 mg/kg cisplatin in the Fischer 344/NHsd rat using multiple dosing strategies.

    PubMed

    Harrison, Ryan T; Seiler, Brittany M; Bielefeld, Eric C

    2016-09-01

    Ototoxicity continues to be a major dose-limiting side effect of cis-diamminedichloroplatinum(II) (cisplatin). With an ongoing need to develop pharmaceutical protection strategies for cisplatin's ototoxicity, there is also a need to develop stable in-vivo mammalian models of cisplatin ototoxicity. The current study examined the difference in ototoxicity of a cumulative 12 mg/kg dose of cisplatin in the Fischer 344/NHsd rat when administered over four different dosing protocols. Hearing sensitivity was measured using free-field auditory brainstem response thresholds under anesthesia. Rats were divided into four groups. The first group was administered 12 mg/kg of cisplatin in a single bolus infusion. The second group was administered two 6 mg/kg infusions separated by 7 days. The third group was administered 3 mg/kg injections once per day for 4 consecutive days. The fourth group was administered 3 mg/kg injections in four injections separated by 3 days each. Hearing thresholds and body weights were measured at 3 and 7 days after the final cisplatin exposure. Postmortem sensory cell counts were used to confirm injury to the auditory system. The 4 consecutive days of 3 mg/kg induced a greater mortality rate and greater hearing loss at day 3 than the other experimental protocols. The 3 mg/kg administered every 3 days induced less sensory cell loss than the other conditions. The findings indicate that 4 consecutive days of 3 mg/kg cisplatin is not a viable ototoxicity model in the Fischer 344/NHsd rat, but that the other models are all effective in inducing comparable cochlear injuries. PMID:27467178

  2. Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients.

    PubMed

    Hassan Alin, M; Ashton, M; Kihamia, C M; Mtey, G J; Björkman, A

    1996-01-01

    The study compared the clinical efficacy and safety of oral artemisinin and oral artesunate as well as artemisinin pharmacokinetics during and after resolution of falciparum malaria. Forty adults with symptomatic falciparum malaria were allocated at random to treatment with either oral artemisinin (500 mg single dose on day 1 followed by 250 mg twice daily for 4 d and then another 500 mg single dose on day 6) or with oral artesunate (100 mg single dose on day 1 followed by 50 mg twice daily for 5 d). Patients were admitted to hospital at the Kibaha Designated District Hospital, Kibaha, Tanzania for the duration of treatment. The patients were seen once weekly for 3 more weeks. The time to parasite clearance (PCT) after oral artesunate (26.4 +/- 3.6 h) was shorter (P = 0.002) than after artemisinin (31 +/- 3.6 h). The fever subsidence time (FST) after oral artesunate (18.9 +/- 4.0 h) was also shorter (P = 0.04) than after artemisinin (21.8 +/- 4.6 h). Parasites were detected in 4 (20%) and 7 (35%) patients after completing treatment with artesunate and artemisinin respectively. In these patients the parasitaemia reappeared at the 3rd or 4th week of follow-up. Standard haematology, blood biochemistry and urinalysis, performed before drug intake and again on days 6 and 14, were normal. No clinical abnormality was observed during the study period. Artemisinin plasma concentrations, determined by high performance liquid chromatography with post-column derivatization and detection by ultraviolet light, were followed up to 8 h after drug administration on days 1 and 6. Artemisinin absorption was rapid, the maximum plasma concentrations (Cmax) being attained at about 3 h. Artemisinin areas under the plasma concentration-time curve (AUC) and the Cmax values were about 6 times higher after the first dose on day 1 than on day 6. This decrease in artemisinin plasma concentration is suggestive of an increase in metabolic capacity due to pronounced autoinduction.

  3. Pharmacokinetics and tolerability of intravenous rizatriptan in healthy females.

    PubMed

    Lee, Y; Ermlich, S J; Sterrett, A T; Goldberg, M R; Blum, R A; Brucker, M J; McLoughlin, D A; Olah, T V; Zhao, J; Rogers, J D

    1998-12-01

    The pharmacokinetics and tolerability of intravenous (i.v.) rizatriptan (MK-0462), a novel 5-HT1D/1B receptor agonist for the acute oral treatment of migraine, were examined in an open, single-dose, four-period, randomized crossover study in healthy females. Results of this study indicated that i.v. rizatriptan (0.5-5 mg) was well tolerated. The disposition kinetics of rizatriptan were linear for i.v. doses up to and including 2.5 mg. Relative to the 0.5 mg dose, geometric mean dose-adjusted AUC ratios were 1.04, 1.09, and 1.18 for 1, 2.5, and 5 mg doses, respectively. Apparent plasma clearance (Cl) ranged between 859 and 941 mL min(-1) from 0.5 to 2.5 mg, but dropped to slightly below 800 mL min(-1) for the 5 mg dose. Therefore, the elimination of rizatriptan appears somewhat dose dependent at the high end of this dose range. Mean plasma half-life (t1/2) was 1.5-2.2 h across all doses while mean residence time in the body (MRT) and steady state volume of distribution (Vss) of rizatriptan remained relatively invariant across doses. Urinary excretion of rizatriptan (Ue) ranged from 14.5 to 34.6% of dose. PMID:9872339

  4. The role of high-dose melphalan and autologous stem cell transplant in the rapidly evolving era of modern multiple myeloma therapy.

    PubMed

    Voorhees, Peter M; Usmani, Saad Z

    2016-09-01

    The advent of the immunomodulatory drugs thalido-mide, lenalidomide, and pomalidomide; the proteasome inhib-itors bortezomib, carfilzomib, and ixazomib; the histone deacet-ylase inhibitor panobinostat; and the monoclonal antibodies elotuzumab and daratumumab has led to dramatic improvements in outcomes for patients with multiple myeloma. Along with progress in nontransplant therapy have come questions regarding the continued role of high-dose melphalan (HDM) supported by autologous stem cell transplant (ASCT) in the treatment of multiple myeloma. Emerging evidence from phase 3 studies demonstrates that consolidation therapy with HDM/ASCT further improves depth of response and progression-free survival in the context of modern therapy for multiple myeloma. Moreover, unprecedented survival data from ongoing phase 3 studies of patients treated with modern myeloma therapy followed by HDM/ASCT in first-line or second-line therapy reaffirm single and tandem HDM/ASCT as important standards of care for eligible patients. Herein, we review the evolving role of HDM/ASCT for the treatment of patients with newly diagnosed or relapsed multiple myeloma. PMID:27673290

  5. Acute arsenic poisoning treated by intravenous dimercaptosuccinic acid (DMSA) and combined extrarenal epuration techniques.

    PubMed

    Hantson, Philippe; Haufroid, Vincent; Buchet, Jean-Pierre; Mahieu, Paul

    2003-01-01

    Arsenic poisoning was diagnosed in a 26-year-old man who had been criminally intoxicated over the last two weeks preceding admission by the surreptitious oral administration of probably 10 g of arsenic trioxide (As2O3). The patient developed severe manifestations of toxic hepatitis and pancreatitis, and thereafter neurological disorders, respiratory distress, acute renal failure, and cardiovascular disturbances. In addition to supportive therapy, extrarenal elimination techniques and chelating agents were used. Dimercaprol (BAL) and dimercaptosuccinic acid (DMSA or succimer) were used simultaneously as arsenic chelating agents for two days, and thereafter DMSA was used alone. DMSA was administered by intravenous (20 mg/kg/d for five days, then 10 mg/kg/d for six days) and intraperitoneal route. Intravenous DMSA infusion was well tolerated and resulted in an increase in arsenic blood concentration immediately after the infusion. Continuous venovenous hemofiltration combined with hemodialysis, and peritoneal dialysis were proposed to enhance arsenic elimination. It was calculated that over an 11-day period 14.5 mg arsenic were eliminated by the urine, 26.7 mg by hemodialysis, 17.8 mg by peritoneal dialysis, and 7.8 mg by continuous venovenous hemofiltration. These amounts appeared negligible with regard to the probable ingested dose. The patient died on day 26 from the consequences of multiple organ failure, with subarachnoid hemorrhage and generalized infection caused by Aspergillus fumigatus.

  6. Investigation into image quality and dose for different patient geometries with multiple cone-beam CT systems

    SciTech Connect

    Gardner, Stephen J.; Studenski, Matthew T.; Giaddui, Tawfik; Galvin, James; Yu, Yan; Xiao, Ying; Cui, Yunfeng

    2014-03-15

    Purpose: To provide quantitative and qualitative image quality metrics and imaging dose for modern Varian On-board Imager (OBI) (ver. 1.5) and Elekta X-ray Volume Imager (XVI) (ver. 4.5R) cone-beam computed tomography (CBCT) systems in a clinical adaptive radiation therapy environment by accounting for varying patient thickness. Methods: Image quality measurements were acquired with Catphan 504 phantom (nominal diameter and with additional 10 cm thickness) for OBI and XVI systems and compared to planning CT (pCT) (GE LightSpeed). Various clinical protocols were analyzed for the OBI and XVI systems and analyzed using image quality metrics, including spatial resolution, low contrast detectability, uniformity, and HU sensitivity. Imaging dose measurements were acquired in Wellhofer Scanditronix i'mRT phantom at nominal phantom diameter and with additional 4 cm phantom diameter using GafChromic XRQA2 film. Calibration curves were generated using previously published in-air Air Kerma calibration method. Results: The OBI system full trajectory scans exhibited very little dependence on phantom thickness for accurate HU calculation, while half-trajectory scans with full-fan filter exhibited dependence of HU calculation on phantom thickness. The contrast-to-noise ratio (CNR) for the OBI scans decreased with additional phantom thickness. The uniformity of Head protocol scan was most significantly affected with additional phantom thickness. The spatial resolution and CNR compared favorably with pCT, while the uniformity of the OBI system was slightly inferior to pCT. The OBI scan protocol dose levels for nominal phantom thickness at the central portion of the phantom were 2.61, 0.72, and 1.88 cGy, and for additional phantom thickness were 1.95, 0.48, and 1.52 cGy, for the Pelvis, Thorax, and Spotlight protocols, respectively. The XVI system scans exhibited dependence on phantom thickness for accurate HU calculation regardless of trajectory. The CNR for the XVI scans decreased

  7. Effect of multiple oral doses of androgenic anabolic steroids on endurance performance and serum indices of physical stress in healthy male subjects.

    PubMed

    Baume, Norbert; Schumacher, Yorck Olaf; Sottas, Pierre-Edouard; Bagutti, Carlo; Cauderay, Michel; Mangin, Patrice; Saugy, Martial

    2006-11-01

    Anabolic androgenic steroids (AAS) are doping agents that are mostly used for improvement of strength and muscle hypertrophy. In some sports, athletes reported that the intake of AAS is associated with a better recovery, a higher training load capacity and therefore an increase in physical and mental performances. The purpose of this study was to evaluate, the effect of multiple doses of AAS on different physiological parameters that could indirectly relate the physical state of athletes during a hard endurance training program. In a double blind settings, three groups (n = 9, 8 and 8) were orally administered placebo, testosterone undecanoate or 19-norandrostenedione, 12 times during 1 month. Serum biomarkers (creatine kinase, ASAT and urea), serum hormone profiles (testosterone, cortisol and LH) and urinary catecholamines (noradrenalin, adrenalin and dopamine) were evaluated during the treatment. Running performance was assessed before and after the intervention phase by means of a standardized treadmill test. None of the measured biochemical variables showed significant impact of AAS on physical stress level. Data from exercise testing on submaximal and maximal level did not reveal any performance differences between the three groups or their response to the treatment. In the present study, no effect of multiple oral doses of AAS on endurance performance or bioserum recovery markers was found.

  8. Effect of multiple oral doses of androgenic anabolic steroids on endurance performance and serum indices of physical stress in healthy male subjects.

    PubMed

    Baume, Norbert; Schumacher, Yorck Olaf; Sottas, Pierre-Edouard; Bagutti, Carlo; Cauderay, Michel; Mangin, Patrice; Saugy, Martial

    2006-11-01

    Anabolic androgenic steroids (AAS) are doping agents that are mostly used for improvement of strength and muscle hypertrophy. In some sports, athletes reported that the intake of AAS is associated with a better recovery, a higher training load capacity and therefore an increase in physical and mental performances. The purpose of this study was to evaluate, the effect of multiple doses of AAS on different physiological parameters that could indirectly relate the physical state of athletes during a hard endurance training program. In a double blind settings, three groups (n = 9, 8 and 8) were orally administered placebo, testosterone undecanoate or 19-norandrostenedione, 12 times during 1 month. Serum biomarkers (creatine kinase, ASAT and urea), serum hormone profiles (testosterone, cortisol and LH) and urinary catecholamines (noradrenalin, adrenalin and dopamine) were evaluated during the treatment. Running performance was assessed before and after the intervention phase by means of a standardized treadmill test. None of the measured biochemical variables showed significant impact of AAS on physical stress level. Data from exercise testing on submaximal and maximal level did not reveal any performance differences between the three groups or their response to the treatment. In the present study, no effect of multiple oral doses of AAS on endurance performance or bioserum recovery markers was found. PMID:16896724

  9. Summarizing EC50 estimates from multiple dose-response experiments: a comparison of a meta-analysis strategy to a mixed-effects model approach.

    PubMed

    Jiang, Xiaoqi; Kopp-Schneider, Annette

    2014-05-01

    Dose-response studies are performed to investigate the potency of a compound. EC50 is the concentration of the compound that gives half-maximal response. Dose-response data are typically evaluated by using a log-logistic model that includes EC50 as one of the model parameters. Often, more than one experiment is carried out to determine the EC50 value for a compound, requiring summarization of EC50 estimates from a series of experiments. In this context, mixed-effects models are designed to estimate the average behavior of EC50 values over all experiments by considering the variabilities within and among experiments simultaneously. However, fitting nonlinear mixed-effects models is more complicated than in a linear situation, and convergence problems are often encountered. An alternative strategy is the application of a meta-analysis approach, which combines EC50 estimates obtained from separate log-logistic model fitting. These two proposed strategies to summarize EC50 estimates from multiple experiments are compared in a simulation study and real data example. We conclude that the meta-analysis strategy is a simple and robust method to summarize EC50 estimates from multiple experiments, especially suited in the case of a small number of experiments.

  10. Cardiovascular effects of intravenous administration of tetracycline in cattle.

    PubMed

    Gyrd-Hansen, N; Rasmussen, F; Smith, M

    1981-03-01

    Tetracycline chloride dissolved in saline was injected intravenously to seven cows. Two doses of tetracycline were used: 5 and 10 mg/kg b.wt, and the injections were given over a period of either 10, 60 or 300 sec. A number of the cows collapsed shortly after the injection was completed, usually when the 10 mg dosage was given in 60 sec. When the same dose was given over a period of 5 min none of the cows collapsed. A more or less pronounced drop in blood pressure could be detected during or shortly after the injection; in those cows which collapsed the blood pressure fell almost to zero. The predominant change in pulse rate in connection with the tetracycline administration was a decrease which could be quite marked, pulse rates falling as low as 10-20 per min. Simultaneously with these changes in blood pressure and pulse rate severe abnormalities in ECG could be observed. Pre-treatment with a normal therapeutic dose of calcium borogluconate intravenously prevented collapse in the cows and diminished the drop in blood pressure associated with an ensuing tetracycline injection. It is concluded that intravenous injection of tetracycline is hazardous, but that collapse can be avoided by giving the injection very slowly over a period of no less than 5 min.

  11. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients.

    PubMed

    de Waal, Esther G M; de Munck, Linda; Hoogendoorn, Mels; Woolthuis, Gerhard; van der Velden, Annette; Tromp, Yvonne; Vellenga, Edo; Hovenga, Sjoerd

    2015-12-01

    Combination therapy for longer periods but at low dose might be an effective and tolerable manner to treat patients with relapsed multiple myeloma (MM). We used bortezomib, dexamethasone and low-dose oral cyclophosphamide as an induction regimen, followed by 1 year of maintenance consisting of bortezomib and cyclophosphamide. Relapsed MM patients were treated with six cycles of bortezomib twice weekly, cyclophosphamide 50 mg daily and dexamethasone. Maintenance therapy was given for 1 year. Primary endpoints were toxicity during re-induction and maintenance therapy. Secondary endpoints were response to treatment and progression-free (PFS) and overall survival (OS). This study included 59 patients. Myelosuppression and neuropathy were the most common side effects. Median follow-up was 27·1 (0·46-54·4) months with an overall response of 71%, and a very good partial response or more of 33%. During maintenance, improved responsiveness was observed in 19% of the patients. The median PFS was 18·4 months (range 0·13-43·5) and the median OS was 28·1 months (range 0·13-54·4). In conclusion, our study demonstrates that treatment with bortezomib, dexamethasone and low-dose cyclophosphamide is an effective and manageable regimen. Adding 1 year of maintenance was feasible, with limited side effects and an increased response rate.

  12. A pharmacokinetic and residual study of sulfadiazine/trimethoprim in mandarin fish (Siniperca chuatsi) with single- and multiple-dose oral administrations.

    PubMed

    Wang, W; Luo, L; Xiao, H; Zhang, R; Deng, Y; Tan, A; Jiang, L

    2016-06-01

    A pharmacokinetic and tissue residue study of sulfadiazine combined with trimethoprim (SDZ/TMP = 5/1) was conducted in Siniperca chuatsi after single- (120 mg/kg) or multiple-dose (an initial dose of 120 mg/kg followed by a 5-day consecutive dose of 60 mg/kg) oral administrations at 28 °C. The absorption half-life (t1/2α ), elimination half-life (t1/2β ), volume of distribution (Vd /F), and the total body clearance (ClB /F) for SDZ and TMP were 4.3 ± 1.7 to 6.3 ± 1.8 h and 2.4 ± 1.0 to 3.9 ± 0.9 h, 25.9 ± 4.5 to 53.0 ± 5.6 h and 11.8 ± 3.5 to 17.1 ± 3.4 h, 2.34 ± 0.78 to 3.67 ± 0.99 L/kg and 0.39 ± 0.01 to 1.33 ± 0.57 L/kg, and 0.03 ± 0.01 to 0.06 ± 0.01 L/kg·h and 0.02 ± 0.01 to 0.05 ± 0.01 L/kg·h, respectively, after the single dose. The elimination half-life (t1/2β ) and mean residue time (MRT) for SDZ and TMP were 68.8 ± 7.8 to 139.8 ± 12.3 h and 34.0 ± 5.5 to 56.1 ± 6.8 h, and 99.3 ± 6.1 to 201.7 ± 11.5 h and 49.1 ± 3.5 to 81.0 ± 5.1 h, respectively, after the multiple-dose administration. The daily oral SDZ/TMP administration might cause a high tissue concentration and long t1/2β , thereby affecting antibacterial activity. The withdrawal time for this oral SDZ/TMP formulation (according to the accepted guidelines in Europe for maximum residue limits, <0.1 mg/kg of tissues for sulfonamides, and <0.05 mg/kg for TMP) should not be <36 days for fish. PMID:26669806

  13. Pharmacokinetic comparison of sustained- and immediate-release formulations of cilostazol after multiple oral doses in fed healthy male Korean volunteers

    PubMed Central

    Kim, Yo Han; Ghim, Jong-Lyul; Jung, Jin Ah; Cho, Sang-Heon; Choe, Sangmin; Choi, Hee Youn; Bae, Kyun-Seop; Lim, Hyeong-Seok

    2015-01-01

    Background A new extended-release form of cilostazol has recently been developed. This study was conducted to compare the pharmacokinetic characteristics of sustained-release (SR) and immediate-release (IR) formulations of cilostazol after multiple oral doses in healthy male Korean volunteers. Methods This was an open-label, randomized, multiple-dose, crossover study conducted in 30 healthy Korean subjects. In each treatment period, subjects received oral doses of 200 mg SR formulation every 24 hours or 100 mg IR formulation every 12 hours for 5 consecutive days in a fed state, with a washout period of 9 days. The plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method. The area under the plasma concentration–time curve within a dosing interval (AUCT), the measured peak plasma concentration at steady state (Cmax,ss), and the time to reach Cmax,ss (tmax,ss) were analyzed using a noncompartmental method. Results A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD]) AUCT (96–120 hours) values for SR and IR were 27,378.0 (10,301.6) ng·h/mL and 27,860.3 (7,152.3) ng·h/mL, respectively. The mean (SD) Cmax,ss values were 2,741.4 (836.0) ng/mL and 2,051.0 (433.2) ng/mL, respectively. The median tmax,ss values were 8.0 hours and 4.0 hours, respectively. The geometric mean ratios (90% confidence intervals) of the SR to IR formulations were 0.937 (0.863–1.017), 0.960 (0.883–1.043), and 0.935 (0.859–1.017) for AUCT and 0.644 (0.590–0.703), 0.586 (0.536–0.642), and 0.636 (0.577–0.702) for dose-normalized Cmax,ss of cilostazol, OPC-13015 (3,4-dehydro-cilostazol), and OPC-13213 (4′-trans-hydroxyl-cilostazol), respectively. All formulations were well tolerated. Conclusion At steady state, the AUCT of cilostazol SR 200 mg is comparable to that of cilostazol IR 100 mg twice a day in healthy male Korean subjects. Both formulations are well

  14. Multiple exposures to indoor contaminants: Derivation of benchmark doses and relative potency factors based on male reprotoxic effects.

    PubMed

    Fournier, K; Tebby, C; Zeman, F; Glorennec, P; Zmirou-Navier, D; Bonvallot, N

    2016-02-01

    Semi-Volatile Organic Compounds (SVOCs) are commonly present in dwellings and several are suspected of having effects on male reproductive function mediated by an endocrine disruption mode of action. To improve knowledge of the health impact of these compounds, cumulative toxicity indicators are needed. This work derives Benchmark Doses (BMD) and Relative Potency Factors (RPF) for SVOCs acting on the male reproductive system through the same mode of action. We included SVOCs fulfilling the following conditions: detection frequency (>10%) in French dwellings, availability of data on the mechanism/mode of action for male reproductive toxicity, and availability of comparable dose-response relationships. Of 58 SVOCs selected, 18 induce a decrease in serum testosterone levels. Six have sufficient and comparable data to derive BMDs based on 10 or 50% of the response. The SVOCs inducing the largest decrease in serum testosterone concentration are: for 10%, bisphenol A (BMD10 = 7.72E-07 mg/kg bw/d; RPF10 = 7,033,679); for 50%, benzo[a]pyrene (BMD50 = 0.030 mg/kg bw/d; RPF50 = 1630), and the one inducing the smallest one is benzyl butyl phthalate (RPF10 and RPF50 = 0.095). This approach encompasses contaminants from diverse chemical families acting through similar modes of action, and makes possible a cumulative risk assessment in indoor environments. The main limitation remains the lack of comparable toxicological data.

  15. Intravenous Solutions for Exploration Missions

    NASA Technical Reports Server (NTRS)

    Miller, Fletcher J.; Niederhaus, Charles; Barlow, Karen; Griffin, DeVon

    2007-01-01

    This paper describes the intravenous (IV) fluids requirements being developed for medical care during NASA s future exploration class missions. Previous research on IV solution generation and mixing in space is summarized. The current exploration baseline mission profiles are introduced, potential medical conditions described and evaluated for fluidic needs, and operational issues assessed. We briefly introduce potential methods for generating IV fluids in microgravity. Conclusions on the recommended fluid volume requirements are presented.

  16. Exposure-safety-efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study.

    PubMed

    Gupta, Neeraj; Labotka, Richard; Liu, Guohui; Hui, Ai-Min; Venkatakrishnan, Karthik

    2016-06-01

    Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy outcomes (hematologic [grade ≥ 3 vs ≤ 2] or non-hematologic [grade ≥ 2 vs ≤ 1] adverse events [AEs], and clinical benefit [≥stable disease vs progressive disease]) using phase 1 data in relapsed/refractory MM (NCT00963820; N = 44). Results Significant relationships to ixazomib exposure were observed for five AEs (neutropenia, thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (p < 0.05). Dose-response relationships indicated a favorable benefit/risk ratio at 3 mg and 4 mg weekly, which are below the maximum tolerated dose of 5.5 mg. At 3 mg, the model predicted that: 37 % of patients will achieve clinical benefit; incidence of grade ≥ 3 neutropenia and thrombocytopenia will be 10 % and 23 %, respectively; and incidence of grade ≥ 2 rash, fatigue, and diarrhea will be 8 %, 19 %, and 19 %, respectively. Conclusions Based on the findings, patients in the phase 3 maintenance trial will initiate ixazomib at a once-weekly dose of 3 mg, increasing to 4 mg if acceptable tolerability after 4 cycles, to provide maximum clinical benefit balanced with adequate tolerability. PMID:27039387

  17. Intravenous zoledronate for osteoporosis: less might be more

    PubMed Central

    Grey, Andrew

    2016-01-01

    Annual administration of 5 mg intravenous zoledronate is moderately effective in reducing fracture risk in older adults, decreasing the relative risk of clinical fracture by 33%. However, almost 10 years after its approval for use in clinical practice there remain very substantial uncertainties about the optimal treatment regimen, that is, the lowest dose and/or longest dosing interval that is efficacious. Several pieces of clinical research suggest that the current recommendation for annual administration of 5 mg zoledronate might represent overtreatment. Clinical trials to clarify the optimal use of zoledronate for reduction of fracture risk should be undertaken. PMID:27493690

  18. Relationships between biomarkers of exposure and toxicokinetics in Fischer 344 rats and B6C3F{sub 1} mice administered single doses of acrylamide and glycidamide and multiple doses of acrylamide

    SciTech Connect

    Tareke, Eden; Twaddle, Nathan C.; McDaniel, L. Patrice; Churchwell, Mona I.; Young, John F.; Doerge, Daniel R. . E-mail: daniel.doerge@fda.hhs.gov

    2006-11-15

    Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells and carcinogenic in rodents. AA is also formed in many commonly consumed starchy foods during cooking. Our previous toxicokinetic investigations of AA and its important genotoxic metabolite, glycidamide (GA), in rodents showed that AA is highly bioavailable from oral routes of administration, is widely distributed to tissues and that the dietary route, in particular, favors metabolism to GA. Measurements of DNA adducts in many tissues supported the hypothesis that AA is carcinogenic in rodent bioassays through metabolism to GA. The current investigation describes the development and validation of methodology for measuring hemoglobin (Hb) adducts with AA and GA in the same rodents previously used for toxicokinetic and DNA adduct measurements. The goal was to investigate possible relationships between these circulating biomarkers of exposure and serum toxicokinetic parameters for AA and GA and tissue GA-DNA adducts in rodents from both single and repeated dosing with AA. Significant correlations were observed between GA-Hb and liver GA-DNA adducts for either single or multiple dosing regimens with AA. Using available GA-Hb adduct data, empirical and allometric relationships permitted estimation of liver DNA adducts in humans in the range of 0.06-0.3 adducts/10{sup 8} nucleotides. This approach may prove useful in extrapolating human cancer risks from findings in rodent bioassays.

  19. Subanaesthetic dose of ketamine in intractable asthma.

    PubMed

    Garg, Dinesh; Kaistha, Sanjay; Sood, Dinesh

    2011-06-01

    A 75-year-old male diagnosed to be a case of intractable asthma resistant to all conventional therapies requiring ventilatory support, was successfully weaned off the ventilator after treatment with subanaesthetic dose of intravenous ketamine. PMID:22315777

  20. Use of intravenous propranolol for control of a large cervicofacial hemangioma in a critically ill neonate.

    PubMed

    Fernando, Shanik J; Leitenberger, Sabra; Majerus, Matt; Krol, Alfons; MacArthur, Carol J

    2016-05-01

    Cervicofacial segmental infantile hemangiomas (IH) may result in airway obstruction requiring use of propranolol to induce hemangioma regression and reestablish the airway. We present the first case using intravenous (IV) propranolol for control of airway obstruction and rapid expansion of cervicofacial IH in the setting of necrotizing enterocolitis (NEC) impaired gastrointestinal function. Intravenous dosing of propranolol was tolerated well in a critically ill neonate with multisystem complications of prematurity. PMID:27063753

  1. A multiple-dose pharmacokinetics of polyethylene glycol recombinant human interleukin-6 (PEG-rhIL-6) in rats*

    PubMed Central

    He, Xue-ling; Yin, Hai-lin; Wu, Jiang; Zhang, Ke; Liu, Yan; Yuan, Tao; Rao, Hai-lin; Li, Liang; Yang, Guang; Zhang, Xue-mei

    2011-01-01

    Radiation therapy has been widely applied in cancer treatment. However, it often causes thrombocytopenia (deficiency of white blood cells) as an adverse effect. Recombinant human interleukin-6 (rhIL-6) has been found to be a very effective way against this thrombocytopenia, but IL-6 has low stability in blood, which reduces its efficacy. To increases the stability and half-life of rhIL-6, it was modified by polyethylene glycol (PEG). The pharmacokinetics and the tissue distribution of PEG-rhIL-6 labeled with 125I were examined after subcutaneous injection in rats. The pharmacokinetic pattern of PEG-rhIL-6 was defined with linear-kinetics, and we fitted a one-compartment model with half-lives of 10.44–11.37 h (absorption, t 1/2Ka) and 19.77–21.53 h (elimination, t 1/2Ke), and peak concentrations at 20.51–21.96 h (t peak) in rats. Half-lives and t peak of PEG-rhIL-6 were longer than those of rhIL-6 previously reported. In the present study, for deposition of PEG-rhIL-6 in rats, the tissue distribution examination showed that blood was the major organ involved, rather than liver. However, as to the elimination of PEG-rhIL-6, the major organ was the kidney. The excretion fraction of the injection dose recovered from urine was 23.32% at 192 h after subcutaneous administration. Less than 6% of PEG-rhIL-6 was eliminated via the feces at 192 h. These results indicate that PEG-rhIL-6 is a good candidate drug formulation for patients with cancer. PMID:21194184

  2. [Azlocillin--synovial fluid levels after intravenous doses].

    PubMed

    Härle, A; Ritzerfeld, W; Wiynck, G; Knoche, U

    1983-01-01

    The corresponding levels of azlocillin in serum and in synovial fluid in the knee-joint were investigated in patients who had undergone aseptic surgery of the lower limbs. The mean synovial fluid concentrations for azlocillin were determined on the basis of 30 samples. Clinically relevant azlocillin levels of approximately 40 mu g/ml were recorded in synovial fluid 10 minutes after start of a short infusion of 5 gm. These increased until about 90 minutes after commencement of antibiotic administration when the maximum level was attained. Subsequently synovial fluid levels decreased slowly and approximately 170 minutes after commencement of the short infusion the mean for serum and synovial concentrations corresponded. The results confirm that with an i.v. infusion of 5 g azlocillin levels can be attained for 3 hours in the synovial fluid that are above the break-point for this antibiotic of 64 mu g/ml. However, despite these good pharmacokinetic data it should be remembered that experience has shown that surgical reintervention is often necessary in addition in joint infections to achieve ultimate cure. PMID:6405553

  3. Impact of graphene oxide on the structure and function of important multiple blood components by a dose-dependent pattern.

    PubMed

    Feng, Ru; Yu, Yueping; Shen, Chaoxuan; Jiao, Yanpeng; Zhou, Changren

    2015-06-01

    Graphene and its derivatives have become great concern in biomedical fields. Though many investigations about their toxicity have been reported, systematic investigation on the interaction with multiple blood components is lacking. In this work, we studied the effects of the graphene oxide (GO) on the structure and function of the blood components, especially, on morphology and hemolysis of red blood cells (RBCs), bovine serum albumin (BSA) and fibrinogen conformation, complement activation, and blood coagulation function. Scanning electron microscopy observation and hemolysis test results showed that the GO can affect RBC morphology and membrane integrity in a concentration-dependent way. Fluorescence and circular dichroism spectra showed that GO could alter the secondary structures and conformation of BSA and fibrinogen. In addition, the presence of GO could also trigger complement activation by detecting their key biomarker molecules in plasma. In the blood clotting process, the GO showed significant adverse effect on the activated partial thromboplastin time but not on prothrombin time of the platelet-poor plasma. Meanwhile, the GO also caused abnormal thromboelastography parameters of the whole blood coagulation. The results obtained in this study provides good insight into understanding the biomedical application of GO in vivo. PMID:25257186

  4. The effect of Laminaria japonica polysaccharides on the recovery of the male rat reproductive system and mating function damaged by multiple mini-doses of ionizing radiations.

    PubMed

    Qiong, Luo; Jun, Liu; Jun, Yan; Yinzhu, Zhou; Xiaoyan, Cui; Mingliang, Yang

    2011-03-01

    To evaluate the radiation-protect effects of Laminaria japonica polysaccharides (LJP) on male reproductive system damage and mating dysfunction induced by multiple mini-dose ionizing radiations, male rats were administrated with radiation and/or LJP. Results showed that mating function (such as erection, mount and ejaculation), sperm count and survival rate in LJP group were significantly better than the corresponding model group after the radiation. The testis organ coefficient, GSH (glutathione) content, serum sex hormones (luteinizing hormone, follicle-stimulating hormone, testosterone and estradiol) levels improved while MDA (malondialdehyde) content decreased. In addition, SOD (superoxide dismutase), GSH-PX (glutathione peroxidase), LDH (lactate dehydrogenase) activities were enhanced while testicular tissue damage was reduced, 14 days after the cessation of radiation; all indicators in the LJP group were similar to the control group. Our results suggest that, LJP has some promoting effects on the recovery of the reproductive system and mating dysfunction induced by radiation.

  5. Fully automated classification of bone marrow infiltration in low-dose CT of patients with multiple myeloma based on probabilistic density model and supervised learning.

    PubMed

    Martínez-Martínez, Francisco; Kybic, Jan; Lambert, Lukáš; Mecková, Zuzana

    2016-04-01

    This paper presents a fully automated method for the identification of bone marrow infiltration in femurs in low-dose CT of patients with multiple myeloma. We automatically find the femurs and the bone marrow within them. In the next step, we create a probabilistic, spatially dependent density model of normal tissue. At test time, we detect unexpectedly high density voxels which may be related to bone marrow infiltration, as outliers to this model. Based on a set of global, aggregated features representing all detections from one femur, we classify the subjects as being either healthy or not. This method was validated on a dataset of 127 subjects with ground truth created from a consensus of two expert radiologists, obtaining an AUC of 0.996 for the task of distinguishing healthy controls and patients with bone marrow infiltration. To the best of our knowledge, no other automatic image-based method for this task has been published before. PMID:26894595

  6. Relative infectivity of hepatitis A virus by the oral and intravenous routes in 2 species of nonhuman primates.

    PubMed

    Purcell, Robert H; Wong, Doris C; Shapiro, Max

    2002-06-01

    Hepatitis A virus (HAV) is naturally transmitted by the fecal-oral route but can also be transmitted intravenously. To determine the relative infectivity of these 2 routes, an infectivity titration of a standard challenge pool of virulent HAV was performed in tamarins and chimpanzees. In both species, 1 oral dose of HAV was equivalent to 10(4.5) intravenous doses. These findings have relevance for attempts to develop live, attenuated HAV vaccines that can be administered orally.

  7. Investigation of the bioavailability of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin following single and multiple oral dosing of a hypericum extract containing tablet.

    PubMed

    Schulz, Hans-Ulrich; Schürer, Michael; Bässler, Dagmar; Weiser, Dieter

    2005-01-01

    The objective of these two open phase I clinical trials was the investigation of the bioavailability of five constituents from a hypericum extract containing tablet, which are discussed as the components contributing to the antidepressant action. Each trial included 18 healthy male volunteers who received the test preparation, containing 612 mg dry extract of St John's wort (STW-3, Laif 600), either as a single oral dose or as a multiple once daily dose over a period of 14 days. Concentration/time curves were determined for hypericin, pseudohypericin, hyperforin, the flavonoid aglycone quercetin, and its methylated form isorhamnetin for 48 h after single dosing and for 24 h on day 14 at the end of 2 weeks of continuous daily dosing. After single dose intake, the key pharmacokinetic parameters were determined as follows: hypericin: area under the curve (AUC(0-infinity)) = 75.96 h x ng/ml, maximum plasma concentration (Cmax) = 3.14 ng/ml, time to reach Cmax (t(max)) = 8.1 h, and elimination half-life (t1/2) = 23.76 h; pseudohypericin: AUC(0-infinity) = 93.03 h x ng/ml, Cmax = 8.50 ng/ml, t(max) = 3.0 h, t1/2 = 25.39 h; hyperforin: AUC(0-max) = 1009.0 h x ng/ml, Cmax = 83.5 nglml, t(max) = 4.4 h, t1/2 = 19.64 h. Quercetin and isohamnetin showed two peaks of maximum plasma concentration separated by about 4 h. Quercetin: AUC(0-infinity) = 318,7 h x ng/ml, Cmax (1) = 47.7 ng/ml, t(max) (1) = 1.17 h, Cmax (2) = 43.8 ng/ml, t(max) (2) = 5.47 h, t1/2 = 4.16 h; isorhamnetin: AUC(0-infinity) = 98.0 h x ng/ml, Cmax (1) = 7.6 ng/ml, t(max) (1) = 1.53 h, Cmax (2) = 9.0 ng/ml, t(max), (2) = 6.42 h, t1/2 = 4.45 h. Under steady state conditions reached during multiple dose administration similar results were obtained. Further pharmacokinetic characteristics calculated from the obtained data were the mean residence time (MRT), the lag-time, the peak-trough fluctuation (PTF), the lowest observed plasma concentration (Cmin), and the average plasma concentration (Cav). The data

  8. Relevance of the selective oestrogen receptor modulators tamoxifen, toremifene and clomiphene in doping field: endogenous steroids urinary profile after multiple oral doses.

    PubMed

    Mazzarino, Monica; Braganò, Maria Cristina; de la Torre, Xavier; Molaioni, Francesco; Botrè, Francesco

    2011-11-01

    The present study was performed to investigate the influence of the intake of selective oestrogen receptor modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5α-androstan-3α,17β-diol, 5β-androstan-3α,17β-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography-mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80 mg for 2 days) or toremifene (120 mg for 2 days) or clomiphene (100 mg for 2 days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3 h, for 3 days prior to the treatment; whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen receptor modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration. The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5α-androstan-3α,17β-diol and 5β-androstan-3α,17β-diol urinary levels and on testosterone/epitestosterone, 5α-androstan-3α,17β-diol/5β-androstan-3α,17β-diol and androsterone/etiocholanolone ratios.

  9. A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients

    PubMed Central

    Fava, M; Johe, K; Ereshefsky, L; Gertsik, L G; English, B A; Bilello, J A; Thurmond, L M; Johnstone, J; Dickerson, B C; Makris, N; Hoeppner, B B; Flynn, M; Mischoulon, D; Kinrys, G; Freeman, M P

    2016-01-01

    We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4–20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions—Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort. PMID:26643541

  10. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma.

    PubMed

    Dimopoulos, Meletios A; Palumbo, Antonio; Corradini, Paolo; Cavo, Michele; Delforge, Michel; Di Raimondo, Francesco; Weisel, Katja C; Oriol, Albert; Hansson, Markus; Vacca, Angelo; Blanchard, María Jesús; Goldschmidt, Hartmut; Doyen, Chantal; Kaiser, Martin; Petrini, Mario; Anttila, Pekka; Cafro, Anna Maria; Raymakers, Reinier; San-Miguel, Jesus; de Arriba, Felipe; Knop, Stefan; Röllig, Christoph; Ocio, Enrique M; Morgan, Gareth; Miller, Neil; Simcock, Mathew; Peluso, Teresa; Herring, Jennifer; Sternas, Lars; Zaki, Mohamed H; Moreau, Philippe

    2016-07-28

    Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated. www.Clinicaltrials.gov identifier NCT01712789. PMID:27226434

  11. Multiple Doses of Erythropoietin Impair Liver Regeneration by Increasing TNF-α, the Bax to Bcl-xL Ratio and Apoptotic Cell Death

    PubMed Central

    Cantré, Daniel; Abshagen, Kerstin; Menger, Michael D.; Vollmar, Brigitte

    2008-01-01

    Background Liver resection and the use of small-for-size grafts are restricted by the necessity to provide a sufficient amount of functional liver mass. Only few promising strategies to maximize liver regeneration are available. Apart from its erythropoiesis-stimulating effect, erythropoietin (EPO) has meanwhile been recognized as mitogenic, tissue-protective, and anti-apoptotic pleiotropic cytokine. Thus, EPO may support regeneration of hepatic tissue. Methodology Rats undergoing 68% hepatectomy received daily either high dose (5000 IU/kg bw iv) or low dose (500 IU/kg bw iv) recombinant human EPO or equal amounts of physiologic saline. Parameters of liver regeneration and hepatocellular apoptosis were assessed at 24 h, 48 h and 5 d after resection. In addition, red blood cell count, hematocrit and serum EPO levels as well as plasma concentrations of TNF-α and IL-6 were evaluated. Further, hepatic Bcl-xL and Bax protein expression were analyzed by Western blot. Principal Findings Administration of EPO significantly reduced the expression of PCNA at 24 h followed by a significant decrease in restitution of liver mass at day 5 after partial hepatectomy. EPO increased TNF-α levels and shifted the Bcl-xL to Bax ratio towards the pro-apoptotic Bax resulting in significantly increased hepatocellular apoptosis. Conclusions Multiple doses of EPO after partial hepatectomy increase hepatocellular apoptosis and impair liver regeneration in rats. Thus, careful consideration should be made in pre- and post-operative recombinant human EPO administration in the setting of liver resection and transplantation. PMID:19079544

  12. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma

    PubMed Central

    Palumbo, Antonio; Corradini, Paolo; Cavo, Michele; Delforge, Michel; Di Raimondo, Francesco; Weisel, Katja C.; Oriol, Albert; Hansson, Markus; Vacca, Angelo; Blanchard, María Jesús; Goldschmidt, Hartmut; Doyen, Chantal; Kaiser, Martin; Petrini, Mario; Anttila, Pekka; Cafro, Anna Maria; Raymakers, Reinier; San-Miguel, Jesus; de Arriba, Felipe; Knop, Stefan; Röllig, Christoph; Ocio, Enrique M.; Morgan, Gareth; Miller, Neil; Simcock, Mathew; Peluso, Teresa; Herring, Jennifer; Sternas, Lars; Zaki, Mohamed H.; Moreau, Philippe

    2016-01-01

    Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated. www.Clinicaltrials.gov identifier NCT01712789. PMID:27226434

  13. Intravenous linezolid administered orally: a novel desensitization strategy.

    PubMed

    Cawley, Michael J; Lipka, Ozana

    2006-04-01

    A 41-year-old woman with a history of myasthenia gravis was admitted to a local hospital because of severe muscle weakness, ptosis, shortness of breath, nausea and vomiting, and fever. Blood cultures revealed Enterococcus faecium resistant to several antimicrobial agents. The organism had minimum inhibitory concentrations above 16 microg/ml for vancomycin and above 2 microg/ml for quinupristin-dalfopristin. In the absence of therapeutic alternatives, treatment with linezolid was required (minimum inhibitory concentration 1.5 microg/ml). The first dose of linezolid resulted in a hypersensitivity reaction consistent with an immunoglobulin E-mediated response requiring medical intervention. Because of a lack of intravenous access and because of limited availability of the oral suspension from the manufacturer, a desensitization protocol was implemented in which the intravenous formulation of linezolid was given orally. The patient was successfully desensitized by using an escalating, 14-dose procedure. We believe this is the first case in the English language literature to describe successful desensitization with the oral administration of intravenous linezolid in a patient with E. faecium bacteremia who was allergic to oxazolidinone. PMID:16553517

  14. Effects of multiple oral dosing on IgE synthesis in mice: oral sensitization by albumin extracts from seeds of Jack fruit (Artocarpus integrifolia) containing lectins.

    PubMed Central

    Restum-Miguel, N; Prouvost-Danon, A

    1985-01-01

    The IgE antibody response was studied in DBA/2 mice; the mice were pretreated orally with albumin extracts from seeds of Jack fruit (Jackalbumin) and subsequently immunized subcutaneously with Jackalbumin mixed with ovalbumin (OA) and a synthetic adjuvant, muramyl dipeptide (MDP). The allergenicity of Jackalbumin was evaluated by its capacity to induce a specific IgE response which was measured by passive cutaneous anaphylaxis (PCA) and by degranulation of washed peritoneal mast cells following antigen challenge (Jackalbumin or OA). Antibody against the crude extracts and anti-lectin (FIISP) IgE responses were also tested by PCA. After being fed eight doses of 1 mg Jackalbumin, DBA/2 mice became immunized: i.e. specific IgE antibody responses were observed and the peritoneal mast cells became sensitized. An increase in IgE response was verified in mice that were pre-fed and subsequently immunized. The results indicated that: the albumin extracts from Jack seeds, containing lectins, can be allergenic by the oral route; multiple oral doses with these extracts can induce an enhancement of the IgE response on subsequent subcutaneous immunization; antigenically, Jackalbumin does not seem to cross-react with OA; the lectins contained in the albumin fraction from Artocarpus seeds were also shown to be allergenic; the IgE titres showed an inverse correlation to the degree of purification of the lectin used for PCA challenge. PMID:3972438

  15. Effect of application sites and multiple doses on nicotine pharmacokinetics in healthy male Japanese smokers following application of the transdermal nicotine patch.

    PubMed

    Sobue, Satoshi; Sekiguchi, Kaneo; Kikkawa, Hironori; Irie, Shin

    2005-12-01

    The transdermal nicotine patch, which contains 25 mg nicotine per 30 cm(2), is designed to deliver approximately 15 mg nicotine to the blood circulation in 16 hours of application for the treatment of smoking cessation. It was applied to 3 different skin sites (upper arm, abdomen, and back) to examine regional variations in percutaneous nicotine absorption in a single-dose, 3-period, crossover study involving 9 healthy male Japanese smokers. Nicotine pharmacokinetics during once-daily application of the transdermal nicotine patch for 5 days was also investigated in 10 healthy smokers. There were statistically significant effects of application sites on percutaneous nicotine absorption. The ratios (90% confidence intervals) of AUC and C(max) for comparison to the upper arm were 102% (88, 117%) and 106% (95, 119%) for the back and 75% (65, 87%) and 75% (66, 84%) for the abdomen, respectively. These suggest that systemic exposure after application to the upper arm was greater compared with the abdomen but equivalent to the back. Following multiple doses, linear pharmacokinetics and no significant accumulation of nicotine concentrations were observed, and steady state was reached by day 2. Only mild itching and erythema were observed at the application sites. The transdermal nicotine patch was well tolerated in both studies.

  16. Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma.

    PubMed

    Kröger, Nicolaus; Shimoni, Avichai; Zagrivnaja, Maria; Ayuk, Francis; Lioznov, Michael; Schieder, Heike; Renges, Helmut; Fehse, Boris; Zabelina, Tatjana; Nagler, Arnon; Zander, Axel R

    2004-11-15

    To improve the antimyeloma effect of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation in multiple myeloma, we investigated in a phase 1/2 study the effect of low-dose thalidomide (100 mg) followed by DLI in 18 patients with progressive disease or residual disease and prior ineffective DLI after allografting. The overall response rate was 67%, including 22% complete remission. Major toxicity of thalidomide was weakness grade I/II (68%) and peripheral neuropathy grade I/II (28%). Only 2 patients experienced mild grade I acute graft versus host disease (aGvHD) of the skin, while no grades II to IV aGvHD was seen. De novo limited chronic GvHD (cGvHD) was seen in 2 patients (11%). The 2-year estimated overall and progression-free survival were 100% and 84%, respectively. Adoptive immunotherapy with low-dose thalidomide and DLI induces a strong antimyeloma effect with low incidence of graft versus host disease.

  17. Effects of multiple oral dosing on IgE synthesis in mice: oral sensitization by albumin extracts from seeds of Jack fruit (Artocarpus integrifolia) containing lectins.

    PubMed

    Restum-Miguel, N; Prouvost-Danon, A

    1985-03-01

    The IgE antibody response was studied in DBA/2 mice; the mice were pretreated orally with albumin extracts from seeds of Jack fruit (Jackalbumin) and subsequently immunized subcutaneously with Jackalbumin mixed with ovalbumin (OA) and a synthetic adjuvant, muramyl dipeptide (MDP). The allergenicity of Jackalbumin was evaluated by its capacity to induce a specific IgE response which was measured by passive cutaneous anaphylaxis (PCA) and by degranulation of washed peritoneal mast cells following antigen challenge (Jackalbumin or OA). Antibody against the crude extracts and anti-lectin (FIISP) IgE responses were also tested by PCA. After being fed eight doses of 1 mg Jackalbumin, DBA/2 mice became immunized: i.e. specific IgE antibody responses were observed and the peritoneal mast cells became sensitized. An increase in IgE response was verified in mice that were pre-fed and subsequently immunized. The results indicated that: the albumin extracts from Jack seeds, containing lectins, can be allergenic by the oral route; multiple oral doses with these extracts can induce an enhancement of the IgE response on subsequent subcutaneous immunization; antigenically, Jackalbumin does not seem to cross-react with OA; the lectins contained in the albumin fraction from Artocarpus seeds were also shown to be allergenic; the IgE titres showed an inverse correlation to the degree of purification of the lectin used for PCA challenge.

  18. [Value of the intravenous route for the use of phenobarbital in asphyxiated full term newborn infants].

    PubMed

    Gold, F; Bourin, M; Granry, J C; Amine, A; Breteau, M; Laugier, J

    1979-06-01

    Phenobarbital (20 mg/kg) was given intravenously to asphyxiated full term neonates who were less than 48 hours old. Further doses were given for 4 days (5 mgs/kg/d). Plasma levels were within the therapeutic range from 5 to 36 hours after the first injection but the maintenance dose always resulted in overdose by 5th day. The exact maintenance dose needs to be determined.

  19. Multiple doses of diacylglycerol and calcium ionophore are necessary to activate AP-1 enhancer activity and induce markers of macrophage differentiation.

    PubMed

    William, F; Wagner, F; Karin, M; Kraft, A S

    1990-10-25

    In contrast to phorbol esters, multiple doses of diacylgycerols are needed to differentiate U937 human monoblastic leukemic cells to a macrophage-like phenotype. Although both of these agents similarly activate protein kinase C in vitro, it is not known why these agents appear to have differing biologic effects. One possibility is that they regulate gene transcription in slightly different ways. Regulation of gene transcription by phorbol esters is complex and involves the stimulation of the transactivating proteins Jun and Fos which form dimers and bind to the AP-1 enhancer elements (5'-TGAGTCA-3'). To understand whether diacylglycerols regulate gene transcription similarly to phorbol esters and to examine whether activation of AP-1 enhancer activity is correlated with differentiation, we have treated U937 human monoblastic leukemic cells with these agents and examined activation of transcription from AP-1 enhancer elements. We find that, although a single dose of diacylglycerol, like phorbol esters, is sufficient to elevate mRNA levels of both the c-jun and c-fos protooncogenes, in contrast to phorbol esters there is no increase in either Jun protein or activation of AP-1 enhancer activity. However, multiple doses of this agent given over 24 h stimulate repeated elevations in c-jun and c-fos mRNA, increases in Jun protein, and enhancer activation. Treatment of U937 cells with ionomycin, a calcium ionophore, also stimulates an increase in c-jun mRNA, but neither activates AP-1 enhancer activity nor stimulates differentiation of these cells. However ionomycin functions to enhance the effects of diacylglycerols both on transcriptional activation and U937 differentiation. These results suggest a complex regulation of AP-1 enhancer activity in U937 cells by diacylglycerols involving both transcriptional and post-transcriptional regulatory mechanisms. Maximal activation of AP-1 enhancer elements, and not changes in jun and fos mRNA, is correlated with increases in

  20. Regional intravenous limb perfusion compared to systemic intravenous administration for marimastat delivery to equine lamellar tissue.

    PubMed

    Underwood, C; Collins, S N; Mills, P C; Van Eps, A W; Allavena, R E; Medina Torres, C E; Pollitt, C C

    2015-08-01

    Pharmaceutical agents with potential for laminitis prevention have been identified. Many of these, including the MMP inhibitor marimastat, are impractical for systemic administration. This study compared local delivery of marimastat by regional limb perfusion (RLP) to systemic intravenous bolus dosing (SIVB), and established whether RLP results in local lamellar drug delivery. Six adult horses received 0.23 mg/kg of marimastat by RLP followed by 0.23 mg/kg marimastat by SIVB, with a 24-h washout period. Lamellar ultrafiltration probes sampled lamellar interstitial fluid as lamellar ultrafiltrate (LUF). LUF and plasma marimastat concentrations (LUF[M] and P[M] respectively) were measured for 24 h after each treatment. Regional pharmacokinetic parameters were calculated using noncompartmental analyses. The LUF C(max) following RLP was 232 [34-457] times that following SIVB. LUF[M] after RLP were higher than those obtained after SIVB for 18 h (P < 0.03). Median LUF[M] were > IC(90) of equine lamellar MMP-2 and MMP-9 for 9 h after tourniquet removal. RLP appeared superior to SIVB for lamellar marimastat delivery (higher LUF C(max),, AUC and T > IC(90) of lamellar MMPs). However, frequent dosing is necessary to achieve therapeutic lamellar concentrations. RLP could be used to investigate whether marimastat prevents experimentally induced laminitis. Further refinement of the technique and dosing interval is necessary before clinical application. PMID:25641095

  1. Pulmonary effects of intravenous atropine induce ventilation perfusion mismatch.

    PubMed

    Gaspari, Romolo J; Paydarfar, David

    2014-05-01

    Atropine is used for a number of medical conditions, predominantly for its cardiovascular effects. Cholinergic nerves that innervate pulmonary smooth muscle, glands, and vasculature may be affected by anticholinergic medications. We hypothesized that atropine causes alterations in pulmonary gas exchange. We conducted a prospective interventional study with detailed physiologic recordings in anesthetized, spontaneously breathing rats (n = 8). Animals breathing a normoxic gas mixture titrated to a partial arterial pressure of oxygen of 110-120 were exposed to an escalating dose of intravenous atropine (0.001, 0.01, 0.1, 5.0, and 20.0 mg/kg body mass). Arterial blood gas measurements were recorded every 2 min (×5) at baseline, and following each of the 5 doses of atropine. In addition, the animals regional pulmonary blood flow was measured using neutron-activated microspheres. Oxygenation decreased immediately following intravenous administration of atropine, despite a small increase in the volume of inspired air with no change in respiratory rate. Arterial blood gas analysis showed an increase in pulmonary dysfunction, characterized by a widening of the alveolar-arteriole gradient (p < 0.003 all groups except for the lowest dose of atropine). The microsphere data demonstrates an abrupt and marked heterogeneity of pulmonary blood flow following atropine treatment. In conclusion, atropine was found to decrease pulmonary gas exchange in a dose-dependent fashion in this rat model.

  2. Efficacy and safety of intravenous iron sucrose in treating adults with iron deficiency anemia

    PubMed Central

    Cançado, Rodolfo Delfini; de Figueiredo, Pedro Otavio Novis; Olivato, Maria Cristina Albe; Chiattone, Carlos Sérgio

    2011-01-01

    Background Iron deficiency is the most common disorder in the world, affecting approximately 25% of the world`s population and the most common cause of anemia. Objective To evaluate the efficacy and safety of intravenous iron sucrose (IS) in the treatment of adults with iron deficiency anemia Methods Eighty-six adult patients with iron deficiency anemia, who had intolerance or showed no effect with oral iron therapy, received a weekly dose of 200 mg of intravenous iron sucrose until the hemoglobin level was corrected or until receiving the total dose of intravenous iron calculated for each patient Results The mean hemoglobin and serum ferritin levels were 8.54 g/dL and 7.63 ng/mL (pre-treatment) and 12.1 g/dL and 99.0 ng/mL (post-treatment) (p-value < 0.0001), respectively. The average increases in hemoglobin levels were 3.29 g/dL for women and 4.58 g/dL for men; 94% of male and 84% of female patients responded (hemoglobin increased by at least 2 g/dL) to intravenous iron therapy. Correction of anemia was obtained in 47 of 69 (68.1%) female patients and in 12 of 17 male (70.6%) patients. A total of 515 intravenous infusions of iron sucrose were administered and iron sucrose was generally well tolerated with no moderate or serious adverse drug reactions recorded by the investigators. Conclusions Our data confirm that the use of intravenous iron sucrose is a safe and effective option in the treatment of adult patients with iron deficiency anemia who lack satisfactory response to oral iron therapy. Intravenous iron sucrose is well tolerated and with a clinically manageable safety profile when using appropriate dosing and monitoring. The availability of intravenous iron sucrose would potentially improve compliance and thereby reduce morbidities from iron deficiency. PMID:23049360

  3. Treatment of aggressive multiple myeloma by high-dose chemotherapy and total body irradiation followed by blood stem cells autologous graft

    SciTech Connect

    Fermand, J.P.; Levy, Y.; Gerota, J.; Benbunan, M.; Cosset, J.M.; Castaigne, S.; Seligmann, M.; Brouet, J.C.

    1989-01-01

    Eight patients with stage III aggressive multiple myeloma, refractory to current chemotherapy in six cases, were treated by high-dose chemotherapy (nitrosourea, etoposide, and melphalan) (HDC) and total body irradiation (TBI), followed by autografting with blood stem cells. These cells were previously collected by leukapheresis performed during hematologic recovery following cytotoxic drug-induced bone marrow aplasia. Seven patients were alive 9 to 17 months after HDC-TBI and graft. One died at day 40 from cerebral bleeding. All living patients achieved a 90% or greater reduction in tumor mass. In two cases, a complete remission (CR) has persisted at a follow-up of 15 and 16 months. Three patients have been well and off therapy with stable minimal residual disease (RD) since 10, 11, and 17 months, respectively. A patient in apparent CR and another with RD have relapsed 9 to 12 months posttreatment. Autologous blood-derived hematopoietic stem cells induced successful and sustained engraftment in all living patients. These results, although still preliminary, indicate that HDC and TBI, followed by blood stem cells autograft, which has both practical and theoretical interest over allogeneic or autologous bone marrow transplantation, deserve consideration in selected patients with multiple myeloma.

  4. Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice

    SciTech Connect

    Kang, Shin-Ae; Tsolmon, Bilegtsaikhan; Mann, Aman P.; Zheng, Wei; Zhao, Lichao; Zhao, Yan Daniel; Volk, David E.; Lokesh, Ganesh L.-R.; Morris, Lynsie; Gupta, Vineet; Razaq, Wajeeha; Rui, Hallgeir; Suh, K. Stephen; Gorenstein, David G.; Tanaka, Takemi

    2015-08-15

    The medical applications of aptamers have recently emerged. We developed an antagonistic thioaptamer (ESTA) against E-selectin. Previously, we showed that a single injection of ESTA at a dose of 100 μg inhibits breast cancer metastasis in mice through the functional blockade of E-selectin. In the present study, we evaluated the safety of different doses of intravenously administered ESTA in single-dose acute and repeat-dose subacute studies in ICR mice. Our data indicated that intravenous administration of up to 500 μg ESTA did not result in hematologic abnormality in either study. Additionally, intravenous injection of ESTA did not affect the levels of plasma cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, GM-CSF, IFN-γ, and TNF-α) or complement split products (C3a and C5a) in either study. However, repeated injections of ESTA slightly increased plasma ALT and AST activities, in accordance with the appearance of small necrotic areas in the liver. In conclusion, our data demonstrated that intravenous administration of ESTA does not cause overt hematologic, organs, and immunologic responses under the experimental conditions. - Highlights: • Intravenous administration of ESTA was well tolerated. • ESTA up to 500 μg does not cause hematologic, organs, and immunologic responses. • ESTA-mediated hepatic abnormality was considered minor.

  5. Intravenous human immunoglobulin for treatment of folliculitis decalvans.

    PubMed

    Ismail, Nuriah; Ralph, Nicola; Murphy, Gillian

    2015-10-01

    We report a case of folliculitis decalvans (FD) successfully treated with intravenous human immunoglobulin (HIG). Many conventional treatments with topical agents and oral antibiotics had failed to achieve disease remission, treatment with HIG at a dose of 2 g/kg for the first month, reduced to 1 g/kg for second to fourth months was therefore started, which resulted in rapid improvement and ultimately complete resolution of FD. Clinical improvement was noted after the first infusion of HIG and remission of inflammation was achieved after the fourth infusion. Disease remission was sustained for six months following the last HIG infusion. The exact mechanism of action of HIG is poorly understood. However, it is thought to act as an immunomodulatory agent by altering different components of immune functions. To our knowledge, this is the first case reported in the literature of FD successfully treated with intravenous HIG.

  6. [Toxicity of prilocaine and bupivacaine in intravenous regional anesthesia].

    PubMed

    Tryba, M; Hausmann, E; Zenz, M; Wellhöner, H H

    1982-08-01

    In a prospective randomized study plasma levels of prilocaine and bupivacaine were analyzed after intravenous regional analgesia (IVRA). 20 patients respectively received either 1 mg/kg bupivacaine or 4 mg/kg prilocaine in an equipotent dosis. Prilocaine proved to be significantly less toxic than bupivacaine. Plasma levels of bupivacaine, expressed as percentage of the toxic limit, were threefold higher than those of prilocaine. In one case the maximum level of bupivacaine reached even 85% of the toxic limit. This demonstrates the possibility of dangerous side effects when exceeding the bupivacaine dose of 1 mg/kg. Methaemoglobin formation following use of prilocaine was of no clinical importance. Prilocaine is the agent of choice for intravenous regional analgesia. The use of bupivacaine for IVRA should be limited to special indications.

  7. Scurvy in an alcoholic patient treated with intravenous vitamins.

    PubMed

    Ong, John; Randhawa, Rabinder

    2014-01-01

    Vitamin C deficiency is rare in developed countries but there is an increased prevalence in chronic alcohol abusers. In the UK, it is common practice to treat patients with chronic alcoholism who are admitted to hospital with intravenous vitamins B1, B2, B3, B6 and C for 2-3 days, followed by oral thiamine and vitamin B-compound tablets. This is a case of a 57-year-old man with a history of chronic alcoholism and chronic obstructive lung disease who was admitted to the intensive care unit for pneumonia requiring ventilatory support. He was given high doses of intravenous vitamins B1, B2, B3, B6 and C for 3 days then oral thiamine and vitamin B compound tablets but developed scurvy 4 days later. He was restarted on oral vitamin C supplementation and showed signs of improvement within 3 days of treatment. PMID:24728889

  8. Scurvy in an alcoholic patient treated with intravenous vitamins.

    PubMed

    Ong, John; Randhawa, Rabinder

    2014-04-11

    Vitamin C deficiency is rare in developed countries but there is an increased prevalence in chronic alcohol abusers. In the UK, it is common practice to treat patients with chronic alcoholism who are admitted to hospital with intravenous vitamins B1, B2, B3, B6 and C for 2-3 days, followed by oral thiamine and vitamin B-compound tablets. This is a case of a 57-year-old man with a history of chronic alcoholism and chronic obstructive lung disease who was admitted to the intensive care unit for pneumonia requiring ventilatory support. He was given high doses of intravenous vitamins B1, B2, B3, B6 and C for 3 days then oral thiamine and vitamin B compound tablets but developed scurvy 4 days later. He was restarted on oral vitamin C supplementation and showed signs of improvement within 3 days of treatment.

  9. Effects of Intrarenal and Intravenous Infusion of the Phosphodiesterase 3 Inhibitor Milrinone on Renin Secretion

    NASA Technical Reports Server (NTRS)

    Kumagai, Kazuhiro; Reid, Ian A.

    1994-01-01

    We have reported that administration of the phosphodiesterase III inhibitor milrinone increases renin secretion in conscious rabbits. The aim of the present study was to determine if the increase in renin secretion results from a direct renal action of milrinone, or from an indirect extrarenal effect of the drug. This was accomplished by comparing the effects of intrarenal and intravenous infusion of graded doses of milrinone on plasma renin activity in unilaterally nephrectomized conscious rabbits. Milrinone was infused into the renal artery in doses of 0.01, 0.1 and 1.0 micro-g/kg/min, and intravenously in the same rabbits in doses of 0.01, 0.1, 1.0 and 10 micro-g/kg/min. Each dose was infused for 15 min. No intrarenal dose of milrinone altered plasma renin activity or arterial pressure, although at the highest dose, there was a small increase in heart rate. Intravenous infusion of milrinone at 1.0 micro-g/kg/min increased plasma renin activity to 176 +/- 55% of the control value (P less than 0.05). Heart rate increased but arterial pressure did not change. Intravenous infusion of milrinone at 1O micro-g/kg/min increased plasma renin activity to 386 +/- 193% of control in association with a decrease in arterial pressure and an increase in heart rate. These results confirm that milrinone increases renin secretion, and indicate that the stimulation is due to an extrarenal effect of the drug.

  10. Pathology, organ distribution, and immune response after single and repeated intravenous injection of rats with clinical-grade parvovirus H1.

    PubMed

    Geletneky, Karsten; Leoni, Anne-Laure; Pohlmeyer-Esch, Gabriele; Loebhard, Stephanie; Baetz, Andrea; Leuchs, Barbara; Roscher, Mandy; Hoefer, Constance; Jochims, Karin; Dahm, Michael; Huber, Bernard; Rommelaere, Jean; Krebs, Ottheinz; Hajda, Jacek

    2015-02-01

    Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated. PMID:25730754

  11. Pancreatic enzyme secretion during intravenous fat infusion.

    PubMed

    Burns, G P; Stein, T A

    1987-01-01

    The nutritional support of patients with pancreatic and high gastrointestinal fistulas and severe pancreatitis frequently involves intravenous fat infusion. There are conflicting reports on the effect of intravenous fat on pancreatic exocrine secretion. In 10 dogs with chronic pancreatic fistulas, pancreatic juice was collected during secretin (n = 10) or secretin + cholecystokinin (n = 4) stimulation, with and without intravenous fat infusion (5 g/hr). The hormonal-stimulated secretion of lipase, amylase, trypsin, total protein, bicarbonate, and water was unchanged during fat infusion. This study supports the use of intravenous fat as a nutritional source when it is desirable to avoid stimulation of the pancreas.

  12. Intravenous glucose preparation as the source of an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae infections in the neonatal unit of a regional hospital in KwaZulu-Natal.

    PubMed

    Moodley, Prashini; Coovadia, Yacoob M; Sturm, A Willem

    2005-11-01

    In the last week of May 2005, staff at Mahatma Gandhi Memorial Hospital in KwaZulu-Natal realised that many babies in the high-care nursery ward had bloodstream infections involving Klebsiella pneumoniae bacteria. Attempts to identify a common source of infection failed. The ward was therefore closed and new babies needing high care were admitted to another empty ward. Despite this, babies still became infected. This resulted in a request for assistance from the Department of Medical Microbiology of the Nelson R Mandela School of Medicine. A search for common factors through case history studies of the 26 infected babies showed that blood cultures of the babies remained positive despite the administration of appropriate antibiotics. Different options that could explain this were investigated. The organism was found in intravenous glucose preparations used for multiple dosing. Unopened vials of the same medication were sterile. The nursery was found to lack proper hand-wash facilities and to be overcrowded and understaffed. Reinforcement of hand hygiene and a ban on the multiple dosing of medicines stopped the outbreak. In conclusion, this outbreak resulted from a combination of factors among which lack of hand hygiene and multiple dosing of an intravenous glucose preparation were most significant.

  13. Clinical applications of intravenous immunoglobulins in neurology

    PubMed Central

    Hughes, R A C; Dalakas, M C; Cornblath, D R; Latov, N; Weksler, M E; Relkin, N

    2009-01-01

    Intravenous immunoglobulin (IVIg) is used increasingly in the management of patients with neurological conditions. The efficacy and safety of IVIg treatment in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain–Barré syndrome (GBS) have been established clearly in randomized controlled trials and summarized in Cochrane systematic reviews. However, questions remain regarding the dose, timing and duration of IVIg treatment in both disorders. Reports about successful IVIg treatment in other neurological conditions exist, but its use remains investigational. IVIg has been shown to be efficacious as second-line therapy in patients with dermatomyositis and suggested to be of benefit in some patients with polymyositis. In patients with inclusion body myositis, IVIg was not shown to be effective. IVIg is also a treatment option in exacerbations of myasthenia gravis. Studies with IVIg in patients with Alzheimer's disease have reported increased plasma anti-Aβ antibody titres associated with decreased Aβ peptide levels in the cerebrospinal fluid following IVIg treatment. These changes at the molecular level were accompanied by improved cognitive function, and large-scale randomized trials are under way. PMID:19883422

  14. Intranasal but not intravenous delivery of the adjuvant α-galactosylceramide permits repeated stimulation of natural killer T cells in the lung

    PubMed Central

    Courtney, Amy N.; Thapa, Prakash; Singh, Shailbala; Wishahy, Ameerah M.; Zhou, Dapeng; Sastry, Jagannadha

    2013-01-01

    Efficient induction of antigen-specific immunity is achieved by delivering multiple doses of vaccine formulated with appropriate adjuvants that can harness the benefits of innate immune mediators. The synthetic glycolipid α-galactosylceramide (α-GalCer) is a potent activator of NKT cells, a major innate immune mediator cell type effective in inducing maturation of DCs for efficient presentation of co-administered antigens. However, systemic administration of α-GalCer results in NKT cell anergy in which the cells are unresponsive to subsequent doses of α-GalCer. We show here that α-GalCer delivered as an adjuvant by the intranasal route, as opposed to the intravenous route, enables repeated activation of NKT cells and DCs, resulting in efficient induction of cellular immune responses to co-administered antigens. We show evidence that after intranasal delivery, α-GalCer is selectively presented by DCs for the activation of NKT cells, not B cells. Furthermore, higher levels of PD-1 expression, a potential marker for functional exhaustion of the NKT cells when α-GalCer is delivered by the intravenous route, are not observed after intranasal delivery. These results support a mucosal route of delivery for the utility of α-GalCer as an adjuvant for vaccines, which often requires repeated dosing to achieve durable protective immunity. PMID:21818755

  15. Intravenous lidocaine as a suppressant of coughing during tracheal intubation in elderly patients.

    PubMed

    Yukioka, H; Hayashi, M; Terai, T; Fujimori, M

    1993-08-01

    The effects of intravenously administered lidocaine on cough suppression in elderly patients over the age of 60 yr during tracheal intubation under general anesthesia were evaluated in two studies. In the first study, 100 patients received a placebo of either 0.5, 1.0, 1.5, or 2.0 mg/kg lidocaine intravenously 1 min before tracheal intubation. All visible coughs were classified as coughing. The incidence of coughing decreased as the dose of lidocaine increased. A dose of 1.5 mg/kg or more of intravenous lidocaine suppressed the cough reflex significantly (P < 0.01). In the second study, 108 patients received 2 mg/kg lidocaine intravenously or a placebo 1, 3, 5, 7, 10, or 15 min before intubation. The same criteria for determining whether a patient did or did not cough during tracheal intubation were used as in Study 1. The incidence of coughing decreased significantly (P < 0.01) when 2 mg/kg lidocaine was injected intravenously between 1 min and 3 min before attempting intubation. The cough reflex was almost entirely suppressed by plasma concentrations of lidocaine in excess of 4 micrograms/mL. The results suggest that intravenous administration of lidocaine is effective in suppressing the cough reflex during tracheal intubation in elderly patients under general anesthesia, but that relatively high plasma concentrations of lidocaine may be required for suppression of coughing. PMID:8346830

  16. Intravenous Iron Carboxymaltose as a Potential Therapeutic in Anemia of Inflammation

    PubMed Central

    Traeger, Lisa; Bäumer, Nicole; Schulze, Isabell; Kuhlmann, Tanja; Müller-Tidow, Carsten

    2016-01-01

    Intravenous iron supplementation is an effective therapy in iron deficiency anemia (IDA), but controversial in anemia of inflammation (AI). Unbound iron can be used by bacteria and viruses for their replication and enhance the inflammatory response. Nowadays available high molecular weight iron complexes for intravenous iron substitution, such as ferric carboxymaltose, might be useful in AI, as these pharmaceuticals deliver low doses of free iron over a prolonged period of time. We tested the effects of intravenous iron carboxymaltose in murine AI: Wild-type mice were exposed to the heat-killed Brucella abortus (BA) model and treated with or without high molecular weight intravenous iron. 4h after BA injection followed by 2h after intravenous iron treatment, inflammatory cytokines were upregulated by BA, but not enhanced by iron treatment. In long term experiments, mice were fed a regular or an iron deficient diet and then treated with intravenous iron or saline 14 days after BA injection. Iron treatment in mice with BA-induced AI was effective 24h after iron administration. In contrast, mice with IDA (on iron deficiency diet) prior to BA-IA required 7d to recover from AI. In these experiments, inflammatory markers were not further induced in iron-treated compared to vehicle-treated BA-injected mice. These results demonstrate that intravenous iron supplementation effectively treated the murine BA-induced AI without further enhancement of the inflammatory response. Studies in humans have to reveal treatment options for AI in patients. PMID:27404499

  17. Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation

    PubMed Central

    Fullerton, James N.; Segre, Elisabetta; De Maeyer, Roel P.H.; Maini, Alexander A.N.; Gilroy, Derek W.

    2016-01-01

    Activation of inflammatory pathways represents a central mechanism in multiple disease states both acute and chronic. Triggered via either pathogen or tissue damage-associated molecular motifs, common biochemical pathways lead to conserved yet variable physiological and immunological alterations. Dissection and delineation of the determinants and mechanisms underlying phenotypic variance in response is expected to yield novel therapeutic advances. Intravenous (IV) administration of endotoxin (gram-negative bacterial lipopolysaccharide), a specific Toll-like receptor 4 agonist, represents an in vivo model of systemic inflammation in man. National Institutes for Health Clinical Center Reference Endotoxin (CCRE, Escherichia coli O:113:H10:K negative) is employed to reliably and reproducibly generate vascular, hematological, endocrine, immunological and organ-specific functional effects that parallel, to varying degrees, those seen in the early stages of pathological states. Alteration of dose (0.06 - 4 ng/kg) and time-scale of exposure (bolus vs. infusion) allows replication of either acute or chronic inflammation and a range of severity to be elicited, with higher doses (2 - 4 ng/kg) frequently being used to create a 'sepsis-like' state. Established and novel medicinal compounds may additionally be administered prior to or post endotoxin exposure to appreciate their effect on the inflammatory cascade. Despite limitations in scope and generalizability, human IV endotoxin challenge offers a unique platform to gain mechanistic insights into inducible physiological responses and inflammatory pathways. Rationally employed it may aid translation of this knowledge into therapeutic innovations. PMID:27213711

  18. Pharmacodynamics and tolerability of repository corticotropin injection in healthy human subjects: A comparison with intravenous methylprednisolone

    PubMed Central

    Lal, Ritu; Bell, Stacie; Challenger, Rashida; Hammock, Vakessa; Nyberg, Mary; Decker, Dima; Young, David

    2015-01-01

    Abstract Repository corticotropin injection (porcine adrenocorticotropic hormone [ACTH] analog) and intravenous methylprednisolone (IVMP) are used to treat inflammatory conditions such as multiple sclerosis (MS) exacerbations and rheumatoid arthritis. This multiple‐dose, randomized, crossover, open‐label study evaluated and compared pharmacodynamic outcomes in subjects who received ACTH analog (80 U subcutaneously) or IVMP (1 g) daily for 5 days. Specific outcome measures included IVMP and cortisol concentrations, total cortisol‐equivalent exposure, immune cell population changes, and tolerability. IVMP and ACTH analog increased granulocyte numbers and decreased lymphocyte counts; effects on both were significantly less pronounced with ACTH analog. Based on total cortisol‐equivalent exposure (assuming linearity), administration of 80 U of ACTH analog equates to 30 mg IVMP. Because IVMP doses significantly higher than 30 mg are usually required to treat MS exacerbations, the lower cortisol‐equivalent exposure of 80 U ACTH analog supports the hypothesis that efficacy of ACTH analog results from both steroid‐dependent and ‐independent properties. Adverse events were mild in severity; subject incidence for adverse‐event reporting was similar following both regimens. The clinical relevance of these findings in autoimmune disease populations is unknown and requires further evaluation. PMID:26120075

  19. Antiviral response and resistance analysis of treatment-naïve HCV-infected patients receiving single and multiple doses of GS-9190.

    PubMed

    Mo, H; Hedskog, C; Svarovskaia, E; Sun, S-C; Jacobson, I M; Brainard, D M; McHutchison, J G; Miller, M D

    2016-08-01

    GS-9190 is a NS5B non-nucleoside analogue with demonstrated effectiveness in a Phase 1 monotherapy study and in combination with other DAAs for treatment of chronic HCV infection. Here, the resistance profile of GS-9190 monotherapy in a Phase 1b study was investigated. Resistance analysis was performed by population sequencing and allele-specific PCR (AS-PCR) for Y448H with an assay cut-off of 0.5%. Phenotypic susceptibility analyses were performed on patient isolates as well as site-directed mutagenesis of mutations selected during monotherapy. No resistance-associated variants were observed in patients before or after receiving single doses of GS-9190 by population sequencing. In contrast, in patients who received GS-9190 for 8 days, mutations Y448H and Y452H in NS5B were observed by population sequencing in 21/36 (58%) and 2/36 (5.6%) patients, respectively, at Day 8 or Day 14. Among the remaining 15 patients who had no detectable Y448H at Day 8 or Day 14 by population sequencing, low frequencies of Y448H ranging from 1.3 to 9.7% were detected in 14 of 15 patients by AS-PCR. By AS-PCR, Y448H remained detectable at reduced frequency in the majority of patients analysed through 4-6 months of follow-up. Chimeric HCV replicons constructed with the NS5B sequence from patients with Y448H and Y448H + Y452H/Y demonstrated 27-fold and 78.5-fold reduced susceptibility to GS-9190. In conclusion, Y448H was rapidly selected in the majority of patients receiving multiple doses of GS-9190 as monotherapy, despite undetectable levels in pretreatment samples. Y448H confers reduced susceptibility to GS-9190 and other NNIs and persisted in most patients for months post-treatment. PMID:27004425

  20. Busulfan, Melphalan, and Bortezomib versus High-Dose Melphalan as a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

    PubMed Central

    Rodriguez, Tulio E.; Hari, Parameswaran; Stiff, Patrick J.; Smith, Scott E.; Sterrenberg, Danielle; Vesole, David H.

    2016-01-01

    High-dose melphalan 200 mg/m2 (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m2 (MEL 140) and VEL 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P =.89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials. PMID:27164062

  1. Drug insight: Safety of intravenous iron supplementation with sodium ferric gluconate complex.

    PubMed

    Michael, Beckie; Fishbane, Steven; Coyne, Daniel W; Agarwal, Rajiv; Warnock, David G

    2006-02-01

    Intravenous iron is necessary for optimal management of anemia in patients receiving hemodialysis and is utilized in the majority of these patients in the US. The availability of nondextran formulations of intravenous iron has significantly improved the safety of its use. The nondextran iron formulation sodium ferric gluconate complex (SFGC) has been extensively studied in the hemodialysis population, with two large phase IV trials documenting its safety. SFGC is efficacious and, at recommended doses, is associated with a low incidence of adverse events. There have been few comparative studies of the nondextran intravenous iron preparations; however, they are known to have different pharmacokinetic characteristics. There is also evidence to indicate that these compounds differ in terms of their cytotoxic and proinflammatory properties, and their propensity to induce oxidative stress. This paper reviews the current literature on the safety of SFGC and examines the emerging safety issues surrounding the use of intravenous iron.

  2. Successful treatment of refractory Trichomonas vaginalis infection using intravenous metronidazole.

    PubMed

    Hawkins, Isobel; Carne, Christopher; Sonnex, Christopher; Carmichael, Andrew

    2015-08-01

    Trichomonas vaginalis is a sexually transmitted protozoan infection resulting in a vulvo-vaginitis and altered vaginal discharge in symptomatic women. Since its introduction in the 1960 s, metronidazole has been the first-line drug for trichomonal infection. Other nitroimidazoles, such as tinidazole, are used as alternative regimens with similar activity but at a greater expense. Treatment failure usually represents patient non-compliance or reinfection, although metronidazole resistance has previously been documented. Sensitivity testing is currently not available in the UK. Patients with disease unresponsive to first-line treatments pose a major challenge, as therapeutic options are limited. This case looks at a patient with refractory disease over an 18-month period, where intravenous infusion of metronidazole resulted in cure after multiple previous therapy failures. There is limited evidence to endorse the use of intravenous metronidazole, and this case report provides further support for its efficacy.

  3. Successful treatment of refractory Trichomonas vaginalis infection using intravenous metronidazole.

    PubMed

    Hawkins, Isobel; Carne, Christopher; Sonnex, Christopher; Carmichael, Andrew

    2015-08-01

    Trichomonas vaginalis is a sexually transmitted protozoan infection resulting in a vulvo-vaginitis and altered vaginal discharge in symptomatic women. Since its introduction in the 1960 s, metronidazole has been the first-line drug for trichomonal infection. Other nitroimidazoles, such as tinidazole, are used as alternative regimens with similar activity but at a greater expense. Treatment failure usually represents patient non-compliance or reinfection, although metronidazole resistance has previously been documented. Sensitivity testing is currently not available in the UK. Patients with disease unresponsive to first-line treatments pose a major challenge, as therapeutic options are limited. This case looks at a patient with refractory disease over an 18-month period, where intravenous infusion of metronidazole resulted in cure after multiple previous therapy failures. There is limited evidence to endorse the use of intravenous metronidazole, and this case report provides further support for its efficacy. PMID:25161176

  4. Electroporation-delivered transdermal neostigmine in rats: equivalent action to intravenous administration

    PubMed Central

    Berkó, Szilvia; Szűcs, Kálmán F; Balázs, Boglárka; Csányi, Erzsébet; Varju, Gábor; Sztojkov-Ivanov, Anita; Budai-Szűcs, Mária; Bóta, Judit; Gáspár, Róbert

    2016-01-01

    Purpose Transdermal electroporation has become one of the most promising noninvasive methods for drug administration, with greatly increased transport of macromolecules through the skin. The cecal-contracting effects of repeated transdermal electroporation delivery and intravenous administration of neostigmine were compared in anesthetized rats. Methods The cecal contractions were detected with implantable strain gauge sensors, and the plasma levels of neostigmine were followed by high-performance liquid chromatography. Results Both intravenously and EP-administered neostigmine (0.2–66.7 μg/kg) increased the cecal contractions in a dose-dependent manner. For both the low doses and the highest dose, the neostigmine plasma concentrations were the same after the two modes of administration, while an insignificantly higher level was observed at a dose of 20 μg/kg after intravenous administration as compared with the electroporation route. The contractile responses did not differ significantly after the two administration routes. Conclusion The results suggest that electroporation-delivered neostigmine elicits action equivalent to that observed after intravenous administration as concerning both time and intensity. Electroporation permits the delivery of even lower doses of water-soluble compounds through the skin, which is very promising for clinical practice. PMID:27274203

  5. Fluoropolymer-Based Emulsions for the Intravenous Delivery of Sevoflurane

    PubMed Central

    Fast, Jonathan P.; Perkins, Mark G.; Pearce, Robert A.; Waters, Ralph M.; Mecozzi, Sandro

    2009-01-01

    Background The intravenous delivery of halogenated volatile anesthetics has been previously achieved using phospholipid-stabilized emulsions, e.g. Intralipid. However, fluorinated volatile anesthetics, such as sevoflurane, are partially fluorophilic and do not mix well with classic non-fluorinated lipids. This effect limits the maximum amount of sevoflurane that can be stably emulsified in Intralipid to 3.5% v/v. This is a significant limitation to the potential clinical use of Intralipid-based emulsions. Methods The authors prepared a 20% v/v sevoflurane emulsion using a novel fluorinated surfactant and tested its effectiveness and therapeutic index by administering it to male Sprague-Dawley rats via intravenous injection into the jugular vein. The median effective dose to induce anesthesia (ED50), median lethal dose (LD50), and therapeutic index (LD50 / ED50) were determined. Anesthesia was measured by loss of the forepaw righting reflex. Results The ED50 and LD50 values were found to be 0.41 and 1.05 mL emulsion / kg body weight, respectively. These lead to a therapeutic index of 2.6, which compares favorably to previously determined values of emulsified isoflurane, as well as values for propofol and thiopental. Conclusions A novel semi-fluorinated surfactant was able to considerably increase the maximum amount of stably emulsified sevoflurane compared to Intralipid. These formulations can be used to rapidly induce anesthesia with bolus dosing from which recovery is smooth and rapid. PMID:18813044

  6. Failure of Intravenous or Intracardiac Delivery of Mesenchymal Stromal Cells to Improve Outcomes after Focal Traumatic Brain Injury in the Female Rat

    PubMed Central

    Turtzo, L. Christine; Budde, Matthew D.; Dean, Dana D.; Gold, Eric M.; Lewis, Bobbi K.; Janes, Lindsay; Lescher, Jacob; Coppola, Tiziana; Yarnell, Angela; Grunberg, Neil E.; Frank, Joseph A.

    2015-01-01

    Mesenchymal stromal cells secrete a variety of anti-inflammatory factors and may provide a regenerative medicine option for the treatment of traumatic brain injury. The present study investigates the efficacy of multiple intravenous or intracardiac administrations of rat mesenchymal stromal cells or human mesenchymal stromal cells in female rats after controlled cortical impact by in vivo MRI, neurobehavior, and histopathology evaluation. Neither intravenous nor intracardiac administration of mesenchymal stromal cells derived from either rats or humans improved MRI measures of lesion volume or neurobehavioral outcome compared to saline treatment. Few mesenchymal stromal cells (<0.0005% of injected dose) were found within 3 days of last dosage at the site of injury after either delivery route, with no mesenchymal stromal cells being detectable in brain at 30 or 56 days post-injury. These findings suggest that non-autologous mesenchymal stromal cells therapy via intravenous or intracardiac administration is not a promising treatment after focal contusion traumatic brain injury in this female rodent model. PMID:25946089

  7. Increased plasma-immune cytokines throughout the high-dose melphalan-induced lymphodepletion in patients with multiple myeloma: a window for adoptive immunotherapy.

    PubMed

    Condomines, Maud; Veyrune, Jean-Luc; Larroque, Marion; Quittet, Philippe; Latry, Pascal; Lugagne, Cécile; Hertogh, Catherine; Kanouni, Tarik; Rossi, Jean-François; Klein, Bernard

    2010-01-15

    High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients with multiple myeloma. However, lymphocyte reconstitution is impaired after HDM. Recent work has suggested that the lymphopenia period occurring after various immunosuppressive or chemotherapy treatments may provide an interesting opportunity for adoptive antitumor immunotherapy. The objective of this study was to determine an immunotherapy window after HDM and ASCT, evaluating T cell lymphopenia, and measuring circulating immune cytokine concentrations in patients with multiple myeloma. The counts of T cell subpopulations reached a nadir at day 8 post-ASCT (day 10 post-HDM) and recovered by day 30. IL-6, IL-7, and IL-15 plasma levels increased on a median day 8 post-ASCT, respectively, 35-fold, 8-fold, and 10-fold compared with pre-HDM levels (p < or = 0.05). The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation. In conclusion, the early lymphodepletion period, occurring 4-11 d post-HDM and ASCT, is associated with an increase of circulating immune cytokines and could be an optimal window to enhance the survival and proliferation of polyclonal T cells present in the ASC autograft and also of specific antimyeloma T cells previously expanded in vitro.

  8. Antigen-specific T-cell immunity in multiple myeloma patients is restored following high-dose therapy: implications for timing of vaccination.

    PubMed

    Svane, I M; Nikolajsen, K; Johnsen, H E

    2007-10-01

    The present study analyses the influence of high-dose chemotherapy (HD) and autologous stem cell transplantation on natural and vaccine induced specific immunity in multiple myeloma patients. Peripheral blood was collected from six multiple myeloma (MM) patients at serial time points in connection with treatment and during a follow-up period of 3 months. T-cell response to cytomegalovirus (CMV), varicella zoster virus (VZV) and tetanus toxoid (TT) was determined by flow cytometry analysis for CD69, TNFalpha, IFNgamma, IL-4 expression and cell proliferation. At diagnosis and prior to induction chemotherapy TNFalpha expressing T cells in 5/6 patients were found specific for CMV, 3/6 for VZV and 4/6 for TT. Serial analyses during treatment conclude impaired immune response, however, 3 months post-transplantation all but one patient had regained cytokine expressing CD8(+) T cells specific for CMV, VZV and TT. The highest percentages of cytokine responding T cells were observed after stimulation with CMV antigen. A striking observation was the low cytokine reactivity (close to zero) measured in G-CSF mobilized blood at the time of leukapheresis. In spite of a general reduction of the CD4/CD8 ratio following transplantation, recovery of antigen specific CD4(+) T cells reactivity generally occurred prior to CD8(+) recovery and often to a higher level. In conclusion, the study demonstrates that natural as well as vaccine induced specific immunity present prior to HD was regained after stem cell transplantation, hence identifying a possible window for future vaccination trials.

  9. Partial intravenous anesthesia in cats and dogs.

    PubMed

    Duke, Tanya

    2013-03-01

    The partial intravenous anesthesia technique (PIVA) is used to lower the inspired concentration of an inhalational anesthetic by concurrent use of injectable drugs. This technique reduces the incidence of undesirable side-effects and provides superior quality of anesthesia and analgesia. Drugs commonly used for PIVA include opioids, alpha-2 adrenergic agonists, injectable anesthetic agents, and lidocaine. Most are administered by intravenous infusion.

  10. A prototype space flight intravenous injection system

    NASA Technical Reports Server (NTRS)

    Colombo, G. V.

    1985-01-01

    Medical emergencies, especially those resulting from accidents, frequently require the administration of intravenous fluids to replace lost body liquids. The development of a prototype space flight intravenous injection system is presented. The definition of requirements, injectable concentrates development, water polisher, reconstitution hardware development, administration hardware development, and prototype fabrication and testing are discussed.

  11. A consortium approach to intravenous certification.

    PubMed

    Kelly, D; Ziemba, S; Shumlas, D; Files, B

    1998-01-01

    Providing education for intravenous therapy without offering redundant courses is a concern for staff development educators. The consortium approach maximizes resources, provides a standard and consistent level of intravenous training, and provides a cost-effective remedy. Problems, solutions, and benefits to students, educators, and hospitals are described in this article. Emergent issues are also discussed.

  12. Cholescintigraphy in acute cholecystitis: use of intravenous morphine

    SciTech Connect

    Choy, D.; Shi, E.C.; McLean, R.G.; Hoschl, R.; Murray, I.P.C.; Ham, J.M.

    1984-04-01

    Conventional cholescintigraphy (60 patients) and a modified protocol (59 patients) were compared in 74 females and 45 males with acute cholecystitis. In the modified protocol, intravenous morphine was administered whenever the gallbladder was not seen 40 minutes after injection of Tc-99m-pyroxylidene-glutamate. Accuracy was 98% with morphine, compared with 88% for the conventional protocol; specificity improved from 83% to 100% with no loss of sensitivity. Low doses of morphine are well tolerated and can result in a highly accurate diagnosis of acute cholecystitis without the need for delayed imaging.

  13. Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities.

    PubMed

    Desikan, R; Barlogie, B; Sawyer, J; Ayers, D; Tricot, G; Badros, A; Zangari, M; Munshi, N C; Anaissie, E; Spoon, D; Siegel, D; Jagannath, S; Vesole, D; Epstein, J; Shaughnessy, J; Fassas, A; Lim, S; Roberson, P; Crowley, J

    2000-06-15

    High-dose therapy (HDT) has increased complete remission (CR) rates and survival in multiple myeloma (MM). We now report on continuous CR (CCR) and associated prognostic factors in 1000 consecutive patients receiving melphalan-based tandem HDT. Five-year CCR was 52% among 112 CR patients without chromosome 13 (triangle up13) abnormalities and with beta-2-microglobulin

  14. A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma.

    PubMed

    Larocca, A; Bringhen, S; Petrucci, M T; Oliva, S; Falcone, A P; Caravita, T; Villani, O; Benevolo, G; Liberati, A M; Morabito, F; Montefusco, V; Passera, R; De Rosa, L; Omedé, P; Vincelli, I D; Spada, S; Carella, A M; Ponticelli, E; Derudas, D; Genuardi, M; Guglielmelli, T; Nozzoli, C; Aghemo, E; De Paoli, L; Conticello, C; Musolino, C; Offidani, M; Boccadoro, M; Sonneveld, P; Palumbo, A

    2016-06-01

    This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients. PMID:26898189

  15. In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy.

    PubMed

    Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W

    2012-01-01

    Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle's geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability. PMID:22419872

  16. In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy

    PubMed Central

    Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W

    2012-01-01

    Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle’s geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability. PMID:22419872

  17. Intravenous self-administration of cocaine and norcocaine by dogs.

    PubMed

    Risner, M E; Jones, B E

    1980-01-01

    The potency of cocaine, relative to d-amphetamine, to initiate and maintain intravenous self-administration behavior by dogs (n = 5) was determined. Response-contingent infusions of cocaine (at unit doses of 0.15, 0.30 and 0.60 mg/kg/infusion) and d-amphetamine (at unit doses of 0.05 and 0.10 mg/kg/infusion) were available during daily 4-h sessions on a FR1 reinforcement schedule. By comparing the dose-response curves of the two drugs, it was found that 1 mg of amphetamine is equivalent to 5.3 mg of cocaine (95% confidence limits = 3.8--9.1 mg). In a second experiment, pretreatment with the alpha-adrenergic antagonist phenoxybenzamine (in doses ranging from 0.125--2.0 mg/kg, IV) did not produce any appreciable changes in responding for cocaine (0.2 mg/kg/infusion) by dogs (n = 9). In contrast, when the same animals were pretreated with the dopaminergic antagonist pimozide (in doses ranging from 5--40 mg/kg, IV), subsequent responding for cocaine was increased in a dose-dependent manner. In a third experiment it was determined that norcocaine, the N-demethylated metabolite of cocaine, would maintain self-administration behavior by dogs (n = 4) when it was substituted for cocaine. As expected, when saline was substituted for cocaine, responding was not maintained.

  18. Pharmacokinetics of acyclovir after intravenous and oral administration.

    PubMed

    de Miranda, P; Blum, M R

    1983-09-01

    Acyclovir pharmacokinetics has been extensively investigated during the various phases of clinical development. Most of the administered drug is eliminated from the body unchanged, via the kidneys by glomerular filtration and tubular secretion. After intravenous dosing of patients with normal renal function, 8 to 14% of the dose is recovered in the urine as the metabolite 9-carboxymethoxymethylguanine. Adequate distribution of acyclovir has been demonstrated in the cerebrospinal fluid, vesicular fluid, vaginal secretions and tissues. The low plasma protein binding of acyclovir precludes drug interactions involving binding displacement. When intravenous doses in the range of 2.5 to 15 mg/kg were given every 8 h to adult patients, dose-independent kinetics was observed. Continuous infusions of acyclovir over an equivalent daily dose range have achieved predictable plasma levels. Acyclovir half-life (T1/2 beta) and total body clearance (Cltot) are influenced significantly by renal function, and dosage adjustments should be made for patients with impaired renal function. For patients with normal renal function (creatinine clearance (Clcr) greater than 80 ml/min/1.73m2) mean T1/2 beta and Cltot were 2.5 h and 327 ml/min/1.73 m2, respectively. In children 1-year-old or older, Cltot normalized by body surface area was essentially the same as in adults with normal renal function, whereas Cltot for neonates was approximately one-third the adult value. In the adult population, age-related decreases in acyclovir Cltot reflect age-related changes in renal function; therefore dosage adjustments based on Clcr will compensate for age effects on acyclovir pharmacokinetics. After oral administration, the bioavailability of acyclovir was approximately 20%.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Intravenous fish oil in adult intensive care unit patients.

    PubMed

    Heller, Axel R

    2015-01-01

    Omega-3 fatty acids contained in fish oils have shown efficacy in the treatment of chronic and acute inflammatory diseases due to their pleiotropic effects on inflammatory cell signalling pathways. In a variety of experimental and clinical studies, omega-3 fatty acids attenuated hyperinflammatory conditions and induced faster recovery. This chapter will shed light on the effects of intravenous fish oil in adult intensive care unit (ICU) patients and will discuss clinical data and recent meta-analyses on the topic. While significant beneficial effects on infection rates and the lengths of ICU and hospital stays have concordantly been identified in three recent meta-analyses on non-ICU surgical patients, the level of evidence is not so clear for critically ill patients. Three meta-analyses published in 2012 or 2013 explored data on the ICU population. Although the present data suggest the consideration of enteral nutrition enriched with fish oil, borage oil and antioxidants in mild to severe acute respiratory distress syndrome, only one of the three meta-analyses found a trend (p = 0.08) of lower mortality in ICU patients receiving intravenous omega-3 fatty acids. Two of the meta-analyses indicated a significantly shorter hospital stay (5.17-9.49 days), and one meta-analysis found a significant reduction in ICU days (1.92). As a result of these effects, cost savings were postulated. Unlike in surgical patients, the effects of fish oil on infection rates were not found to be statistically significant in ICU patients, and dose-effect relationships were not established for any cohort. Thus, obvious positive secondary outcome effects with intravenous fish oil have not yet been shown to transfer to lower mortality in critically ill patients. There is a need for adequately powered, well-planned and well-conducted randomized trials to give clear recommendations on the individual utility and dosage of intravenous omega-3 fatty acids in critical illness. PMID:25471809

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

    PubMed

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

    1981-05-01

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

  1. Therapeutic horseback riding outcomes of parent-identified goals for children with autism spectrum disorder: an ABA' multiple case design examining dosing and generalization to the home and community.

    PubMed

    Holm, Margo B; Baird, Joanne M; Kim, Young Joo; Rajora, Kuwar B; D'Silva, Delma; Podolinsky, Lin; Mazefsky, Carla; Minshew, Nancy

    2014-04-01

    We examined whether different doses of therapeutic riding influenced parent-nominated target behaviors of children with autism spectrum disorder (ASD) (a) during the session (b) at home, and (c) in the community. We used a single subject multiple Baseline, multiple case design, with dosing of 1, 3, and 5 times/week. Three boys with ASD, 6-8 years of age participated, and counts of target behaviors were collected in each setting and phase of the study. Compared to Baseline, 70% of the target behaviors were better during Intervention and improvement was retained in 63% of the behaviors during Withdrawal. Increased doses of therapeutic riding were significant for magnitude of change, and the effect of the therapeutic riding sessions generalized to home and community. PMID:24091469

  2. Therapeutic horseback riding outcomes of parent-identified goals for children with autism spectrum disorder: an ABA' multiple case design examining dosing and generalization to the home and community.

    PubMed

    Holm, Margo B; Baird, Joanne M; Kim, Young Joo; Rajora, Kuwar B; D'Silva, Delma; Podolinsky, Lin; Mazefsky, Carla; Minshew, Nancy

    2014-04-01

    We examined whether different doses of therapeutic riding influenced parent-nominated target behaviors of children with autism spectrum disorder (ASD) (a) during the session (b) at home, and (c) in the community. We used a single subject multiple Baseline, multiple case design, with dosing of 1, 3, and 5 times/week. Three boys with ASD, 6-8 years of age participated, and counts of target behaviors were collected in each setting and phase of the study. Compared to Baseline, 70% of the target behaviors were better during Intervention and improvement was retained in 63% of the behaviors during Withdrawal. Increased doses of therapeutic riding were significant for magnitude of change, and the effect of the therapeutic riding sessions generalized to home and community.

  3. Therapeutic Horseback Riding Outcomes of Parent-Identified Goals for Children with Autism Spectrum Disorder: An ABA′ Multiple Case Design Examining Dosing and Generalization to the Home and Community

    PubMed Central

    Baird, Joanne M.; Kim, Young Joo; Rajora, Kuwar B.; D’Silva, Delma; Podolinsky, Lin; Mazefsky, Carla; Minshew, Nancy

    2014-01-01

    We examined whether different doses of therapeutic riding influenced parent-nominated target behaviors of children with autism spectrum disorder (ASD) (a) during the session (b) at home, and (c) in the community. We used a single subject multiple Baseline, multiple case design, with dosing of 1, 3, and 5 times/week. Three boys with ASD, 6–8 years of age participated, and counts of target behaviors were collected in each setting and phase of the study. Compared to Baseline, 70 % of the target behaviors were better during Intervention and improvement was retained in 63 % of the behaviors during Withdrawal. Increased doses of therapeutic riding were significant for magnitude of change, and the effect of the therapeutic riding sessions generalized to home and community. PMID:24091469

  4. Optical detection of intravenous infiltration

    NASA Astrophysics Data System (ADS)

    Winchester, Leonard W.; Chou, Nee-Yin

    2006-02-01

    Infiltration of medications during infusion therapy results in complications ranging from erythema and pain to tissue necrosis requiring amputation. Infiltration occurs from improper insertion of the cannula, separation of the cannula from the vein, penetration of the vein by the cannula during movement, and response of the vein to the medication. At present, visual inspection by the clinical staff is the primary means for detecting intravenous (IV) infiltration. An optical sensor was developed to monitor the needle insertion site for signs of IV infiltration. Initial studies on simulated and induced infiltrations on a swine model validated the feasibility of the methodology. The presence of IV infiltration was confirmed by visual inspection of the infusion site and/or absence of blood return in the IV line. Potential sources of error due to illumination changes, motion artifacts, and edema were also investigated. A comparison of the performance of the optical device and blinded expert observers showed that the optical sensor has higher sensitivity and specificity, and shorter detection time than the expert observers. An improved model of the infiltration monitoring device was developed and evaluated in a clinical study on induced infiltrations of healthy adult volunteers. The performance of the device was compared with the observation of a blinded expert observer. The results show that the rates of detection of infiltrations are 98% and 82% for the optical sensor and the observer, respectively. The sensitivity and specificity of the optical sensor are 0.97 and 0.98, respectively.

  5. Asymmetric generalization and interaction profiles in rhesus monkeys discriminating intravenous cocaine or intravenous heroin from vehicle.

    PubMed

    Platt, Donna M; Rowlett, James K; Spealman, Roger D

    2010-03-01

    Many polydrug abusers combine cocaine with heroin in the form of a "speedball." This study investigated the discriminative stimulus (DS) effects of speedballs in rhesus monkeys trained to discriminate either intravenous cocaine or intravenous heroin from vehicle. Initial substitution tests revealed an asymmetry in the generalization profile of dopamine and opioid agonists such that mu agonists partially substituted for cocaine, but direct and indirect dopamine agonists did not substitute for heroin. Subsequent speedball tests in which drug mixtures were administered by coinjecting the component drugs while keeping the dose-ratio constant revealed an additional asymmetry. In cocaine-trained monkeys, coadministration of cocaine and heroin produced leftward shifts in the cocaine dose-response function. Heroin's cocaine-enhancing effects were mimicked by the mu agonists fentanyl and methadone and less consistently by the delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80) and reversed by the mu antagonist naltrexone and the delta antagonist naltrindole. In heroin-trained monkeys, coadministration of cocaine and heroin attenuated the DS effects of heroin. Cocaine's heroin-attenuating effects were mimicked by the D1-like agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine (SKF 81297) and the D2-like agonist R-(-)-propylnorapomorphine and reversed by the D1-like antagonist (6aS-trans)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H- benzo[d] aphtha[2,1-b]azepin-12-ol hydrobromide (SCH 39166) and the D2-like antagonist raclopride. Attenuation of the effects of heroin was accompanied by decreases in response rate. These results suggest that heroin enhances the DS effects of cocaine via mu, and to a lesser extent delta, receptor mechanisms; whereas cocaine-induced inhibition of the DS effects of heroin probably was due at least in part to masking of the heroin DS presumably

  6. Higher infused lymphocyte dose predicts higher lymphocyte recovery, which in turn, predicts superior overall survival following autologous hematopoietic stem cell transplantation for multiple myeloma.

    PubMed

    Hiwase, Devendra K; Hiwase, Smita; Bailey, Michael; Bollard, Geraldine; Schwarer, Anthony P

    2008-01-01

    Autologous stem cell transplantation (ASCT) is the standard of care for patients with multiple myeloma (MM) younger than 70 years. However, despite this aggressive therapy most patients will still die of progressive disease. Recent reports have suggested that lymphocyte recovery is an important predictor of relapse or progressive disease in a number of hematologic malignancies including MM. We have conducted retrospective analysis of factors that could predict overall (OS) and progression free survival (PFS) in patients with MM who had ASCT. One hundred nineteen patients with multiple myeloma underwent ASCT. The median OS and PFS were 64 and 32 months, respectively. Univariate and multivariate analysis using Cox proportional hazards regression model showed that absolute lymphocyte count on day 30 following ASCT (ALC-30), international staging system (ISS) stage at diagnosis, and age at diagnosis significantly influenced OS and PFS following ASCT. OS (96 versus 48 months, P = .04) and PFS (43 versus 29 months, P = .03) following ASCT were higher in patients with ALC-30 >or=1.0 x 10(9)/L compared to patients ALC-30 <1.0 x 10(9)/L. Higher ALC-60, ALC-100, ALC-180, and ALC-365 did not predict superior OS and PFS. Patients with early-stage disease had significantly higher OS (ISS stages I, II, and III: 96, 53, and 29 months, respectively; P = .0023) and PFS (ISS stages I, II, and III: 55.5, 31, and 12 months, respectively; P = .027) compared to patients with advanced-stage disease at diagnosis. On univariate analysis, the type of initial chemotherapy (melphalan, VAD, PCAB), lymphocyte count on day of leukapheresis, and the lymphocyte dose infused (LY-DO) significantly influenced lymphocyte recovery following ASCT. Patients who received higher lymphocyte dose (LY-DO) >or=0.2 x 10(9)/kg had higher median ALC-15 (0.25 versus 0.19 x 10(9)/L; P = .3), ALC-30 (1.20 versus 0.99 x 10(9)/L; P = .08), ALC-60 (1.90 versus 1.01 x 10(9)/L; P = .013), ALC-100 (1.58 versus 1.03 x 10

  7. Curcumin pretreatment mediates antidiabetogenesis via functional regulation of adrenergic receptor subtypes in the pancreas of multiple low-dose streptozotocin-induced diabetic rats.

    PubMed

    Naijil, George; Anju, T R; Jayanarayanan, S; Paulose, C S

    2015-09-01

    Lifestyle modification pivoting on nutritional management holds tremendous potential to meet the challenge of management of diabetes. The current study hypothesizes that regular uptake of curcumin lowers the incidence of diabetes by functional regulation of pancreatic adrenergic receptor subtypes. The specific objective of the study was to identify the regulatory pathways implicated in the antidiabetogenesis effect of curcumin in multiple low-dose streptozotocin (MLD-STZ)-induced diabetic Wistar rats. Administration of MLD-STZ to curcumin-pretreated rats induced a prediabetic condition. Scatchard analysis, real-time polymerase chain reaction, and confocal microscopic studies confirmed a significant increase in α2-adrenergic receptor expression in the pancreas of diabetic rats. Pretreatment with curcumin significantly decreased α2-adrenergic receptor expression. The diabetic group showed a significant decrease in the expression of β-adrenergic receptors when compared with control. Pretreatment significantly increased β-adrenergic receptor expression to near control. When compared with the diabetic rats, a significant up-regulation of CREB, phospholipase C, insulin receptor, and glucose transporter 2 were observed in the pretreated group. Curcumin pretreatment was also able to maintain near control levels of cyclic adenosine monophosphate, cyclic guanosine monophosphate, and inositol triphosphate. These results indicate that a marked decline in α2-adrenergic receptor function relents sympathetic inhibition of insulin release. It also follows that escalated signaling through β-adrenergic receptors mediates neuronal stimulation of hyperglycemia-induced β-cell compensatory response. Curcumin-mediated functional regulation of adrenergic receptors and modulation of key cell signaling molecules improve pancreatic glucose sensing, insulin gene expression, and insulin secretion. PMID:26255758

  8. Acute paraquat exposure determines dose-dependent oxidative injury of multiple organs and metabolic dysfunction in rats: impact on exercise tolerance.

    PubMed

    Novaes, Rômulo D; Gonçalves, Reggiani V; Cupertino, Marli C; Santos, Eliziária C; Bigonha, Solange M; Fernandes, Geraldo J M; Maldonado, Izabel R S C; Natali, Antônio J

    2016-04-01

    This study investigated the pathological morphofunctional adaptations related to the imbalance of exercise tolerance triggered by paraquat (PQ) exposure in rats. The rats were randomized into four groups with eight animals each: (a) SAL (control): 0.5 ml of 0.9% NaCl solution; (b) PQ10: PQ 10 mg/kg; (c) PQ20: PQ 20 mg/kg; and (d) PQ30: PQ 30 mg/kg. Each group received a single injection of PQ. After 72 hours, the animals were subjected to an incremental aerobic running test until fatigue in order to determine exercise tolerance, blood glucose and lactate levels. After the next 24 h, lung, liver and skeletal muscle were collected for biometric, biochemical and morphological analyses. The animals exposed to PQ exhibited a significant anticipation of anaerobic metabolism during the incremental aerobic running test, a reduction in exercise tolerance and blood glucose levels as well as increased blood lactate levels during exercise compared to control animals. PQ exposure increased serum transaminase levels and reduced the glycogen contents in liver tissue and skeletal muscles. In the lung, the liver and the skeletal muscle, PQ exposure also increased the contents of malondialdehyde, protein carbonyl, 8-hydroxy-2'-deoxyguanosine, superoxide dismutase and catalase, as well as a structural remodelling compared to the control group. All these changes were dose-dependent. Reduced exercise tolerance after PQ exposure was potentially influenced by pathological remodelling of multiple organs, in which glycogen depletion in the liver and skeletal muscle and the imbalance of glucose metabolism coexist with the induction of lipid, protein and DNA oxidation, a destructive process not counteracted by the upregulation of endogenous antioxidant enzymes. PMID:27277193

  9. Curcumin pretreatment mediates antidiabetogenesis via functional regulation of adrenergic receptor subtypes in the pancreas of multiple low-dose streptozotocin-induced diabetic rats.

    PubMed

    Naijil, George; Anju, T R; Jayanarayanan, S; Paulose, C S

    2015-09-01

    Lifestyle modification pivoting on nutritional management holds tremendous potential to meet the challenge of management of diabetes. The current study hypothesizes that regular uptake of curcumin lowers the incidence of diabetes by functional regulation of pancreatic adrenergic receptor subtypes. The specific objective of the study was to identify the regulatory pathways implicated in the antidiabetogenesis effect of curcumin in multiple low-dose streptozotocin (MLD-STZ)-induced diabetic Wistar rats. Administration of MLD-STZ to curcumin-pretreated rats induced a prediabetic condition. Scatchard analysis, real-time polymerase chain reaction, and confocal microscopic studies confirmed a significant increase in α2-adrenergic receptor expression in the pancreas of diabetic rats. Pretreatment with curcumin significantly decreased α2-adrenergic receptor expression. The diabetic group showed a significant decrease in the expression of β-adrenergic receptors when compared with control. Pretreatment significantly increased β-adrenergic receptor expression to near control. When compared with the diabetic rats, a significant up-regulation of CREB, phospholipase C, insulin receptor, and glucose transporter 2 were observed in the pretreated group. Curcumin pretreatment was also able to maintain near control levels of cyclic adenosine monophosphate, cyclic guanosine monophosphate, and inositol triphosphate. These results indicate that a marked decline in α2-adrenergic receptor function relents sympathetic inhibition of insulin release. It also follows that escalated signaling through β-adrenergic receptors mediates neuronal stimulation of hyperglycemia-induced β-cell compensatory response. Curcumin-mediated functional regulation of adrenergic receptors and modulation of key cell signaling molecules improve pancreatic glucose sensing, insulin gene expression, and insulin secretion.

  10. Intravenous ampicillin pharmacokinetics in the third trimester of pregnancy.

    PubMed

    Kubacka, R T; Johnstone, H E; Tan, H S; Reeme, P D; Myre, S A

    1983-01-01

    The pharmacokinetics of a single dose of intravenous ampicillin were studied in nine patients during their third trimester of pregnancy. Each volunteer was given either 500 mg (5.7-8.8 mg/kg) or 1 g (15.4-21.4 mg/kg) of sodium ampicillin by rapid infusion. Postinfusion plasma concentration-time curves followed biexponential decay in all subjects. Calculated parameters included a mean plasma distribution volume of 177.1 +/- 97.5 ml/kg, tissue or peripheral distribution volume of 246.2 +/- 143.9 ml/kg, elimination half-life of 1.60 +/- 0.51 h, and total body clearance of 4.59 +/- 1.48 ml/min/kg. Dose-dependent disposition was not observed. Gestation-specific drug therapy research during pregnancy is discussed. PMID:6845399

  11. Clinical perspectives of intravenous ketamine anaesthesia in peafowl (Pavo cristatus).

    PubMed

    Athar, M; Shakoor, A; Muhammad, G; Sarwar, M N; Chaudhry, N I

    1996-01-01

    A total of 29 peafowl (Pavo cristatus), rectified surgically for infraorbital abscesses (n = 22), lacerated wounds (n = 4), and fractures of tibia (n = 2) and radius (n = 1), were anaesthetized by the intravenous administration of ketamine hydrochloride (Inj. Calypsol, Gedeon Richter, Hungary) in a dose of 15 20 mg/kg body weight. Divided doses (10 mg + 5 mg + 5 mg) were used with an interval of 1-2 min. No premedication was undertaken in any of the birds. Anaesthesia lasted for about 15 min and the birds gained their feet completely after 30 min to 3 hours. The respiration rate was markedly depressed (8-10/min) and the respiratory pattern was deep abdominal. Only a slight increase was observed in the heart rate. Analgesia was incomplete and muscle relaxation was not satisfactory. Mild salivation was also noticed in some of the birds (n = 3). Recovery, although not smooth, was uneventful.

  12. Clinical perspectives of intravenous ketamine anaesthesia in peafowl (Pavo cristatus).

    PubMed

    Athar, M; Shakoor, A; Muhammad, G; Sarwar, M N; Chaudhry, N I

    1996-01-01

    A total of 29 peafowl (Pavo cristatus), rectified surgically for infraorbital abscesses (n = 22), lacerated wounds (n = 4), and fractures of tibia (n = 2) and radius (n = 1), were anaesthetized by the intravenous administration of ketamine hydrochloride (Inj. Calypsol, Gedeon Richter, Hungary) in a dose of 15 20 mg/kg body weight. Divided doses (10 mg + 5 mg + 5 mg) were used with an interval of 1-2 min. No premedication was undertaken in any of the birds. Anaesthesia lasted for about 15 min and the birds gained their feet completely after 30 min to 3 hours. The respiration rate was markedly depressed (8-10/min) and the respiratory pattern was deep abdominal. Only a slight increase was observed in the heart rate. Analgesia was incomplete and muscle relaxation was not satisfactory. Mild salivation was also noticed in some of the birds (n = 3). Recovery, although not smooth, was uneventful. PMID:9055460

  13. Pharmacokinetics of Intravenous Nitrosylcobalamin, an Antitumor Agent, in Healthy Beagle Dogs: A Pilot Study

    PubMed Central

    Sysel, Annette M.; Horne, Walter I.; Steiner, Jörg M.; Suchodolski, Jan S.; Bauer, Joseph A.

    2014-01-01

    Background/Aim Nitrosylcobalamin (NO-Cbl) is a cobalamin-based anti-tumor agent. This study evaluated the pharmacokinetic parameters of NO-Cbl following intravenous administration in dogs. Materials and Methods Four dogs received 10 mg/kg, 20 mg/kg and 40 mg/kg intravenous bolus doses of NO-Cbl, with a 14-day washout period between doses. Blood samples were collected at baseline and post-dosing, and noncompartmental pharmacokinetic parameters were determined. Results Average peak serum concentrations of 2265, 5523 and 13,866 pg/mL were achieved following single-dose bolus intravenous administration of 10 mg/kg, 20 mg/kg and 40 mg/kg of NO-Cbl respectively. The average area under the curve was 12,697 h × pg/mL, 24,497 h × pg/mL and 44,976 h × pg/mL respectively, with an average elimination half-life of 16.2 h, 13.5 h and 13.1 h respectively. Conclusion These results can be used to determine the dose and dosing intervals for clinical trials evaluating NO-Cbl in humans and companion animals. PMID:22993315

  14. When conventional treatment fails: the role of intravenous immunoglobulin in recurrent pregnancy loss secondary to antiphospholipid syndrome

    PubMed Central

    Chay, Jacklyn; Lust, Karin; Kubler, Paul; Callaway, Leonie

    2013-01-01

    Recurrent pregnancy loss (RPL) is a well-recognized complication of antiphospholipid syndrome (APS). First line therapy consists of low dose aspirin and heparin. Despite conventional therapy some women fail to achieve a successful pregnancy outcome. We describe the case of a patient who had two live births following intravenous immunoglobulin therapy despite previous failure with conventional therapy for RPL in the setting of APS. We will summarize the available literature on intravenous immunoglobulin for this indication.

  15. Partial intravenous anesthesia in cats and dogs

    PubMed Central

    Duke, Tanya

    2013-01-01

    The partial intravenous anesthesia technique (PIVA) is used to lower the inspired concentration of an inhalational anesthetic by concurrent use of injectable drugs. This technique reduces the incidence of undesirable side-effects and provides superior quality of anesthesia and analgesia. Drugs commonly used for PIVA include opioids, alpha-2 adrenergic agonists, injectable anesthetic agents, and lidocaine. Most are administered by intravenous infusion. PMID:23997266

  16. Intravenous iron-containing products: EMA procrastination.

    PubMed

    2014-07-01

    A European reassessment has led to identical changes in the summaries of product characteristics (SPCs) for all intravenous iron-containing products: the risk of serious adverse effects is now highlighted, underlining the fact that intravenous iron-containing products should only be used when the benefits clearly outweigh the harms. Unfortunately, iron dextran still remains on the market despite a higher risk of hypersensitivity reactions than with iron sucrose. PMID:25162093

  17. Intravenous iron-containing products: EMA procrastination.

    PubMed

    2014-07-01

    A European reassessment has led to identical changes in the summaries of product characteristics (SPCs) for all intravenous iron-containing products: the risk of serious adverse effects is now highlighted, underlining the fact that intravenous iron-containing products should only be used when the benefits clearly outweigh the harms. Unfortunately, iron dextran still remains on the market despite a higher risk of hypersensitivity reactions than with iron sucrose.

  18. Comparison of the morphine-sparing effect of intraoperative dexmedetomidine with and without loading dose following general anesthesia in multiple-fracture patients: A prospective, randomized, controlled clinical trial.

    PubMed

    Zhao, Jin-Ning; Kong, Min; Qi, Bin; Ge, Dong-Jian

    2016-08-01

    Intraoperative dexmedetomidine (DEX) with or without loading dose both promote morphine-sparing effect in patient-controlled analgesia on postoperative acute pain. However, the contribution of the loading dose to this effect is largely unknown, especially in long-lasting surgeries. The present study was designed to investigate the role of a loading dose of DEX in this morphine-sparing effect in multiple-fracture patients following general anesthesia.Eighty-six patients scheduled multiple-fracture surgeries under general anesthesia were allocated into 3 groups which were maintained with propofol/remifentanil/Ringer solution (PRR), propofol/remifentanil/DEX with (PRDw), or without (PRDo) DEX loading dose before induction, respectively. Time to first morphine request and 24-hour morphine consumption was monitored. Pain intensity was evaluated with visual analog scale.During the first 24 hours following surgery, patients in the PRDw/o group showed increased time to first request of postoperative morphine and decreased total morphine consumption as compared with PRR patients. There was no significant difference with respect to these parameters between patients from the PRDw and PRDo groups. More patients from the PRDw groups experienced intraoperative bradycardia when compared to those from the PRR or PRDo group.This randomized controlled trial indicates that the morphine-sparing effect of intraoperative DEX was not affected by a loading dose in long-time surgeries. PMID:27537587

  19. Minimal stimulation using gonadotropin-releasing hormone (GnRH) antagonist and recombinant human follicle-stimulating hormone versus GnRH antagonist multiple-dose protocol in low responders undergoing in vitro fertilization/intracytoplasmic sperm injection.

    PubMed

    Kim, Chung-Hoon; Kim, So-Ra; Cheon, Yong-Pil; Kim, Sung-Hoon; Chae, Hee-Dong; Kang, Byung-Moon

    2009-12-01

    This prospective randomized study was performed to investigate the effectiveness of minimal stimulation using recombinant human FSH (rhFSH) and GnRH antagonist compared with GnRH antagonist multiple-dose protocol (MDP) in low responders undergoing IVF/intracytoplasmic sperm injection. Our study demonstrated that minimal stimulation in natural cycles provides similar pregnancy rates to the GnRH antagonist MDP with fewer dose and days of rhFSH used and thus can be a cost-effective alternative as a last chance before oocyte donation in low responders.

  20. Intravenous magnesium for acute asthma?

    PubMed

    2003-10-01

    Each year in the UK, around 1,500 people die from asthma. Standard treatment has been based on bronchodilators (e.g. beta 2-stimulants) and anti-inflammatory drugs (corticosteroids). The recently revised British Guideline on the Management of Asthma suggests also using a single dose of i.v. magnesium sulphate in patients with acute severe asthma, an unlicensed indication. Here we discuss the rationale for giving i.v. magnesium and whether it offers any advantage for patients with acute severe asthma.

  1. Intravenous iron, inflammation, and oxidative stress: is iron a friend or an enemy of uremic patients?

    PubMed

    Garneata, Liliana

    2008-01-01

    Intravenous iron supplementation is a recognized therapy for anemia in chronic hemodialysis patients, especially in those treated with erythropoietin. The vast majority of patients with chronic kidney disease (CKD) seem to be iron-deficient, as evaluated by the usual parameters and by iron staining on bone marrow biopsy, because of multiple forms of interference with all phases of iron metabolism. The need for iron supplementation in CKD patients becomes obvious. Intravenous iron was demonstrated to be superior to oral iron in hemodialysis patients. There is also evidence for the superiority of intravenous iron in peritoneal dialysis and in nondialysis-dependent CKD patients. On the other hand, intravenous iron could promote cytotoxicity and tissue injury, and exacerbate oxidative stress and thus endothelial dysfunction, as well as inflammation and the progression of both CKD and cardiovascular disease. Nevertheless, correction of anemia is effective in reducing oxidative stress and, consequently, cardiovascular risk. The overall risk-benefit ratio favors the use of intravenous iron alone or with an erythropoietic stimulating agent in the management of renal anemia. Clinical judgment is necessary in each individual case to diagnose iron deficiency and effectively use intravenous iron.

  2. Intravenous administration of lidocaine directly acts on spinal dorsal horn and produces analgesic effect: An in vivo patch-clamp analysis

    PubMed Central

    Kurabe, Miyuki; Furue, Hidemasa; Kohno, Tatsuro

    2016-01-01

    Intravenous lidocaine administration produces an analgesic effect in various pain states, such as neuropathic and acute pain, although the underlying mechanisms remains unclear. Here, we hypothesized that intravenous lidocaine acts on spinal cord neurons and induces analgesia in acute pain. We therefore examined the action of intravenous lidocaine in the spinal cord using the in vivo patch-clamp technique. We first investigated the effects of intravenous lidocaine using behavioural measures in rats. We then performed in vivo patch-clamp recording from spinal substantia gelatinosa (SG) neurons. Intravenous lidocaine had a dose-dependent analgesic effect on the withdrawal response to noxious mechanical stimuli. In the electrophysiological experiments, intravenous lidocaine inhibited the excitatory postsynaptic currents (EPSCs) evoked by noxious pinch stimuli. Intravenous lidocaine also decreased the frequency, but did not change the amplitude, of both spontaneous and miniature EPSCs. However, it did not affect inhibitory postsynaptic currents. Furthermore, intravenous lidocaine induced outward currents in SG neurons. Intravenous lidocaine inhibits glutamate release from presynaptic terminals in spinal SG neurons. Concomitantly, it hyperpolarizes postsynaptic neurons by shifting the membrane potential. This decrease in the excitability of spinal dorsal horn neurons may be a possible mechanism for the analgesic action of intravenous lidocaine in acute pain. PMID:27188335

  3. Intravenous Oxycodone, Hydrocodone and Morphine in Recreational Opioid Users: Abuse Potential and Relative Potencies

    PubMed Central

    Stoops, William W.; Hatton, Kevin W.; Lofwall, Michelle R.; Nuzzo, Paul A.; Walsh, Sharon L.

    2010-01-01

    Rationale Nonmedical use and abuse of prescription opioids is an increasing public health problem. Intravenous (IV) administration of opioid analgesics intended for oral use is not uncommon, yet little is known about the relative abuse potential of these drugs when administered intravenously to recreational opioid abusers without physical dependence. Methods This inpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential of IV doses of oxycodone, hydrocodone and morphine. Nine healthy adult participants reporting recreational opioid use and histories of IV opioid use completed 11 experimental sessions, including one active-dose practice session. IV doses were infused over 5-min and included three identical doses of each opioid (5, 10 and 20 mg/10 ml) and saline placebo. Physiological, subjective and performance effects were collected before and for 6 h after drug administration. Results All three opioids produced prototypical mu agonist effects (e.g., miosis; increased ratings of liking) that were generally dose-related. Pharmacodynamic effects were observed within 5 min of IV administration. Physiological effects were more prolonged than subjective effects for all three drugs. While the magnitude of effects was generally comparable across drugs and qualitatively similar, valid potency assays indicated the following potency relationship: oxycodone > morphine > hydrocodone. Conclusions There were modest potency differences between oxycodone, hydrocodone and morphine, but their overall profile of effects was similar, indicating significant abuse potential when administered intravenously. PMID:20665209

  4. Pharmacokinetics and Safety of FV-100, a Novel Oral Anti-Herpes Zoster Nucleoside Analogue, Administered in Single and Multiple Doses to Healthy Young Adult and Elderly Adult Volunteers▿

    PubMed Central

    Pentikis, Helen S.; Matson, Mark; Atiee, George; Boehlecke, Brian; Hutchins, Jeff T.; Patti, Joseph M.; Henson, Geoffrey W.; Morris, Amy

    2011-01-01

    FV-100 is the prodrug of the highly potent anti-varicella zoster virus bicyclic nucleoside analogue CF-1743. To characterize the pharmacokinetics and safety of oral FV-100, 3 randomized, double-blind, placebo-controlled clinical trials were conducted: (i) a single-ascending-dose study in 32 healthy subjects aged 18 to 55 years (100-, 200-, 400-, and 800-mg doses) with an evaluation of the food effect in the 400-mg group; (ii) a multiple-ascending-dose study in 48 subjects aged 18 to 55 years (100 mg once daily [QD], 200 mg QD, 400 mg QD, 400 mg twice a day, and 800 mg QD for 7 days); and (iii) a 2-part study in subjects aged 65 years and older with a single 400-mg dose in 15 subjects and a 400-mg QD dosing regimen for 7 days in 12 subjects. FV-100 was rapidly and extensively converted to CF-1743, the concentration of which remained above that required to reduce viral activity by 50% for the 24-hour dosing period. Renal excretion of CF-1743 was very low. A high-fat meal reduced exposure to CF-1743; a low-fat meal did not. Pharmacokinetic parameters for the elderly subjects were comparable to those for the younger subjects. FV-100 was well tolerated by all subjects. The pharmacokinetic and safety profiles of FV-100 support its continued investigation for the treatment of herpes zoster and prevention of postherpetic neuralgia with once-daily dosing and without dose modifications for elderly or renally impaired patients. PMID:21444712

  5. The evaluation of the effect of the venous tonic 263-E on capillary permeability in the rabbit after administration by intradermal and intravenous routes.

    PubMed

    Sim, A K; Haworth, D; Esteve, J; Rodriguez, L

    1981-01-01

    The effects of 2,5-dihydroxybenzene-1,4-disulphonic acid-bisdiethylamine salt (263-E) and trihydroxyethylrutoside (Vitamin P4) on capillary permeability have been compared in the rabbit. Both drugs were administered by intradermal and intravenous routes. Histamine and bradykinin were injected intradermally to increase permeability. 263-E was sown to be a potent inhibitor of permeability changes induced by histamine and bradykinin intravenous routes. Vitamin P4 maximally inhibited permeability at the lowest intravenous dose level but with increasing dose the inhibition became negligible. After intradernal administration, vitamin P4 did not inhibit permeability but potentiated the permeability response induced by histamine and bradykinin.

  6. A method for predicting gamma-radiation dose rates in the premises of the multiple forced circulation circuit of an RBMK-1000 reactor from the data of chemical and radiospectrometric monitoring of coolant

    NASA Astrophysics Data System (ADS)

    Chernikov, O. G.; Kovalev, S. M.; Epikhin, A. I.; Kozlov, E. P.; Petrov, S. I.; Rodionov, Yu. A.; Kritskii, V. G.; Styazhkin, P. S.

    2009-05-01

    A mathematical model for predicting gamma-radiation dose rate in the premises of the multiple forced circulation circuit is developed, which is based on the data of water chemistry in the circuit, radionuclide composition of coolant, and hydraulic characteristics of equipment. Data on approbation of the model are presented that were obtained during the shutdown of power units at the Leningrad and Smolensk nuclear power stations.

  7. A PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR intravenous and ingested DIMETHYLARSINIC ACID (DMAV) IN MICE.

    EPA Science Inventory

    A physiologically based pharmacokinetic (PBPK) model for the organoarsenical dimethylarsinic acid (DMA(V)) was developed in mice. The model was calibrated using tissue time course data from multiple tissues in mice administered DMA(V) intravenously. The final model structure was ...

  8. Total intravenous anesthesia for major burn surgery

    PubMed Central

    Cancio, Leopoldo C; Cuenca, Phillip B; Walker, Stephen C; Shepherd, John M

    2013-01-01

    Total intravenous anesthesia (TIVA) is frequently used for major operations requiring general anesthesia in critically ill burn patients. We reviewed our experience with this approach. Methods: During a 22-month period, 547 major burn surgeries were performed in this center’s operating room and were staffed by full-time burn anesthesiologists. The records of all 123 TIVA cases were reviewed; 112 records were complete and were included. For comparison, 75 cases were selected at random from a total of 414 non-TIVA general anesthetics. Some patients had more than one operation during the study: as appropriate for the analysis in question, each operation or each patient was entered as an individual case. For inter-patient analysis, exposure to 1 or more TIVAs was used to categorize a patient as member of the TIVA group. Results: Excision and grafting comprised 78.2% of the operations. 14 TIVA regimens were used, employing combinations of 4 i.v. drugs: ketamine (K, 91 cases); i.v. methadone (M, 62); fentanyl (F, 58); and propofol (P, 21). The most common regimens were KM (34 cases); KF (26); KMF (16); and K alone (8). Doses used often exceeded those used in non-burn patients. TIVA was preferred for those patients who were more critically ill prior to surgery, with a higher ASA score (3.87 vs. 3.11). Consistent with this, inhalation injury (26.7 vs. 1.6%), burn size (TBSA, 36.3 vs. 15.8%), and full-thickness burn size (FULL, 19.8 vs. 6.5%) were higher in TIVA than in non-TIVA patients. Despite this, intraoperative pressor use was as common in TIVA as in non-TIVA cases (23.9 vs. 22.7%). Conclusions: TIVA was used in patients whose inhalation injury rate and TBSA were greater than those of non-TIVA patients. TIVA cases were not associated with increased hemodynamic instability. TIVA is a viable approach to general anesthesia in critically ill burn patients. PMID:23638329

  9. Management of severe refractory thrombocytopenia in dengue hemorrhagic fever with intravenous anti-D immune globulin.

    PubMed

    Kharya, Gaurav; Yadav, Satya Prakash; Katewa, Satyendra; Sachdeva, Anupam

    2011-11-01

    Dengue hemorrhagic fever (DHF) is a potentially lethal complication of dengue fever due to shock and/or bleeding. Bleeding in DHF is due to thrombocytopenia and/or coagulopathy. The authors present their experience of usage of intravenous anti-D in 5 children with DHF and severe refractory thrombocytopenia (<10,000/mm(3)). It was administered in a dose of 50 to 75 μg/kg. Mean platelet count was 6800/mm(3) before and 33,600, 44,600, and 79,000/mm(3) after intravenous anti-D administration at 24, 48, and 72 hours, respectively. Average drop in hemoglobin after administration of anti-D was 2.28 g/dL. Intravenous anti-D can possibly be a treatment option for refractory thrombocytopenia in DHF.

  10. Heparin and related drugs for venous thromboembolism prophylaxis: subcutaneous or intravenous continuous infusion?

    PubMed

    Izadpanah, Mandana; Khalili, Hossein; Dashti-Khavidaki, Simin; Mohammadi, Mostafa

    2015-03-01

    In this article, the most evidenced approaches of unfractionated heparin administration for prevention of venous thromboembolism in medical and surgical hospitalized patients will be reviewed. Present data were collected by searching Scopus, PubMed, MEDLINE, Science direct, Clinical trials and Cochrane database systematic reviews. Subcutaneous low doses of unfractionated heparin (10000-15000 IU) in two or three divided doses per day are commonly administrated for venous thromboembolism prevention in different medical and surgical populations. In some populations such as obese surgical and critically ill patients, due to altered pharmacokinetics behavior of unfractionated heparin, continuous intravenous infusion of the low doses of unfractionated heparin has been proposed.

  11. Pomalidomide for Multiple Myeloma

    Cancer.gov

    A summary of results from a phase III trial that compared the combination of pomalidomide (Pomalyst®) and low-dose dexamethasone versus high-dose dexamethasone alone in patients with multiple myeloma that has progressed despite other treatments.

  12. Safety and pharmacokinetics of lisdexamfetamine dimesylate in adults with clinically stable schizophrenia: a randomized, double-blind, placebo-controlled trial of ascending multiple doses.

    PubMed

    Martin, Patrick; Dirks, Bryan; Gertsik, Lev; Walling, David; Stevenson, Annette; Corcoran, Mary; Raychaudhuri, Aparna; Ermer, James

    2014-12-01

    To assess the safety and pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, this double-blind study enrolled adults with clinically stable schizophrenia who were adherent (≥12 weeks) to antipsychotic pharmacotherapy. The participants received placebo or ascending LDX doses (50, 70, 100, 150, 200, and 250 mg) daily for 5 days at each dose (dose periods, 1-6; days, 1-5). Of the 31 enrolled participants, 27 completed the study (placebo, n = 6; LDX, n = 21). Treatment-emergent adverse events (AEs) were reported by 4 participants receiving placebo and by 23 participants receiving LDX (all doses) with no serious AEs while on active treatment. For all periods, the mean postdose change on day 5 (up to 12 hours postdose) in systolic and diastolic blood pressure and pulse, respectively, ranged from -4.62 to 8.05 mm Hg, -3.67 to 4.43 mm Hg, and -3.57 to 14.43 beats per minute for placebo and -3.83 to 11.25 mm Hg, -1.55 to 5.80 mm Hg, and -0.36 to 21.26 beats per minute for LDX. With ascending LDX dose, the mean (SD) maximum plasma concentration for LDX-derived d-amphetamine ranged from 51.68 (10.28) to 266.27 (56.55) ng/mL. The area under the plasma concentration-time curve for 24 hours ranged from 801.8 (170.2) to 4397.9 (1085.9) ng[BULLET OPERATOR]h/mL. The d-amphetamine maximum plasma concentration and area under the plasma concentration-time curve increased linearly with ascending LDX dose. Antipsychotic agents did not markedly affect d-amphetamine pharmacokinetics. Over a wide range of ascending doses, LDX safety profile in adults with schizophrenia was consistent with previous findings with no unexpected treatment-emergent AEs. Pulse tended to increase with LDX dose; overall, blood pressure did not increase with LDX dose. Consistent with previous studies, pharmacokinetic parameters increased linearly with increasing LDX dose.

  13. [Intravenous drug users and the HIV epidemic].

    PubMed

    Skretting, A

    1992-06-10

    Data are taken from a study of 1,765 arrested intravenous drug users at the Oslo Central Police Station. Intravenous drug users in Oslo seem to get themselves tested for HIV regularly. In 1990-91 the average number of HIV-tests was 5.3, and the time since last test was, an average, between eight and nine months. Most intravenous drug users do not share needles and syringes. The most important source of needles and syringes in Oslo is an ambulant bus which can be found in city centre at night. HIV-seropositive drug users seem to have more regular contact with treatment programmes than those who are HIV-seronegative. Most of the HIV-seropositive drug users who are under treatment are to be found in a few institutions.

  14. Effects of intravenous immunoglobulins on T-cell mediated, concanavalin A-induced hepatitis in mice.

    PubMed

    Shirin, H; Bruck, R; Aeed, H; Hershkoviz, R; Lider, O; Kenet, G; Avni, Y; Halpern, Z

    1997-12-01

    Concanavalin A (ConA) activates T lymphocytes and causes T-cell mediated hepatic injury in mice. The intravenous administration of human immunoglobulins has beneficial effects in T-cell mediated diseases such as experimental autoimmune encephalomyelitis and adjuvant arthritis. In the present study, we examined the effects of intravenous immunoglobulins in a mouse model of T-cell mediated, acute liver injury induced by concanavalin A. Balb/c mice were inoculated with 12 mg/kg concanavalin A with or without intravenous immunoglobulins at doses of 0.4, 0.6, 0.8 g/kg body wt. The serum levels of liver enzymes, tumor necrosis factor-alpha, interferon-gamma and interleukin-6 were assayed 2, 6 and 24 h after concanavalin A administration. Intravenous immunoglobulins did not prevent concanavalin A-induced hepatitis, as manifested by elevation of serum aminotransferases and histopathological evaluation. The serum levels of tumor necrosis factor-alpha in mice pretreated with immunoglobulins, measured 2 h after ConA treatment were reduced, while interferon-gamma levels measured 6 h after ConA inoculation were 5-fold higher than control levels. There was no effect of intravenous immunoglobulins on the release of interleukin 6. In conclusion, these results indicate that intravenous immunoglobulin is not effective in preventing T-cell mediated concanavalin A-induced hepatitis. The increased secretion of interferon-gamma and the incomplete suppression of tumor necrosis factor-alpha release may explain the lack of efficacy of intravenous immunoglobulin in this experimental model. PMID:9455732

  15. Electrophysiological study of intravenous pinaverium bromide in cardiology.

    PubMed

    Guerot, C; Khemache, A; Sebbah, J; Noel, B

    1988-01-01

    Pinaverium bromide is a musculotropic spasmolytic agent which acts by inhibiting transmembrane calcium movements, an effect similar to that of verapamil. Because of this, an investigation was carried out to see if it had any electrophysiological effects in patients with various cardiac disorders. In an open study, 10 patients received 2 mg pinaverium bromide intravenously. In a double-blind study, 10 patients received 4 mg pinaverium bromide intravenously and 10 patients placebo. Patients included those with either normal or pathological basal conduction, such as bundle-branch block and 1st degree atrioventricular block. Measurements were made of electrophysiological parameters before and 10 minutes after injection. The results showed that neither of the two doses of pinaverium bromide had any effect on atrial excitability, sino-atrial conduction, node and trunk atrioventricular conduction or on intraventricular conduction. No significant difference was seen in comparison with placebo. Pinaverium bromide had no anti-arrhythmic properties in these studies. Local, cardiac and general clinical tolerability was good in all patients. PMID:3219882

  16. Preparation of intravenous cholesterol tracer using current good manufacturing practices.

    PubMed

    Lin, Xiaobo; Ma, Lina; Racette, Susan B; Swaney, William P; Ostlund, Richard E

    2015-12-01

    Studies of human reverse cholesterol transport require intravenous infusion of cholesterol tracers. Because insoluble lipids may pose risk and because it is desirable to have consistent doses of defined composition available over many months, we investigated the manufacture of cholesterol tracer under current good manufacturing practice (CGMP) conditions appropriate for phase 1 investigation. Cholesterol tracer was prepared by sterile admixture of unlabeled cholesterol or cholesterol-d7 in ethanol with 20% Intralipid(®). The resulting material was filtered through a 1.2 micron particulate filter, stored at 4°C, and tested at time 0, 1.5, 3, 6, and 9 months for sterility, pyrogenicity, autoxidation, and particle size and aggregation. The limiting factor for stability was a rise in thiobarbituric acid-reacting substances of 9.6-fold over 9 months (P < 0.01). The emulsion was stable with the Z-average intensity-weighted mean droplet diameter remaining at 60 nm over 23 months. The zeta potential (a measure of negative surface charge protecting from aggregation) was unchanged at -36.2. Rapid cholesterol pool size was 25.3 ± 1.3 g. Intravenous cholesterol tracer was stable at 4°C for 9 months postproduction. CGMP manufacturing methods can be achieved in the academic setting and need to be considered for critical components of future metabolic studies.

  17. Preparation of intravenous cholesterol tracer using current good manufacturing practices.

    PubMed

    Lin, Xiaobo; Ma, Lina; Racette, Susan B; Swaney, William P; Ostlund, Richard E

    2015-12-01

    Studies of human reverse cholesterol transport require intravenous infusion of cholesterol tracers. Because insoluble lipids may pose risk and because it is desirable to have consistent doses of defined composition available over many months, we investigated the manufacture of cholesterol tracer under current good manufacturing practice (CGMP) conditions appropriate for phase 1 investigation. Cholesterol tracer was prepared by sterile admixture of unlabeled cholesterol or cholesterol-d7 in ethanol with 20% Intralipid(®). The resulting material was filtered through a 1.2 micron particulate filter, stored at 4°C, and tested at time 0, 1.5, 3, 6, and 9 months for sterility, pyrogenicity, autoxidation, and particle size and aggregation. The limiting factor for stability was a rise in thiobarbituric acid-reacting substances of 9.6-fold over 9 months (P < 0.01). The emulsion was stable with the Z-average intensity-weighted mean droplet diameter remaining at 60 nm over 23 months. The zeta potential (a measure of negative surface charge protecting from aggregation) was unchanged at -36.2. Rapid cholesterol pool size was 25.3 ± 1.3 g. Intravenous cholesterol tracer was stable at 4°C for 9 months postproduction. CGMP manufacturing methods can be achieved in the academic setting and need to be considered for critical components of future metabolic studies. PMID:26416797

  18. Intravenous vs. left ventricular injection of ionic contrast material: hemodynamic implications for digital subtraction angiography

    SciTech Connect

    Mancini, G.B.; Ostrander, D.R.; Slutsky, R.A.; Shabetai, R.; Higgins, C.B.

    1983-03-01

    Because of the increased use of intravenous injection of contrast material for the evaluation of cardiac structure and function by digital subtraction techniques, a study was done to assess the hemodynamic effects of contrast material when used in this fashion in man. In 10 patients, with each serving as his own control, the effects of intravenous and intraventricular injections of sodium meglumine diatrizoate (Renografin 76) in the same dose were compared. There was no difference between these two methods with respect to changes in pulmonary wedge pressures, systemic pressures, and pulmonary vascular resistance. The elevation of mean pulmonary artery and right atrial pressure was greater after the intraventricular injection (p <0.05). The elevated cardiac output and systemic vascular resistance returned to control values somewhat more quickly after the intravenous injection (p<0.001 and p<0.05, respectively); and the increase in cardiac output was greater after the intravenous injection at 1 min (p<0.05), but less than after the intraventricular injection at 2 min (p<0.05). Despite the detection of these statistically significant differences, the magnitude and timing of these differences are too small to justify the notion that imaging by intravenous injections of standard ionic contrast media provides any substantial hemodynamic benefits or decreased risk to the patient.

  19. Cytogenetic adaptive response with multiple small X-ray doses in mouse germ cells and its biological influence on the offspring of adapted males.

    PubMed

    Cai, L; Wang, P; Piao, X G

    1994-06-01

    Cytogenetic adaptive response of mouse germ cells was studied by exposing male mice to a sequence of 4 conditioning doses of 0.05 Gy each (D1) administered at 10-day intervals and subsequently to a single challenging dose of 1.5 Gy (D2). In concurrent experiments, male mice after treatment with D1 doses alone were mated to unirradiated females and the F1 males were given the D2 dose. Chromosomal aberrations in both spermatocytes and bone-marrow cells and UV-induced UDS in splenocytes of these mice were studied. Adapted mice (i.e., D1 + D2 exposures) responded with a significantly lower frequency of chromosomal aberrations than the non-adapted (D2 exposure only) controls. The relative reduction in frequencies was, however, similar to that observed in earlier work with a single conditioning dose of 0.05 Gy. The frequencies of chromosomal aberrations in spermatocytes and bone-marrow cells as well as the levels of UV-induced UDS in splenocytes of the F1 males in the group D1 to fathers + D2 to F1 males were the same as those in F1 males which received only the D2 exposure. PMID:7515464

  20. Intravenous lidocaine and mexiletine in the management of trigeminal autonomic cephalalgias.

    PubMed

    Marmura, Michael J

    2010-04-01

    Lidocaine and mexiletine are class 1B antiarrhythmic drugs that act on sodium channels. Lidocaine is also an important anesthetic and topical agent that is useful in the treatment of multiple pain disorders, and mexiletine is commonly used for neuropathic pain and myotonia. Both intravenous lidocaine and mexiletine are increasingly used to treat pain syndromes and appear to be particularly effective in neuropathic pain. This suggests a role for these agents in patients with headache disorders. This article describes the role of intravenous lidocaine and mexiletine in the management of headache and trigeminal autonomic cephalalgias based on the published literature to date and provides practical guidelines for their use. PMID:20425204

  1. Response and Tolerance to Oral Vasodilator Uptitration after Intravenous Vasodilator Therapy in Advanced Decompensated Heart Failure

    PubMed Central

    Verbrugge, Frederik H.; Dupont, Matthias; Finucan, Michael; Gabi, Alaa; Hawwa, Nael; Mullens, Wilfried; Taylor, David O.; Young, James B.; Starling, Randall C.; Wilson Tang, W.H.

    2015-01-01

    Aims To assess the hemodynamic response and tolerance to aggressive oral hydralazine/isosorbide dinitrate (HYD/ISDN) uptitration after intravenous vasodilator therapy in advanced decompensated heart failure (ADHF). Methods and Results Medical records of 147 consecutive ADHF patients who underwent placement of a pulmonary artery catheter and received intravenous vasodilator therapy were reviewed. Intravenous sodium nitroprusside and sodium nitroglycerin as first-line agent for those with preserved blood pressures were utilized in 143 and 32 patients, respectively. Sixty-one percent of patients were converted to oral HYD/ISDN combination therapy through a standardized conversion protocol. These patients had a significantly higher admission mean pulmonary arterial wedge pressure compared to patients not converted (28 ± 7 versus 25 ± 8 mmHg, respectively; P-value=0.024). Beneficial hemodynamic response to decongestive therapy, defined as low cardiac filling pressures and cardiac index ≥2.20 L/min/m² without emergent hypotension, was achieved in 32% and 29% of patients who did or did not receive oral HYD/ISDN, respectively (P-value=0.762). HYD/ISDN dosing was progressively and consistently decreased up to the moment of hospital discharge and during outpatient follow-up primarily due to incident hypotension. Conclusion The use of a standardized hemodynamically-guided uptitration protocol for conversion from intravenous to oral vasodilators may warrant subsequent dose reductions upon stabilization. PMID:26213182

  2. Intravenous hydralazine for blood pressure management in the hospitalized patient: its use is often unjustified.

    PubMed

    Campbell, Patrick; Baker, William L; Bendel, Stephen D; White, William B

    2011-01-01

    Due to observations of increased off-label use of intravenous hydralazine in area hospitals, we studied its use in a university teaching hospital. Patients were prospectively identified between April and October 2010 with a pharmacy order for intravenous hydralazine. Demographic and clinical information, including pretreatment blood pressure (BP), change in BP and heart rate within 2 hours after administration of hydralazine, and adverse events were obtained. Ninety-four patients (mean age, 69 ± 18 years, 48% women, 89% with known hypertension) received 201 intravenous hydralazine doses (mean dose of 11.4 ± 4.3 mg). Only 4 (2%) patients had evidence of an urgent hypertensive condition. Following hydralazine, BP was reduced by 24/9 ± 29/15 mmHg and heart rate increased by 4 ± 13 beats per minute. Changes from baseline in BP were related to baseline BP. Seventeen patients experienced an adverse event, the most common being hypotension (n = 11). Intravenous hydralazine is commonly prescribed for non-urgent cases of hypertension in the hospitalized patient. While changes in systolic BP are related to baseline BP values, they are highly variable, and associated with hypotension. Thus, this agent may not be useful for treating hypertension in many hospitalized patients and may cause harm if used inappropriately.

  3. Assessment of the pharmacodynamics of intranasal, intravenous and oral scopolamine

    NASA Technical Reports Server (NTRS)

    Tietze, Karen J.

    1990-01-01

    Space motion sickness is an important issue in the space medical sciences program. One of the objectives of the ongoing clinical experimental protocol Pharmacokinetics of Intranasal Scopolamine in Normal Subjects is to evaluate the pharmacodynamics of scopolamine using salivary flow rate and pH profiles and cognitive performance tests as pharmacodynamic parameters. Normal volunteers collected saliva and performed the NTI Multiresource Performance Battery tests at designed time intervals to establish control saliva flow rates, salivary pH profiles, and the characteristics of the learning curve for the performance program under normal conditions. In the clinical part of the study, saliva samples and performance test scores are collected from healthy nonsmoking subjects after receiving a single 0.4 mg dose of either intranasal, intravenous, or oral scopolamine.

  4. Intravenous immunoglobulins in peripheral neuropathy associated with vasculitis

    PubMed Central

    Levy, Y; Uziel, Y; Zandman, G; Amital, H; Sherer, Y; Langevitz, P; Goldman, B; Shoenfeld, Y

    2003-01-01

    Objective: To present patients who exhibited various inflammatory diseases accompanied with vasculitic peripheral neuropathies for which intravenous immunoglobulin (IVIg) was used for treatment. Methods: Six patients with Sjögren's syndrome, systemic lupus erythematosus (SLE), vaccination induced vasculitis, Churg-Strauss vasculitis, mixed cryoglobulinaemia associated with hepatitis C infection, or sarcoidosis were included. All developed vasculitic peripheral neuropathy, and were treated with high dose IVIg (2 g/kg body weight). The patients were followed up for 1–5 years after this treatment. Results: In four patients (Sjögren's syndrome, Churg-Strauss vasculitis, SLE, and vaccination induced vasculitis) the neuropathy resolved after IVIg treatment. Conclusion: IVIg may be beneficial in cases of resistant vasculitic peripheral neuropathy. IVIg should probably be considered as a sole or adjuvant treatment for patients with contraindications to conventional treatment, or alternatively, for patients in whom conventional treatment has failed. PMID:14644864

  5. Survey of nursing practice related to decanting intravenous solutions.

    PubMed

    Sulzbach, L M; Munro, B H

    1991-11-01

    A survey instrument was mailed to a stratified random sample of 1000 nurses from the membership list of the American Association of Critical-Care Nurses to determine whether there are generally accepted standards for decanting intravenous (IV) solutions before the addition of medication. Four hundred seventy-eight surveys were returned from 47 states and the District of Columbia. Of those, 475 were usable. Seventy-one percent of the respondents did not decant. Of those who did decant (29%), 79% used a needle and syringe to withdraw a volume equal to that of the medication to be added. The results of this study indicate that no generally accepted standards of practice exist for the preparation of IV solutions. Patients may not, therefore, be receiving the dose prescribed by the physician. Nurses need to develop standards for accurate administration of IV solutions.

  6. Treatment of pieris ingestion in goats with intravenous lipid emulsion.

    PubMed

    Bischoff, Karyn; Smith, Mary C; Stump, Samuel

    2014-12-01

    Seven goats and one ram presented with clinical signs including regurgitation, obtundation, anorexia, apparent pain, and bloat. The animals had escaped from their barn, and it was discovered that they had ingested leaves of Pieris japonica, Japanese pieris, a grayanotoxin-containing plant. Animals were treated with antibiotics, calcium borogluconate, B vitamins, and activated charcoal within the first 24-h postexposure, which was followed by the recovery of the ram and two goats and the death of two goats. Approximately 36 h after Japanese pieris ingestion, one of the three remaining anorectic goats was dosed with intravenous lipid emulsion (ILE). This goat recovered within a few hours. The remaining two goats were given ILE the next day and appeared to recover, but one died a week later of aspiration pneumonia.

  7. [Experiences with intravenous sulprostone administration in massive postpartal hemorrhage].

    PubMed

    Schönegg, W; Wessel, J; Schmidt-Gollwitzer, K

    1987-11-01

    Forty-three patients at the University Gynecology Clinic in Charlottenburg were given the prostaglandin E2 derivative sulprostone for severe postpartal hemorrhage. It was administered intravenously in a dose of 1.7 mcg/min (100 mcg/100 ml/h), with short-term increases to three times this amount in isolated cases. The drug proved highly efficacious (rapid onset and lasting effect). In 80% of the cases there were no side effects. Rises in body temperature occurred in six patients and in one patient a venous irritation developed in the arm into which the drug was infused. An RDS occurred, though it was considered that there was not necessarily a causal connection between this and the sulprostone infusion. In the authors' experience this drug has an established place in the treatment of atonic postpartal hemorrhage emergencies.

  8. Single-dose rasburicase 6 mg in the management of tumor lysis syndrome in adults.

    PubMed

    McDonnell, Anne M; Lenz, Kristi L; Frei-Lahr, Debra A; Hayslip, John; Hall, Philip D

    2006-06-01

    Rasburicase is currently approved at a dosage of 0.15-0.2 mg/kg once/day for 5 days in pediatric patients with cancer to lower plasma uric acid concentrations and manage tumor lysis syndrome (TLS). Information on rasburicase dosing in adults is limited, with some data on using rasburicase as a single dose instead of multiple daily doses. Therefore, we evaluated the efficacy of a single dose of rasburicase for preventing or managing TLS in adults. We collected retrospective data for 11 adults with hematologic malignancies who received a single 6-mg dose of rasburicase. All patients received intravenous hydration with urinary alkalinization and allopurinol; however, due to adverse reactions, two patients received short courses of allopurinol. Only patients at high risk for TLS (e.g., large tumor burden, increasing uric acid concentration) or those with TLS received rasburicase. The single dose of rasburicase 6 mg resulted in a median 0.0773-mg/kg dose (range 0.0232-0.1361 mg/kg). The single 6-mg dose rapidly lowered uric acid concentrations in 10 of the 11 patients. The median uric acid concentration of 11.7 mg/dl (range 7.4-17.4 mg/dl) declined to 2.0 mg/dl (range 0.5-15.4 mg/dl) within a day after rasburicase administration (p=0.022). In these 10 patients, uric acid concentrations remained low despite subsequent chemotherapy, and none required additional rasburicase doses. The only patient who did not respond to the single 6-mg rasburicase dose was a morbidly obese man (259 kg, body mass index 87 kg/m2) who subsequently responded to an additional dose of rasburicase 12 mg. These results warrant further investigation of a single 6-mg dose of rasburicase in adults with TLS or at high-risk for developing TLS.

  9. Pharmacokinetics of intravenous and subcutaneous cefovecin in alpacas.

    PubMed

    Cox, S; Sommardahl, C; Seddighi, R; Videla, R; Hayes, J; Pistole, N; Hamill, M; Doherty, T

    2015-08-01

    The purpose of this study was to determine the pharmacokinetics of cefovecin after intravenous and subcutaneous dose of 8 mg/kg to alpacas. Bacterial infections requiring long-term antibiotic therapy such as neonatal bacteremia, pneumonia, peritonitis, dental, and uterine infections are a significant cause of morbidity and mortality in this species. However, few antimicrobials have been evaluated and proven to have favorable pharmacokinetics for therapeutic use. Most antimicrobials that are currently used require daily injections for many days. Cefovecin is a long-acting cephalosporin that is formulated for subcutaneous administration, and its long-elimination half-life allows for 14-day dosing intervals in dogs and cats. The properties of cefovecin may be advantageous for medical treatment of camelids due to its broad spectrum, route of administration, and long duration of activity. Pharmacokinetic evaluation of antimicrobial drugs in camelids is essential for the proper treatment and prevention of bacterial disease, and to minimize development of antibiotic resistant bacterial strains due to inadequate antibiotic concentrations. Cefovecin mean half-life, volume of distribution at steady-state, and clearance after intravenous administration were 10.3 h, 86 mL/kg, and 7.07 mL·h/kg. The bioavailability was 143%, while half-life, C(max), and T(max) were 16.9 h, 108 μg/mL, and 2.8 h following subcutaneous administration. In the absence of additional microbial susceptibility data for alpaca pathogens, the current cefovecin dosage regimen prescribed for dogs (8 mg/kg SC every 14 days) may need to be optimized for the treatment of infections in this species.

  10. Health Instruction Packages: Venipuncture and Intravenous Therapy.

    ERIC Educational Resources Information Center

    Gray, P. Allen, Jr.; And Others

    Text, illustrations, and exercises are utilized in these five learning modules to instruct nursing students in techniques for initiating intravenous (I.V.) therapy. The first module, "Selection of a Venipuncture Site: Arm" by P. Allen Gray, Jr., describes the utilization of a tourniquet in locating filled veins in the arm. The second module,…

  11. Eastern Equine Encephalitis Treated With Intravenous Immunoglobulins

    PubMed Central

    Mukerji, Shibani S.; Lam, Alice D.

    2016-01-01

    We report the case of a 68-year-old man from southeastern Massachusetts presenting with encephalitis due to eastern equine encephalitis (EEE) virus. Despite the high morbidity and mortality rate of EEE, the patient made a near complete recovery in the setting of receiving early intravenous immunoglobulins. PMID:26740855

  12. Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects

    PubMed Central

    Rocha, José Francisco; Almeida, Luis; Falcão, Amílcar; Palma, P Nuno; Loureiro, Ana I; Pinto, Roberto; Bonifácio, Maria João; Wright, Lyndon C; Nunes, Teresa; Soares-da-Silva, Patrício

    2013-01-01

    Aims The aim of this study was to assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone. Methods This randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days. Results Opicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such a half-life translates into a putative underlying rate constant that is comparable with the estimated dissociation rate constant of the COMT–opicapone complex. Conclusion Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen. PMID:23336248

  13. A placebo controlled double-blind evaluation of the pharmacodynamics of fengabine vs amitriptyline following single and multiple doses in elderly volunteers.

    PubMed Central

    Fairweather, D B; Kerr, J S; Hilton, S; Hindmarch, I

    1993-01-01

    1. The effects of fengabine were compared with those of amitriptyline in healthy elderly volunteers. Doses were administered double-blind and assessments were made before and after ingestion. 2. Psychomotor performance and cognitive ability were measured using tests of choice reaction time, tracking, critical flicker fusion threshold, memory scanning and word recognition. Subjective feelings were assessed using the Leeds sleep evaluation questionnaire (LSEQ) and line analogue rating scales (LARS). 3. Pharmacokinetic data suggest that fengabine may induce its own metabolism following repeated dosing. 4. The findings of this study show that fengabine 200 mg and 400 mg does not produce any noticeable behavioural toxicity in elderly volunteers, in contrast to amitriptyline which had a disruptive effect throughout. PMID:8471403

  14. Plasma disposition of enrofloxacin following intravenous and intramuscular administration in donkeys.

    PubMed

    Sekkin, S; Gokbulut, C; Kum, C; Karademir, U

    2012-11-01

    This study was designed to investigate the plasma disposition and systemic availability of enrofloxacin (ENR) following intramuscular and intravenous administrations. Six donkeys (Equus asinus) were used in this study. The animals were allocated into two groups (intramuscular and intravenous groups). After a 2-week washout period, the experiment was repeated with the groups reversed according to a two-phase crossover design. In phase I, group I received intravenously the commercially available injectable solution of ENR at the dose of 5 mg/kg and group II received intramuscularly the same ENR formulation at the same dose rate. Blood samples were collected 1 hour prior to drug administration and various times between 5 minutes and 48 hours post-treatments. The samples were analysed by high performance liquid chromatography with fluorescence detector. The half-life and mean residence time of ENR (12.08 hours and 17.85 hours) after intramuscular route were significantly longer compared with intravenous administration (9.54 hours and 7.46 hours, respectively) and these were associated with a flip-flop phenomenon. A marked proportion of ENR (20-21 per cent) was metabolised to ciprofloxacin (CPR) following both administration routes and the half-life of CPR paralleled that of the parent drug after intramuscular administration. Mean absorption time was relatively long (10.39 hours), and the bioavailability of ENR was 76.56 per cent after intramuscular route in the donkeys. The plasma concentration is lower after intramuscular administration at a dose rate of 5 mg/kg, and may need a higher dose to provide sufficient plasma concentration in donkeys compared with horses.

  15. Radiation dose implications of digital angiographic systems.

    PubMed

    Hynes, D M; Gershater, R; Edmonds, E W; Rowlands, J A; Baranoski, D; Turow, D G

    1984-08-01

    Digital subtraction angiography (DSA) has been widely accepted and applied. The concentration of iodine in the vessels of interest is low in intravenous DSA. The resultant images can be improved to some extent by increasing the radiation dose. Therefore DSA could become, and possibly could remain, a relatively high-dose procedure. The contributions to dose from the various components of the examination such as fluoroscopy, positioning, test exposures, and final acquisition runs are considered separately. Individual segments of a DSA examination are discussed to show how and where opportunities arise to reduce doses to the lowest levels consistent with satisfactory images. PMID:6377858

  16. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.

    PubMed

    Ghobrial, Irene M; Siegel, David S; Vij, Ravi; Berdeja, Jesus G; Richardson, Paul G; Neuwirth, Rachel; Patel, Chirag G; Zohren, Fabian; Wolf, Jeffrey L

    2016-06-01

    The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies. PMID:26800393

  17. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.

    PubMed

    Ghobrial, Irene M; Siegel, David S; Vij, Ravi; Berdeja, Jesus G; Richardson, Paul G; Neuwirth, Rachel; Patel, Chirag G; Zohren, Fabian; Wolf, Jeffrey L

    2016-06-01

    The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies.

  18. Effects of concurrent intravenous morphine sulfate and naltrexone hydrochloride on end-tidal carbon dioxide

    PubMed Central

    2012-01-01

    Background Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT) releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV) morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO2), a measure of respiratory-depression, were evaluated and these data are reported here. Methods Single-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO2 was measured by noninvasive capnography. Results Significant differences in EtCO2 least-squares means across all treatments for maximal effect (Emax) and area under the effect curve (AUE0-2, AUE0-8, AUE0-24) were detected (all p ≤ 0.0011). EtCO2 Emax values for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p < 0.0001) and were not significantly different vs placebo (41.9 mm Hg). Median time to reach maximal effect (TEmax) was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h). Conclusions Results provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO2 when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation. PMID:22420453

  19. Understanding the causes of intravenous medication administration errors in hospitals: a qualitative critical incident study

    PubMed Central

    Keers, Richard N; Williams, Steven D; Cooke, Jonathan; Ashcroft, Darren M

    2015-01-01

    Objectives To investigate the underlying causes of intravenous medication administration errors (MAEs) in National Health Service (NHS) hospitals. Setting Two NHS teaching hospitals in the North West of England. Participants Twenty nurses working in a range of inpatient clinical environments were identified and recruited using purposive sampling at each study site. Primary outcome measures Semistructured interviews were conducted with nurse participants using the critical incident technique, where they were asked to discuss perceived causes of intravenous MAEs that they had been directly involved with. Transcribed interviews were analysed using the Framework approach and emerging themes were categorised according to Reason's model of accident causation. Results In total, 21 intravenous MAEs were discussed containing 23 individual active failures which included slips and lapses (n=11), mistakes (n=8) and deliberate violations of policy (n=4). Each active failure was associated with a range of error and violation provoking conditions. The working environment was implicated when nurses lacked healthcare team support and/or were exposed to a perceived increased workload during ward rounds, shift changes or emergencies. Nurses frequently reported that the quality of intravenous dose-checking activities was compromised due to high perceived workload and working relationships. Nurses described using approaches such as subconscious functioning and prioritising to manage their duties, which at times contributed to errors. Conclusions Complex interactions between active and latent failures can lead to intravenous MAEs in hospitals. Future interventions may need to be multimodal in design in order to mitigate these risks and reduce the burden of intravenous MAEs. PMID:25770226

  20. Investigation of pharmacokinetic data of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin revealed from single and multiple oral dose studies with a hypericum extract containing tablet in healthy male volunteers.

    PubMed

    Schulz, Hans-Ulrich; Schürer, Michael; Bässler, Dagmar; Weiser, Dieter

    2005-01-01

    Hypericins, hyperforin and flavonoids are discussed as the main components contributing to the antidepressant action of St. John's wort (Hypericum perforatum). Therefore, the objective of the two open phase I clinical trials was to obtain pharmacokinetic data of these constituents from a hypericum extract containing tablet: hypericin, pseudohypericin, hyperforin, the flavonoid aglycone quercetin, and it