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Sample records for 14c-labeled therapeutic dose

  1. Tamoxifen Forms DNA Adducts In Human Colon After Administration Of A Single [14C]-Labeled Therapeutic Dose.

    Brown, K; Tompkins, E M; Boocock, D J; Martin, E A; Farmer, P B; Turteltaub, K W; Ubick, E; Hemingway, D; Horner-Glister, E; White, I H

    2007-05-23

    Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the U.S. for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated but much interest has focussed on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to ten women as a single [{sup 14}C]-labeled therapeutic (20 mg) dose, {approx}18 h prior to undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with HPLC separation of enzymatically digested DNA, a peak corresponding to authentic dG-N{sup 2}-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1-7 adducts/10{sup 9} nucleotides. No [{sup 14}C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests this tissue has the potential to activate tamoxifen to {alpha}-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of inter-individual variability, when present it was {approx}10-100 times higher than that reported for other suspect human colon carcinogens such as PhIP. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

  2. Systemic distribution of sup 14 C-labeled formaldehyde applied in the root canal following pulpectomy

    Hata, G.I.; Nishikawa, I.; Kawazoe, S.; Toda, T.

    1989-11-01

    The systemic distribution of {sup 14}C-labeled formaldehyde which had been placed in the root canals of the canines of cats following pulpectomies was studied using liquid scintillation counting and whole-body autoradiographic technique. Radioactive {sup 14}C which had been placed in the canals was found in the plasma 30 min after the root canal procedure. The recovery of systemic {sup 14}C radioactivity increased with time. In addition, it seemed that approximately 3% of the dose placed in the teeth was excreted in the urine within 36 h. Whole-body autoradiograms indicated extensive concentration of {sup 14}C radioactivity in tissues other than those analyzed with the liquid scintillation technique.

  3. Synthesis of two sup 14 C-labeled catechol-o-methyltransferase inhibitors

    Karlsson, Carita; Honkanen, Erkki (Orion Corporation Ltd., Espoo (Finland). Research Center)

    1991-02-01

    {sup 14}C-labelled 3-(3,4-dihydroxy-5-nitrophenylmethylidene)-2,4-pentanedione and {sup 14}C-labelled E-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide have been synthesized from (carbonyl-{sup 14}C)vanillin. (author).

  4. Synthesis of [sup 14]C-labeled copolymers for drug delivery studies

    Rhee, S.W.; Reist, E.J. (SRI International, Menlo Park, CA (United States)); Rock, M.T.

    1994-02-01

    [sup 14]C-labeled polyanhydride copolymers [(20:80)/1,3-bis(p-carboxyphenoxy)-propane (CPP):sebacic acid (SA)] were synthesized according to schemes I and II: [sup 14]C-labeled sebacic acid (2,9-[sup 14]C[sub 2]) and [sup 14]C-labeled CPP 1,3-bis(p-carboxyphenoxy)-propane (labeled at C-1, C-3 of the propyl group) were transformed to the corresponding mixed anhydrides as prepolymers respectively by reaction with acetic anhydride. The labeled mixed anhydride prepolymers were condensed with unlabeled counter-prepolymers to give the labeled polyanhydride copolymers. The labeled copolymers were identified and characterized by gel permeation chromatography (GPC). (author).

  5. Production of 14C-labeled gas in BACTEC Neisseria Differentiation kits by Neisseria cinerea.

    Boyce, J M; Mitchell, E B; Knapp, J S; Buttke, T M

    1985-09-01

    Six strains of Neisseria cinerea were tested in BACTEC Neisseria Differentiation kits (Johnston Laboratories, Inc., Towson, Md.), and all yielded positive glucose growth indices and negative maltose and fructose growth indices. These results were similar to those achieved with Neisseria gonorrhoeae. However, most of the N. cinerea isolates tested yielded 3-h glucose growth indices that were lower than those obtained with gonococci. 14C-labeled gas was produced significantly faster (P less than 0.02) by N. gonorrhoeae than by N. cinerea. Additional studies suggested that the 14C-labeled gas produced by N. cinerea was carbon dioxide. N. cinerea strains were similar to Branhamella catarrhalis strains because both species failed to produce detectable acid from glucose, maltose, sucrose, fructose, and lactose in cysteine-tryptic agar media. However, in contrast to N. cinerea strains, B. catarrhalis strains did not metabolize glucose in BACTEC Neisseria Differentiation kits.

  6. Production of 14C-labeled gas in BACTEC Neisseria Differentiation kits by Neisseria cinerea.

    Boyce, J M; Mitchell, E B; Knapp, J S; Buttke, T M

    1985-01-01

    Six strains of Neisseria cinerea were tested in BACTEC Neisseria Differentiation kits (Johnston Laboratories, Inc., Towson, Md.), and all yielded positive glucose growth indices and negative maltose and fructose growth indices. These results were similar to those achieved with Neisseria gonorrhoeae. However, most of the N. cinerea isolates tested yielded 3-h glucose growth indices that were lower than those obtained with gonococci. 14C-labeled gas was produced significantly faster (P less tha...

  7. Distribution of /sup 14/C-labelled ochratoxin A in pregnant mice

    Appelgren, L.E.; Arora, R.G.

    1983-10-01

    Autoradiography was used to study the distribution of /sup 14/C-labelled ochratoxin A for up to 4 hr after its iv administration to mice at various stages of pregnancy. The highest /sup 14/C concentration was consistently found in the bile throughout the experimental period. The concentration of radioactivity in the tissues was found, in decreasing order, in the liver, kidney, blood, salivary glands, large vessels, brown fat, myocardium, uterus and lymphatic tissues. The toxin was shown to cross the placental barrier on day 9 of pregnancy, at which time it is most effective in producing fetal malformations.

  8. Modulation of (14) C-labeled glucose metabolism by zinc during aluminium induced neurodegeneration.

    Singla, Neha; Dhawan, D K

    2015-09-01

    Aluminium (Al) is one of the most prominent metals in the environment and is responsible for causing several neurological disorders, including Alzheimer's disease. On the other hand, zinc (Zn) is an essential micronutrient that is involved in regulating brain development and function. The present study investigates the protective potential of Zn in the uptake of (14) C-labeled amino acids and glucose and their turnover in rat brain slices during Al intoxication. Male Sprague Dawley rats (140-160 g) were divided into four different groups: normal control, Al treated (100 mg/kg body weight/day via oral gavage), Zn treated (227 mg/liter in drinking water), and Al + Zn treated. Radiorespirometric assay revealed an increase in glucose turnover after Al exposure that was attenuated after Zn treatment. Furthermore, the uptake of (14) C-labeled glucose was increased after Al treatment but was appreciably decreased upon Zn supplementation. In addition, the uptakes of (14) C-lysine, (14) C-leucine, and (14) C-aspartic acid were also found to be elevated following Al exposure but were decreased after Zn treatment. Al treatment also caused alterations in the neurohistoarchitecture of the brain, which were improved after Zn coadministration. Therefore, the present study suggests that Zn provides protection against Al-induced neurotoxicity by regulating glucose and amino acid uptake in rats, indicating that Zn could be a potential candidate for the treatment of various neurodegenerative disorders.

  9. Distribution of /sup 14/C-labelled acrylamide and betaine in foetuses of rats, rabbits, beagle dogs and miniature pigs

    Ikeda, G.J.; Miller, E.; Sapienza, P.P.; Michel, T.C.; King, M.T.; Turner, V.A.; Blumenthal, H.; Jackson, W.E.; Levin, S.

    1983-02-01

    (/sup 14/C)Acrylamide and (/sup 14/C)betaine hydrochloride were administered in a single iv dose to pregnant rats, rabbits, beagle dogs and miniature pigs late in gestation (1-2 days before expected parturition). Dosages used were 10 mg/kg for rats and 5 mg/kg for the other species. The compounds were allowed to equilibrate in the animal (for 1 hr in rats and for 2 hr in the other species); the dam was then killed and the foetuses were removed by caesarean section. Each foetus was weighed and analysed for radioactivity, either by homogenization of the whole foetus (rat and rabbit) or by determining separately the radioactivity in individual organs and tissues (dog and pig). Foetal uptake of the polar compound betaine hydrochloride was much lower than that of the more lipophilic acrylamide. The sex of the foetus did not appear to affect uptake of either compound. There were no significant differences in total uptake of isotope attributable to the position of the foetus within the uterus in any of the four species given either acrylamide or betaine. Similarly, uterine position did not affect the uptake of acrylamide or betaine by individual tissues of foetal dogs or pigs. Since the distributions of /sup 14/C-labelled acrylamide and betaine hydrochloride were essentially uniform throughout a litter, it would not be necessary to sample all of the members of a litter to obtain a representative picture of foetal distribution.

  10. Method for evaluating the potential of {sup 14}C labeled plant polyphenols to cross the blood-brain barrier using accelerator mass spectrometry

    Janle, Elsa M., E-mail: janle@purdue.ed [Purdue University, Department of Foods and Nutrition, 700 West State Street, West Lafayette, IN 47907-0259 (United States); Lila, Mary Ann [University of Illinois, Department of Natural Resources and Environmental Sciences Urbana IL (United States); Grannan, Michael; Wood, Lauren; Higgins, Aine [Purdue University, Department of Foods and Nutrition, 700 West State Street, West Lafayette, IN 47907-0259 (United States); Yousef, Gad G.; Rogers, Randy B. [University of Illinois, Department of Natural Resources and Environmental Sciences Urbana IL (United States); Kim, Helen [University of Alabama at Birmingham, Department of Pharmacology, Birmingham AB (United States); Jackson, George S. [Purdue University, Department of Physics, West Lafayette, IN (United States); Weaver, Connie M. [Purdue University, Department of Foods and Nutrition, 700 West State Street, West Lafayette, IN 47907-0259 (United States)

    2010-04-15

    Bioactive compounds in botanicals may be beneficial in preventing age-related neurodegenerative diseases, but for many compounds conventional methods may be inadequate to detect if these compounds cross the blood-brain barrier or to track the pharmacokinetics in the brain. By combining a number of unique technologies it has been possible to utilize the power of AMS to study the pharmacokinetics of bioactive compounds in the brain at very low concentrations. {sup 14}C labeled compounds can be biosynthesized by plant cell suspension cultures co-incubated with radioisotopically-labeled sucrose and isolated and separated into a series of bioactive fractions. To study the pharmacokinetics and tissue distribution of {sup 14}C labeled plant polyphenols, rats were implanted with jugular catheters, subcutaneous ultrafiltration probes and brain microdialysis probes. Labeled fractions were dosed orally. Interstitial fluid (ISF) and brain microdialysate samples were taken in tandem with blood samples. It was often possible to determine {sup 14}C in blood and ISF with a beta-counter. However, brain microdialysate samples {sup 14}C levels on the order of 10{sup 7} atoms/sample required AMS technology. The Brain Microdialysate{sub AUC}/Serum{sub AUC} ranged from .021- to .029, with the higher values for the glycoside fractions. By using AMS in combination with traditional methods, it is possible to study uptake by blood, distribution to ISF and determine the amount of a dose which can reach the brain and follow the pharmacokinetics in the brain.

  11. Decomposition of /sup 14/C-labelled lignin, holocellulose and lignocellulose by mycorrhizal fungi

    Trojanowski, J.; Huettermann, A.; Haider, K.

    1984-01-01

    Five different species of known ecto-mycorrhizal fungi: Cenococcum geophilum, Amanita muscaria, Tricholoma aurantium, Rhizopogon luteolus and Rhizopogon roseolus were studied for their ability to metabolize the major components of plant cell walls. All strains were able to decompose /sup 14/C-labelled plant lignin, /sup 14/C-lignocellulose and /sup 14/C-DHP-lignin at a rate which was lower than the one observed for the known white rot fungi Heterobasidion annosum and Sporotrichum pulverulentum. Also /sup 14/C-(U)-holocellulose was relatively less degradable for the mycorrhizal fungi than for the white rotters. On the other hand, aromatic monomers like /sup 14/C-vanillic acid were decomposed to a much higher extent by two species of mycorrhizal fungi compared to the activity observed for Heterobasidion annosum. The results of the experiments reveal that these stains of mycorrhizal fungi are well able to utilize the major components of plant material and thus can contribute to litter decomposition in the forest floor.

  12. Dynamics of {sup 14}C-labeled glucose and ammonium in saline arable soils

    Vuelvas-Solorzano, Alma; Hernandez-Matehuala, Rosalina [Instituto Tecnologico de Celaya, Celaya Gto. (Mexico). Dept. de Ing. Bioquimica. Lab. de Bioingenieria; Conde-Barajas, Eloy; Cardenas-Manriquez, Marcela [Instituto Tecnologico de Celaya, Celaya Gto. (Mexico). Dept. de Ing. Ambiental. Lab. de Bioingenieria], e-mail: marcela@itc.mx; Luna-Guido, Marco L.; Dendooven, Luc [Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional (Cinvestav), D.F. (Mexico). Dept. de Biotecnologia y Bioingenieria. Lab. de Ecologia de Suelos], e-mail: dendoove@cinvestav.mx

    2009-07-15

    Organic matter dynamics and nutrient availability in saline agricultural soils of the State of Guanajuato might provide information for remediation strategies. {sup 14}C labeled glucose with or without 200 mg kg{sup -}1 of NH{sub 4} {sup +}-N soil was added to two clayey agricultural soils with different electrolytic conductivity (EC), i.e. 0.94 dS m{sup -}1 (low EC; LEC) and 6.72 dS m{sup -}1 (high EC; HEC), to investigate the effect of N availability and salt content on organic material decomposition. Inorganic N dynamics and production of CO{sub 2} and {sup 14}CO{sub 2} were monitored. Approximately 60 % of the glucose-{sup 14}C added to LEC soil evolved as {sup 14}CO{sub 2}, but only 20 % in HEC soil after the incubation period of 21 days. After one day, < 200 mg {sup 14}C was extractable from LEC soil, but > 500 mg {sup 14}C from HEC soil. No N mineralization occurred in the LEC and HEC soils and glucose addition reduced the concentrations of inorganic N in unamended soil and soil amended with NH{sub 4}{sup +}-N. The NO{sub 2}{sup -} and NO{sub 3}{sup -} concentrations were on average higher in LEC than in HEC soil, with exception of NO{sub 2}{sup -} in HEC amended with NH{sub 4}{sup +}-N. It was concluded that increases in soil EC reduced mineralization of the easily decomposable C substrate and resulted in N-depleted soil. (author)

  13. Mineralization and Transfer Processes of {sup 14}C-labeled Pesticides in Outdoor Lysimeters

    Grundmann, Sabine; Doerfler, Ulrike, E-mail: doerfler@gsf.de; Ruth, Bernhard; Loos, Christine [GSF - National Research Center for Environment and Health, Institute of Soil Ecology (Germany); Wagner, Tobias [GSF - National Research Center for Environment and Health, Institute of Biochemical Plant Pathology (Germany); Karl, Heidrun; Munch, Jean Charles; Schroll, Reiner [GSF - National Research Center for Environment and Health, Institute of Soil Ecology (Germany)

    2008-04-15

    A recently designed two-chamber-lysimeter-test-system allows the detailed investigation of degradation, transport and transfer processes of {sup 14}C-labeled substances in soil-plant-atmosphere-systems under outdoor conditions. With this test system it is feasible to distinguish between {sup 14}C-emissions from soil surfaces and {sup 14}C-emissions from plant surfaces in soil monoliths under real environmental conditions. Special soil humidity sensors allow the measurement of soil water content near to the soil surface, in 1 and 5 cm depth. The behavior of organic chemicals can be followed for a whole vegetation period and a mass balance for the applied chemical can be established. Some selected results of the herbicides isoproturon and glyphosate - using the two-chamber-lysimeter-test-system - are presented to demonstrate its applicability for the identification and quantification of the processes that govern pesticide behavior in soil-plant-systems. Mineralization of {sup 14}C-isoproturon was very different in four different soils; the mineralization capacity of the soils ranged from 2 to 60%. Leaching of isoproturon in general was very low, but depending on the soil type and environmental conditions isoproturon and its metabolites could be leached via preferential flow, especially shortly after application. For the herbicide {sup 14}C-glyphosate no accumulation of residues in the soil and no leaching of the residues to deeper soil layers could be observed after three applications. Glyphosate was rapidly degraded to AMPA in the soil. Glyphosate and AMPA were accumulated in soy bean nodules.

  14. Mineralisation of (14)C-labelled polystyrene plastics by Penicillium variabile after ozonation pre-treatment.

    Tian, Lili; Kolvenbach, Boris; Corvini, Nora; Wang, Songfeng; Tavanaie, Nasrin; Wang, Lianhong; Ma, Yini; Scheu, Stefan; Corvini, Philippe François-Xavier; Ji, Rong

    2016-07-19

    Large amounts of polystyrene (PS), one of the most widely used plastics in the world, end up in the environment through industrial discharge and littering, becoming one of the major components of plastic debris. Such plastics, especially the small-sized microplastics and nanoplastics, have received increasing concerns in terms of their potential environmental risks. Feasible approaches for the degradation of PS in waste materials and in the environment are highly desirable. Physicochemical pretreatments of PS may be applied to enhance biological degradation. In the present study, we synthesized (14)C-labelled PS polymers, either uniformly labelled on the ring ([U-ring-(14)C]-PS) or labelled at the β-carbon position of the alkyl chain ([β-(14)C]-PS), and investigated the mineralisation of the (14)C-PS polymers by the fungus Penicillium variabile CCF3219 as well as the effect of ozonation as a physico-chemical pre-treatment on the mineralisation by the fungi. Biodegradation of the (14)C-PS polymers was studied in liquid medium (pH 7.5, without additional carbon substrate) with P. variabile for 16 weeks. During the incubation time, (14)CO2 was captured to calculate the mineralisation of (14)C-PS and the remaining polymers were analysed by means of scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectrometry and gel-permeation chromatography (GPC). The results showed that the fungi mineralised both labelled polymers, and that the [U-ring-(14)C]-PS with a lower molecular weight led to a higher mineralisation rate. Ozonation pre-treatment strongly enhanced mineralisation of [β-(14)C]-PS. SEM analysis showed that the surface of the ozonated [β-(14)C]-PS became uneven and rough after the incubation, indicating an attack on the polymer by P. variabile. FT-IR analysis showed that ozonation generated carbonyl groups on the [β-(14)C]-PS and the amount of the carbonyl groups decreased after incubation of the [β-(14)C]-PS with P. variabile. GPC

  15. Preparation of {sup 14}C-Labeled Multi-walled Carbon Nano-tubes for Biodistribution Investigations

    Georgin, D.; Czarny, B.; Botquin, M.; Mayne-L' Hermite, M.; Pinault, M.; Bouchet-Fabre, B.; Carriere, M.; Poncy, J.L.; Chau, Q.; Maximilien, R.; Dive, V.; Taran, F. [CEA, IBITECS, SCBM, 91191 Gif sur Yvette (France); CEA, IBITECS, SIMOPRO, 91191 Gif sur Yvette (FR); CEA, IRAMIS, SPAM, 91191 Gif sur Yvette (FR); CEA, IRAMIS, SCM, 91191 Gif sur Yvette (FR); CEA, IRCM, SREIT, 91680 Bruyeres le Chatel (FR)

    2009-07-01

    A new method allowing the {sup 14}C-labeling of carboxylic acid functions of carbon nano-tubes is described. The key step of the labeling process is a de-carbonylation reaction that has been developed and optimized with the help of a screening method. The optimized process has been successfully applied to multi-walled carbon nano-tubes (MWNTs), and the corresponding {sup 14}C-labeled nano-tubes were used to investigate their in vivo behavior. Preliminary results obtained after i.v. contamination of rats revealed liver as the main target organ. Radiolabeling of NTs with a long-life radioactive nucleus like {sup 14}C, coupled to a highly sensitive autoradiographic method, that provides a unique detection threshold, will make it possible to determine for a long time period whether or not NTs remain in any organs after animal exposure. (authors)

  16. Comparative pharmacokinetics between a microdose and therapeutic dose for clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen), and phenobarbital in human volunteers.

    Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline; Weaver, Richard John; Gesson, Charlotte; Brian Houston, J; Oosterhuis, Berend; Bjerrum, Ole J; Grynkiewicz, Grzegorz; Alder, Jane; Rowland, Malcolm; Garner, Colin

    2011-06-14

    A clinical study was conducted to assess the ability of a microdose (100 μg) to predict the human pharmacokinetics (PK) following a therapeutic dose of clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen) and phenobarbital, both within the study and by reference to the existing literature on these compounds and to explore the source of any nonlinearity if seen. For each drug, 6 healthy male volunteers were dosed with 100 μg (14)C-labelled compound. For clarithromycin, sumatriptan, and propafenone this labelled dose was administered alone, i.e. as a microdose, orally and intravenously (iv) and as an iv tracer dose concomitantly with an oral non-labelled therapeutic dose, in a 3-way cross over design. The oral therapeutic doses were 250, 50, and 150 mg, respectively. Paracetamol was given as the labelled microdose orally and iv using a 2-way cross over design, whereas phenobarbital was given only as the microdose orally. Plasma concentrations of total (14)C and parent drug were measured using accelerator mass spectrometry (AMS) or HPLC followed by AMS. Plasma concentrations following non-(14)C-labelled oral therapeutic doses were measured using either HPLC-electrochemical detection (clarithromycin) or HPLC-UV (sumatriptan, propafenone). For all five drugs an oral microdose predicted reasonably well the PK, including the shape of the plasma profile, following an oral therapeutic dose. For clarithromycin, sumatriptan, and propafenone, one parameter, oral bioavailability, was marginally outside of the normally acceptable 2-fold prediction interval around the mean therapeutic dose value. For clarithromycin, sumatriptan and propafenone, data obtained from an oral and iv microdose were compared within the same cohort of subjects used in the study, as well as those reported in the literature. For paracetamol (oral and iv) and phenobarbital (oral), microdose data were compared with those reported in the literature only. Where 100 μg iv (14)C-doses were

  17. Bioavailability of bound residue derived from 14 C-labeled chlorsulfuron in soil and its mechanism of phytotoxicity

    YE Qing-fu; WU Jian-min; SUN Jin-he

    2004-01-01

    The bioavailability of bound residue(BR) derived from 14 C-labeled chlorsulfuron in soil and effect of themain components of the BR on growth of rape( brassica napus) and rice( Oryza sativa L. ) were investigated. Theresults showed that the BR with the concentration of 0.28 and 0.56 nmol/g air-dried soil, which was calculated byspecial radioactivity of 14C-labeled chlorsulfuron parent compound, resulted in significant depression effect on growthof rape seedling. It was assured that the main components(2-amino-4-methoxyl-6-methyl-1,3,5-triazine, 2-amino-4-hydroxyl-6-methyl-1,3,5-triazine, and 2-chloro-benzenesul-fonamide) of the BR did not inhibit the growth of rape andrice. LC-MS analysis demonstrated that the parent compound previously bound to the soil matrix could be againreleased and transformed into methanol-extractable residue during the course of rape growth. It was concluded thatthe molecular leading to the phytotoxicity to rape and rice in the BR is still the parent compound.

  18. [Quantifying soil autotrophic microbes-assimilated carbon input into soil organic carbon pools following continuous 14C labeling].

    Shi, Ran; Chen, Xiao-Juan; Wu, Xiao-Hong; Jian, Yan; Yuan, Hong-Zhao; Ge, Ti-Da; Sui, Fang-Gong; Tong, Cheng-Li; Wu, Jin-Shui

    2013-07-01

    Soil autotrophic microbe has been found numerous and widespread. However, roles of microbial autotrophic processes and the mechanisms of that in the soil carbon sequestration remain poorly understood. Here, we used soils incubated for 110 days in a closed, continuously labeled 14C-CO2 atmosphere to measure the amount of labeled C incorporated into the microbial biomass. The allocation of 14C-labeled assimilated carbon in variable soil C pools such as dissolved organic C (DOC) and microbial biomass C (MBC) were also examined over the 14C labeling span. The results showed that significant amounts of 14C-SOC were measured in paddy soils, which ranged from 69.06-133.81 mg x kg(-1), accounting for 0.58% to 0.92% of the total soil organic carbon (SOC). The amounts of 14C in the dissolved organic C (14C-DOC) and in the microbial biomass C (14C-MBC) were dependent on the soils, ranged from 2.54 to 8.10 mg x kg(-1), 19.50 to 49.16 mg x kg(-1), respectively. There was a significantly positive linear relationship between concentrations of 14C-SOC and 14C-MBC (R2 = 0.957**, P < 0.01). The 14C-DOC and 14C-MBC as proportions of total DOC, MBC, were 5.65%-24.91% and 4.23%-20.02%, respectively. Moreover, the distribution and transformation of microbes-assimilated-derived C had a greater influence on the dynamics of DOC and MBC than that on the dynamics of SOC. These data provide new insights into the importance of microorganisms in the fixation of atmospheric CO2 and of the potentially significant contributions made by microbial autotrophy to terrestrial C cycling.

  19. Metabolism of /sup 14/C-labeled doxylamine succinate (Bendectin) in the rhesus monkey (Macaca mulatta)

    Slikker, W. Jr.; Holder, C.L.; Lipe, G.W.; Korfmacher, W.A.; Thompson, H.C. Jr.; Bailey, J.R.

    1986-05-01

    The time-course of the metabolic fate of (/sup 14/C)doxylamine was determined after the p.o. administration of 13 mg/kg doxylamine succinate as Bendectin plus (/sup 14/C)doxylamine succinate to the rhesus monkey. Urine and plasma samples were analyzed by reversed-phase high performance liquid chromatography (HPLC), chemical derivatization, and mass spectrometry. The cumulative 48-hr urinary metabolic profile contained 81% of the administered radiolabeled dose and consisted of at least six radiolabeled peaks. They were peak 1: unknown polar metabolites (8% of dose); peak 2: 2-(1-phenyl-1-(2-pyridinyl)ethoxy) acetic acid, 1-(1-phenyl-1(2-pyridinyl)ethoxy) methanol, and another minor metabolite(s) (31%); peak 3: doxylamine-N-oxide (1%); peak 4a: N,N-didesmethyldoxylamine (17%); peak 4b: doxylamine (4%); and peak 5: N-desmethyldoxylamine (20%). The plasma metabolic profile was the same as the urinary profile except for the absence of doxylamine-N-oxide. The maximum plasma concentrations and elapsed time to attain these concentrations were as follows. Peak 1: 540 ng/mL, 4 hr; peak 2: 1700 ng/mL, 1 hr; peak 4a: 430 ng/mL, 4 hr; peak 4b: 930 ng/mL, 2 hr; and peak 5: 790 ng/mL, 2 hr. These data suggest that in the monkey, doxylamine metabolism follows at least four pathways: a minor pathway to the N-oxide; a minor pathway to unknown polar metabolites; a major pathway to mono- and didesmethyldoxylamine via successive N-demethylation; and a major pathway to side-chain cleavage products (peak 2) via direct side-chain oxidation and/or deamination.

  20. Use of an intravenous microdose of 14C-labeled drug and accelerator mass spectrometry to measure absolute oral bioavailability in dogs; cross-comparison of assay methods by accelerator mass spectrometry and liquid chromatography-tandem mass spectrometry.

    Miyaji, Yoshihiro; Ishizuka, Tomoko; Kawai, Kenji; Hamabe, Yoshimi; Miyaoka, Teiji; Oh-hara, Toshinari; Ikeda, Toshihiko; Kurihara, Atsushi

    2009-01-01

    A technique utilizing simultaneous intravenous microdosing of (14)C-labeled drug with oral dosing of non-labeled drug for measurement of absolute bioavailability was evaluated using R-142086 in male dogs. Plasma concentrations of R-142086 were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and those of (14)C-R-142086 were measured by accelerator mass spectrometry (AMS). The absence of metabolites in the plasma and urine was confirmed by a single radioactive peak of the parent compound in the chromatogram after intravenous microdosing of (14)C-R-142086 (1.5 microg/kg). Although plasma concentrations of R-142086 determined by LC-MS/MS were approximately 20% higher than those of (14)C-R-142086 as determined by AMS, there was excellent correlation (r=0.994) between both concentrations after intravenous dosing of (14)C-R-142086 (0.3 mg/kg). The oral bioavailability of R-142086 at 1 mg/kg obtained by simultaneous intravenous microdosing of (14)C-R-142086 was 16.1%, this being slightly higher than the value (12.5%) obtained by separate intravenous dosing of R-142086 (0.3 mg/kg). In conclusion, on utilizing simultaneous intravenous microdosing of (14)C-labeled drug in conjunction with AMS analysis, absolute bioavailability could be approximately measured in dogs, but without total accuracy. Bioavailability in humans may possibly be approximately measured at an earlier stage and at a lower cost.

  1. Plasma Pharmacokinetics and Routes of Excretion of [14C]-Labeled Arruva, a High-Potency Sweetener, Following Oral Administration to Beagle Dogs.

    Casterton, Phillip L; Crincoli, Christine M; Brathwaite, Witty A; Rihner, Marisa O; Nikiforov, Andrey I; Thomas, Jennifer A

    2014-05-01

    [(14)C]-Labeled arruva [sodium/potassium (2R,4R)-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl) pentanoate] was administered as a single gavage dose (10 mg/kg bw) to male and female Beagle dogs and 1 bile duct-cannulated male. The mean peak arruva plasma concentration equivalent of 1.2 µg/g occurred at first sampling time point of 1 hour postdosing. The mean area under the concentration versus time curve from 0 hour postdosing to the last time point was approximately 20 µg·h/g and the mean terminal plasma elimination half-life ranged from 15 hours in females to 21 hours in males. Over 168 hours postdosing, 35% to 50% of the administered arruva was eliminated in the urine with 44% to 53% eliminated in feces; 1.3% of the administered dose was recovered in bile. Arruva and its derivatives were identified using tandem mass spectrometry, and the relative percentage of each substance was quantified via radio high-performance liquid chromatography. Over a 168-hour collection period, combined urine and feces extract data from the 6 noncannulated dogs showed that approximately 91% of the dose was excreted as unchanged parent arruva (41% in urine and 50% in feces). In the cannulated male, 95.3% was excreted as unchanged parent arruva; 50.2% in urine, 43.9% in feces, and 1.3% in bile. Lactone and lactam derivatives of arruva and 1 unidentified substance were detected in urine only during the first 24 hours postdosing with the greatest amounts detected during the first 6 hours of collection; up to 1% of lactone or lactam derivatives were detected in bile samples. Plasma pharmacokinetics data indicated rapid absorption of arruva with the majority of radioactivity located in the feces collected in the first 48 hours.

  2. Metabolism of 35S- and 14C-labeled 1-methyl-2-mercaptoimidazole in vitro and in vivo.

    Taurog, A; Dorris, M L; Guziec, F S

    1989-01-01

    We previously described an in vitro incubation system for studying the mechanism of inhibition of thyroid peroxidase (TPO)-catalyzed iodination by the antithyroid drug 1-methyl-2-mercaptoimidazole (MMI). Inhibition of iodination in this system may be reversible or irreversible, depending on the relative concentrations of iodide and MMI and on the TPO concentration. Metabolism of the drug occurs under both conditions, and in the present investigation we used 35S- and 14C-labeled MMI together with reverse phase HPLC to examine the metabolic products associated with reversible and irreversible inhibition of iodination by MMI. Under conditions of reversible inhibition, MMI was rapidly metabolized and disappeared completely from the incubation mixture. With [35S]MMI, the earliest detectable 35S-labeled product was MMI disulfide, which reached a peak after a few minutes and then declined to undetectable levels. Coincident with the decrease in disulfide was the appearance of two 35S peaks, the major one corresponding to sulfate/sulfite, and the other to a component eluting at 7.5 min. Similar results were obtained for the disulfide and for the 7.5 min metabolite with [14C]MMI. The major 14C-labeled metabolite containing no S appeared to be 1-methylimidazole. Under conditions of irreversible inhibition, MMI disulfide was also the earliest detectable 35S-labeled metabolite. However, MMI decreased more slowly, and after reaching a nadir at about 6 min returned gradually to a level about halfway between the initial and the minimum value. The reformation of MMI appeared to involve the nonenzymatic disproportionation of MMI disulfide. Formation of the 7.5 min peak was also observed, but there was no formation of sulfate/sulfite. The difference in metabolic pattern between the reversible and irreversible conditions is primarily related to the rapid inactivation of TPO that occurs under irreversible conditions. The metabolism of [35S]MMI in thyroids of rats injected with the

  3. Evolution of CO{sub 2} during birnessite-induced oxidation of {sup 14}C-labeled catechol

    Majcher, E.H.; Chorover, J.; Bollag, J.M.; Huang, P.M.

    2000-02-01

    Phenolic compounds undergo several transformation processes in soil and water (i.e., partial degradation, mineralization, and polymerization), many of which have been attributed primarily to biological activity. Results from previous work indicate that naturally occurring Mn oxides are also capable of oxidizing phenolic compounds. In the present study, {sup 14}C-labeled catechol was reacted with birnessite (manganese oxide) in aqueous suspension of pH 4. The mass of catechol-derived c in solid, solution, and gas phases was quantified as a function of time. Between 5 and 16% of the total catechol C was liberated as CO{sub 2} from oxidation and abiotic ring cleavage under various conditions. Most of the {sup 14}C (55--83%) was incorporated into the solid phase in the form of stable organic reaction products whereas solution phase {sup 14}C concentrations increased from 16 to 39% with a doubling of total catechol added. Polymerization and CO{sub 2} evolution appear to be competitive pathways in the transformation of catechol since their relative importance was strongly dependent on initial birnessite-catechol reaction conditions. Solid phase Fourier transform infrared (FTIR) spectra are consistent with the presence of phenolic, quinone, and aromatic ring cleavage products. Carbon dioxide release appears to be limited by availability of reactive birnessite surface sites and it is diminished in the presence of polymerized reaction products.

  4. The cerebral metabolism of amino acids and related metabolites as studied by {sup 13}C and {sup 14}C labelling

    Hassel, B.

    1995-11-01

    The present investigations show the feasibility of analyzing the cerebral metabolism of amino acids and related metabolites by {sup 13}C-and {sup 14}C-labelling using labelled acetate and glucose as markers for glial and neuronal metabolism, respectively. Using [{sup 13}C]acetate, it was shown that glial cells export {approx}60% of their TCA cycle intermediates, mostly as glutamine, and that this glutamine is used by neurons partly as an energy reserve, and partly it is converted directly to glutamate and GABA. Using [{sup 13}C]glucose, the glial process or pyruvate carboxylation was shown to compensate fully for the loss of glutamine. The mechanism of action of two neurotoxins, fluorocitrate and 3-nitropropionate was elucidated. The latter toxin was shown to inhibit the TCA cycle of GABAergic neurons selectively. Formation of pyruvate and lactate from glial TCA cycle intermediates was demonstrated in vivo. This pathway may be important for glial inactivation of transmitter glutamate and GABA. The results illustrate glianeuronal interactions, and they suggest the applicability of {sup 13}CNMR spectroscopy to the detailed study of the cerebral metabolism of amino acids in the intact, unanesthetized human brain. 174 refs.

  5. Biokinetics and radiation dosimetry of {sup 14}C-labelled triolein, urea, glycocholic acid and xylose in man. Studies related to nuclear medicine 'breath tests' using accelerator mass spectrometry

    Gunnarsson, Mikael

    2002-08-01

    {sup 14}C-labelled substances have been used in biomedical research and clinical medicine for over 50 years. Physicians and scientists however, often hesitate to use these substances in patients and volunteers because the radiation dosimetry is unclear. In this work detailed long-term biokinetic and dosimetric estimation have been carried out for four clinically used {sup 14}C-breath tests: {sup 14}C-triolein (examination of fat malabsorption), urea (detection of Helicobacter pylori infection in the stomach), glycocholic acid and xylose (examination of bacterial overgrowth in the small intestine) by using the highly sensitive accelerator mass-spectrometry (AMS) technique. The AMS technique has been used to measure low {sup 14}C concentrations in small samples of exhaled air, urine, faeces and tissue samples and has improved the base for the estimation of the absorbed dose to various organs and tissues and the effective dose to man. The high sensitivity of the AMS system has also made it possible to perform {sup 14}C breath tests on patient groups which were earlier subject for restriction (e.g. small children). In summary, our results show that for adult patients - and in the case of {sup 14}C-urea breath test also for children down to 3 years of age - the dose contributions are comparatively low, both described as organ doses and as effective doses. For adults, the latter is: {sup 14}C-glycocholic acid - 0.4 mSv/MBq, {sup 14}C-triolein - 0.3 mSv/MBq, {sup 14}C-xylose - 0.1 mSv/MBq and {sup 14}C-urea - 0.04 mSv/MBq. Thus, from a radiation protection point of view there is no reason for restrictions in using any of the {sup 14}C-labelled radiopharmaceutical included in this work in the activities normally used (0.07-0.2 MBq for a 70 kg patient)

  6. Production of the {sup 14}C-labeled insecticidal protein Cry1Ab for soil metabolic studies using a recombinant Escherichia coli in small-scale batch fermentations

    Valldor, Petra; Miethling-Graff, Rona; Dockhorn, Susanne; Martens, Rainer; Tebbe, Christoph C. [Federal Research Institute for Rural Areas, Forestry and Fisheries, Braunschweig (Germany). Thuenen Institute (vTI) for Biodiversity

    2012-10-15

    Insecticidal Cry proteins naturally produced by Bacillus thuringiensis are a major recombinant trait expressed by genetically modified crops. They are released into the soil during and after cropping. The objective of this study was to produce {sup 14}C-labeled Cry1Ab proteins for soil metabolic studies in scope of their environmental risk assessment. Cry1Ab was synthesized as a protoxin by Escherichia coli HB101 pMP in 200-mL liquid batch culture fermentations and purified from inclusion bodies after trypsin digestion. For cultivation, U-{sup 14}C-glycerol was the main carbon source. Inclusion bodies were smaller and Cry1Ab yield was lower when the initial amount of total organic carbon in the cultivation broth was below 6.4 mg C L{sup -1}. Concentrations of 12.6 g {sup 14}C-labeled glycerol L{sup -1} (1 % v/v) resulted in the production of 17.1 mg {sup 14}C-Cry1Ab L{sup -1} cultivation medium. {sup 14}C mass balances showed that approx. 50 % of the label was lost by respiration and 20 % remained in the growth media, while the residual activity was associated with biomass. Depending on the production batch, 0.01 to 0.05 % of the total {sup 14}C originated from Cry1Ab. In the presence of 2.04 MBq {sup 14}C-labeled carbon sources, a specific activity of up to 268 Bq mg{sup -1} {sup 14}C-Cry1Ab was obtained. A more than threefold higher specific activity was achieved with 4.63 MBq and an extended cultivation period of 144 h. This study demonstrates that {sup 14}C-labeled Cry1Ab can be obtained from batch fermentations with E. coli in the presence of a simple {sup 14}C-labeled carbon source. It also provides a general strategy to produce {sup 14}C-labeled proteins useful for soil metabolic studies. (orig.)

  7. 14C-labeled propionate metabolism in vivo and estimates of hepatic gluconeogenesis relative to Krebs cycle flux.

    Landau, B R; Schumann, W C; Chandramouli, V; Magnusson, I; Kumaran, K; Wahren, J

    1993-10-01

    Purposes of this study were 1) to estimate in humans, using 14C-labeled propionate, the rate of hepatic gluconeogenesis relative to the rate of Krebs cycle flux; 2) to compare those rates with estimates previously made using [3-14C]lactate and [2-14C]acetate; 3) to determine if the amount of ATP required for that rate of gluconeogenesis could be generated in liver, calculated from that rate of Krebs cycle flux and splanchnic balance measurements, previously made, and 4) to test whether hepatic succinyl-CoA is channeled during its metabolism through the Krebs cycle. [2-14C]propionate, [3-14C]-propionate, and [2,3-14C]succinate were given along with phenyl acetate to normal subjects, fasted 60 h. Distributions of 14C were determined in the carbons of blood glucose and of glutamate from excreted phenylacetylglutamine. Corrections to the distributions for 14CO2 fixation were made from the specific activities of urinary urea and the specific activities in glucose, glutamate, and urea previously found on administering [14C]-bicarbonate. Uncertainties in the corrections and in the contributions of pyruvate and Cori cyclings limit the quantitations. The rate of gluconeogenesis appears to be two or more times the rate of Krebs cycle flux and pyruvate's decarboxylation to acetyl-CoA, metabolized in the cycle, less than one-twenty-fifth the rate of its decarboxylation. Such estimates were previously made using [3-14C]lactate. The findings support the use of phenyl acetate to sample hepatic alpha-ketoglutarate. Ratios of specific activities of glucose to glutamate and glucose to urinary urea and expired CO2 indicate succinate's extensive metabolism when presented in trace amounts to liver. Utilizations of the labeled compounds by liver relative to other tissues were in the order succinate = lactate > propionate > acetate. ATP required for gluconeogenesis and urea formation was approximately 40% of the amount of ATP generated in liver. There was no channeling of succinyl-CoA in

  8. Synthesis of enantiomerically pure [(14) C]-labelled morpholine derivatives for a class of trace amine-associate receptor 1 agonists.

    Edelmann, Martin R; Hartung, Thomas; Trussardi, René; Iding, Hans; Galley, Guido; Pflieger, Philippe; Norcross, Roger D

    2016-12-01

    Various agonists of the trace amine-associate receptor 1, under consideration as potential clinical development candidates, were labelled with carbon-14 for use in preclinical in vitro and in vivo drug metabolism studies. Herein, the [(14) C]-radiosynthesis of 2-phenyl-substituted morpholines 1 is described. After evaluating and optimizing different synthetic routes, 4-iodonitrobenzene 3 was selected as starting material for the 14-step synthesis. Incorporation of carbon-14 into the acetyl moiety allowed a safe and efficient synthesis of [(14) C]-labelled 4-nitroacetophenone 2 in five steps and 38% yield. Further transformation of 2 to the target compounds 1 was achieved in a 9-step synthesis. In a representative example, [(14) C]-labelled 1 was obtained in an overall yield of 11% and was isolated in >99% radiochemical purity and a specific activity of 47 mCi/mmol.

  9. A Radiochemical Biotechnological Approach: Preliminary Study of Lactose Uptake Rate by Kefir Cells, Using 14C-labeled Lactose, in Anaerobic Fermentation

    Golfinopoulos, A.; Soupioni, M.; Kanellaki, M.; Koutinas, A. A.

    2008-08-01

    The effect of initial lactose concentration on lactose uptake rate by kefir free cells, during the lactose fermentation, was studied in this work. For the investigation 14C-labelled lactose was used due to the fact that labeled and unlabeled molecules are fermented in the same way. The results illustrated lactose uptake rates are about up to two fold higher at lower initial ∘Bé densities as compared with higher initial ∘Bé densities.

  10. Therapeutic effects of low radiation doses

    Trott, K.R. (Dept. of Radiation Biology, St. Bartholomew' s Medical College, London (United Kingdom))

    1994-01-01

    This editorial explores the scientific basis of radiotherapy with doses of < 1 Gy for various non-malignant conditions, in particular dose-effect relationships, risk-benefit considerations and biological mechanisms. A review of the literature, particularly clinical and experimental reports published more than 50 years ago was conducted to clarify the following problems. 1. The dose-response relationships for the therapeutic effects on three groups of conditions: non-malignant skin disease, arthrosis and other painful degenerative joint disorders and anti-inflammatory radiotherapy; 2. risks after radiotherapy and after the best alternative treatments; 3. the biological mechanisms of the different therapeutic effects. Radiotherapy is very effective in all three groups of disease. Few dose-finding studies have been performed, all demonstrating that the optimal doses are considerable lower than the generally recommended doses. In different conditions, risk-benefit analysis of radiotherapy versus the best alternative treatment yields very different results: whereas radiotherapy for acute postpartum mastitis may not be justified any more, the risk-benefit ratio of radiotherapy of other conditions and particularly so in dermatology and some anti-inflammatory radiotherapy appears to be more favourable than the risk-benefit ratio of the best alternative treatments. Radiotherapy can be very effective treatment for various non-malignant conditions such as eczema, psoriasis, periarthritis humeroscapularis, epicondylitis, knee arthrosis, hydradenitis, parotitis and panaritium and probably be associated with less acute and long-term side effects than similarly effective other treatments. Randomized clinical studies are required to find the optimal dosage which, at present, may be unnecessarily high.

  11. The metabolic disposition of /sup 14/C-labelled carmoisine in the rat after oral and intravenous administration

    Galli, C.L.; Marinovich, M.; Costa, L.G.

    1982-08-01

    The absorption, distribution and excretion of the red azo dye carmoisine (Ext. D and C No. 10) was studied in male rats. (/sup 14/C)Carmoisine was administered in a dose of 200 mg/kg (25 microCi) by gavage or in the same dose (200 mg/kg; 3 microCi) by intravenous injection, and radioactivity was measured in blood, tissue, faeces and urine at different times after dosing. After oral administration of the dye, no radioactivity was detected in the brain, adipose tissue, muscle, testes, spleen or lung, and recovery of the administered activity in faeces and urine was almost complete by 32 hr. The radioactivity profile of the blood indicated rapid but poor absorption of (/sup 14/C)carmoisine, a maximum radioactivity content corresponding to 0.01% of the dose per ml of blood being reached within 10 min. The decay curve for /sup 14/C radioactivity in the blood after iv injection of (/sup 14/C)carmoisine indicated rapid distribution to the tissues and could be described in terms of a two-compartment mathematical model. The highest levels of radioactivity occurred in the gastro-intestinal tract and liver after the injection but after 24 hr no radioactivity was detectable in these or other tissues. All the radioactivity was recovered in the faeces and urine in the 24 hr following iv injection, the 79% of the dose present in faeces indicating active excretion of the dye and its metabolites in the bile and poor reabsorption from the intestine. The bioavailability of (/sup 14/C)carmoisine, calculated from the blood-radioactivity curves after oral and iv administration, was less than 10%.

  12. Aerobic biotransformation of 14C-labeled 8-2 telomer B alcohol by activated sludge from a domestic sewage treatment plant.

    Wang, Ning; Szostek, Bogdan; Folsom, Patrick W; Sulecki, Lisa M; Capka, Vladimir; Buck, Robert C; Berti, William R; Gannon, John T

    2005-01-15

    This study investigated the biodegradation potential of 3-(14)C,1H,1H,2H,2H-perfluorodecanol [CF3(CF2)6(14)CF2CH2CH2OH, 14C-labeled 8-2 telomer B alcohol or 14C-labeled 8-2 TBA] by diluted activated sludge from a domestic wastewater treatment plant under aerobic conditions. After sample extraction with acetonitrile, biotransformation products were separated and quantified by LC/ARC (on-line liquid chromatography/accurate radioisotope counting) with a limit of quantification about 0.5% of the 14C counts applied to the test systems. Identification of biotransformation products was performed by quadrupole time-of-flight mass spectrometry. Three transformation products have been identified: CF3(CF2)6(14)CF2CH2COOH (8-2 saturated acid); CF3(CF2)6(14)CF=CHCOOH (8-2 unsaturated acid); and CF3(CF2)6(14)COOH (perfluorooctanoic acid, PFOA), representing 27, 6.0, and 2.1% of the initial 14C mass (14C counts applied) after 28 days, respectively. A transformation product, not yet reported in the literature, has also been observed and tentatively identified as CF3(CF2)6(14)CH2CH2COOH (2H,2H,3H,3H-perfluorodecanoic acid); it accounted for 2.3% of the mass balance after 28 days. The 2H,2H,3H,3H-perfluorodecanoic acid is likely a substrate for beta-oxidation, which represents one of the possible pathways for 8-2 telomer B alcohol degradation. The 8-2 saturated acid and 8-2 unsaturated acid cannot be directly used as substrates for beta-oxidation due to the proton deficiency in their beta-carbon (C3 carbon) and their further catabolism may be catalyzed by some other still unknown mechanisms. The 2H,2H,3H,3H-perfluorodecanoic acid may originate either from the major transformation product CF3(CF2)6(14)CF2CH2COOH or from other unidentified transformation products via multiple steps. Approximately 57% of the starting material remained unchanged after 28 days, likely due to its strong adsorption to the PTFE (poly(tetrafluoroethylene)) septa of the test vessels. No CF3(CF2)6(14)CF2COOH

  13. Therapeutic dose from a pyroelectric electron accelerator.

    Fullem, T Z; Fazel, K C; Geuther, J A; Danon, Y

    2009-11-01

    Simple heating of pyroelectric crystals has been used as the basis for compact sources of X rays, electrons, ions and neutrons. We report on the evaluation of the feasibility of using a portable pyroelectric electron accelerator to deliver a therapeutic dose to tissue. Such a device could be mass produced as a handheld, battery-powered instrument. Experiments were conducted with several crystal sizes in which the crystal was heated inside a vacuum chamber and the emitted electrons were allowed to penetrate a thin beryllium window into the surrounding air. A Faraday cup was used to count the number of electrons that exited the window. The energy of these electrons was determined by measuring the energy spectrum of the X rays that resulted from the electron interactions with the Faraday cup. Based on these measurements, the dose that this source could deliver to tissue was calculated using Monte Carlo calculations. It was found that 10(13) electrons with a peak energy of the order of 100 keV were emitted from the beryllium window and could deliver a dose of 1664 Gy to a 2-cm-diameter, 110-microm-deep region of tissue located 1.5 cm from the window with air between the window and the tissue. This dose level is high enough to consider this technology for medical applications in which shallow energy deposition is beneficial.

  14. Studies on the percutaneous absorption of /sup 14/C-labelled Flurbiprofen, 3. Whole body autoradiography of rats and guinea-pigs

    Nagao, Soshichi; Sakai, Takeo; Hayakawa, Toru (Nihon Univ., Tokyo. Coll. of Agriculture and Veterinary Medicine)

    1983-03-01

    Whole body autoradiography was carried out to clarify and compare the distribution of /sup 14/C-labelled Flurbiprofen which was applied to the skin as an ointment in rats and guinea-pigs. Both in rats and guinea-pigs almost the same autoradiogram was gained. The radioactivity was strongest at the skin area inspite of the time elapse, showing that the drug was fixed in the site of skin applied. In other parts of the body, however, it was small except the kidney and intestine. It seemed that the absorption of the drug was a little although the migration of the drug into the blood circulation is fast at the beginning as was shown in pigs previously. A stronger radioactivity in the kidney and intestine might indicate that a main pathway of excretion of this drug was through those two organs. Absorption, distribution and excretion of the drug were not different between rats and guinea-pigs, similar to those observed in pigs.

  15. Preparation of 14-C-labelled 1,4-Dideoxy-1,4-imino-D-arabinitol: Cyanosilylation of Cyclic Imines using KCN in a One-Pot Synthesis

    Lundt, Inge; Malle, Birgitte Mølholm; Foged, Christian;

    1999-01-01

    A new method for C-C bond formation was developed based on in situ cyanosilylation of cyclic Schiff bases using KCN, TMSCl, KI and ZnI2. This method was used to prepare the potent -glucosidase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol 14-C labelled at C-5.Keywords: in situ cyanosilylation; 14-C...

  16. Using Position-Specific 13C and 14C Labeling and 13C-PLFA Analysis to Assess Microbial Transformations of Free Versus Sorbed Alanine

    Apostel, C.; Herschbach, J.; Bore, E. K.; Kuzyakov, Y.; Dippold, M. A.

    2015-12-01

    Sorption of charged or partially charged low molecular weight organic substances (LMWOS) to soil mineral surfaces delays microbial uptake and therefore mineralization of LMWOS to CO2, as well as all other biochemical transformations. We used position-specific labeling, a tool of isotope applications novel to soil sciences, to compare the transformation mechanisms of sorbed and non-sorbed alanine in soil. Alanine as an amino acid links C- and N-cycles in soil and therefore is a model substance for the pool of LMWOS. To assess transformations of sorbed alanine, we added position-specific and uniformly 13C and 14C labeled alanine tracer to soil that had previously been sterilized by γ-radiation. The labeled soil was added to non-sterilized soil from the same site and incubated. Soil labeled with the same tracers without previous sorption was prepared and incubated as well. We captured the respired CO2 and determined its 14C-activity at increasing time intervals. The incorporation of 14C into microbial biomass was determined by chloroform fumigation extraction (CFE), and utilization of individual C positions by distinct microbial groups was evaluated by 13C-phospholipid fatty acid analysis (PLFA). A dual peak in the respired CO2 revealed two sorption mechanisms. To compare the fate of individual C atoms independent of their concentration and pool size in soil, we applied the divergence index (DI). The DI reveals the convergent or divergent behavior of C from individual molecule positions during microbial utilization. Alanine C-1 position was mainly oxidized to CO2, while its C-2 and C-3 were preferentially incorporated in microbial biomass and PLFA. This indicates that sorption by the COOH group does not protect this group from preferential oxidation. Microbial metabolism was determinative for the preferential oxidation of individual molecule positions. The use of position-specific labeling revealed mechanisms and kinetics of microbial utilization of sorbed and non

  17. Calculating radiation exposures during use of (14)C-labeled nutrients, food components, and biopharmaceuticals to quantify metabolic behavior in humans.

    Kim, Seung-Hyun; Kelly, Peter B; Clifford, Andrew J

    2010-04-28

    (14)C has long been used as a tracer for quantifying the in vivo human metabolism of food components, biopharmaceuticals, and nutrients. Minute amounts (nutrients to be organized into models suitable for quantitative hypothesis testing and determination of metabolic parameters. In vivo models are important for specification of intake levels for food components, biopharmaceuticals, and nutrients. Accurate estimation of the radiation exposure from ingested (14)C is an essential component of the experimental design. Therefore, this paper illustrates the calculation involved in determining the radiation exposure from a minute dose of orally administered (14)C-beta-carotene, (14)C-alpha-tocopherol, (14)C-lutein, and (14)C-folic acid from four prior experiments. The administered doses ranged from 36 to 100 nCi, and radiation exposure ranged from 0.12 to 5.2 microSv to whole body and from 0.2 to 3.4 microSv to liver with consideration of tissue weighting factor and fractional nutrient. In comparison, radiation exposure experienced during a 4 h airline flight across the United States at 37000 ft was 20 microSv.

  18. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

    Judge Bryan S

    2011-03-01

    Full Text Available Abstract Background Acetaminophen-cysteine adducts (APAP-CYS are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose. Methods Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated. Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection. Results Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20 nmol/ml, Trial 2- 0.1 (0.09 nmol/ml and Trial 3- 0.3 (0.12 nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml. No subject had detectable APAP

  19. Application of capillary gas chromatography-reaction interface/mass spectrometry to the selective detection of sup 13 C-, sup 15 N-, sup 2 H-, and sup 14 C-labeled drugs and their metabolites

    Chace, D.H.

    1989-01-01

    A novel reaction interface/mass spectrometer (RIMS) technique has been applied to the selective detection of {sup 13}C-, {sup 15}N-, {sup 2}H-, and {sup 14}C-labeled phenytoin and its metabolites in urine following separation by capillary gas chromatography. The microwave-powered reaction interface converts materials from their original forms into small molecules whose mass spectra serve to identify and quantify the nuclides. The presence of each element is followed by monitoring the isotopic variants of CO{sub 2}, NO, H{sub 2}, or CH{sub 4} that are produced by the reaction interface. Chromatograms showing only enriched {sup 13}C and {sup 15}N were produced using the net {sup 13}CO{sub 2} or {sup 15}NO signal derived by subtracting the abundance of naturally occurring isotopes from the observed M + 1 signal. When hydrogen was used as a reactant gas, a selective chromatogram of {sup 2}H (D) was obtained by measuring HD at m/Z 3.0219, and a chromatogram showing {sup 14}C was obtained by measuring {sup 14}CH{sub 4} at m/Z 18.034 with a high resolution. For a stable isotope detection, metabolites representing less than 1.5% of the total labeled compounds could be detected in the chromatogram. Detection limits of 170 pCi/mL (34 pCi on column that is equivalent to 187 pg) of a {sup 14}C- labeled metabolite was detected. To identify many of these labeled peaks (metabolites), the chromatographic analysis was repeated with the reaction interface turned off and mass spectra obtained at the retention times found in the RIMS experiment. In addition to the ability of GC-RIMS to detect the presence of {sup 13}C-, {sup 15}N-, and {sup 2}H- (D), it can also quantify the level of enrichment. Enrichment of {sup 13}C and {sup 15}N is quantified by measuring the ratio of excess {sup 13}CO{sub 2} to total {sup 12}CO{sub 2} or excess {sup 15}NO to total {sup 14}NO.

  20. Convulsive seizures with a therapeutic dose of isoniazid.

    Tsubouchi, Kazuya; Ikematsu, Yuuki; Hashisako, Mikiko; Harada, Eiji; Miyagi, Hiroto; Fujisawa, Nobumitsu

    2014-01-01

    An 86-year-old woman who had been treated for tuberculous peritonitis and pulmonary tuberculosis, exhibited a disturbance of consciousness and tonic-clonic convulsions seven days after the administration of the antituberculous drug isoniazid. As her serum vitamin B6 level was remarkably low, she was diagnosed with convulsive seizures due to vitamin B6 deficiency associated with isoniazid treatment. Seizures refractory to standard anticonvulsant therapy were controlled with the administration of pyridoxine. Most reported cases of isoniazid-induced convulsive seizures occurred as a result of an overdose due to attempted suicide. This report presents a case of convulsive seizures that occurred in association with the short-term administration of a therapeutic dose of isoniazid.

  1. Production of manganese peroxidase and organic acids and mineralization of {sup 14}C-labelled lignin ({sup 14}C-DHP) during solid-state fermentation of wheat straw with the white rot fungus Nematoloma frowardii

    Hofrichter, M.; Scheibner, K.; Fritsche, W. [Friedrich Schiller Univ., Jena (Germany). Inst. of Microbiology; Vares, T.; Kalsi, M.; Galkin, S.; Hatakka, A. [Univ. of Helsinki (Finland). Dept. of Applied Chemistry and Microbiology

    1999-05-01

    The basidiomycetous fungus Nematoloma frowardii produced manganese peroxidase (MnP) as the predominant ligninolytic enzyme during solid-state fermentation (SSF) of wheat straw. The purified enzyme had a molecular mass of 50 kDa and an isoelectric point of 3.2. In addition to MnP, low levels of laccase and lignin peroxidase were detected. Synthetic {sup 14}C-ring-labelled lignin ({sup 14}C-DHP) was efficiently degraded during SSF. Approximately 75% of the initial radioactivity was released as {sup 14}CO{sub 2}, while only 6% was associated with the residual straw material, including the well-developed fungal biomass. On the basis of this finding the authors concluded that at least partial extracellular mineralization of lignin may have occurred. This conclusion was supported by the fact that they detected high levels of organic acids in the fermented straw, which rendered MnP effective and therefore made partial direct mineralization of lignin possible. Experiments performed in a cell-free system, which simulated the conditions in the straw cultures, revealed that MnP in fact converted part of the {sup 14}C-DHP to {sup 14}CO{sub 2} and {sup 14}C-labelled water-soluble products in the presence of natural levels of organic acids.

  2. Deferasirox at therapeutic doses is associated with dose-dependent hypercalciuria.

    Wong, Phillip; Polkinghorne, Kevan; Kerr, Peter G; Doery, James C G; Gillespie, Matthew T; Larmour, I; Fuller, Peter J; Bowden, Donald K; Milat, Frances

    2016-04-01

    Deferasirox is an oral iron chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies. Whilst initial long-term studies established the renal safety of deferasirox, there are now increasing reports of hypercalciuria and renal tubular dysfunction. In addition, urolithiasis with rapid loss of bone density in patients with β thalassemia major has been reported. We conducted a cross-sectional cohort study enrolling 152 adult patients comprising of β thalassemia major (81.5%), sickle cell disease (8%), thalassemia intermedia (2%), HbH disease (6.5%) and E/β thalassemia (2%). Cases were matched with normal control subjects on age, gender and serum creatinine. Iron chelator use was documented and urine calcium to creatinine ratios measured. At the time of analysis, 88.8% of patients were receiving deferasirox and 11.2% were on deferoxamine. Hypercalciuria was present in 91.9% of subjects on deferasirox in a positive dose-dependent relationship. This was not seen with subjects receiving deferoxamine. At a mean dose of 30.2±8.8mg/kg/day, deferasirox was associated with an almost 4 fold increase in urine calcium to creatinine ratio (UCa/Cr). Hypercalciuria was present at therapeutic doses of deferasirox in a dose-dependent manner and warrants further investigation and vigilance for osteoporosis, urolithiasis and other markers of renal dysfunction.

  3. ANTI-HYPERGLYCEMIC ACTIVITY OF SIMVASTATIN ALONE (THERAPEUTIC DOSE AND COMBINATION OF SIMVASTATIN AND GLIPIZIDE (SUB THERAPEUTIC DOSES ON ALLOXAN INDUCED HYPERGLYCEMIA IN ALBINO RATS

    V.S. Harish Kumar*, N.R. Sindhu, Rajashri S. Patil and Umakant Patil

    2012-11-01

    Full Text Available The present study was designed to evaluate anti-hyperglycemic activity of simvastatin alone and the combination of sub therapeutic doses of simvastatin and glipizide. Hyperglycemia was induced experimentally in albino rats by subcutaneous injection of alloxan in a dose of 175 mg/kg body weight. After 72 hours of alloxan treatment, rats showing hyperglycemia (blood glucose level of 400 mg/dl and above were included in the study. They were divided into four groups of 6 animals each (n=24. Oral administration of normal saline 0.5 ml, glipizide 2.5 mg/kg body weight, simvastatin 10 mg/kg body weight and sub therapeutic doses of both test (simvastatin 5 mg/kg body weight and standard (glipizide 1.25 mg/kg body weight drugs, was done respectively into each of the four groups for 30 consecutive days in order to assess the effect in terms of reduction in blood glucose level. Blood glucose was estimated on 0th, 10th, 20th, and 30th days of study in fixed time intervals. In the test group, there was a gradual fall in the blood glucose level which reached up to 308.3 mg/dl by 30th day of study (P < 0.001. In case of combination of sub therapeutic doses of simvastatin and glipizide, the fall in blood glucose level was gradual and sustained and it reached up to 201.5 mg/dl by the 30th day (P < 0.001. These observations are comparable with the results obtained in case of glipizide treated rats, the standard group. Simvastatin appreciably lowered the blood glucose level, but the combination of sub therapeutic doses of simvastatin and glipizide, by virtue of their possible synergistic effect produced further reduction in the blood glucose level. This study provides evidence in support of a potential anti-hyperglycemic effect of simvastatin and its combination with glipizide. Thus the combined treatment of simvastatin and glipzide may have added benefit for the diabetic patients associated with hyperlipidemia.

  4. Enhanced therapeutic tumour dose of /sup 131/I-MIBG by accelerated diuresis

    Darte, L.; Tennvall, J.

    1988-10-01

    Different biokinetics of intravenously (i.v.) administered /sup 131/I-MIBG in the same patient, a child with abdominal neuroblastoma, is demonstrated with and without accelerated elimination by means of hyperhydration. By hyperhydration it was possible to increase the estimated tumour dose by a factor of 2.1 without affecting the whole body dose. The present results indicate that, if accelerated diuresis is implemented, higher radioactivity of /sup 131/I-MIBG can be administered and thereby an increased therapeutic tumour dose achieved.

  5. Employing the therapeutic operating characteristic (TOC) graph for individualised dose prescription

    Hoffmann, A.L.; Huizenga, H.; Kaanders, J.H.A.M.

    2013-01-01

    BACKGROUND: In current practice, patients scheduled for radiotherapy are treated according to 'rigid' protocols with predefined dose prescriptions that do not consider risk-taking preferences of individuals. The therapeutic operating characteristic (TOC) graph is applied as a decision-aid to assess

  6. Health risks associated with low dose diagnostic or therapeutic radiation exposures

    Boreham, D.R. [McMaster Univ., Dept. of Medical Physics and Applied Radiation Sciences, Hamilton, Ontario (Canada)

    2007-07-01

    The health risks to humans associated with exposure to low doses of ionizing radiation have been extrapolated from effects observed at high doses, dose rates, and mixed radiation qualities using a linear no threshold model. Based on this approach, it has been argued that human exposure to low doses of diagnostics X-rays and gamma-rays increase an individual's risk of developing cancer throughout their life-time. Also, repeated medical diagnostic procedures involving low dose exposures will have an additive effect and consequently further increase health risk. The specific aim of this seminar will be to address the relative risk associated with diagnostic X-rays from CT scans and gamma-rays from positron emission tomography (PET) scans. Objectives of the talk will include: 1) Defining low dose exposures at a cellular level and relate that to diagnostic or therapeutic exposures, 2) Describing modern tools in molecular cytogenetics to estimate radiation exposure and assess radiation risk, 3) Identifying the different cellular mechanisms that influence radiation risk at high and low dose exposures and relate that to individual radiation risk. (author)

  7. Acute pancreatitis related to therapeutic dosing with colchicine: a case report

    Ting Joseph

    2007-08-01

    Full Text Available Abstract Background Colchicine is used in the treatment and prophylaxis of gout. It possesses a narrow therapeutic window, frequently resulting in dose-limiting gastrointestinal side-effects such as diarrhoea and emesis. As colchicine is a cellular anti-mitotic agent, the most serious effects include myelosuppression, myoneuropathy and multiple organ failure. This occurs with intentional overdose or with therapeutic dosing in patients with reduced clearance of colchicine due to pre-existing renal or hepatic impairment. Acute pancreatitis has rarely been reported, and only in association with severe colchicine overdose accompanied by multi-organ failure. Case presentation We report a case of acute pancreatitis without other organ toxicity related to recent commencement of colchicine for acute gout, occurring in an elderly male with pre-existing renal impairment. Conclusion 1 Colchicine should be used with care in elderly patients or patients with impaired renal function. 2 Aside from myelosuppression, myoneuropathy and multiple organ failure, colchicine may now be associated with acute pancreatitis even with therapeutic dosing; this has not previously being reported.

  8. Psychosis with paranoid delusions after a therapeutic dose of mefloquine: a case report

    Browning Joseph

    2006-08-01

    Full Text Available Abstract Background Convenient once-a-week dosing has made mefloquine a popular choice as malaria prophylaxis for travel to countries with chloroquine-resistant malaria. However, the increased use of mefloquine over the past decade has resulted in reports of rare, but severe, neuropsychiatric adverse reactions, such as anxiety, depression, hallucinations and psychosis. A direct causality between mefloquine and severe reactions among travelers has been partly confounded by factors associated with foreign travel and, in the case of therapeutic doses of mefloquine, the central nervous system manifestations of Plasmodium infection itself. The present case provides a unique natural history of mefloquine-induced neuropsychiatric toxicity and revisits its dose-dependent nature. Case presentation This report describes an acute exacerbation of neuropsychiatric symptoms after an unwarranted therapeutic dose (1250 mg of mefloquine in a 37-year-old male previously on a once-a-week prophylactic regimen. Neuropsychiatric symptoms began as dizziness and insomnia of several days duration, which was followed by one week of escalating anxiety and subtle alterations in behaviour. The patient's anxiety culminated into a panic episode with profound sympathetic activation. One week later, he was hospitalized after developing frank psychosis with psychomotor agitation and paranoid delusions. His psychosis remitted with low-dose quetiapine. Conclusion This report suggests that an overt mefloquine-induced psychosis can be preceded by a prodromal phase of moderate symptoms such as dizziness, insomnia, and generalized anxiety. It is important that physicians advise patients taking mefloquine prophylaxis and their relatives to recognize such symptoms, especially when they are accompanied by abrupt, but subtle, changes in behaviour. Patients with a history of psychiatric illness, however minor, may be at increased risk for a mefloquine-induced neuropsychiatric toxicity

  9. EFFECT OF THERAPEUTIC AND DOUBLE THERAPEUTIC DOSES OF IVERMECTIN ON OXIDATIVE STATUS AND REPRODUCTIVE HORMONES IN MALE RABBITS

    Ali Hafez El-Far

    2013-01-01

    Full Text Available To investigate the biochemical alterations of oxidative status and male sexual hormones, thyroid hormones, cortisol, liver function and kidney function; sixty male New Zealand White rabbits were equally allotted according to their body weight into two groups. Control samples were collected before subcutaneous injection of rabbits by ivermectinin Therapeutic (TD and Double Therapeutic Doses (DTD. After injection blood samples were collected from ear vein at 1st, 3rd and 7th day of experiment and subjected to the biochemical analysis of urea, uric acid, creatinine, aspartate transaminase, alanine transaminase, lactate dehydrogenase, creatine phosphokinase, triiodothyronine, thyroxin, nitric oxide, total antioxidant capacity, cortisol, testosterone and free testosterone. The obtained data of both TD and DTD revealed a significant increase in urea, uric acid, creatinine, aspartate transaminase, alanine transaminase, lactate dehydrogenase, creatine phosphokinase, triiodothyronine, thyroxin, nitric oxide, cortisol, testosterone and free testosterone while total antioxidant capacity levels were significantly decreased. From the date data of the current study on TD and DTD with a higher value in the DTD. We can conclude that ivermectin induced deleterious effects on kidneys and hepatic functions, oxidative stress, weight loss and increased testosterone and free testosterone.

  10. Changes in circulating lymphocyte subpopulations in pigs receiving therapeutic doses of ceftiofur and tulathromycin

    Czyżewska-Dors Ewelina

    2016-12-01

    Full Text Available Introduction: The aim of the study was to evaluate the effect of administration of therapeutic doses of ceftiofur and tulathromycin on the circulating lymphocyte subpopulations in healthy pigs. Material and Methods: The study was conducted on thirty healthy 7- to 10-week-old pigs, assigned to three groups: the TUL group, injected with tulathromycin (n = 10; the CEF group, injected with ceftiofur (n = 10; and the C group, the control with no antibiotic administration (n = 10. Blood samples were collected before, during, and after treatment with antimicrobials. Lymphocyte subpopulations circulating in the blood were determined by immunostaining and flow cytometry analyses. Results: Following administration of a therapeutic dose of tulathromycin, there were no changes in the lymphocyte subpopulations circulating in blood. In contrast, administration of ceftiofur at the recommended dose decreased the absolute number of CD3+, CD21+, CD4+CD8-, CD4-CD8+, and double positive CD4CD8 cells. Conclusion: Results from the study indicate that ceftiofur possesses the ability to modulate the immune system in healthy pigs by decreasing lymphocyte subpopulations circulating in blood.

  11. Dose-response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies.

    Webb, Nicholas E; Montefiori, David C; Lee, Benhur

    2015-09-29

    A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose-response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120-gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations.

  12. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats.

    Jan B W J Cornelissen

    Full Text Available High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10, and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application.

  13. Toward endobronchial Ir-192 high-dose-rate brachytherapy therapeutic optimization

    Gay, H A [Department of Radiation Oncology, Brody School of Medicine at East Carolina University, Greenville, NC (United States); Allison, R R [Department of Radiation Oncology, Brody School of Medicine at East Carolina University, Greenville, NC (United States); Downie, G H [Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC (United States); Mota, H C [Department of Radiation Oncology, Brody School of Medicine at East Carolina University, Greenville, NC (United States); Austerlitz, C [Department of Radiation Oncology, Brody School of Medicine at East Carolina University, Greenville, NC (United States); Jenkins, T [Department of Radiation Oncology, Brody School of Medicine at East Carolina University, Greenville, NC (United States); Sibata, C H [Department of Radiation Oncology, Brody School of Medicine at East Carolina University, Greenville, NC (United States)

    2007-06-07

    A number of patients with lung cancer receive either palliative or curative high-dose-rate (HDR) endobronchial brachytherapy. Up to a third of patients treated with endobronchial HDR die from hemoptysis. Rather than accept hemoptysis as an expected potential consequence of HDR, we have calculated the radial dose distribution for an Ir-192 HDR source, rigorously examined the dose and prescription points recommended by the American Brachytherapy Society (ABS), and performed a radiobiological-based analysis. The radial dose rate of a commercially available Ir-192 source was calculated with a Monte Carlo simulation. Based on the linear quadratic model, the estimated palliative, curative and blood vessel rupture radii from the center of an Ir-192 source were obtained for the ABS recommendations and a series of customized HDR prescriptions. The estimated radius at risk for blood vessel perforation for the ABS recommendations ranges from 7 to 9 mm. An optimized prescription may in some situations reduce this radius to 4 mm. The estimated blood perforation radius is generally smaller than the palliative radius. Optimized and individualized endobronchial HDR prescriptions are currently feasible based on our current understanding of tumor and normal tissue radiobiology. Individualized prescriptions could minimize complications such as fatal hemoptysis without sacrificing efficacy. Fiducial stents, HDR catheter centering or spacers and the use of CT imaging to better assess the relationship between the catheter and blood vessels promise to be useful strategies for increasing the therapeutic index of this treatment modality. Prospective trials employing treatment optimization algorithms are needed.

  14. Evaluation of human pharmacokinetics, therapeutic dose and exposure predictions using marketed oral drugs.

    McGinnity, D F; Collington, J; Austin, R P; Riley, R J

    2007-06-01

    In this article approaches to predict human pharmacokinetics (PK) are discussed and the capability of the exemplified methodologies to estimate individual PK parameters and therapeutic dose for a set of marketed oral drugs has been assessed. For a set of 63 drugs where the minimum efficacious concentration (MEC) and human PK were known, the clinical dose was shown to be well predicted or in some cases over-estimated using a simple one-compartment oral PK model. For a subset of these drugs, in vitro potency against the primary human targets was gathered, and compared to the observed MEC. When corrected for plasma protein binding, the MEC of the majority of compounds was GFR. For approximately 90% of compounds studied, the predicted CL using in vitro-in vivo (IVIV) extrapolation together with a CL(renal) estimate, where appropriate, was within 2-fold of that observed clinically. Encouragingly volume of distribution at steady state (V(ss)) estimated in preclinical species (rat and dog) when corrected for plasma protein binding, predicted human V(ss) successfully on the majority of occasions--73% of compounds within 2-fold. In this laboratory, absorption estimated from oral rat PK studies was lower than the observed human absorption for most drugs, even when solubility and permeability appeared not to be limiting. Preliminary data indicate absorption in the dog may be more representative of human for compounds absorbed via the transcellular pathway. Using predicted PK and MEC values estimated from in vitro potency assays there was a good correlation between predicted and observed dose. This analysis suggests that for oral therapies, human PK parameters and clinical dose can be estimated from a consideration of data obtained from in vitro screens using human derived material and in vivo animal studies. The benefits and limitations of this holistic approach to PK and dose prediction within the drug discovery process are exemplified and discussed.

  15. Methodology for management of therapeutic dose of I-131; Metodologia para administrar dosis terapeutica de I-131

    Basteris M, J.; Gomez D, R. [Universidad Autonoma de Yucatan, Facultad de Medicina, Merida, Yucatan (Mexico)

    2007-07-01

    The present work suggests the use of measures guided to eliminate the resulting chronic sialoadenitis of the treatment previously described with a therapeutic dose bigger than ablative of Iodine 131, as well as the use of citric fruits to stimulate the salivation, the administration of liquid post-dose is included to accelerate the gastric emptying avoiding the secondary effects as the vomit. (Author)

  16. A therapeutic dose of ketoprofen causes acute gastrointestinal bleeding, erosions, and ulcers in rats.

    Shientag, Lisa J; Wheeler, Suzanne M; Garlick, David S; Maranda, Louise S

    2012-11-01

    Perioperative treatment of several rats in our facility with ketoprofen (5 mg/kg SC) resulted in blood loss, peritonitis, and death within a day to a little more than a week after surgery that was not related to the gastrointestinal tract. Published reports have established the 5-mg/kg dose as safe and effective for rats. Because ketoprofen is a nonselective nonsteroidal antiinflammatory drug that can damage the gastrointestinal tract, the putative diagnosis for these morbidities and mortalities was gastrointestinal toxicity caused by ketoprofen (5 mg/kg). We conducted a prospective study evaluating the effect of this therapeutic dose of ketoprofen on the rat gastrointestinal tract within 24 h. Ketoprofen (5 mg/kg SC) was administered to one group of rats that then received gas anesthesia for 30 min and to another group without subsequent anesthesia. A third group was injected with saline followed by 30 min of gas anesthesia. Our primary hypothesis was that noteworthy gastrointestinal bleeding and lesions would occur in both groups treated with ketoprofen but not in rats that received saline and anesthesia. Our results showed marked gastrointestinal bleeding, erosions, and small intestinal ulcers in the ketoprofen-treated rats and minimal damages in the saline-treated group. The combination of ketoprofen and anesthesia resulted in worse clinical signs than did ketoprofen alone. We conclude that a single 5-mg/kg dose of ketoprofen causes acute mucosal damage to the rat small intestine.

  17. An unusual case of hypothermia associated with therapeutic doses of olanzapine: a case report

    Ratnayake Shiroma L

    2011-05-01

    Full Text Available Abstract Introduction We report a case of a 42-year-old man who had symptomatic hypothermia as a result of taking olanzapine for paranoid schizophrenia. According to published data, only a few cases of hypothermia associated with olanzapine have been reported since its introduction into clinical use. Case presentation A 42-year-old Sri Lankan man with schizophrenia who was being treated with a therapeutic dose of olanzapine presented with reduced level of consciousness. He had a core temperature of 32°C and was bradycardic. At the time of admission, the electrocardiogram showed sinus bradycardia with J waves. He did not have any risk factors for developing hypothermia except the use of olanzapine. There was improvement in his clinical condition with reversal of electrocardiogram changes following gradual rewarming and the omission of olanzapine. Conclusion Hypothermia induced by antipsychotic medications is not uncommon, but olanzapine-induced hypothermia is rare and occurrence has been reported during initiation or increasing the dose. But here the patient developed hypothermia without dose adjustment.

  18. Synthesis of {sup 14}C-labelled hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), 2,4,6-trinitrotoluene (TNT), nitrocellulose (NC) and glycidyl azide polymer (GAP) for use in assessing the biodegradation potential of these energetic compounds

    Ampleman, G.; Thiboutot, S.; Lavigne, J.; Marois, A. [Defence Research Establishment Valcartier, Courcelette, PQ (Canada); Hawari, J.; Jones, A.M.; Rho, D. [National Research Council of Canada, Ottawa, ON (Canada)

    1995-06-01

    Within the framework of an R and D project on bioremediation of soils contaminated with energetic compounds, the biodegradation of energetic products such as hexogen (RDX), trinitrotoluene (TNT), nitrocellulose (NC) and glycidyl azide polymer (GAP) is under study. Microcosm assays must be performed with radioactive carbon-14 labelled products in order to follow the biodegradation process. {sup 14}C-RDX was prepared by nitration of hexamethylenetetramine (HMTA) according to the Hale process. {sup 14}C-ring and methyl labelled TNTs synthesized according to the Dorey and Carper procedure. {sup 14}C-cellulose was synthesized from {sup 14}C-glucose by Acetobacter xylinum. Nitration of the {sup 14}C-cellulose yielded {sup 14}C-nitrocellulose. {sup 14}C-glycidyl azide polymer was obtained by polymerization and azidation of {sup 14}C-epichlorohydrin (ECH) which was synthesized from {sup 14}C-glycerol. Hydrochlorination of {sup 14}C-glycerol and epoxidation of the resulting {sup 14}C-1,3-dichloro 2-propanol yielded {sup 14}C-ECH. The syntheses of these {sup 14}C-labelled explosives are described in this paper. (Author).

  19. Green Synthesis of Silver Nanorods and Optimization of Its Therapeutic Cum Toxic Dose.

    Suganya, T R; Devasena, T

    2015-12-01

    Germinated Fenugreek seeds are relatively rich in flavonoids and polyphenols than dry seeds. Therefore, germinated fenugreek seeds possess better pharmacological activities. We have used an aqueous extract of germinated fenugreek seeds to reduce silver nitrate into nanoscale silver rods. The silver nanorods showed Surface Plasmon peak at 450 nm as revealed from UV visible spectrum. Field Emission Scanning Electron Microscopy images revealed the monodispersity and rod morphology. X ray diffraction spectrum revealed the FCC crystal structure of nanorods. Fourier transform infrared spectroscopy peaks revealed the interaction between the phytochemicals of germinated fenugreek seeds and the silver nanorods. Characterization studies reveal the validation of the proposed green synthesis protocol to produce monodispersed silver nanorods with phytochemical capping. The phytosynthesized silver nanorods exhibited anticancer activity in skin cancer cell line, which may be due to its nanoscale dimension and the surface functionalization. For the first time, we have optimized the therapeutic cum toxic dose of phytostabilized silver nanorods using skin cancer cell model.

  20. Spectral studies of photomodification of blood by therapeutic doses of optical radiation at different wavelengths

    Zalesskaya, G. A.; Maslova, T. O.

    2011-02-01

    We analyze changes in electronic and IR absorption spectra of samples of blood and its components, in the fluorescence spectra of plasma, as well as in the gas composition of blood, the hemoglobin concentration, and acid-base balance indices, upon the irradiation of blood by therapeutic doses of optical radiation at 254, 632.8, 670, and 806 nm. We show that the irradiation of blood by radiation at these wavelengths initiates similar molecular changes in blood and its components and that monochromatic incoherent light acts equally as efficiently as laser radiation. We find that, if the blood irradiation wavelength is in the range of the absorption bands of hemoglobin, the hemoglobin acts as a primary photoacceptor and that the dissociation of hemoglobin complexes with ligands directly in erythrocytes is a primary photoprocess. We conclude that the photomodification of blood should be attributed to therapeutic methods capable of controlling the balance between the production of active forms of oxygen and their inhibition by antioxidant systems of the organism.

  1. Effect of prenatal and postnatal exposure to therapeutic doses of chlorimipramine on emotionality in the rat.

    Rodríguez Echandía, E L; Broitman, S T

    1983-01-01

    Prenatal administration of high doses of tricyclic antidepressants have been reported to produce teratogenic and behavioral effects in rat offspring. In the present work, behavioral abnormalities are described in offspring of rats treated with therapeutic doses of chlorimipramine (CIM) during pregnancy (CIM-P), lactation (CIM-L) and during the whole pregnancy-lactation period (CIM-PL). CIM-P treatment did not produce teratogenic effects, did not affect number or body weight of pups at birth and did not induce neonatal mortality. At 2 months of age, the CIM-P males showed a significant increase in digging and grooming (familiar environment test), a decrease in "exploration" (novel environment test) and a decrease in active social interactions (social behavior test). Females were more resistant than males to the prenatal CIM treatment. The results suggest increased emotionality in CIM-P pups. Some behavioral abnormalities were also observed in the tests performed at 4 months of age. CIM-L treatment had minor effects on litter behavior. CIM-PL treatment potentiated the effects of the CIM-P treatment. In the CIM-PL males, impairment of exploration of a novel environment still remained in the tests performed at 4 months of age. It is speculated that when prenatal brain development is altered by CIM, further postnatal treatment may impair compensatory processes occurring in early postnatal life.

  2. Dose evaluation of therapeutic radiolabeled bleomycin complexes based on biodistribution data in wild-type rats:Effect of radionuclides in absorbed dose of different organs

    Hassan Yousefnia; Samaneh Zolghadri; Amir Reza Jalilian; Mohammad Ghannadi-Maragheh

    2015-01-01

    Bleomycins (BLMs), as tumor-seeking antibiotics, have been used for over 20 years in treatment of several types of cancers. Several radioisotopes are used in radiolabeling of BLMs for therapeutic and diagnostic purpos-es. An important points in developing new radiopharmaceuticals, especially therapeutic agents, is the absorbed dose delivered in critical organs. In this work, absorbed dose to organs after injection of 153Sm-, 177Lu-and 166Ho-labeled BLM was investigated by radiation dose assessment resource (RADAR) method based on biodis-tribution data in wild-type rats. The absorbed dose effect of the radionuclides was evaluated. The maximum absorbed dose for the complexes was observed in the kidneys, liver and lungs. For all the radiolabeled BLMs, bone and red marrow received considerable absorbed dose. Due to the high energy beta particles emitted by 166Ho, higher absorbed dose is observed for 166Ho-BLM in the most organs. The reported data can be useful for the determination of the maximum permissible injected activity of the radiolabeled BLMs in the treatment planning programs.

  3. Thyroid Remnant Estimation by Diagnostic Dose I131 Scintigraphy or TcO4-99m Scintigraphy after Thyroidectomy: A Comparison with Therapeutic Dose I131 Imaging

    Guanghui Liu

    2016-01-01

    Full Text Available In this clinical study, we have compared routine diagnostic dose 131I scan and TcO4-99m thyroid scintigraphy with therapeutic dose 131I imaging for accurate thyroid remnant estimation after total thyroidectomy. We conducted a retrospective review of the patients undergoing total thyroidectomy for differentiated thyroid carcinoma (DTC and subsequently receiving radioactive iodine (RAI treatment to ablate remnant thyroid tissue. All patients had therapeutic dose RAI whole body scan, which was compared with that of diagnostic dose RAI, TcO4-99m thyroid scan, and ultrasound examination. We concluded that therapeutic dose RAI scan reveals some extent thyroid remnant in all DTC patients following total thyroidectomy. Diagnostic RAI scan is much superior to ultrasound and TcO4-99m thyroid scan for the postoperative estimation of thyroid remnant. Ultrasound and TcO4-99m thyroid scan provide little information for thyroid remnant estimation and, therefore, would not replace diagnostic RAI scan.

  4. Observational infant exploratory [14C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis

    Garner, C.R.; Park, K.B.; French, N.S.; Earnshaw, C.; Schipani, A.; Selby, A.M.; Byrne, L.; Siner, S.; Crawley, F.P.; Vaes, W.H.J.; Duijn, E. van; ligt, R. de; Varendi, H.; Lass, J.; Grynkiewicz, G.; Maruszak, W.; Turner, M.A.

    2015-01-01

    Aims The aims of the study were to compare [14C]-paracetamol ([14C]-PARA) paediatric pharmacokinetics (PK) after administration mixed in a therapeutic dose or an isolated microdose and to develop further and validate accelerator mass spectrometry (AMS) bioanalysis in the 0-2 year old age group. Meth

  5. Therapeutic efficacy of high-dose vitamin C on acute pancreatitis and its potential mechanisms

    Wei-Dong Du; Song-Bai Zheng; Zu-Rong Yuan; Jian Sun; Jian-Xiong Tang; Ai-Qun Cheng; Da-Ming Shen; Chun-Jin Huang; Xiao-Hua Song; Xiao-Feng Yu

    2003-01-01

    AIM: To observe the therapeutic efficacy of high-dose Vitamin C (Vit. C) on acute pancreatitis (AP), and to explore its potential mechanisms.METHODS: Eghty-four AP patients were divided into treatment group and control group, 40 healthy subjects were taken as a normal group. In the treatment group,Vit. C (10 g/day) was given intravenously for 5 days,whereas in the control group, Vit. C (1 g/day) was given intravenously for 5 days. Symptoms, physical signs, duration of hospitalization, complications and mortality rate were monitored. Meanwhile, serum amylase, urine amylase and leukocyte counts were also determined. The concentration of plasma vitamin C (P-VC), plasma lipid peroxide (P-LPO),plasma vitamin E (P-VE), plasma β-carotene (P-13-CAR),whole blood glutathione (WB-GSH) and the activity of erythrocyte surperoxide dimutase (E-SOD) and erythrocyte catalase (E-CAT) as well as T lymphocyte phenotype were measured by spectrophotometry in the normal group and before and after treatment with Vit. C in the treatment and the control group.RESULTS: Compared with the normal group, the average values of P-VC, P-VE, P-β-CAR, WB-GSH and the activity of E-SOD and E-CAT in AP patients were significantly decreased and the average value of P-LPO was significantly increased, especially in severe acute pancreatitis (SAP) patients (P<0.05. P-VC, P=0.045; P-VE, P=0.038; P=0.041;P-β-CAR, P=0.046; WB-GSH, P=0.039; E-SOD, P=0.019;E-CAT, P =0.020; P-LPO, P =0.038). Compared with the normal group, CD3 and CD4 positive cells in AP patients were significantly decreased. The ratio of CD4/CD8 and CD4 positive cells were decreased, especially in SAP patients (P<0.05. CD4/CD8, P =0.041; CD4, P =0.019). Fever and vomiting disappeared, and leukocyte counts and amylase in urine and blood become normal quicker in the treatment group than in the control group. Moreover, patients in treatment group also had a higher cure rate, a lower complication rate and a shorter in-ward days compared with

  6. Comparison of the therapeutic dose of warfarin in HIV-infected and HIV-uninfected patients: a study of clinical practice

    Jackson, B S; Mokoena, T

    2017-01-01

    Background People infected with HIV are prone to venous thrombosis. Treatment of thrombosis is primarily with warfarin. No studies have addressed the effects of HIV infection on warfarin dose. The aims of this study were to determine whether the therapeutic dose of warfarin and induction time to therapeutic dose in HIV-infected patients differ from that in HIV-uninfected patients. Methods A prospective and retrospective descriptive study of induction time to therapeutic warfarin dose, as well as of ambulant therapeutic warfarin dose, was performed. HIV-infected and HIV-uninfected patients being treated after deep venous thrombosis with or without pulmonary embolism were compared. Sex and use of antiretroviral drugs (ARVs) were also compared in the groups. Results 234 patients were entered into the study. Induction time to therapeutic warfarin dose did not differ between the 2 groups. The mean therapeutic dose of warfarin was higher in the HIV-infected than the HIV-uninfected group: 6.06 vs 5.72 mg/day, but this was not statistically significant (p=0.29). There was no difference in therapeutic warfarin dose between ARV-naïve groups—HIV-uninfected and HIV-infected patients not on ARVs. Conclusions There appears to be little effect of HIV infection on warfarin dosing. Warfarin therapy should be administered conventionally in HIV-infected patients. PMID:28179414

  7. Absorption kinetics and steady-state plasma concentrations of theophylline following therapeutic doses of two sustained-release preparations

    Andersen, O; Nielsen, M K; Eriksen, P B;

    1983-01-01

    Ten healthy volunteers received two sustained-release preparations as a single and multiple dose regimen in an open crossover study. Plasma theophylline concentrations were measured by an enzyme immunoassay. The limited fluctuation of the theophylline levels at steady state, with twice daily...... formulation, whereas this was not the case for the other (r = 0.27 and 0.49). The daily dose necessary to keep the plasma concentration within the therapeutic range of 55-110 mumole/liter varied from 7.9 to 22.9 mg/kg. Only mild side effects were recorded, but they were not correlated to the plasma...... theophylline concentration....

  8. Changes of Spleen in Wistar Rats Exposed to Therapeutic Doses of Dexamethasone and Medroxyprogesterone Acetate Evaluated by Stereological Parameters.

    Mitevska, Elida; Kostadinova-Petrova, Irena; Kostovska, Nevena

    2015-01-01

    The aim of our investigation was to evaluate the immunosuppressive effect of medroxyprogesterone acetate (MPA) determining the volume densities of the structural components of the spleen. The volume densities of the same structural components of spleen were determined after administration of dexamethasone too, in order to see whether the morphological changes induced by MPA are in the same line with the changes caused by dexamethasone. 60 female Wistar rats were divided into 5 groups. The control group of rats was administered physiological solution. The remaining, 4 experimental groups were administered: dexamethasone at a therapeutic daily dose of 0.6 mg/kg bw and maximal therapeutic dose of 3 mg/kg bw, and MPA at a therapeutic dose of 30 mg/kg bw and maximal therapeutic dose of 150 mg/kg bw. The drugs were applied intramuscularly for 7 days. Spleen paraffin sections were stained according to the methods: hematoxylin-eosin, Masson and Elastica van-Gieson. Stereological measurements were performed by using the Weibl's multipurpose test system (M-42). The histological analyses of the structural components of the spleen in rats treated with dexamethasone and MPA have shown reduction of the white pulp and the marginal zone and an apparent decrease of the cellular density of the lymphocyte component of the pulp. The stereological analysis of the spleen showed significant decrease of the splenic pulp volume density and significant increase of the connective tissue volume density. Reducing the presence of splenic pulp was mainly due to the decrease in the volume density of all structural components of the white pulp. Changes were observed in all drug treated groups of rats. Our results have shown that the MPA provoked changes suggested atrophy of the spleen lymphoid tissue. Although the atrophic changes of the spleen were significant after the application of both dexamethasone and MPA, the white pulp was significantly more sensitive substrate for dexamethasone than for

  9. New method for the induction of therapeutic amenorrhea: low dose endometrial afterloading irradiation. Clinical and hormonal studies

    Gronroos, M.; Turunen, T.; Raekallio, J.; Ruotsalinen, P.; Salmi, T. (Turku Univ. (Finland). Dept. of Obstetrics and Gynecology)

    1982-08-01

    The authors present a new method for the induction of therapeutic amenorrhea: low dose endometrial afterloading irradiation. The problem with this method has been how to inactivate the endometrium while maintaining the physiological function of the ovaries. In 5/29 young patients regular or irregular bleedings occurred after an endometrial dose of 11+-1 Gy. These subjects were given a repeat low dose intrauterine irradiation. Thereafter no bleedings were found in four out of five patients. Two to 9 years after the repeat irradiation the plasma levels of E/sub 1/, E/sub 2/, FSH and LH corresponded closely to those of healthy women in reproductive age in three out of five patients; some high plasma P levels indicated ovulation. In two patients the E/sub 1/, E/sub 2/, and P values were more likely postmenopausal but, on the other hand, FSH and LH values reproductive ones. 19 refs.

  10. Anticonvulsants for Nerve Agent-Induced Seizures: The Influence of the Therapeutic Dose of Atropine

    2007-01-01

    Organophosphorous nerve agents-induced cological Basis of Therapeutics, 10th ed. (Hardman JG, Limbird LE, and ( Gilman seizures and efficacy of atropine...us.army.mil Taylor P (2001) Anticholinesterase agents, in Goodman and Gilman’s The Pharrna-

  11. The synthesis of 14 C-labelled carbon dots and their accumulation in marine phytoplankton%14C-标记碳点的合成及其在海洋浮游植物体内的 生物富集应用研究

    李家梦; 杨柳燕; 缪爱军

    2016-01-01

    为了探究光敏性碳基纳米材料的生物富集过程,通过一步微波热解反应合成14 C标记的碳点,并以海洋原甲藻(Prorocentrummicans)和东海原甲藻(Prorocentrumdonghaiense)作为受试生物,定量分析了这两种生物对碳点(C-dots)的吸收动力学差异.由于生物细胞的遮挡效应可能会影响胞内标记碳点的测定,实验中首先比较了生物样品三种处理方法(对生物样品分别直接测定,超清洗,超声破碎)的效果差异,发现对生物细胞样品进行超声破碎的处理效果最好,并且在超声5 min的条件下测定效果最佳.随后,开展实验进一步探究了短时间内碳点在生物细胞内的富集过程.结果表明,碳点在这两种生物体内的富集量都随时间呈现线性增加的趋势.当我们以三种生物富集量表示方法作图(pg·cell-1,pg·μm-2和pg·μm-3)时,发现采用以单位体积的生物富集量作图最科学,并且发现这两种原甲藻对碳点的生物富集量随时间的变化趋势极为接近,克服了藻细胞大小带来的差异,更为科学地阐述了水生生物体内碳点的富集量的变化.%To investigate the bioaccumulation of carbon-based nanomaterial,we synthesized the14 C-labeled carbon dots (C-dots)by one-way microwave pyrolysis.Two marine algae,Prorocentrum micans and Prorocentrum donghaiense were used as the objective organisms,and their accumulation of C-dots was compared.As the 14 C signal from the C-dots may be quenched inside the cells,the results of the different ultrasonicating methods were compared,and the counting number was the highest when the cells were ultrasonicated for 5 minutes.After the optimization of the cell processing methods,we further explored the bioaccumulation kinetics of C-dots by both algae and the accumulation results with different units(pg·cell-1 ,pg·μm-2 ,and pg·μm-3 )were compared.As expected,cellular concentration of C-dots increased linearly with exposure time regardless of

  12. Dose to the Developing Dentition During Therapeutic Irradiation: Organ at Risk Determination and Clinical Implications

    Thompson, Reid F., E-mail: Reid.Thompson@uphs.upenn.edu [Center for Proton Therapy, Paul Scherrer Institute, Villigen (Switzerland); Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Schneider, Ralf A., E-mail: ralf.schneider@psi.ch [Center for Proton Therapy, Paul Scherrer Institute, Villigen (Switzerland); Albertini, Francesca; Lomax, Antony J.; Ares, Carmen; Goitein, Gudrun [Center for Proton Therapy, Paul Scherrer Institute, Villigen (Switzerland); Hug, Eugen B. [Center for Proton Therapy, Paul Scherrer Institute, Villigen (Switzerland); ProCure Therapy Centers, New York, New York (United States)

    2013-05-01

    Purpose: Irradiation of pediatric facial structures can cause severe impairment of permanent teeth later in life. We therefore focused on primary and permanent teeth as organs at risk, investigating the ability to identify individual teeth in children and infants and to correlate dose distributions with subsequent dental toxicity. Methods and Materials: We retrospectively reviewed 14 pediatric patients who received a maximum dose >20 Gy(relative biological effectiveness, RBE) to 1 or more primary or permanent teeth between 2003 and 2009. The patients (aged 1-16 years) received spot-scanning proton therapy with 46 to 66 Gy(RBE) in 23 to 33 daily fractions for a variety of tumors, including rhabdomyosarcoma (n=10), sarcoma (n=2), teratoma (n=1), and carcinoma (n=1). Individual teeth were contoured on axial slices from planning computed tomography (CT) scans. Dose-volume histogram data were retrospectively obtained from total calculated delivered treatments. Dental follow-up information was obtained from external care providers. Results: All primary teeth and permanent incisors, canines, premolars, and first and second molars were identifiable on CT scans in all patients as early as 1 year of age. Dose-volume histogram analysis showed wide dose variability, with a median 37 Gy(RBE) per tooth dose range across all individuals, and a median 50 Gy(RBE) intraindividual dose range across all teeth. Dental follow-up revealed absence of significant toxicity in 7 of 10 patients but severe localized toxicity in teeth receiving >20 Gy(RBE) among 3 patients who were all treated at <4 years of age. Conclusions: CT-based assessment of dose distribution to individual teeth is feasible, although delayed calcification may complicate tooth identification in the youngest patients. Patterns of dental dose exposure vary markedly within and among patients, corresponding to rapid dose falloff with protons. Severe localized dental toxicity was observed in a few patients receiving the

  13. Using Six Sigma to improve once daily gentamicin dosing and therapeutic drug monitoring performance.

    Egan, Sean

    2012-08-07

    BACKGROUND: Safe, effective therapy with the antimicrobial gentamicin requires good practice in dose selection and monitoring of serum levels. Suboptimal therapy occurs with breakdown in the process of drug dosing, serum blood sampling, laboratory processing and level interpretation. Unintentional underdosing may result. This improvement effort aimed to optimise this process in an academic teaching hospital using Six Sigma process improvement methodology. METHODS: A multidisciplinary project team was formed. Process measures considered critical to quality were defined, and baseline practice was examined through process mapping and audit. Root cause analysis informed improvement measures. These included a new dosing and monitoring schedule, and standardised assay sampling and drug administration timing which maximised local capabilities. Three iterations of the improvement cycle were conducted over a 24-month period. RESULTS: The attainment of serum level sampling in the required time window improved by 85% (p≤0.0001). A 66% improvement in accuracy of dosing was observed (p≤0.0001). Unnecessary dose omission while awaiting level results and inadvertent disruption to therapy due to dosing and monitoring process breakdown were eliminated. Average daily dose administered increased from 3.39 mg\\/kg to 4.78 mg\\/kg\\/day. CONCLUSIONS: Using Six Sigma methodology enhanced gentamicin usage process performance. Local process related factors may adversely affect adherence to practice guidelines for gentamicin, a drug which is complex to use. It is vital to adapt dosing guidance and monitoring requirements so that they are capable of being implemented in the clinical environment as a matter of routine. Improvement may be achieved through a structured localised approach with multidisciplinary stakeholder involvement.

  14. Achievement of Therapeutic Goals with Low-Dose Imiglucerase in Gaucher Disease: A Single-Center Experience

    Irina Tukan

    2013-01-01

    Full Text Available Gaucher disease, a lysosomal storage disorder, is a multisystem disorder with variable and unpredictable onset and severity. Disease-specific enzyme replacement therapy (ERT has been shown to reverse or ameliorate disease-specific hepatosplenomegaly and anemia and thrombocytopenia. ERT also impacts bone manifestations, including bone crises, bone pain, and appearance of new osteonecrosis, and improves bone mineral density to varying degrees. The objective of this study was to assess achievement of predefined therapeutic goals based on international registry outcomes for Israeli patients with Gaucher disease receiving imiglucerase for four consecutive years on a low-dose regimen followed in a single center. All data were taken from patient files. The therapeutic goals were taken from standards published in the literature for disease-specific clinical parameters. Among 164 patients at baseline, values for spleen and liver volumes, hemoglobin and platelet counts, and Z-scores for lumbar spine and femoral were significantly different from the goal. After four years ERT, there was a significant improvement ( in each of the therapeutic goal parameters from baseline. 15.2% of these patients achieved all hematology-visceral goals. In children, there was achievement of linear growth and puberty. This survey highlights the good overall response in symptomatic patients receiving low-dose ERT with imiglucerase in Israel.

  15. Long-Term Impact of Immunosuppressants at Therapeutic Doses on Male Reproductive System in Unilateral Nephrectomized Rats: A Comparative Study

    Yehui Chen

    2013-01-01

    Full Text Available Cyclosporine, tacrolimus, and sirolimus are commonly used in renal transplant recipients to prevent rejection. However, information for comparative effects of these agents on the male productive system is extremely limited and controversial. In a physiologically and clinically relevant rat model of unilateral nephrectomy, we demonstrated that long-term oral administration of both cyclosporine and sirolimus at doses equivalent to the therapeutic levels used for postrenal transplant patients significantly affects testicular development and the hypothalamic-pituitary-gonadal axis accompanied by profound histological changes of testicular structures on both light and electron microscopic examinations. Spermatogenesis was also severely impaired as indicated by low total sperm counts along with reduction of sperm motility and increase in sperm abnormality after treatment with these agents, which may lead to male infertility. On the other hand, treatment with therapeutic dose of tacrolimus only induced mild reduction of sperm count without histological evidence of testicular injury. The current study clearly demonstrates that commonly used immunosuppressants have various impacts on male reproductive system even at therapeutic levels. Our data provide useful information for the assessment of male infertility in renal transplant recipients who wish to father children. Clinical trials to address these issues should be urged.

  16. Nonconvulsive status epilepticus in the elderly associated with newer antidepressants used at therapeutic doses: A report of three cases

    Go Taniguchi

    2015-01-01

    All three patients were male and were 73 years of age or older. One patient was recently diagnosed with temporal lobe epilepsy and treated with low-dose lamotrigine. In all patients, newer antidepressants were initiated because of depressive symptoms. After titrating to therapeutic doses (paroxetine 20 mg/day, sertraline 50 mg/day, and combination of sertraline 50 mg/day and mirtazapine 30 mg/day in one patient each, impaired consciousness appeared. Electroencephalography (EEG showed generalized slow waves with intermittent spike–slow-wave complexes. Intravenous injection of antiepileptic drugs improved EEG findings and clinical symptoms. After discontinuance of the abovementioned antidepressants, NCSE did not recur in any of patients. These reports raise the question of whether the newer antidepressants, like classic antidepressants, might also induce NCSE in the elderly, even when used at therapeutic doses. Physicians should consider monitoring for possible NCSE when using newer antidepressants in patients who may have low drug tolerability. Active continuous video-EEG monitoring is essential when behavioral and psychological symptoms or change in consciousness level is suspected.

  17. Dose enhancement in gold nanoparticle-aided radiotherapy for the therapeutic photon beams using Monte Carlo technique

    Nitin Ramesh Kakade

    2015-01-01

    Full Text Available Background: Gold nanoparticle (GNP-aided radiation therapy (RT is useful to make the tumor more sensitive to radiation damage because of the enhancement in the dose inside the tumor region. Polymer gel dosimeter (PGD can be a good choice for the physical measurement of dose enhancement produced by GNP inside the gel. Materials and Methods: The present study uses EGSnrc Monte Carlo code to estimate dose enhancement factor (DEF due to the introduction of GNPs inside the PGD at different concentrations (7 and 18 mg Au/g of gel when irradiated by therapeutic X-rays of energy 100 kVp, 150 kVp, 6 MV, and 15 MV. The simulation was also carried out to quantify the dose enhancement in PAGAT gel and tumor for 100 kVp X-rays. Results: For 100 kVp X-rays, average DEF of 1.86 and 2.91 is observed in the PAGAT gel dosimeter with 7 and 18 mg Au/g of gel, respectively. Average DEF of 1.69 and 2.61 is recorded for 150 kVp X-rays with 7 and 18 mg Au/g of gel, respectively. No clinically meaningful DEF was observed for 6 and 15 MV photon beams. Furthermore, the dose enhancement within the PAGAT gel dosimeter and tumor closely matches with each other. Conclusion: The polymer gel dosimetry can be a suitable method of dose estimation and verification for clinical implementation of GNP-aided RT. GNP-aided RT has the potential of delivering high localized tumoricidal dose with significant sparing of normal structures when the treatment is delivered with low energy X-rays.

  18. Therapeutic dose simulation of a 6 MV Varian Linac photon beam using GEANT4

    Salama, E.; Ali, A. S.; Khaled, N. E.; Radi, A.

    2015-10-01

    A developed program in C++ language using GEANT4 libraries was used to simulate the gantry of a 6 MV high energy photon linear accelerator (Linac). The head of a clinical linear accelerator based on the manufacturer's detailed information is simulated. More than 2× 109 primary electrons are used to create the phase space file. Evaluation of the percentage depth dose (PDD) and flatness symmetry (lateral dose profiles) in water phantom were performed. Comparisons between experimental and simulated data were carried out for three field sizes; 5 × 5, 10 × 10 and 15 × 15 cm2. A relatively good agreement appeared between computed and measured PDD. Electron contamination and spatial distribution for both photons and electrons in the simulated beam are evaluated. Moreover, the obtained lateral dose profiles at 15, 50, and 100 mm depth are compatible with the measured values. The obtained results concluded that, GEANT4 code is a promising applicable Monte Carlo program in radiotherapy applications.

  19. Radial dose distributions from protons of therapeutic energies calculated with Geant4-DNA

    Wang, He; Vassiliev, Oleg N.

    2014-07-01

    Models based on the amorphous track structure approximation have been successful in predicting the biological effects of heavy charged particles. Development of such models remains an active area of research that includes applications to hadrontherapy. In such models, the radial distribution of the dose deposited by delta electrons and directly by the particle is the main characteristic of track structure. We calculated these distributions with Geant4-DNA Monte Carlo code for protons in the energy range from 10 to 100 MeV. These results were approximated by a simple formula that combines the well-known inverse square distance dependence with two factors that eliminate the divergence of the radial dose integral at both small and large distances. A clear physical interpretation is given to the asymptotic behaviour of the radial dose distribution resulting from these two factors. The proposed formula agrees with the Monte Carlo data within 10% for radial distances of up to 10 μm, which corresponds to a dose range covering over eight orders of magnitude. Differences between our results and those of previously published analytical models are discussed.

  20. Methodology to administer therapeutic dose of I-131; Metodologia para administrar dosis terapeutica de I-131

    Basteris M, J.; Gomez D, R. [Universidad Autonoma de Yucatan, Facultad de Medicina, Merida, Yucatan (Mexico)

    2007-07-01

    The present work suggests the use of measures guided to eliminate the resulting chronic sialoadenitis of the treatment of the thyroid cancer with Iodine-131, as well as the use of citric fruits to stimulate the salivation, the post-dose administration of liquids to accelerate the gastric emptying avoiding the secondary effects as the vomit is included. (Author)

  1. Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study

    Wit, D. de; Erp, N. van; Hartigh, J. den; Wolterbeek, R..; Hollander-van Deursen, M. den; Labots, M.; Guchelaar, H.J.; Verheul, H.M.; Gelderblom, H.

    2015-01-01

    BACKGROUND: Patients treated with the standard dose of pazopanib show a large interpatient variability in drug exposure defined as the area under the plasma concentration-time curve (AUC0-24h). The primary objective of this study was to evaluate the feasibility of pharmacokinetics (PK)-guided indivi

  2. Is dosing of therapeutic immunoglobulins optimal? – A review of a 3-decade long debate in Europe.

    Jacqueline eKerr

    2014-12-01

    Full Text Available The consumption of immunoglobulins (Ig is increasing due to better recognition of antibody deficiencies, an aging population and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals and infusion rates are paving the way towards more individualized therapy regimens.In primary antibody deficiencies adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic ‘per kg’ dosing.Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications, certain autoimmune disorders, immunosuppressive agents or biologics. This antibody failure, as shown by test immunisation, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings (e.g. ITP selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review the developments in dosing of therapeutic immunoglobulins have been

  3. Therapeutic efficacy of small doses of colchicine combined with glucocorticoid for acute gouty arthritis

    Ying LIU

    2015-10-01

    Full Text Available Objective To observe the clinical effect of small dose of colchicine combined with glucocorticoid for acute gouty arthritis. Methods Ninety-two patients with acute gouty arthritis were equally and randomly divided into small doses of colchicine combined with dexamethasone treatment group (treatment group and conventional large dose colchicine treatment group (control group between January 2009 and December 2013. The articular lesion scoring and clinical efficacy evaluation were performed at 3, 6, 12, 24, 48, and 72h after treatment. Erythrocyte sedimentation rate (ESR, white blood cells, hepatorenal function and glomerular filtration rate (GFR were determined before and 72h after treatment respectively. The gastrointestinal adverse events and recurrence rate were observed within one month after treatment. Results The articular lesion scores were significantly decreased at 6, 12, 48, and 72h after treatment in treatment group compared with control group (P0.05. Serum uric acid, glutamic-pyruvic transaminase in serum (SGPT, and GFR did not show any change before and 72h after the treatment, and there was also no significant difference between groups (P>0.05. The incidence of gastrointestinal adverse events were obviously higher in control group (76.1% compared with that of the treatment group (P<0.05, and the differences was statistically significant. There was no statistical difference in recurrence rate between the control group and treatment group after a follow-up of one month. Conclusions Compared with conventional large dose colchicine, small dose of colchicine combined with dexamethasone can more rapidly and effectively control acute gouty arthritis, with good tolerability and safety, thus being worthy of popularization clinically. DOI: 10.11855/j.issn.0577-7402.2015.08.10

  4. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve.

    Celik, Ilhan; Sürücü, Oguzkan; Dietz, Carsten; Heymach, John V; Force, Jeremy; Höschele, Iris; Becker, Christian M; Folkman, Judah; Kisker, Oliver

    2005-12-01

    We show here that recombinant endostatin protein has a biphasic effect on the inhibition of endothelial cell migration in vitro. In tumor-bearing animals, there is a similar biphasic effect on the inhibition of tumor growth and on circulating endothelial cells after once-daily s.c. injections. This biphasic effect is revealed as a U-shaped curve in which efficacy is optimal between very low and very high doses depending on the tumor type. This result may be applicable to other inhibitors of endothelial growth and to angiogenesis. Furthermore, these results have important implications for clinicians who administer angiogenesis inhibitors for cancer or other angiogenesis-dependent diseases. When these results are taken together with two previous reports of angiogenesis inhibitors with a U-shaped dose-response, they suggest that other regulators of endothelial growth may display a similar pattern.

  5. Amodiaquine-associated adverse effects after inadvertent overdose and after a standard therapeutic dose

    Adjei, G O; Goka, B Q; Rodrigues, O P;

    2009-01-01

    , the occurrence of bradycardia after a standard dose of amodiaquine, which coincided with the time of expected peak concentrations of the active metabolite of amodiaquine, suggests a direct drug effect. These less reported adverse effects are likely to increase in parallel with the increased use of amodiaquine......, is reported. Both subjects were homozygous for the wild type allele of cytochrome P450 2C8, the main enzyme responsible for amodiaquine metabolism. In both subjects, plasma concentrations of N-desethylamodiaquine and N-bis-desethylamodiaquine, the main metabolites of amodiaquine, were normal. No other drugs......A case of an acute dystonic reaction in a child presumptively treated for malaria with amodiaquine, and a case of persistent asymptomatic bradycardia in another child with mild pulmonary stenosis treated with a standard dose of amodiaquine for parasitologically confirmed uncomplicated malaria...

  6. Therapeutic effect of low-dose imatinib on pulmonary arterial hypertension in dogs.

    Arita, Shinji; Arita, Noboru; Hikasa, Yoshiaki

    2013-03-01

    This was a pilot study to determine the effectiveness of low-dose imatinib therapy for hemodynamic disturbances, including pulmonary arterial hypertension (PAH), and clinical manifestations caused by chronic heart failure in dogs. Six client-owned dogs with PAH were administered imatinib mesylate orally, 3 mg/kg body weight q24h, for 30 d. Physical examination, blood biochemical tests, radiography, and Doppler echocardiography were performed prior to imatinib administration and again 30 days after administration. Clinical scores were significantly reduced after imatinib treatment. Systolic pulmonary arterial pressure, heart rate, maximum tricuspid regurgitation velocity, left atrium/aorta ratio, right and left ventricular Tei indexes, early diastolic transmitral flow wave/mitral annulus velocity ratio, and plasma atrial natriuretic peptide concentration decreased significantly after therapy. Diastolic blood pressure, stroke volume, cardiac output, and left ventricular fractional shortening increased significantly after therapy. These results indicate that low-dose imatinib therapy was effective for heart failure in dogs with PAH.

  7. Plasma quetiapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 2000–2011

    Bowskill, Sally V.J.; Patel, Maxine X.; Flanagan, Robert J.

    2013-01-01

    Objective: Suggested predose plasma quetiapine target ranges for effective therapy in schizophrenia lie between 50 and 500 µg/l. We aimed to examine data from a quetiapine therapeutic drug monitoring (TDM) service to assess the plasma quetiapine concentrations attained at specified doses in clinical practice. Method: We studied TDM data from patients given immediate-release quetiapine in the period 2000–2011. Results: There were 946 samples from 487 patients (257 males, age at time of first sample, median [range] 34 [14–87] years, and 230 females, age at time of first sample, median [range] 38 [10–92] years). The plasma quetiapine concentration was <50 and <100 µg/l in 30% and 50% of samples, respectively (no quetiapine detected in 9% of samples). The relationship between dose and plasma quetiapine was poor. The mean (95% confidence interval [CI]) quetiapine dose was higher (t = 3.6, df = 446, p <0.01) in males versus females (641 [600–1240] and 548 [600–943] mg/day, respectively), although there was no difference in median dose (600 mg/day) or in the mean (95% CI) plasma quetiapine concentrations attained. Smoking habit had no discernible effect on plasma quetiapine concentration. Conclusions: There was a poor relationship between dose and plasma quetiapine concentration in this study, as found by others. This is probably because of the short plasma half-life of the drug, at least in part. Nevertheless, quetiapine TDM can help assess adherence and measurement of quetiapine metabolites, notably N-desalkylquetiapine, as well as quetiapine itself may enhance the value of quetiapine TDM in future. PMID:24167685

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

    Damal K

    2013-11-01

    Full Text Available Kavitha Damal, Emily Stoker, John F FoleyRocky Mountain Multiple Sclerosis Research Group, Salt Lake City, UT, USAAbstract: Multiple sclerosis (MS is a debilitating neurological disorder that affects nearly 2 million adults, mostly in their prime of 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.Keywords: multiple sclerosis, immunomodulation, interferons, glatiramer acetate, monoclonal antibodies, dimethyl fumarate

  9. Outliers on the dose-response curve: how to minimize this problem using therapeutic drug monitoring, an underutilized tool in psychiatry.

    Preskorn, Sheldon H

    2010-05-01

    This column continues the discussion of outliers on the dose-response curve begun in earlier columns. It focuses on therapeutic drug monitoring (TDM) as an underutilized tool in psychiatry to minimize this problem. The scientific rationale for dose adjustment based on TDM is presented and its efficiency is contrasted with dose adjustment based on clinical assessment of response. In current practice, the use of TDM with psychiatric drugs is generally restricted to drugs with narrow therapeutic windows or drugs imported into psychiatry from neurology where TDM is more commonly used. Examples of each of these types of drugs are cited.

  10. Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

    Iordanskiy, Sergey [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States); Van Duyne, Rachel [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States); Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Sampey, Gavin C; Woodson, Caitlin M; Fry, Kelsi; Saifuddin, Mohammed; Guo, Jia; Wu, Yuntao [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States); Romerio, Fabio [Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 (United States); Kashanchi, Fatah, E-mail: fkashanc@gmu.edu [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States)

    2015-11-15

    The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4{sup +} T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4{sup +} T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4{sup +} T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the “Shock and Kill” strategy for latently HIV-1 infected cells. - Highlights: • X-ray irradiation

  11. The effect of intramuscular injection of spiramycin at therapeutic dose on some blood biochemical and hematological parameters in Assaf sheep

    Ibrahim M. ALZuheir

    2012-12-01

    Full Text Available Spiramycin is used to treatment of different bacterial and protozoal infection in different animal species including sheep, to the authors’ knowledge there are no studies about effects of spiramycin in sheep blood biochemical and hematological parameters. This study was designated to determine the effects of spiramycin intramuscular treatment at therapeutic dose (64,000 IU/kg for five days in some blood biochemical and hematological parameters in healthy Assaf sheep (n=8. The results showed that spiramycin treatment caused decrease in calcium and creatinine level (PP>0.05. After treatment, hematological parameters tend to decrease toward normal references range of red blood cell count, haemoglobin concentration, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and red blood cell distribution width (PP>0.05. All the measured biochemical and hematological parameters were in the normal references range after the treatment. These results suggested that spiramycin given in therapeutic regimen to healthy Assaf sheep caused only minor inconclusive changes in the measured hematological and biochemical profiles; and thus can be used safely in treating susceptible infections in sheep. These results might be accepted as a starting point for future experiments to evaluate the effects spiramycin on the different systems and parameters.  

  12. Optimization of the therapeutic dose of {sup 131}I for thyroid differentiated carcinoma; Otimizacao da dose terapeutica com {sup 131}I para carcinoma diferenciado da tiroide

    Lima, Fabiana Farias de

    2002-09-01

    reduction for many organs, such as the narrow and gonads, of up to 78.4%.Possible benefits to the institution also include the use of less radioactive material and a reduction in radiation exposures to the staff during the manipulation and administration of the {sup 131} I. To facilitate the calculations of the optimum therapeutic activity of {sup 131} I for individual patients, a simple and fast dose planning program was created (PlanDose). The program has been set up to evaluate thryroid remant ablation, but it can also be used for the calculation of the activity to be administered for treatment of hyperthyroidism. This protocol of calculated optimal patient-specific {sup 131} I. activities allows a better determination of the necessary ablative dose for patients with differentiated carcinoma of the thyroid, and is an example of optimizing the practice of radiation protection. (author)

  13. Sand as thermoluminescent dosimeter to therapeutic doses Arena como dosímetro termoluminiscente para dosis terapéuticas

    Juana Salcedo

    2010-06-01

    Full Text Available This work describes the characteristic thermoluminiscent of sand coming from Coveñas beaches, for its use as therapeutic dose dosimeter. The selected samples, annealed at 400oC during 1 hour, were irradiated to different doses using an unit of 60Co Theratron 780C in air to ambient temperature. The reading was carried out in a Harshaw TLD 4500. The main dosimetric properties of the material (glow curve, response reproducibility, reutilization, linearity and thermal decay have been studied in detail. The glow curve of the sand samples presents a peaks TL at about 145◦C. The results show that the material has a linear response to the dose from 50 cGy until 1000 cGy. The studied sand samples can be used as thermoluminescent dosimeters for applications in different areas. The importance of this work is that the sand is a natural substance available in large quantities, low cost and can be used in clinical physics to evaluate the dose received by the patient during medical treatment.Este trabajo describe las características termoluminiscentes de arena proveniente de las playas de Coveñas para su uso como dosímetro en dosis terapéuticas. Las muestras seleccionadas, tratadas térmicamente a 400◦C por una hora, fueron irradiadas a diferentes dosis usando una unidad de 60Co Theratron 780C en aire a temperatura ambiente. La lectura se realizó en un Harshaw TLD 4500. Las principales propiedades dosimétricas del material (curva de brillo, reproducibilidad de la respuesta, reutilización, linealidad y decaimiento térmico han sido estudiadas en detalle. La curva de brillo de las muestras de arena presenta un pico TL alrededor de los 145◦C. Los resultados muestran que el material tiene una respuesta lineal con la dosis desde 50 cGy hasta 1000 cGy. Las muestras de arena estudiadas se pueden utilizar como dos´ımetros termoluminiscentes para aplicaciones en diferentes áreas. La importancia de este trabajo radica en que la arena es una sustancia

  14. Development of a methodology to determine optimized therapeutic doses of {sup 131}I for the treatment of hyperthyroidism

    Araujo, Francisco de; Santas, Bernardo Maranhao; Dantas, Ana Leticia Almeida; Lucena, Eder Augusto [Instituto de Radioprotecao e Dosimetria (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil)]. E-mail: faraujo@ird.gov.br; Melo, Rossana Corbo de; Rebelo, Ana Maria de Oliveira [Universidade Federal, Rio de Janeiro, RJ (Brazil). Faculdade de Medicina

    2007-07-01

    Several methods can be used to determine the activity of {sup 131}I to be administered for the treatment of hyperthyroidism. However, some of them do not take into consideration the dose absorbed by the thyroid, while others do not consider all the parameters necessary for dose calculation. The relationship between the dose absorbed by the thyroid and the activity administered depends basically on three parameters: mass of the organ, iodine uptake and effective half-life of iodine in the thyroid. Such parameters should be individually determined for each patient in order to optimize the administered activity. The objective of this work is to develop a methodology to evaluate therapeutic doses through the determination of biokinetic parameters and the activity of {sup 131}I deposited in the thyroid of patients submitted to the treatment of hyperthyroidism with {sup 131}I. A neck-thyroid phantom developed at the In Vivo Monitoring Laboratory of IRD, containing a known amount of {sup 131}I, was used to calibrate a scintillation camera and a uptake probe available at the Nuclear Medicine Center of the University Hospital of Rio de Janeiro. The optimization of the counting geometry was carried out by the determination of the characteristic curves of the view angle of the collimator-detector assembly. The calculation of the calibration factor of the scintillation camera allows the determination of activities in the thyroid of patients in pre-established time periods through a 48-hours uptake curve. The view angle of the collimator-detector assembly presented values compatible with the size of the organ for distances of 25 cm (uptake probe) and 45.8 cm (scintillation camera). The calibration factors (in cpm/kBq) and the associated uncertainty related to these distances were 39.3 {+-} 0.8 and 4.3 {+-} 0.2 respectively. The time period between 14 and 30 hours of the retention curve allows the calculation of the activity between those two points. It is concluded that the use

  15. Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice.

    Mayer, Lawrence D; Harasym, Troy O; Tardi, Paul G; Harasym, Natashia L; Shew, Clifford R; Johnstone, Sharon A; Ramsay, Euan C; Bally, Marcel B; Janoff, Andrew S

    2006-07-01

    Anticancer drug combinations can act synergistically or antagonistically against tumor cells in vitro depending on the ratios of the individual agents comprising the combination. The importance of drug ratios in vivo, however, has heretofore not been investigated, and combination chemotherapy treatment regimens continue to be developed based on the maximum tolerated dose of the individual agents. We systematically examined three different drug combinations representing a range of anticancer drug classes with distinct molecular mechanisms (irinotecan/floxuridine, cytarabine/daunorubicin, and cisplatin/daunorubicin) for drug ratio-dependent synergy. In each case, synergistic interactions were observed in vitro at certain drug/drug molar ratio ranges (1:1, 5:1, and 10:1, respectively), whereas other ratios were additive or antagonistic. We were able to maintain fixed drug ratios in plasma of mice for 24 hours after i.v. injection for all three combinations by controlling and overcoming the inherent dissimilar pharmacokinetics of individual drugs through encapsulation in liposomal carrier systems. The liposomes not only maintained drug ratios in the plasma after injection, but also delivered the formulated drug ratio directly to tumor tissue. In vivo maintenance of drug ratios shown to be synergistic in vitro provided increased efficacy in preclinical tumor models, whereas attenuated antitumor activity was observed when antagonistic drug ratios were maintained. Fixing synergistic drug ratios in pharmaceutical carriers provides an avenue by which anticancer drug combinations can be optimized prospectively for maximum therapeutic activity during preclinical development and differs from current practice in which dosing regimens are developed empirically in late-stage clinical trials based on tolerability.

  16. Early treatment with addition of low dose prednisolone to methotrexate improves therapeutic outcome in severe psoriatic arthritis

    Vikram K Mahajan

    2013-01-01

    Full Text Available Psoriatic arthritis (PsA is increasingly being recognized to cause progressive joint damage and disability. PsA unresponsive to non-steroidal anti-inflammatory drugs (NSAIDs, the conventional first-line choice of treatment, is usually managed with disease-modifying antirheumatic drugs (DMARDs especially methotrexate. An 18-year-old HIV-negative male had progressively severe PsA of 4-month duration that was nearly confining him to a wheel chair. He did not respond to multiple NSAIDs, alone or in combination with methotrexate (15 mg/week, given for 4 weeks. Addition of prednisolone (10 mg on alternate days controlled his symptoms within a week. The NSAIDs could be withdrawn after 4 weeks as the treatment progressed. The doses were tapered for methotrexate (5 mg/week and prednisolone (2.5 mg on alternate days every 8 weekly subsequently during 15 months of follow-up without recurrence/deformities or drug toxicity. For years, the use of corticosteroids in psoriasis has been criticized for their propensity to exacerbate the skin disease on withdrawal. However, monitored use of corticosteroids, even in low doses, combined with DMARDs may be a good therapeutic option in early stage of the PsA rather than ′steroid rescue′ later. This will help in early control of joint inflammation, prevent joint damage and maintain long-term good functional capacity and quality of life. This may be useful when the cost or availability of biologics precludes their use. However, we discourage the use of corticosteroids as monotherapy.

  17. Partition of bispyridinium oximes (trimedoxime and K074) administered in therapeutic doses into different parts of the rat brain.

    Karasova, Jana Zdarova; Zemek, Filip; Bajgar, Jiri; Vasatova, Martina; Prochazka, Petr; Novotny, Ladislav; Kuca, Kamil

    2011-04-05

    The penetration of acetylcholinesterase reactivators (oximes) into the central nervous system is typically restricted by the blood-brain barrier. Although oximes are highly hydrophilic compounds, some contradictory results confirming permeation into the brain exist. The aim of this study is to verify the penetration of oximes through the blood-brain barrier and to detect their levels achieved in different brain regions 60 min after the administration. It was confirmed that oximes are able to penetrate into the brain after injection of therapeutic doses corresponding with 5% of LD(50). The level in whole brain was 0.58% for trimedoxime and 0.85% for the experimental drug oxime K074 as the percentage of their plasma concentration. The highest concentration was found in frontal cortex (trimedoxime 2.27%; oxime K074 0.95%) and lowest in basal ganglia (trimedoxime 0.86%; oxime K074 0.42%). Entry of oximes into the brain is minimal, but some low reactivation effect should be expected. The reactivation potency of oximes might be higher or lower, depending on the real oxime concentration in a given area.

  18. Therapeutic and immunomodulatory effects of glucosamine in combination with low-dose cyclosporine a in a murine model of imiquimod-induced psoriasis.

    Kim, Chang-Hyun; Kim, Ji-Young; Lee, Ai-Young

    2015-06-05

    Although cyclosporine A (CsA) is a potent immunomodulating agent and is commonly used as a systemic agent for the management of psoriasis patients, current clinical treatments are not always effective due to the clinical inefficacy of low-doses and numerous harmful effects of higher doses. Currently, the combined use of two other systemic drugs often has better therapeutic efficacy and is safer than low or high dose of a single drug. Glucosamine (Glu) also has immunomodulatory properties for autoimmune diseases. The aims of our study were to investigate the therapeutic efficacy of Glu in combination with low-dose CsA on imiquimod (IMQ)-induced psoriasis-like dermatitis in mice and to determine its immunomodulatory mechanism. We found that combined treatment with Glu (300 mg/kg) and low-dose (10 or 20mg/kg) CsA strongly ameliorated the development of psoriasis-like skin lesions and reduced the levels of Th1 cytokine (TNF-α) and Th17 cytokines (IL-17, IL-22, and IL-23) in the serum and dorsal skin. Histological findings also showed that the thickening of epidermis, stratum corneum, and inflammatory cell infiltration. Particularly, these combined treatments increased the number of CD4(+)CD25(+) regulatory T (Treg) cells in splenic. These results suggest that use of a combination of each drug might be used as an efficacious and safe alternative therapeutic strategy, as well as may provide an immunomodulatory approach for T cell-mediated autoimmune diseases, including psoriasis.

  19. Therapeutical evaluation of different dose regimens of praziquantel in schistosomiasis mansoni, based on the quantitative oogram technique

    Aloísio Sales da Cunha

    1987-10-01

    Full Text Available A clinical trial involving 80 patients of both sexes, from ages 15 to 55, with chronic intestinal or hepatointestinal schistosomiasis mansoni, was carried out to evaluate the therapeutical efficacy of different dose regimens of praziquantel. The patients were randomly allocated into four groups with an equal number of cases and were then treated with one of the following dosages: 60 mg/kg for 1 day; 60 mg/kg daily for 2 days; 60 mg/kg daily for 3 days; and 30 mg/kg daily for 6 days. The assessment of parasitological cure was based on the quantitative oogram technique through rectal mucosa biopsies which were undertaken prior to, as well as, 1,2,4 and 6 months post-treatment. Concurrently, stool examinations according to the qualitative Hoffman, Pons & Janer (HPJ and the quantitative Kato-Katz (K-K methods were also performed. The best tolerability was observed with 30 mg/kg daily for 6 days whereas the highest incidence of side-effects (mainly dizziness and nausea was found with 60 mg/kg daily for 3 days. No serious adverse drug reaction has occurred. The achieved cure rates were: 25% with 60 mg/kg for 1 day; 60% with 60 mg/kg daily for 2 days; 89.5% with 60 mg/kg daily for 3 days; and 90% with 30 mg/kg daily for 6 days. At the same time there has been a downfall of 64%, 73%, 87% and 84% respectively, in the median number of viable S. mansoni ova per gram of tissue. Thus, a very clear direct correlation between dose and effect could be seen. The corresponding cure rates according to stool examinations by HPJ were 39%, 80%, 100% and 95%; by K-K 89%, 100%, 100% and 100%. This discrepancy in results amongst the three parasitological methods is certainly due to their unequal accuracy. In fact, when the number of viable eggs per gram of tissue fell below 5,000 the difference in the percentage of false negative findings between HPJ (28% and K-K (80% became significative. When this number dropped to less than 2,000 the percentage of false negative

  20. POSSIBLE ADVERSE EFFECTS OF ONCE-DAILY ORAL THERAPEUTIC DOSE OF EITHER GLUCOSAMINE SULFATE OR GLUCOSAMINE/CHONDROITIN SULFATE ON BLOOD CELLS COUNT IN RATS

    Noushi Abeer Amer

    2013-10-01

    Full Text Available This study was designed to investigate the possible adverse effects that may be induced by once-daily therapeutic doses of either glucosamine sulfate or glucosamine/chondroitin sulfate administered orally to rats for 30 days on blood cells (RBCs, WBCs and platelets counts. Forty three white healthy adult Albino rats of both sexes were selected randomly for this study. They were divided into three groups (І, ІІ, ІІІ. Group І received 0.05 ml distilled water, group ІІ received once daily therapeutic dose of glucosamine sulphate and group ІІІ received once daily therapeutic dose of glucosamine sulphate/chondroitin sulphate orally. The treatment period was for 30 days. At day 31, the animals were subjected to light ether anaesthesia and blood was withdrawn from the eye by retro-orbital puncture for the estimation of blood cells (RBCs, WBCs and platelets count. Treatment with single daily therapeutic dose of either GS alone or GS/CS for 30 days on blood cells count in rats produced a non significant change in RBCs counts compared to control and to each other. There were no statistically significant differences in total WBCs count at day 31 in animals administered once daily therapeutic dose of either GS or GS/CS orally compared to control group. In contrast, there was a statistically significant elevation in total WBCs count in GS/CS- treated rats compared to that in the GS-treated rats. The results of this study also showed that there was statistically significant decrease in neutrophils percentage in both drug treatment groups compared to control group. A statistically significant reduction in the percentage of monocytes was observed in GS/CS group compared to the corresponding percentage in animals of control group; while, there were non-significant differences in the percentage of monocytes in GS treated rats compared to that in the control group. There were no significant differences in the percentage of monocytes at day 31 of GS

  1. A simple and fast physics-based analytical method to calculate therapeutic and stray doses from external beam, megavoltage x-ray therapy.

    Jagetic, Lydia J; Newhauser, Wayne D

    2015-06-21

    State-of-the-art radiotherapy treatment planning systems provide reliable estimates of the therapeutic radiation but are known to underestimate or neglect the stray radiation exposures. Most commonly, stray radiation exposures are reconstructed using empirical formulas or lookup tables. The purpose of this study was to develop the basic physics of a model capable of calculating the total absorbed dose both inside and outside of the therapeutic radiation beam for external beam photon therapy. The model was developed using measurements of total absorbed dose in a water-box phantom from a 6 MV medical linear accelerator to calculate dose profiles in both the in-plane and cross-plane direction for a variety of square field sizes and depths in water. The water-box phantom facilitated development of the basic physical aspects of the model. RMS discrepancies between measured and calculated total absorbed dose values in water were less than 9.3% for all fields studied. Computation times for 10 million dose points within a homogeneous phantom were approximately 4 min. These results suggest that the basic physics of the model are sufficiently simple, fast, and accurate to serve as a foundation for a variety of clinical and research applications, some of which may require that the model be extended or simplified based on the needs of the user. A potentially important advantage of a physics-based approach is that the model is more readily adaptable to a wide variety of treatment units and treatment techniques than with empirical models.

  2. An unusual case of death probably triggered by the association of buprenorphine at therapeutic dose with ethanol and benzodiazepines and with very low norbuprenorphine level.

    Bardy, Guillaume; Cathala, Philippe; Eiden, Céline; Baccino, Eric; Petit, Pierre; Mathieu, Olivier

    2015-01-01

    Buprenorphine is largely prescribed for maintenance treatment in opioid dependence due to its safety profile. Nevertheless, fatalities at therapeutic dose have been described when associated with other central nervous system depressants, such as ethanol or benzodiazepines. Here, we report a case of death due to association of buprenorphine at therapeutic dose with benzodiazepines and ethanol. Although toxicity has been often attributed to its metabolite norbuprenorphine rather than to buprenorphine itself, in our case, norbuprenorphine was not detected in urine and bile and only in traces in blood. Moreover, the presence in blood of free buprenorphine but not of glucuronide metabolites argues for an unusual early death, at the beginning of buprenorphine metabolism. We propose that in the context of prior toxic impregnation, buprenorphine directly (and not via its metabolite norbuprenorphine) acted as a triggering factor by blocking the ventilatory response, rapidly leading to fatal respiratory depression.

  3. Subacute therapeutic dosing of artemether-lumefantrine and artesunate-amodiaquine combination preserves plasma cholesterol, renal antioxidant status, and organ weights in rats.

    Otuechere, Chiagoziem A; Edewor, Gloria; Kale, Oluwafemi Ezekiel; Ekor, Martins

    2012-01-01

    Recent instances of breakdowns of malaria control programs and the constant emergence of drug-resistant parasites to monotherapies have shored up the use of artemisinin-based combination therapy (ACT) as the malaria therapy of choice. We evaluated a subacute therapeutic dosing of artemether-lumefantrine and artesunate-amodiaquine on plasma cholesterol, renal antioxidants, and organ weights in rats. Sixteen albino rats were grouped into three. Group A (n = 5) served as the control. Groups B (n = 6) and C (n = 5) were administered, twice daily, oral therapeutic doses of artemether-lumefantrine (1.14/6.86 mg/kg/d) and artesunate-amodiaquine (2.86/8.58 mg/kg/d), respectively, for seven days. From our results, ACTs did not significantly (P > 0.05) alter catalase, superoxide dismutase, glutathione S-transferase, myeloperoxidase, and total glutathione levels when compared with the control. Plasma total cholesterol levels also decreased insignificantly (P > 0.05). Organ-system weights were not significantly (P > 0.05) different from control rats. Artesunate-amodiaquine, but not artemether-lumefantrine, significantly increased (P artesunate-amodiaquine and artemether-lumefantrine may preserve renal antioxidants and organ weights in vivo. However, caution is required above therapeutic indications or in chronic doses as this may predispose to renal oxidative stress.

  4. The influence of position deviation on RAIU and,the corresponding therapeutic dose calculations in patients with Graves hyperthyroidism

    李从心

    2013-01-01

    Objective To evaluate the influence of inappropriate position deviation on radioactive iodine uptake(RAIU),effective half-life(Teff)and the corresponding dose variances in patients suffering from Graves hyperthyroidism.Methods RAIU was examined in 20 patients with

  5. Therapeutic Doses of Nonsteroidal Anti-Inflammatory Drugs Inhibit Osteosarcoma MG-63 Osteoblast-Like Cells Maturation, Viability, and Biomineralization Potential

    E. De Luna-Bertos

    2013-01-01

    Full Text Available Nonsteroidal anti-inflammatory drugs (NSAIDs are frequently used to reduce pain and inflammation. However, their effect on bone metabolisms is not well known, and results in the literature are contradictory. The present study focusses on the effect of dexketoprofen, ketorolac, metamizole, and acetylsalicylic acid, at therapeutic doses, on different biochemical and phenotypic pathways in human osteoblast-like cells. Osteoblasts (MG-63 cell line were incubated in culture medium with 1–10 μM of dexketoprofen, ketorolac, metamizole, and acetylsalicylic acid. Flow cytometry was used to study antigenic profile and phagocytic activity. The osteoblastic differentiation was evaluated by mineralization and synthesis of collagen fibers by microscopy and alkaline phosphatase activity (ALP by spectrophotometric assay. Short-term treatment with therapeutic doses of NSAIDs modulated differentiation, antigenic profile, and phagocyte activity of osteoblast-like cells. The treatment reduced ALP synthesis and matrix mineralization. However, nonsignificant differences were observed on collagen syntheses after treatments. The percentage of CD54 expression was increased with all treatments. CD80, CD86, and HLA-DR showed a decreased expression, which depended on NSAID and the dose applied. The treatments also decreased phagocyte activity in this cellular population. The results of this paper provide evidences that NSAIDs inhibit the osteoblast differentiation process thus reducing their ability to produce new bone mineralized extracellular matrix.

  6. A simple dose regimen of artesunate and amodiaquine based on age or body weight range for uncomplicated falciparum malaria in children: comparison of therapeutic efficacy with standard dose regimen of artesunate and amodiaquine and artemether-lumefantrine.

    Gbotosho, Grace O; Sowunmi, Akintunde; Okuboyejo, Titilope M; Happi, Christian T; Folarin, Onikepe O; Adewoye, Elsie O

    2012-07-01

    A new dose regimen of artesunate and amodiaquine (NDRAA) based on age or body weight range was compared with standard dose regimen of artesunate and amodiaquine (SDRAA) calculated according to body weight and with fixed-dose artesunate-amodiaquine (FDAA) and artemether-lumefantrine (AL) in 304 children afflicted by malaria aged 15 years or younger. In initial comparison (n = 208), children on NDRAA received 1-3 times amodiaquine per kilogram of body weight and 1-1.5 times of artesunate per kilogram of body weight compared with those receiving SDRAA. Parasite but not fever clearance was significantly faster in children who received NDRAA (19.4 ± 8.4 hours vs. 24.6 ± 15.5 hours, P = 0.003). Polymerase chain reaction-uncorrected cure rates on days 28-42 were also significantly higher in children who received NDRAA (P < 0.02 in all cases). Therapeutic responses in children younger than 5 years (n = 96) treated with NDRAA, FDAA, and AL were similar. Changes in hematocrit values and reported adverse events after commencing therapy were similar in those who received NDRAA and SDRAA. All drug regimens were well tolerated. NDRAA based on age or body weight range is simple, is therapeutically superior to SDRAA calculated according to body weight, and is as efficacious as AL in children younger than 5 years.

  7. Separation of lipoproteins for quantitative analysis of 14C-labeled lipid soluble compounds

    Carbon-14 tracer studies using accelerator mass spectrometry (AMS) have provided novel insights into nutrient metabolism and whole body metabolite flux. In addition to a baseline separation of analytes, a critical requirement specific to the AMS analysis was a stable carbon baseline within the anal...

  8. Synthesis of {sup 14}C-labeled levamisole and {sup 13}C-labeled tetramisole

    Feil, V.J. [US Department of Agriculture, Agricultural Research Service, Biosciences Research Lab., Fargo, ND (United States)

    1996-12-01

    The syntheses of {sup 14}C-ring labeled levamisole ([-]-2,3,5,6-tetrahydro-6-phenyl [{sup 14}C]-UL imidazo[2,1-b]thiazole) from acetophenone-ring-UL-{sup 14}C in 5 steps plus resolution with a 7.5% overall yield, and {sup 13}C{sub 6}-ring labeled tetramisole ([{+-}]-2,3,5,6-tetrahydro-6-phenyl [{sup 13}C{sub 6}]imidazo[2,1-b]thiazole) from benzene-{sup 13}C{sub 6} in 6 steps with a 9.0% overall yield are described. (author).

  9. Subacute Therapeutic Dosing of Artemether-Lumefantrine and Artesunate-Amodiaquine Combination Preserves Plasma Cholesterol, Renal Antioxidant Status, and Organ Weights in Rats

    Chiagoziem A. Otuechere

    2012-01-01

    Full Text Available Recent instances of breakdowns of malaria control programs and the constant emergence of drug-resistant parasites to monotherapies have shored up the use of artemisinin-based combination therapy (ACT as the malaria therapy of choice. We evaluated a subacute therapeutic dosing of artemether-lumefantrine and artesunate-amodiaquine on plasma cholesterol, renal antioxidants, and organ weights in rats. Sixteen albino rats were grouped into three. Group A (n=5 served as the control. Groups B (n=6 and C (n=5 were administered, twice daily, oral therapeutic doses of artemether-lumefantrine (1.14/6.86 mg/kg/d and artesunate-amodiaquine (2.86/8.58 mg/kg/d, respectively, for seven days. From our results, ACTs did not significantly (P>0.05 alter catalase, superoxide dismutase, glutathione S-transferase, myeloperoxidase, and total glutathione levels when compared with the control. Plasma total cholesterol levels also decreased insignificantly (P>0.05. Organ-system weights were not significantly (P>0.05 different from control rats. Artesunate-amodiaquine, but not artemether-lumefantrine, significantly increased (P<0.05 lactate dehydrogenase activity and also afforded a 27.2% decrease in heart weight when compared with control. Also, both ACTs increased (P<0.05 lipid peroxidation. Overall, artesunate-amodiaquine and artemether-lumefantrine may preserve renal antioxidants and organ weights in vivo. However, caution is required above therapeutic indications or in chronic doses as this may predispose to renal oxidative stress.

  10. Pharmacist-managed dose adjustment feedback using therapeutic drug monitoring of vancomycin was useful for patients with methicillin-resistant Staphylococcus aureus infections: a single institution experience

    Hirano, Ryuichi; Sakamoto, Yuichi; Kitazawa, Junichi; Yamamoto, Shoji; Tachibana, Naoki

    2016-01-01

    Background Vancomycin (VCM) requires dose adjustment based on therapeutic drug monitoring. At Aomori Prefectural Central Hospital, physicians carried out VCM therapeutic drug monitoring based on their experience, because pharmacists did not participate in the dose adjustment. We evaluated the impact of an Antimicrobial Stewardship Program (ASP) on attaining target VCM trough concentrations and pharmacokinetics (PK)/pharmacodynamics (PD) parameters in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. Materials and methods The ASP was introduced in April 2012. We implemented a prospective audit of prescribed VCM dosages and provided feedback based on measured VCM trough concentrations. In a retrospective pre- and postcomparison study from April 2007 to December 2011 (preimplementation) and from April 2012 to December 2014 (postimplementation), 79 patients were treated for MRSA infection with VCM, and trough concentrations were monitored (pre, n=28; post, n=51). In 65 patients (pre, n=15; post, n=50), 24-hour area under the concentration–time curve (AUC 0–24 h)/minimum inhibitory concentration (MIC) ratios were calculated. Results Pharmacist feedback, which included recommendations for changing dose or using alternative anti-MRSA antibiotics, was highly accepted during postimplementation (88%, 29/33). The number of patients with serum VCM concentrations within the therapeutic range (10–20 μg/mL) was significantly higher during postimplementation (84%, 43/51) than during preimplementation (39%, 11/28) (P400) was significantly higher during postimplementation (84%, 42/50) than during preimplementation (53%, 8/15; P=0.013). There were no significant differences in nephrotoxicity or mortality rate. Conclusion Our ASP increased the percentage of patients that attained optimal VCM trough concentrations and PK/PD parameters, which contributed to the appropriate use of VCM in patients with MRSA infections. PMID:27789965

  11. Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance.

    Kareva, Irina; Waxman, David J; Lakka Klement, Giannoula

    2015-03-28

    The administration of chemotherapy at reduced doses given at regular, frequent time intervals, termed 'metronomic' chemotherapy, presents an alternative to standard maximal tolerated dose (MTD) chemotherapy. The primary target of metronomic chemotherapy was originally identified as endothelial cells supporting the tumor vasculature, and not the tumor cells themselves, consistent with the emerging concept of cancer as a systemic disease involving both tumor cells and their microenvironment. While anti-angiogenesis is an important mechanism of action of metronomic chemotherapy, other mechanisms, including activation of anti-tumor immunity and a decrease in acquired therapeutic resistance, have also been identified. Here we present evidence supporting a mechanistic explanation for the improved activity of cancer chemotherapy when administered on a metronomic, rather than an MTD schedule and discuss the implications of these findings for further translation into the clinic.

  12. Assessment of absorbed dose and therapeutic response of tumor in repeated high-dose I-131 anti-CD20 monoclonal antibody (rituximab) radioimmunotherapy for non-Hodgkin's lymphoma

    Byun, Byung Hyun; Lim, Sang Moo; Kim, Kyeong Min [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)] (and others)

    2007-07-01

    We assessed the therapeutic dose absorbed to the tumor and response in repeated RIT with I-131 rituximab for NHL. Patients with NHL (n=6) were administered a therapeutic dose of I-131 rituximab (192.527.0 mCi). The number of repeated administration was 3 for all patients. Total 12 measurable tumor regions were assessed at the time of each RIT. Whole-body (WB) planar images with anterior and posterior views were acquired sequentially at 5 min, 5hr, 24hr, 48hr, and 72hr post-injection using gamma camera. F-18-FDG PET/CT was performed before (within 7 days) and after (on Day 30) RIT. From PET/CT image acquired before RIT, maximum intensity projection (MIP) image of coronal view was acquired. Serial WB planar images were overlaid to the coronal MIP PET image, respectively, by means of registration using 4 fiducial marks (bilateral shoulder and buttock) implemented in AMIDE software. On registered MIP PET and WB planar images, both 2D-ROIs were drawn on the region of tumor and background nearby tumor. The shape of 2D-ROI of tumor was determined from the MIP PET image. The volume of tumor was measured from the CT image, the % change of tumor volume before and after RIT was used in evaluation of the therapeutic response. The values of CT-based tumor volume were 8.216.3cc. The values of absorbed dose for tumor and the % changes of tumor volume before and after RIT were 231.8603.0rad, and 55.548.7%, respectively, and did not show the linear relationship (r=0.2787). The values of absorbed dose for tumor and the % changes of tumor volume did not correlate with the number of repeated administration (p>0.05, ANOVA). Aligning PET and planar images could estimate the quantitative values of absorbed dose to tumor. The data suggest that repeated RIT with I-131 rituximab is necessary for NHL, because single-RIT is insufficient to achieve remission of disease.

  13. A rational quantitative approach to determine the best dosing regimen for a target therapeutic effect: a unified formalism for antibiotic evaluation.

    Li, Jun; Nekka, Fahima

    2013-02-21

    The determination of an optimal dosing regimen is a critical step to enhance the drug efficacy and avoid toxicity. Rational dosing recommendations based on mathematical considerations are increasingly being adopted in the process of drug development and use. In this paper, we propose a quantitative approach to evaluate the efficacy of antibiotic agents. By integrating both pharmacokinetic (PK) and pharmacodynamic (PD) information, this approach gives rise to a unified formalism able to measure the cause-effect of dosing regimens. This new pharmaco-metric allows to cover a whole range of antibiotics, including the two well known concentration and time dependent classes, through the introduction of the Hill-dependency concept. As a direct fallout, our formalism opens a new path toward the bioequivalence evaluation in terms of PK and PD, which associates the in vivo drug concentration and the in vitro drug effect. Using this new approach, we succeeded to reveal unexpected, but relevant behaviors of drug performance when different drug regimens and drug classes are considered. Of particular notice, we found that the doses required to reach the same therapeutic effect, when scheduled differently, exhibit completely different tendencies for concentration and time dependent drugs. Moreover, we theoretically confirmed the previous experimental results of the superiority of the once daily regimen of aminoglycosides. The proposed methodology is appealing for its computational features and can easily be applicable to design fair clinical protocols or rationalize prescription decisions.

  14. Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model

    Maria Gomis-González

    2016-08-01

    Full Text Available Fragile X syndrome (FXS is the most common monogenetic cause of intellectual disability. The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1 knockout (KO mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1 receptor. In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects. In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD. In addition, low doses of rimonabant (from 0.01 mg/kg equally normalized the cognitive deficit in the mouse model of FXS. These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice. These data further support targeting CB1 receptors as a relevant therapy for FXS.

  15. Measurement of charged particle yields from therapeutic beams in view of the design of an innovative hadrontherapy dose monitor

    Battistoni, G.; Bellini, F.; Bini, F.; Collamati, F.; Collini, F.; De Lucia, E.; Durante, M.; Faccini, R.; Ferroni, F.; Frallicciardi, P. M.; La Tessa, C.; Marafini, M.; Mattei, I.; Miraglia, F.; Morganti, S.; Ortega, P. G.; Patera, V.; Piersanti, L.; Pinci, D.; Russomando, A.; Sarti, A.; Schuy, C.; Sciubba, A.; Senzacqua, M.; Solfaroli Camillocci, E.; Vanstalle, M.; Voena, C.

    2015-02-01

    Particle Therapy (PT) is an emerging technique, which makes use of charged particles to efficiently cure different kinds of solid tumors. The high precision in the hadrons dose deposition requires an accurate monitoring to prevent the risk of under-dosage of the cancer region or of over-dosage of healthy tissues. Monitoring techniques are currently being developed and are based on the detection of particles produced by the beam interaction into the target, in particular: charged particles, result of target and/or projectile fragmentation, prompt photons coming from nucleus de-excitation and back-to-back γ s, produced in the positron annihilation from β + emitters created in the beam interaction with the target. It has been showed that the hadron beam dose release peak can be spatially correlated with the emission pattern of these secondary particles. Here we report about secondary particles production (charged fragments and prompt γ s) performed at different beam and energies that have a particular relevance for PT applications: 12C beam of 80 MeV/u at LNS, 12C beam 220 MeV/u at GSI, and 12C, 4He, 16O beams with energy in the 50-300 MeV/u range at HIT. Finally, a project for a multimodal dose-monitor device exploiting the prompt photons and charged particles emission will be presented.

  16. Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model

    Gomis-González, Maria; Busquets-Garcia, Arnau; Matute, Carlos; Maldonado, Rafael; Mato, Susana; Ozaita, Andrés

    2016-01-01

    Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability. The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1) receptor. In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects. In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg) manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg) equally normalized the cognitive deficit in the mouse model of FXS. These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice. These data further support targeting CB1 receptors as a relevant therapy for FXS. PMID:27589806

  17. Pharmacist-managed dose adjustment feedback using therapeutic drug monitoring of vancomycin was useful for patients with methicillin-resistant Staphylococcus aureus infections: a single institution experience

    Hirano R

    2016-10-01

    Full Text Available Ryuichi Hirano,1 Yuichi Sakamoto,2 Junichi Kitazawa,2 Shoji Yamamoto,1 Naoki Tachibana2 1Department of Pharmacy, 2Laboratory Medicine and Blood Transfusion, Aomori Prefectural Central Hospital, Aomori-shi, Japan Background: Vancomycin (VCM requires dose adjustment based on therapeutic drug monitoring. At Aomori Prefectural Central Hospital, physicians carried out VCM therapeutic drug monitoring based on their experience, because pharmacists did not participate in the dose adjustment. We evaluated the impact of an Antimicrobial Stewardship Program (ASP on attaining target VCM trough concentrations and pharmacokinetics (PK/pharmacodynamics (PD parameters in patients with methicillin-resistant Staphylococcus aureus (MRSA infections. Materials and methods: The ASP was introduced in April 2012. We implemented a prospective audit of prescribed VCM dosages and provided feedback based on measured VCM trough concentrations. In a retrospective pre- and postcomparison study from April 2007 to December 2011 (preimplementation and from April 2012 to December 2014 (postimplementation, 79 patients were treated for MRSA infection with VCM, and trough concentrations were monitored (pre, n=28; post, n=51. In 65 patients (pre, n=15; post, n=50, 24-hour area under the ­concentration–time curve (AUC 0–24 h/minimum inhibitory concentration (MIC ratios were calculated. Results: Pharmacist feedback, which included recommendations for changing dose or using alternative anti-MRSA antibiotics, was highly accepted during postimplementation (88%, 29/33. The number of patients with serum VCM concentrations within the therapeutic range (10–20 μg/mL was significantly higher during postimplementation (84%, 43/51 than during preimplementation (39%, 11/28 (P<0.01. The percentage of patients who attained target PK/PD parameters (AUC 0–24 h/MIC >400 was significantly higher during postimplementation (84%, 42/50 than during preimplementation (53%, 8/15; P=0.013. There were

  18. 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

    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…

  19. Measurement of charged particle yields from therapeutic beams in view of the design of an innovative hadrontherapy dose monitor

    Battistoni, G; Bini, F; Collamati, F; Collini, F; De Lucia, E; Durante, M; Faccini, R; Ferroni, F; Frallicciardi, P M; La Tessa, C; Marafini, M; Mattei, I; Miraglia, F; Morganti, S; Ortega, P G; Patera, V; Piersanti, L; Pinci, D; Russomando, A; Sarti, A; Schuy, C; Sciubba, A; Senzacqua, M; Solfaroli Camillocci, E; Vanstalle, M; Voena, C

    2015-01-01

    Particle Therapy (PT) is an emerging technique, which makes use of charged particles to efficiently cure different kinds of solid tumors. The high precision in the hadrons dose deposition requires an accurate monitoring to prevent the risk of under-dosage of the cancer region or of over-dosage of healthy tissues. Monitoring techniques are currently being developed and are based on the detection of particles produced by the beam interaction into the target, in particular: charged particles, result of target and/or projectile fragmentation, prompt photons coming from nucleus de-excitation and back-to-back γ s, produced in the positron annihilation from β + emitters created in the beam interaction with the target. It has been showed that the hadron beam dose release peak can be spatially correlated with the emission pattern of these secondary particles. Here we report about secondary particles production (charged fragments and prompt γ s) performed at different beam and energies that have a particular relevan...

  20. Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses

    Mahmoud Ameri

    2014-05-01

    Full Text Available This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC. Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.

  1. Exposure to Non-Therapeutic INR in a High Risk Cardiovascular Patient: Potential Hazard Reduction with Genotype-guided Warfarin (Coumadin®) Dosing

    Rodríguez-Vélez, Rosángela; Ortiz-Rivera, Oscar J.; Bower, Bruce; Gorowski, Krystyna; Windemuth, Andreas; Villagra, David; Kocherla, Mohan; Seip, Richard L; D'Agostino, Darrin; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

    2013-01-01

    A case to illustrate the utility of genetic screening in warfarin (Coumadin®) management is reported. A 45 year-old woman of Puerto Rican ancestry was admitted to the emergency room twice within one month with chest pain. She was diagnosed with congestive heart failure, which was stabilized both times. At her second release, warfarin therapy was initiated at 5 mg/day to prevent thrombus formation and was lowered to 3.75 mg/day at day 7 by her primary physician. International Normalized Ratio (INR) test results in the follow-up period at days 1, 7, and 10 of warfarin therapy were 4.5, 6.5, and 7.3, respectively—far in excess of the therapeutic range, despite the lower dosage in effect from day 7 onward. the patient achieved target INR over the next 43 days after downward adjustment of the dose to a dose of 1.5 mg/day by trial and error. DNA-typing specific for the CYP2C9*2, *3, *4, *5, *6 alleles and seven variants in the VKORC1 gene, including the VKORC1-1639 G>A polymorphism, revealed the presence of combinatorial CYP2C9*2/*3 and VKORC1-1639 G/A genotypes in this patient. Entering the patient's demographic and genotype status data into independent algorithms available in the public domain to predict effective warfarin dose yielded predicted doses which ranged from 1.5 to 1.8 mg/day. Notably, the prediction of 1.5 mg/day, which was generated by the online resource www.warfarindosing.org, coincided with the patient's actual effective warfarin dose. We conclude that the rapid rise in INR observed upon the initiation of warfarin therapy and the final effective warfarin dose of 1.5 mg/day, are attributable in some part to the presence of two minor alleles in CYP2C9, which together significantly reduce warfarin metabolism. Warfarin genotyping can therefore inform the clinician of the predicted effective warfarin dose. the results highlight the potential for warfarin genetic testing to improve patient care. PMID:21261182

  2. Acute dosing of latrepirdine (Dimebon™, a possible Alzheimer therapeutic, elevates extracellular amyloid-β levels in vitro and in vivo

    Sano Mary

    2009-12-01

    Full Text Available Abstract Background Recent reports suggest that latrepirdine (Dimebon™, dimebolin, a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD. However, the mechanism(s underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-β (Aβ peptide in the brain, and Aβ-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of latrepirdine on levels of extracellular Aβ using in vitro and in vivo experimental systems. Results We evaluated extracellular levels of Aβ in three experimental systems, under basal conditions and after treatment with latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + latrepirdine (500pM-5 μM. Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of latrepirdine (1 μM or 10 μM. Drug-naïve Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + latrepirdine (3.5 mg/kg. Picomolar to nanomolar concentrations of acutely administered latrepirdine increased the extracellular concentration of Aβ in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01, while a clinically relevant acute dose of latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01. Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 μM and led to more modest

  3. Development of a methodology to determine optimized therapeutic doses of {sup 131}I for the treatment of hyperthyroidism

    Araujo, F.; Moura, M.B.; Pereira, A.C., E-mail: faraujo@ird.gov.br [Instituto de Medicna Nuclear (IMEN), Goiania, GO (Brazil); Dantas, B.M.; Dantas, A.L.A.; Lucena, E.A. [Instituto de Radioprotecao e Dosimetria (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil); Melo, R.C.; Rebelo, A.M.O. [Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ (Brazil). Faculdade de Medicina

    2008-07-01

    Several methods can be used to determine the activity of {sup 131}I to be administered for the treatment of hyperthyroidism. However, some of them do not take into consideration the dose absorbed by the thyroid, while others do not consider all the parameters necessary for dose calculation. The relationship between the dose absorbed by the thyroid and the activity administered depends basically on three parameters: mass of the organ, iodine uptake and effective half-life of iodine in the thyroid. Such parameters should be individually determined for each patient in order to optimize the administered activity. The objective of this work is to develop a methodology for individualized treatment with {sup 131}I in patients with hyperthyroidism of the Grave's Disease. A neck-thyroid phantom developed at the In Vivo Monitoring Laboratory of IRD, containing a known amount of {sup 131}I, was used to calibrate a scintillation camera and a uptake probe available at the Nuclear Medicine Center of the University Hospital of Rio de Janeiro and Instituto de Medicina Nuclear - IMEN, of Goiania. The optimization of the counting geometry was carried out by the determination of the characteristic curves of the view angle of the collimator-detector assembly. The view angle of the collimator-detector assembly presented values compatible with the size of the organ for distances of 25 cm (uptake probe) and 45.8 cm (scintillation camera). The calibration factors (in cpm/kBq) and the associated uncertainty related to these distances were (39.3 ± 0.78), (58.1 ± 2.38) to uptake probe SCT-13004 e 13002, respectively and 4.3 ± 0.17 to scintillation camera. The time period between 14 and 30 hours of the retention curve allows the calculation of the activity between those two points. It is concluded that the use of diagnose equipment available at the hospital (scintillation camera and uptake probe) has shown to be a suitable procedure in terms of effectiveness, simplicity and cost

  4. Therapeutic efifcacy and bone marrow protection of the mdr1 gene and over-dose chemotherapy with doxorubicin for rabbits with VX2 hepatocarcinoma

    Yi Wang; Xian-Qing Jin; Shan Wang; Qiao Wang; Qing Luo; Xiao-Ji Luo

    2006-01-01

    BACKGROUND: Malignant tumors are common diseases threatening to the health and life of human being. Clinically, the multidrug resistance of tumor cells and bone marrow depression caused by chemotherapeutic agents are the main obstacles to the treatment of tumors, and both are related to the mdr1 gene. The over expression of the mdr1 gene in tumor cells contributes to the multidrug resistance of malignant tumor cells. With little expression of the mdr1 gene, bone marrow cells particularly susceptible to multidrug resistance-sensitive agents, which cause serious toxicity in bone marrow. This study was undertaken to assess therapeutic efifcacy of transplantation of bone marrow mononuclear cells transferred with the mdr1 gene and over-dose chemotherapy with doxorubicin for VX2 hepatocarcinoma of rabbits. METHODS: The mdr1 gene was transferred into the bone marrow mononuclear cells of rabbits, which was co-cultured with retroviral vector-containing supernatant, and the cells were autotransplanted into a rabbit model with VX2 hepatocarcinoma. After chemotherapy with doxorubicin, the protective effects of the mdr1 gene and therapeutic efifcacy of over-dose chemotherapy were observed. RESULTS:The mdr1 gene was transferred successfully into the bone marrow mononuclear cells, with a transduction efifciency of 35%. After autotransplantation, the mdr1 gene was expressed functionally in bone marrow with a positive rate of 8%, indicating that the gene played an important role in bone marrow protection. The rabbits with VX2 hepatocarcinoma, which had received the mdr1 gene-transduced cells, survived after chemotherapy with a 3-fold dose of adriamycin, and their white blood cell counts were (4.26±1.03)×104/L. Since hepatocarcinoma cells were eradicated, the survival time (97.00±46.75 d) of the rabbits was extended (P CONCLUSIONS:The transferring of the mdr1 gene into bone marrow mononuclear cells could confer chemoprotection to bone marrow, and over-dose chemotherapy could be

  5. Intranasal administration of a therapeutic HIV vaccine (Vacc-4x induces dose-dependent systemic and mucosal immune responses in a randomized controlled trial.

    Kristin Brekke

    Full Text Available Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant.Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β.Vacc-4x proliferative T cell responses increased only among the vaccinated (p ≤ 0.031. The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037 and developed larger DTH (p = 0.005 than the adjuvant group. Rectal (distal Vacc-4x IgA and IgG antibodies also increased (p = 0.043 in this group. In contrast, the high dose generated higher nasal (local Vacc-4x IgA (p = 0.028 and serum IgG (p = 0.030 antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = -0.82, p < 0.001 and high regulation (r = 0.61, p = 0.010 at baseline.Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further investigation.ClinicalTrials.gov NCT01473810.

  6. Measurement of Antibiotic Consumption: A Practical Guide to the Use of the Anatomical Therapeutic Chemical Classification and Defined Daily Dose System Methodology in Canada

    James M Hutchinson

    2004-01-01

    Full Text Available Despite the global public health importance of resistance of microorganisms to the effects of antibiotics, and the direct relationship of consumption to resistance, little information is available concerning levels of consumption in Canadian hospitals and out-patient settings. The present paper provides practical advice on the use of administrative pharmacy data to address this need. Focus is made on the use of the Anatomical Therapeutic Chemical classification and Defined Daily Dose system. Examples of consumption data from Canadian community and hospital settings, with comparisons to international data, are used to incite interest and to propose uses of this information. It is hoped that all persons responsible for policy decisions regarding licensing, reimbursement, prescribing guidelines, formulary controls or any other structure pertaining to antimicrobial use become conversant with the concepts of population antibiotic consumption and that this paper provides them with the impetus and direction to begin accurately measuring and comparing antibiotic use in their jurisdictions.

  7. MO-H-19A-04: Multichannel CW Ultrasonic Thermometry for Imaging Therapeutic Dose Fields in Water

    Tosh, R [NIST, Gaithersburg, MD (United States)

    2014-06-15

    Purpose: To develop a scalable, multichannel ultrasonic thermometry system suitable for imaging clinical-beam dose distributions in a water phantom. Method: A small, glass-walled rectangular water phantom (15 cm × 20 cm × 30 cm) was filled with distilled water, and two ultrasonic transducers were placed on the outside, against opposing walls, approximately 5 cm below the water line, and were aligned to optimize transmission/reception of ultrasound between them. Two synchronized lock-in amplifiers were connected to the transducers to enable full-duplex operation of two separate ultrasonic frequency channels configured to transmit simultaneously through the same volume of water and thereby provide independent measurements of the temperature-dependent ultrasonic phase lag. Controlled heating of the water via immersed power resistors provided a means to study dependence of measured phase lag on temperature change for both channels; cross-correlation of the phase outputs enabled much smaller temperature fluctuations in the phantom to be used to ascertain the noise floor and achievable temperature resolution. Results: Temperature measurements from both channels, converted from phase measurements via polynomials available in the literature, exhibited the expected linear dependence of ultrasonic phase on temperature change (measured via calibrated thermistor probe). Cross-correlation analysis of phase fluctuations yielded rms noise estimates of approximately 1-2 microKelvin, comparable to that observed in standard water calorimeters. Conclusion: Phase-sensitive detection of cw ultrasound has been shown to provide temperature sensitivity needed for calorimetry of external treatment beams, and the present simple demonstration establishes that multiple channels may be run simultaneously without phase disturbances that currently affect time-of-flight techniques utilizing phase-detection. Immediate plans include doubling the number of sensors, to enable a simple tomographic

  8. Comparison of IMRT planning with two-step and one-step optimization: a strategy for improving therapeutic gain and reducing the integral dose

    Abate, A.; Pressello, M. C.; Benassi, M.; Strigari, L.

    2009-12-01

    The aim of this study was to evaluate the effectiveness and efficiency in inverse IMRT planning of one-step optimization with the step-and-shoot (SS) technique as compared to traditional two-step optimization using the sliding windows (SW) technique. The Pinnacle IMRT TPS allows both one-step and two-step approaches. The same beam setup for five head-and-neck tumor patients and dose-volume constraints were applied for all optimization methods. Two-step plans were produced converting the ideal fluence with or without a smoothing filter into the SW sequence. One-step plans, based on direct machine parameter optimization (DMPO), had the maximum number of segments per beam set at 8, 10, 12, producing a directly deliverable sequence. Moreover, the plans were generated whether a split-beam was used or not. Total monitor units (MUs), overall treatment time, cost function and dose-volume histograms (DVHs) were estimated for each plan. PTV conformality and homogeneity indexes and normal tissue complication probability (NTCP) that are the basis for improving therapeutic gain, as well as non-tumor integral dose (NTID), were evaluated. A two-sided t-test was used to compare quantitative variables. All plans showed similar target coverage. Compared to two-step SW optimization, the DMPO-SS plans resulted in lower MUs (20%), NTID (4%) as well as NTCP values. Differences of about 15-20% in the treatment delivery time were registered. DMPO generates less complex plans with identical PTV coverage, providing lower NTCP and NTID, which is expected to reduce the risk of secondary cancer. It is an effective and efficient method and, if available, it should be favored over the two-step IMRT planning.

  9. SU-E-J-08: Comparison of Unintended Radiation Doses to Organs at Risk Resulting From the Out-Of-Field Therapeutic Beams and From Image-Guidance X-Ray Procedures

    Ding, G; Wang, L [Vanderbilt University, Nashville, TN (United States)

    2015-06-15

    Purpose: The unintended radiation dose to organs at risk (OAR) can be contributed from imaging guidance procedures as well as from leakage and scatter of therapeutic beams. This study compares the imaging dose with the unintended out-of-field therapeutic dose to patient sensitive organs. Methods: The Monte Carlo EGSnrc user codes, BEAMnrc and DOSXYZnrc, were used to simulate kV X-ray sources from imaging devices as well as the therapeutic IMRT/VMAT beams and to calculate doses to target and OARs on patient treatment planning CT images. The accuracy of the Monte Carlo simulations was benchmarked against measurements in phantoms. The dose-volume histogram was utilized in analyzing the patient organ doses. Results: The dose resulting from Standard Head kV-CBCT scans to bone and soft tissues ranges from 0.7 to 1.1 cGy and from 0.03 to 0.3 cGy, respectively. The dose resulting from Thorax scans on the chest to bone and soft tissues ranges from 1.1 to 1.8 cGy and from 0.3 to 0.6 cGy, respectively. The dose resulting from Pelvis scans on the abdomen to bone and soft tissues range from 3.2 to 4.2 cGy and from 1.2 to 2.2 cGy, respectively. The out-of-field doses to OAR are sensitive to the distance between the treated target and the OAR. For a typical Head-and-Neck IMRT/VMAT treatment the out-of-field doses to eyes are 1–3% of the target dose, or 2–6 cGy per fraction. Conclusion: The imaging doses to OAR are predictable based on the imaging protocols used when OARs are within the imaged volume and can be estimated and accounted for by using tabulated values. The unintended out-of-field doses are proportional to the target dose, strongly depend on the distance between the treated target and OAR, and are generally higher comparing to the imaging dose. This work was partially supported by Varian research grant VUMC40590.

  10. The value of population pharmacokinetics and simulation for postmarketing safety evaluation of dosing guidelines for drugs with a narrow therapeutic index: buflomedil as a case study.

    Bourguignon, Laurent; Ducher, Michel; Matanza, David; Bleyzac, Nathalie; Uhart, Mathieu; Odouard, Emmanuel; Maire, Pascal; Goutelle, Sylvain

    2012-04-01

    Population pharmacokinetics and simulation techniques currently play an important role in new drug development. This paper illustrates the potential value of those methods in postmarketing safety assessment, using buflomedil in elderly patients as an example. We retrospectively assessed the risk of buflomedil overdosing associated with the latest dosing recommendations of the French Drug Agency (AFSSAPS). First, buflomedil concentrations measured in 24 elderly patients were analysed with a nonparametric population approach. Then, the pharmacokinetic model was used to perform a 1000-patient Monte Carlo simulation for the two recommended buflomedil dosage regimens. The maximum concentrations calculated after 10 days of therapy were compared with levels observed in reported cases of toxicity to assess the probability of overdosing. A three-compartment model best fit concentration data. Population predictions showed little bias (-0.14 mg/L) and good precision (8.73 mg(2) /L(2)). Overall results of the simulation study showed that the application of the two recommended dosage regimens of buflomedil was associated with overdosing (C(max) > 10 mg/L) and potential toxicity in 2.9% of geriatric patients. In patients with mild renal impairment, who may receive the higher-dosage regimen by therapeutic error, the probability of overdosing was 6.2%. Despite specific dosing recommendations in case of renal impairment, this study shows that the use of buflomedil could be associated with significant risk of overdosing in geriatric patients. Such results might have enhanced decision-making when buflomedil safety was reassessed by AFSSAPS in 2006. The retrospective case of buflomedil illustrates how these methods may be valuable in postmarketing safety evaluation of potentially toxic drugs.

  11. Effects of the chronic ingestion of therapeutic doses of chlorimipramine on the behavioral action of agonists and antagonists of serotonin in male rats.

    Rodríguez Echandía, E L; Broitman, S T; Fóscolo, M R

    1983-08-01

    Locomotor activity and hole-board exploration (frequency and time spent head-dipping) were impaired in male rats by injecting IP the 5-HT agonists, fluoxetine and 5-HTP. This treatment produced also myoclonus and increased the time spent resting during trials. The chronic ingestion of chlorimipramine (CIM) or the injection of the 5-HT receptor blocker, methysergide (15 mg/kg) prevented the action of the 5-HT agonists on locomotion and resting and blocked the appearance of myoclonus. Both CIM and methysergide prevented to a minor degree the fluoxetine-5-HTP-induced decrease of exploration. The chronic ingestion of CIM clearly potentiated the effects of methysergide on hole-board exploration. Results suggest that the chronic treatment with therapeutic doses of CIM reduces the functional activity of some 5-HT systems in the brain of the rat, probably by blockade of post-synaptic 5-HT receptors. This does not preclude, however, that CIM may also alter some NA systems.

  12. Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on peak and trough plasma levels.

    Francart, Suzanne J; Hawes, Emily M; Deal, Allison M; Adcock, Dorothy M; Gosselin, Robert; Jeanneret, Cheryl; Friedman, Kenneth D; Moll, Stephan

    2014-06-01

    Knowledge of anticoagulation status during rivaroxaban therapy is desirable in certain clinical situations. It was the study objective to determine coagulation tests most useful for assessing rivaroxaban's anticoagulant effect. Peak and trough blood samples from 29 patients taking rivaroxaban 20 mg daily were collected. Mass spectrometry and various coagulation assays were performed. "On-therapy range" was defined as the rivaroxaban concentrations determined by LC-MS/MS. A "misprediction percentage" was calculated based on how often results of each coagulation assay were in the normal reference range, while the rivaroxaban concentration was in the "on-therapy" range. The on-therapy range was 8.9-660 ng/ml. The misprediction percentages for prothrombin time (PT) and activated partial thromboplastin time (aPTT), using multiple reagents and coagulometers, ranged from 10%-52% and 31%-59%, respectively. PT, aPTT and activated clotting time (ACT) were insensitive to trough rivaroxaban: 59%, 62%, and 80% of samples had a normal result, respectively. Over 95% of PT and ACT values were elevated at peak. Four different rivaroxaban calibrated anti-Xa assays had R² values >0.98, demonstrating strong correlations with rivaroxaban drug levels. In conclusion, PT, aPTT and ACT are often normal in patients on therapeutic doses of rivaroxaban. However, PT and ACT may have clinical utility at higher drug plasma levels. Rivaroxaban calibrated anti-factor Xa assays can accurately identify low and high on-therapy rivaroxaban drug levels and, therefore, have superior utility in all clinical situations where assessment of anticoagulation status may be beneficial.

  13. [A method of the interactive visual optimization of the therapeutic dose field in contact radiation therapy of malignant tumors (theoretical aspects of the problem)].

    Klepper, L Ia

    2003-01-01

    The mathematical and interpretation tasks of a directed shaping of dose fields in the contrast radiation therapy of malignant tumors are defined on the basis of the dose-field homogeneity parameter. A schematic iterative algorithm of how to solve the tasks is described. A method for the visual optimization of such field is elaborated; it is based on preset limits to the dose field in the lesion focus and in the healthy organs and tissues. The dose field is shaped by an applicator with multiple terminal fixed positions of irradiation sources--the effect is achieved due to variability of their exposure duration.

  14. Comparison of therapeutic efficacy and clinical parameters between recombinant human thyroid stimulating hormone and thyroid hormone withdrawal in high-dose radioiodine treatment with differentiated thyroid cancer

    Choi, Se Hun; Na, Chang Ju; Kim, Jeong Hun; Han, Yeon Hee; KIm, Hee Kwon; Jeong, Hwan Jeong; Sohn, Myung Hee; Lim, Seok Tae [Dept. of Nuclear Medicine, Chonbuk National University Medical School and Hospital, Jeonju (Korea, Republic of)

    2015-06-15

    High-dose radioiodine treatment (HD-RIT) after injection of recombinant human thyroid stimulating hormone (rh-TSH) has become widely used. This study compared the therapeutic efficacy of HD-RIT and clinical parameters between rh-TSH supplement and thyroid hormone withdrawal (THW) after total thyroidectomy in patients with differentiated thyroid cancer. We retrospectively reviewed 266 patients (47 male and 219 female; age, 49.0 ± 10.9 years) with differentiated thyroid cancer detected from September 2011 to September 2012. Patients comprised THW (217, 81.6 %) and rh-TSH (49, 18.4 %). Inclusion criteria were: first HD-RIT; any TN stage; absence of distant metastasis. To evaluate the complete ablation of the remnant thyroid tissue or metastasis, we reviewed stimulated serum thyroglobulin (sTg), I-123 whole-body scan (RxWBS) on T4 off-state, and thyroid ultrasonography (US) or [F-18]-fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) 6–8 months after HD-RIT. We defined a complete ablation state when all three of the follow-up conditions were satisfied; <2.0 ng/ml of the sTg, I-123 RxWBS (−), and thyroid US or F-18 FDG PET/CT (−). If one of the three was positive, ablation was considered incomplete. We also compared various clinical biomarkers (body weight, body mass index, liver and kidney function) between THW and rh-TSH groups. The rates of complete ablation were 73.7 % (160/217) for the THW group and 73.5 % (36/49) for the rh-TSH group. There was no significant difference between the two groups (p = 0.970). The follow-up aspartate transaminase (p = 0.001) and alanine transaminase (p = 0.001) were significantly higher in the THW group. The renal function parameters of blood urea nitrogen (p = 0.001) and creatinine (p = 0.005) tended to increase in the THW group. The change of body weight was + Δ0.96 (±1.9) kg for the THW group and was decreased by -Δ1.39 (±1.5) kg for the rh-TSH group. The change

  15. Modeling vertical movement of organic matter in a soil incubated for 41 years with "1"4C labeled straw

    Bruun, S.; Christensen, B.T.; Thomsen, I.K.

    2007-01-01

    The distribution of organic matter (OM) in the soil profile reflects the balance between inputs and decomposition at different depths as well as transport of OM within the profile. In this study we modeled movement of OM in the soil profile as a result of mechanisms resulting in dispersive...

  16. Synthesis of [sup 14]C-labelled sodium pariprazole (E3810). [Anti-ulcer agent; ATPase inhibitor

    Tagami, Katsuya; Chiku, Shigeru; Sohda, Shigeru (Eisai Co., Ltd., Ibaraki (Japan). Tsukuba Research Labs.)

    1993-09-01

    Sodium pariprazole (E3810), an inhibitor of H[sup +],K[sup +]-ATPase, was synthesized labelled with carbon-14, starting from 2-mercapto[2-[sup 14]C]-benzimidazole with a specific activity of 888 MBq/mmol. It was obtained in 49.3% radiochemical yield with a radiochemical purity of more than 98%. (author).

  17. EVALUATION OF CO2 DURING BIRNESSITE-INDUCED OXIDATION OF 14C-LABELED CATECHOL. (R823847)

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  18. Metabolic fate of the (14)C-labeled herbicide clodinafop-propargyl in a sediment-water system.

    Yuan, Ye; Weitzel, Pascal; Schäffer, Andreas; Schmidt, Burkhard

    2015-01-01

    The metabolic fate of (14)C-phenyl-labeled herbicide clodinafop-propargyl ((14)C-CfP) was studied for 28 days in lab assays using a sediment-water system derived from a German location. Mineralization was 5.21% of applied (14)C after 28 days exhibiting a distinct lag phase until day 14 of incubation. Portions of radioactivity remaining in water phases decreased at moderate rate to 18.48% after 28 days; 62.46% were still detected in water after 14 days. Soxhlet extraction of the sediment using acetonitrile released 35.56% of applied (14)C with day 28, while 33.99% remained as non-extractable residues. A remarkable increase of bound (14)C was observed between 14 and 28 days correlating with the distinct increase of mineralization. No correlation was found throughout incubation with microbial activity of the sediment as determined by dimethyl sulfoxide reduction. Dissolved oxygen and pH value of water phases remained almost constant for 28 days. Analyses of Soxhlet extracts of the sediment and ethyl acetate extracts of water phases by radio-TLC and radio-HPLC revealed that CfP was rapidly cleaved to free acid clodinafop (Cf), which was further (bio-) transformed. DT50 values (based on radio-HPLC) were below 1 day (CfP) and slightly above 28 days (Cf). Further metabolites were not detected. Fractionation of humic and non-humic components of the sediment demonstrated that CfP's non-extractable residues were predominantly associated with fulvic acids up to 14 days of incubation (3.36%), whereas after 28 days, the majority of radioactivity was found in the humin/mineral fraction (13.30% of applied (14)C). Due to high-performance size-exclusion chromatography of the fulvic acids fraction derived from assays incubated for 28 days, this portion of (14)C was firmly, possibly covalently bound to fulvic acids and did not consist of CfP or Cf. Using an isolation strategy comprising preincubation of sediment with CfP and mineralization of (14)C-CfP as criterion, a microorganism was isolated from the sediment examined. It grew on (14)C-CfP as sole carbon source with evolution of (14)CO2. The bacterium was characterized by growth on commonly used carbon sources and 16S rDNA sequence analysis. Its sequence exhibited high similarity with that of Nocardioides aromaticivorans strain H-1 (98.85%; DSM 15131, JCM 11674).

  19. Synthesis and evaluation of [{sup 14}C]-Labelled and fluorescent-Tagged paclitaxel derivatives as new biological probes

    Rao, C.S.; Chu, J.-J.; Lai, Y.-K. [Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan (China); Liu, R.-S. [Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan (China)

    1998-11-01

    Our present report deals with the preparation of hitherto unreported 7-([carbonyl-{sup 14}C]-acetyl)paclitaxel 4 and two new bioactive 7-substituted fluorescent taxoids (FITC 9 and rhodamine 11), as well as evaluation towards their applications as biological probes. The results in this report demonstrate that (a) the new paclitaxel derivatives 4, 9, 11 could be prepared with good yields starting from paclitaxel; (b) the [{sup 14}C]acetylation step was found to be better by using [{sup 14}C]acetic anhydride rather than [{sup 14}C]sodium acetate; (c) the radiochemical purity of 4 was 96% and its specific activity was 48 mCi/mmol; (d) the cytotoxicity of 4 was close to that of paclitaxel whereas 9, 11 were far less active than paclitaxel, but these cytotoxic levels were good enough for their biological applications; (e) the drug-quantitation by flow cytometric analysis using 9 and 11 was proved to be equally efficient with respect to the radioactivity-based determination employing 4; (f) the intracellular fluorescence mapping by 9 and 11 was found to be effective and the microtubule network pattern was visible in both the cases; (g) the overall fluorescence imaging efficiency was better with 11 while the intensity of fluorescence was higher with 9; (h) staining of nucleolus was observed in fluorescence studies of both 9 and 11. Based on these results, the newly prepared paclitaxel derivatives can be considered as efficient biological probes and should find further use in relevant applications. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  20. 14C labelling of algal pigments to estimate the contribution of different taxa to primary production in natural seawater

    Gieskes, Winfried W.C.; Kraaij, Gijs W; Buma, Anita

    1993-01-01

    Several attempts have been made in the past to measure taxon-specific growth rates in natural phytoplankton populations in order to evaluate the conditions leading to success of individual taxa, to estimate the specific role of the various taxonomic components of algae in the food web and in nutrien

  1. Relocation of carbon from decomposition of {sup 14}C-labelled needle and fine root litter in peat soil

    Domish, T.; Laine, J.; Laiho, R. [Helsinki Univ. (Finland). Dept. of Forest Ecology; Finer, L. [Finnish Forest Research Inst. (Finland). Joensuu Research Station; Karsisto, M. [Finnish Forest Research Inst. (Finland). Dept. of Forest Ecology

    1996-12-31

    Drainage of peatlands promotes a shift of biomass and production from the ground vegetation to the trees. Thus, the above-ground (e.g. needles) and below-ground (roots) litter production of trees increases. Fine roots in particular are an important factor in the carbon and nutrient cycle in forest ecosystems. A major part of the annual net primary production of trees may be allocated below ground, the relative proportion being smaller on fertile sites than on less fertile ones. For modelling the carbon balance of drained peatlands, it is important to know the fate of carbon from newly introduced and decomposing litter. Newly added and fertilised tree litter material may be decomposed at a rate different than litter from the ground vegetation. The objectives of this study are to study the pathways of decomposing litter carbon in peat soil and to evaluate the use of the litterbag method in a controlled environment. (9 refs.)

  2. /sup 14/C-labelled propoxur metabolic studies on Anopheles Stephensi from the south coast of Iran

    Hossaini, M.A.; Manouchehri, A.V.; Zareh, Z. (Atomic Energy Organization of Iran, Teheran. Nuclear Research Centre)

    1984-08-01

    /sup 14/C-propoxur (Baygonsub(circled R)) was synthesized through the reaction of o-isopropoxyphenol with methyl isocyanate-/sup 14/C. The product was isolated chromatographically on Florisil and crystallized from carbon tetrachloride. The purity and structure were confirmed using infrared spectra, melting point, co-chromatography of Florisil column, and silica-gel G thin-layer chromatography. The purity was found to be at least 99%. The rate of absorption and other characteristics of /sup 14/C-propoxur resistance in Anopheles Stephensi from the south coast of Iran was investigated. The mortality of strain adults was 100% after a one hour exposure when 1 ppm /sup 14/C-propoxur was used. Moreover, the mortality was not changed when a lower concentration (5 ppm) was used. On the other hand, the absorbance of /sup 14/C-propoxur in several strains of A. Stephensi has been determined. The identity and TLC characteristics of products formed after 1 and 2 hours exposure, resp., to /sup 14/C-propoxur have also been investigated. 5 refs.

  3. Calibration and validation of the {sup 14}C-labelled polyethylene glycol-binding assay for tannins in tropical browse

    Mlambo, V. [Animal Production Unit, FAO/IAEA Agriculture and Biotechnology Laboratory, Seibersdorf (Austria)]. E-mail: vmlambo@agric.uniswa.sz; Makkar, H.P.S. [Animal Production and Health Section, Joint FAO/IAEA Division of Nuclear Techniques in Agriculture and Food, International Atomic Energy Agency, Vienna (Austria)

    2005-08-19

    This study evaluates the radiolabelled polyethylene glycol (PEG)-binding procedure [Silanikove, N., Shinder, D., Gilboa, N., Eyal, M., Nitsan, Z., 1996. Polyethylene glycol-binding to plant samples as an assay for the biological effects of tannins: predicting the negative effects of tannins in Mediterranean browse on rumen degradation. J. Agric. Food Chem. 44, 3230-3234] for tannin analysis, using 27 tropical browse plants. In this method, the amount of PEG bound to a plant sample is assumed to be a reflection of its tannin content. The method was modified to exclude the use of non-tanniniferous substrate for estimating non-specific binding (NSB) in tannin-containing substrates. Non-specific binding values varied widely (0.4-2.8 mg PEG/100 mg DM tannin-free substrate) when the tannin-free substrate was changed from wheat straw to either rye grass or maize shoots. We therefore propose a modified radiolabelled PEG-binding method to estimate the level of PEG-binding (PEGb) to tannin-containing foliage without using tannin-free substrate to correct for non-specific binding. In this approach, incremental levels of each tanniniferous substrate were used to generate PEGb values. The resultant linear response was analysed and tannin activity was expressed as the slope of the response curve (PEGbSlope) observed for each substrate. The slope takes into account the non-specific binding in each substrate, thus PEGbSlope does not require correction for NSB using tannin-free samples. This approach improved the correlation between PEGb and the {sup 125}I-labelled bovine serum albumin precipitation assay. Relationships between the modified PEG-binding assay and radiolabelled bovine serum albumin assay, in vitro tannin bioassay and colorimetric assays are presented. (author)

  4. Fate and stability of 14C-labeled 2,4,6-trinitrotoluene in contaminated soil following microbial bioremediation processes.

    Weiss, Martin; Geyer, Roland; Günther, Thomas; Kaestner, Matthias

    2004-09-01

    Biological treatment of 2,4,6-trinitrotoluene (TNT) in soil rarely results in complete mineralization of the parent compound. More often, the largest proportion of the TNT carbon is incorporated into the soil organic matrix. Therefore, we evaluated the stability of nonextractable residues from various bioremediation processes of 14C-TNT in soils. The extractable amounts of the residual radioactivity varied between 7 and 33% and thus the nonextractable amount between 93 and 67% (3-15% in fulvic acids, 26-46% in humic acids, and 27-44% in the humin fraction). The residue-containing soils were analyzed for the release of radioactivity after treatment by physical (freeze and thaw, grinding of soil, and steam extraction), chemical (acid rain and addition of metal complexing agent), and biological methods (addition of compost, white rot fungi, radical-generating enzymes, and germination of plants). Freeze and thaw treatment and grinding of the soil did not alter the partitioning of the label significantly. Steam extraction and acid rain extraction increased the water extractability to 11 to 29% and to 51.6% in the native TNT-contaminated soil. The addition of ethylenediamine-tetraacetate (EDTA) increased the extractability from 7 to 12%. After biological treatment, only slightly increased extractability (residues formed during microbial transformation of TNT may be biogenic residues with low mobilization potential and low hazardous impact.

  5. Comparison of depth-dose distributions of proton therapeutic beams calculated by means of logical detectors and ionization chamber modeled in Monte Carlo codes

    Pietrzak, Robert; Konefał, Adam; Sokół, Maria; Orlef, Andrzej

    2016-08-01

    The success of proton therapy depends strongly on the precision of treatment planning. Dose distribution in biological tissue may be obtained from Monte Carlo simulations using various scientific codes making it possible to perform very accurate calculations. However, there are many factors affecting the accuracy of modeling. One of them is a structure of objects called bins registering a dose. In this work the influence of bin structure on the dose distributions was examined. The MCNPX code calculations of Bragg curve for the 60 MeV proton beam were done in two ways: using simple logical detectors being the volumes determined in water, and using a precise model of ionization chamber used in clinical dosimetry. The results of the simulations were verified experimentally in the water phantom with Marcus ionization chamber. The average local dose difference between the measured relative doses in the water phantom and those calculated by means of the logical detectors was 1.4% at first 25 mm, whereas in the full depth range this difference was 1.6% for the maximum uncertainty in the calculations less than 2.4% and for the maximum measuring error of 1%. In case of the relative doses calculated with the use of the ionization chamber model this average difference was somewhat greater, being 2.3% at depths up to 25 mm and 2.4% in the full range of depths for the maximum uncertainty in the calculations of 3%. In the dose calculations the ionization chamber model does not offer any additional advantages over the logical detectors. The results provided by both models are similar and in good agreement with the measurements, however, the logical detector approach is a more time-effective method.

  6. Comparison of depth-dose distributions of proton therapeutic beams calculated by means of logical detectors and ionization chamber modeled in Monte Carlo codes

    Pietrzak, Robert [Department of Nuclear Physics and Its Applications, Institute of Physics, University of Silesia, Katowice (Poland); Konefał, Adam, E-mail: adam.konefal@us.edu.pl [Department of Nuclear Physics and Its Applications, Institute of Physics, University of Silesia, Katowice (Poland); Sokół, Maria; Orlef, Andrzej [Department of Medical Physics, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Gliwice (Poland)

    2016-08-01

    The success of proton therapy depends strongly on the precision of treatment planning. Dose distribution in biological tissue may be obtained from Monte Carlo simulations using various scientific codes making it possible to perform very accurate calculations. However, there are many factors affecting the accuracy of modeling. One of them is a structure of objects called bins registering a dose. In this work the influence of bin structure on the dose distributions was examined. The MCNPX code calculations of Bragg curve for the 60 MeV proton beam were done in two ways: using simple logical detectors being the volumes determined in water, and using a precise model of ionization chamber used in clinical dosimetry. The results of the simulations were verified experimentally in the water phantom with Marcus ionization chamber. The average local dose difference between the measured relative doses in the water phantom and those calculated by means of the logical detectors was 1.4% at first 25 mm, whereas in the full depth range this difference was 1.6% for the maximum uncertainty in the calculations less than 2.4% and for the maximum measuring error of 1%. In case of the relative doses calculated with the use of the ionization chamber model this average difference was somewhat greater, being 2.3% at depths up to 25 mm and 2.4% in the full range of depths for the maximum uncertainty in the calculations of 3%. In the dose calculations the ionization chamber model does not offer any additional advantages over the logical detectors. The results provided by both models are similar and in good agreement with the measurements, however, the logical detector approach is a more time-effective method. - Highlights: • Influence of the bin structure on the proton dose distributions was examined for the MC simulations. • The considered relative proton dose distributions in water correspond to the clinical application. • MC simulations performed with the logical detectors and the

  7. Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia.

    Rodriguez-Tudela, J.L.; Almirante, B.; Rodriguez-Pardo, D.; Laguna, F.; Donnelly, J.P.; Mouton, J.W.; Pahissa, A.; Cuenca-Estrella, M.

    2007-01-01

    We report on the correlation of the outcomes for two cohorts of patients who had been treated for candidemia (126 episodes) or oropharyngeal candidiasis (110 episodes) with various doses of fluconazole and the MIC of fluconazole obtained by using the EUCAST standard for fermentative yeasts. Of 145 e

  8. Lack of significant effect of bilastine administered at therapeutic and supratherapeutic doses and concomitantly with ketoconazole on ventricular repolarization: results of a thorough QT study (TQTS) with QT-concentration analysis.

    Tyl, Benoît; Kabbaj, Meriam; Azzam, Sara; Sologuren, Ander; Valiente, Román; Reinbolt, Elizabeth; Roupe, Kathryn; Blanco, Nathalie; Wheeler, William

    2012-06-01

    The effect of bilastine on cardiac repolarization was studied in 30 healthy participants during a multiple-dose, triple-dummy, crossover, thorough QT study that included 5 arms: placebo, active control (400 mg moxifloxacin), bilastine at therapeutic and supratherapeutic doses (20 mg and 100 mg once daily, respectively), and bilastine 20 mg administered with ketoconazole 400 mg. Time-matched, triplicate electrocardiograms (ECGs) were recorded with 13 time points extracted predose and 16 extracted over 72 hours post day 4 dosing. Four QT/RR corrections were implemented: QTcB; QTcF; a linear individual correction (QTcNi), the primary correction; and a nonlinear one (QTcNnl). Moxifloxacin was associated with a significant increase in QTcNi at all time points between 1 and 12 hours, inclusively. Bilastine administration at 20 mg and 100 mg had no clinically significant impact on QTc (maximum increase in QTcNi, 5.02 ms; upper confidence limit [UCL] of the 1-sided, 95% confidence interval, 7.87 ms). Concomitant administration of ketoconazole and bilastine 20 mg induced a clinically relevant increase in QTc (maximum increase in QTcNi, 9.3 ms; UCL, 12.16 ms). This result was most likely related to the cardiac effect of ketoconazole because for all time points, bilastine plasma concentrations were lower than those observed following the supratherapeutic dose.

  9. Initial dosing regimen of vancomycin to achieve early therapeutic plasma concentration in critically ill patients with MRSA infection based on APACHE II score.

    Imaura, Masaharu; Yokoyama, Haruko; Kohata, Yuji; Kanai, Riichiro; Kohyama, Tomoki; Idemitsu, Wataru; Maki, Yuichi; Igarashi, Takashi; Takahashi, Hiroyuki; Kanno, Hiroshi; Yamada, Yasuhiko

    2016-06-01

    It is essential to assure the efficacy of antimicrobials at the initial phase of therapy. However, increasing the volume of distribution (Vd) of hydrophilic antimicrobials in critically ill patients leads to reduced antimicrobial concentration in plasma and tissue, which may adversely affect the efficacy of that therapy. The aim of the present study was to establish a theoretical methodology for setting an appropriate level for initial vancomycin therapy in individual patients based on Acute Physiology and Chronic Health Evaluation (APACHE) II score. We obtained data from patients who received intravenous vancomycin for a suspected or definitively diagnosed Gram-positive bacterial infection within 72 h after admission to the intensive care unit. The Vd and elimination half-life (t 1/2) of vancomycin values were calculated using the Bayesian method, and we investigated the relationship between them and APACHE II score. There were significant correlations between APACHE II scores and Vd/actual body weight (ABW), as well as t 1/2 (r = 0.58, p < 0.05 and r = 0.74, p < 0.01, respectively). Our results suggested that the Vd and t 1/2 of vancomycin could be estimated using the following regression equations using APACHE II score.[Formula: see text] [Formula: see text]We found that APACHE II score was a useful index for predicting the Vd and t 1/2 of vancomycin, and used that to establish an initial vancomycin dosing regimen comprised of initial dose and administration interval for individual patients.

  10. Dose effect evaluation and therapeutic window of the neuro-EPO nasal application for the treatment of the focal ischemia model in the Mongolian gerbil.

    Teste, Iliana Sosa; Tamos, Yuneidys Mengana; Cruz, Yamila Rodríguez; Cernada, Adriana Muñoz; Rodríguez, Janette Cruz; Martínez, Nelvis Subirós; Antich, Rosa Maria Coro; González-Quevedo, Alina; Rodríguez, Julio Cesar García

    2012-01-01

    Cerebrovascular disease is the third leading cause of death and the leading cause of disability in Cuba and in several developed countries. A possible neuroprotective agent is the rHu-EPO, whose effects have been demonstrated in models of brain ischemia. The Neuro-EPO is a derivative of the rHu-EPO that avoids the stimulation of erythropoiesis. The aim of this study was to determine the Neuro-EPO delivery into the central nervous system (CNS) to exert a neuroprotective effect in cerebral ischemia model of the Mongolian gerbil. The Neuro-EPO in a rate of 249.4 UI every 8 hours for 4 days showed 25% higher viability efficacy (P > 0.01), improving neurological score and behavior of the spontaneous exploratory activity, the preservation of CA3 areas of the hippocampus, the cortex, and thalamic nuclei in the focal ischemia model of the Mongolian gerbil. In summary, this study, the average dose-used Neuro-EPO (249.4 UI/10 μL/every 8 hours for 4 days), proved to be valid indicators of viability, neurological status, and spontaneous exploratory activity, being significantly lower than that reported for the systemically use of the rHu-EPO as a neuroprotectant. Indeed, up to 12 h after brain ischemia is very positive Neuro-EPO administration by the nasal route as a candidate for neuroprotection.

  11. Successful therapeutic response of resistant cases of mucocutaneous leishmaniasis to a very low dose of antimony Resposta terapêutica bem sucedida de casos resistentes de leishmaniose mucocutânea a doses muito baixas de antimônio

    Manoel Paes de Oliveira-Neto

    2006-08-01

    Full Text Available Two mucocutaneous leishmaniasis cases resistant to therapy are reported here. After the failure of initial therapies (antimony, amphotericin B and/or pentamidine patients received a low-dose schedule: one ampoule of meglumine antimoniate (405mg of pentavalent antimony [Sb v] by intramuscular injection, three times a week until complete healing of the lesions. One patient was cured with a total of 30 ampoules in 10 weeks and the other received 36 ampoules in 12 weeks. Both remain clinically cured after one year of follow-up.São relatados dois casos de leishmaniose mucocutânea resistentes ao tratamento. Depois das terapêuticas iniciais (antimônio, anfotericina B e/ou pentamidina, os pacientes receberam um esquema alternativo: uma ampola de antimoniato de meglumina (405mg de antimônio pentavalnte [Sb v] por via intramuscular, três vezes por semana até a cura completa das lesões. Um paciente recebeu um total de 30 ampolas durante 10 semanas e o outro, 36 ampolas durante 12 semanas. Ambos permanecem clinicamente curados até um ano após o tratamento.

  12. Effects of single therapeutic doses of promethazine, fexofenadine and olopatadine on psychomotor function and histamine-induced wheal- and flare-responses: a randomized double-blind, placebo-controlled study in healthy volunteers.

    Kamei, Hiroyuki; Isaji, Ami; Noda, Yukihiro; Ishikawa, Kazuhiro; Senzaki, Koji; Yamada, Kiyofumi; Sugiura, Kazumitsu; Tomita, Yasushi; Nabeshima, Toshitaka

    2012-05-01

    Since most first-generation antihistamines have undesirable sedative effects on the central nervous systems (CNS), newer (second-generation) antihistamines have been developed to improve patients' quality of life. However, there are few reports that directly compare the antihistaminic efficacy and impairment of psychomotor functions. We designed a double-blind, placebo controlled, crossover study to concurrently compare the clinical effectiveness of promethazine, a first-generation antihistamine, and fexofenadine and olopatadine, second-generation antihistamines, by measuring their potency as peripheral inhibitors of histamine-induced wheal and flare. Further, we investigated their sedative effects on the CNS using a battery of psychomotor tests. When single therapeutic doses of fexofenadine (60 mg), olopatadine (5 mg) and promethazine (25 mg) were given in a double-blind manner to 24 healthy volunteers, all antihistamines produced a significant reduction in the wheal and flare responses induced by histamine. In the comparison among antihistamines, olopatadine showed a rapid inhibitory effect compared with fexofenadine and promethazine, and had a potent effect compared with promethazine. In a battery of psychomotor assessments using critical flicker fusion, choice reaction time, compensatory tracking, rapid visual information processing and a line analogue rating scale as a subjective assessment of sedation, promethazine significantly impaired psychomotor function. Fexofenadine and olopatadine had no significant effect in any of the psychomotor tests. Promethazine, fexofenadine and olopatadine did not affect behavioral activity, as measured by wrist actigraphy. These results suggest that olopatadine at a therapeutic dose has greater antihistaminergic activity than promethazine, and olopatadine and fexofenadine did not cause cognitive or psychomotor impairment.

  13. Monitoring low molecular weight heparins at therapeutic levels: dose-responses of, and correlations and differences between aPTT, anti-factor Xa and thrombin generation assays.

    Owain Thomas

    Full Text Available Low molecular weight heparins (LMWH's are used to prevent and treat thrombosis. Tests for monitoring LMWH's include anti-factor Xa (anti-FXa, activated partial thromboplastin time (aPTT and thrombin generation. Anti-FXa is the current gold standard despite LMWH's varying affinities for FXa and thrombin.To examine the effects of two different LMWH's on the results of 4 different aPTT-tests, anti-FXa activity and thrombin generation and to assess the tests' concordance.Enoxaparin and tinzaparin were added ex-vivo in concentrations of 0.0, 0.5, 1.0 and 1.5 anti-FXa international units (IU/mL, to blood from 10 volunteers. aPTT was measured using two whole blood methods (Free oscillation rheometry (FOR and Hemochron Jr (HCJ and an optical plasma method using two different reagents (ActinFSL and PTT-Automat. Anti-FXa activity was quantified using a chromogenic assay. Thrombin generation (Endogenous Thrombin Potential, ETP was measured on a Ceveron Alpha instrument using the TGA RB and more tissue-factor rich TGA RC reagents.Methods' mean aPTT at 1.0 IU/mL LMWH varied between 54s (SD 11 and 69s (SD 14 for enoxaparin and between 101s (SD 21 and 140s (SD 28 for tinzaparin. ActinFSL gave significantly shorter aPTT results. aPTT and anti-FXa generally correlated well. ETP as measured with the TGA RC reagent but not the TGA RB reagent showed an inverse exponential relationship to the concentration of LMWH. The HCJ-aPTT results had the weakest correlation to anti-FXa and thrombin generation (Rs0.62-0.87, whereas the other aPTT methods had similar correlation coefficients (Rs0.80-0.92.aPTT displays a linear dose-response to LMWH. There is variation between aPTT assays. Tinzaparin increases aPTT and decreases thrombin generation more than enoxaparin at any given level of anti-FXa activity, casting doubt on anti-FXa's present gold standard status. Thrombin generation with tissue factor-rich activator is a promising method for monitoring LMWH's.

  14. Tissue distribution and elimination of BDE 47 in mice following a single oral dose

    Staskal, D. [Curriculum in Toxicology, Chapel Hill, NC (United States); Diliberto, J.; DeVito, M.; Birnbaum, L. [US EPA, ORD, NHEERL, ETD, RTP (United States)

    2004-09-15

    2,2',4,4'-Tetrabromodiphenyl ether (BDE 47) is a polybrominated diphenyl ether (PBDE) congener which is part of a class of brominated flame retardants (BFRs) commonly used in a variety of highly flammable consumer goods. Concern for the effects of PBDEs has increased significantly in recent years as their presence has been detected in environmental samples and in human tissues at steadily increasing concentrations. Despite its small contribution to the PBDE global production and usage, BDE 47 is the major congener found in environmental samples and human tissue. Limited toxicology studies suggest that BDE 47 is a developmental neurotoxicant and an endocrine disruptor however, several data gaps exist and must be investigated in order to evaluate the human health risk of BDE 47. This study investigated basic toxicokinetic properties of BDE 47 in female C57BL/6J mice. Here we report the effect of time on the absorption, distribution, and excretion following a single, oral dose of 14C-labeled BDE 47. Animals were administered 1.0mg BDE 47/kg bw, a dose chosen based on previous studies. Distribution and elimination were monitored at several time points ranging from 1 hour to 21 days following exposure. Data from these basic toxicokinetic studies will be applied to studies investigating the toxicokinetics of BDE 47 in a developmental model as well as in the development of a physiologically-based pharmacokinetic (PBPK) model.

  15. 快速滴定法加量美托洛尔治疗急性心肌梗死的疗效%Therapeutic effect of increasing dose of metoprolol by rapid titration method on acute myocardial in-farction

    陈少伟; 孙智山; 黄河; 吴名星; 周贻

    2014-01-01

    目的:观察常规加量法及快速滴定法加量美托洛尔治疗急性心肌梗死(AMI)的疗效。方法:将发病24h 内诊断为 AMI 且无美托洛尔禁忌证的住院患者60例随机分成两组,在常规治疗的基础上采用不同方法给予美托洛尔,常规加量组采用7d 加量法,快速滴定组采用3d 加量法,两组均在达目标剂量190mg/d 后,以此量维持之,观察两组的疗效。结果:①在随访期间,两组均无患者再发心肌梗死、心衰而再次住院治疗,没有出现猝死等现象;②3月后门诊行心脏超声检查,与常规加量组比较,快速滴定组左室舒张末内径[LVEDd,(55.00±7.56) mm 比(50.00±5.81) mm]显著降低(P <0.01),左室射血分数[LVEF,(49.13±10.18)%比(57.84±10.34)%]显著升高(P <0.01)。结论:快速滴定法可以更早达到患者美托洛尔的目标量,更早抑制肾素释放,阻断肾素-血管紧张素系统,改善心肌重构和心功能。%Objective:To observe and compare the therapeutic effect of metoprolol by routine increasing dose method and rapid titration method on acute myocardial infarction (AMI).Methods:A total of 60 inpatients,who were di-agnosed with AMI within 24h and without contraindications for metoprolol,were randomly divided into two groups:routine therapy group (received metoprolol using routine methods,the dose was added in seven days)and rapid ti-tration group (metoprolol was added in three days using titration).The dosage maintained with 190 mg/d after both groups reaching the target dose of 190mg/d;then therapeutic effects were observed in both groups.Results: ①There were no re-myocardial infarction,rehospitalization caused by heart failure and sudden death etc.in both groups;② Patients received echocardiography in outpatients after three months.Compared with routine increasing dose group,there was significant reduction in left ventricular end-diastolic diameter

  16. Three years of antibacterial consumption in Indonesian Community Health Centers: The application of anatomical therapeutic chemical/defined daily doses and drug utilization 90% method to monitor antibacterial use

    Ivan S Pradipta

    2015-01-01

    Full Text Available Context: Irrational use of antibacterial drugs in Community Health-Care Centers (CHCs may lead to increased resistance, morbidity, and mortality. Aims: The aim of this study was to determine patterns of antibacterial use at CHCs in a district of Indonesia and use this as data for an antibiotic policy. Settings and Design: The observational-descriptive study was conducted in a district of Indonesia to obtain antibacterial use from 2008 to 2010. Subjects and Methods: The data obtained from the report on the use of medicines were classified and processed using the anatomical therapeutic chemical (ATC and defined daily doses (DDD method, with DDD/1000 patients as a unit measurement. The number of patients was obtained from attending patients in that research period. The most abundant antibacterial drugs use segment was identified by the drug utilization 90% (DU90% method. Statistical Analysis Used: Descriptive analysis were performed in this study. Results: Fourteen kinds of antibacterial drugs were used in 61 CHCs. The total of antibacterial drug use during the period 2008-2010 was 871.36 DDD/1000 patients/day. Declining antibacterial use was observed between 2008 and 2010. Six kinds of antibacterial drugs were the most commonly used. The data show that the average use per visit was as high as 24.41 DDD. Conclusions: Amoxicillin, sulfamethoxazole and trimethoprim are antibacterials that have to be reconsidered by physicians for use in the Bandung CHC. The high use of antibacterial drugs, as described in the study, can be used as reference to develop an antimicrobial stewardship program and increase awareness of resistance, adverse drug reaction and drug interaction of antibacterial drugs.

  17. Therapeutic drug monitoring, a practical application

    Kees Neef, C.; Touw, D.J.

    2010-01-01

    Therapeutic Drug Monitoring (TDM) is an indispensable tool in therapeutic handling and medication safety. A definition of TDM is: Therapeutic drug monitoring is a system of quality assurance of a drug management system, aiming that the right drug is given tot the right patient in the right dose in o

  18. Analysis on the Safety of Collecting Two Therapeutic Doses of Apheresis Platelet%单采2个治疗量血小板的安全性分析

    黄彦; 符雪丽; 梁若鹄

    2013-01-01

    目的 探讨献血者单采2个治疗量的血小板(PLT)的安全性及个体影响因素,以建立科学、合理、安全的献血者筛选标准.方法 选择2011年6月至2012年6月,于本站行单采2个治疗量PLT的389例献血者为研究对象.按献血者献血前PLT计数(PLT前)不同,将其分为3组:A组(PLT前<250×109,n=118);B组[PLT前为(250~299)×109,n=150];C组(PLT前≥300×109,n=121).以1个治疗量PLT产品的PLT,红细胞(RBC),白细胞(WBC)计数作为产品质量目标;献血者采血后PLT,红细胞比容(HCT),处理全血量作为献血者安全性评价指标,考察献血者献血前PLT高低对PLT产品质量和献血者安全性指标的影响.结果 本研究389例献血者中安全性指标达标率为97.17%;各组安全性评价指标之间差异,有统计学意义(P值均<0.05).采血后,献血者的PLT,HCT,RBC显著下降(P值均<0.05),但仍在安全范围内.12例献血者发生献血反应,发生率为3.08%.2个治疗剂量PLT产品中,383袋合格,合格率为98.46%.结论选择体重≥60 kg,PLT前≥220×109,HCT前为0.40~0.48的献血者,采用智能化血细胞分离机,1位供者单采2个治疗量血小板安全可行.%Objective To explore the safety of blood donors who donated two therapeutic doses of apheresis platelet (PLT),and set up a scientific,reasonable and safe screening standard of blood donors.Method From June 2011 to June 2012,a total of 389 blood donors who donated two therapeutic doses of apheresis PLT in our blood station were included in this study.According to the different of PLT count before donation,all the donors were divided into three groups,such as:A group (PLT<250 × 109,n=118),Bgroup [PLT were (250-299)×109,n=150] and C group (PLT≥300× 109,n=121).The influnence of blood donors' PLT level on PLT product quality and safety indicators of donors were investigated.Results In this study,the safety index compliance rate of 389 cases of blood donors was 97.17 % ; each

  19. 多次活性炭灌胃对大鼠血浆敌敌畏浓度的影响%Therapeutic effects of multi-dose activated charcoal on the acute dichlorvos poisoning in rats

    袁丽; 王娜娜; 代恒; 韩振坤; 赵敏

    2010-01-01

    Objective To assess the therapeutic effects of activated charcoal on the acute dichlorvos poisoning in rats. Method Thirty male clean grade Wistar rats were randomly (random number) divided into three groups: control group (group A, n = 10), single dose activated charcoal group (group B, n = 10) and multi-dose activated charcoal (group C, n=10). The rats of group A were suffered from 35 mg/kg dichlorvos exposure by oral without activated charcoal and senna. The rats of group B received 35 mg/kg dichlorvos exposure by oral with 175 mg/kg activated charcoal given immediately after dichlorvos exposure and 35 mg/kg senna given half an hour later. In the group C, 35 mg/kg dichlorvos was given to rats by oral with 175 mg/kg activated charcoal given immediately after dichlorvos exposure and 35 mg/kg senna given half an hour later and then every four hours. Blood samples were collected from the carotid artery at different intervals after exposure. DDVP concentration and total blood acetyl-cholinesterase activity were detected. Differences in serum DDVP concentration, Cmax, AUC (0→∞ ), MRT and acetylcholinesterase among three groups were calculated by using ANOVA. Results Serum DDVP levels in single dose group and in multi-dose group were significantly different from those in control group (P 0.05). Another four hours later, no differences in acetylcholinesterase were found a-mong three groups (P > 0.05). Conclusions The peak concentrations of dichlorvos in blood are lower in group B and group C, and the blood acetylcholinesterase inhibition is quelled by activated charcoal. Therefore, the effects of multi - dose of activated charcoal is better than that of single dose of activated charcoal.%目的 探讨活性炭灌胃对急性有机磷农药中毒的治疗作用.方法 30只雄性清洁级Wistar大鼠随机(随机数字法)分成3组:对照组(A组)、单次活性炭番泻叶组(B组)和多次活性炭番泻叶组(C组),每组10只.A组按35 mg/kg剂量经口敌敌

  20. Therapeutic Effects of High Dose Dexamethasone Combined with Ulinastatin in Treating Sever Pulmonary Contusion%大剂量地塞米松联合乌司他丁治疗严重肺挫伤

    陈喜云; 钮海弟; 徐善明; 钟金龙

    2011-01-01

    目的:研究大剂量地塞米松联合乌司他丁治疗严重肺挫伤的疗效与安全性.方法:选择58例严重肺挫伤患者,随机分为A组(n=29)和B组(n=29).A组接受常规治疗,包括使用地塞米松20~40 mg,2次/d,连续3 d.B组在常规治疗的基础上联合乌司他丁20万U加入0.9%氯化钠液100 mL静脉滴注,每8 h 1次,连用7 d;2组患者治疗第1、第7天行血气分析,并检测治疗第1、第4、第7天血清肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)的含量.比较治疗期间2组患者急性呼吸窘迫综合征(ARDS)的发生率.结果:治疗前2组血气分析指标及血清TNF-α、IL-6水平无显著差异(P>0.05);治疗后B组血气分析指标较同期A组显著改善(P<0.05),血清TNF-α、IL-6水平较A组显著下降更明显(P<0.05).ARDS发生率B组显著低于A组(P<0.05).结论:大剂量地塞米松联合应用乌司他丁能显著抑制炎症介质的释放,有效保护严重肺挫伤患者的肺功能.%Objective:To observe the therapeutic effects of high dose dexamethasone combined with Ulinastatin in treating sever pulmonary contusion. Methods.A total of 58 patients with sever pulmonary contusion were randomly divided into Group A(n = 29) and Group B(n = 29). Both Groups received routine treatment, including dexamethasone (20-40 mg intravenous drip twice one day and continued 3 days), while the patients of Group B(n = 29) were given Ulinastatin (200 kU intravenous drip once every 8 hours and continued 7 days) in addition. Blood gas analysis were detected on the 1st and 7th day and serum tumor necrnsis factor alpha(TNF-α) and interleukin 6(IL-6) levels were measured on 1st, 4th and 7th day in both groups. Results:The results of blood gas analysis and serum TNF-α, IL-6 levels were not different in both groups before therapy(P>0. 05). The results of blood gas anslysis in Group B were higher than those of Group A after treatment (P<0. 05). TNF-α and IL-6 in Group B decreased more significantly than

  1. Neuroprotective effect of high-dose hyperbaric oxygenation on rats with acute cerebral infarction in super-early stage Curative comparison between 9-hour and 18-hour therapeutic protocols

    2007-01-01

    BACKGROUND: Previously, only single short-time low-dose hyperbaric oxygenation (HBO) protocol was administrated to treat acute ischemic stroke in early stage and the conflicting results were obtained. There are few studies to report the outcome of administering long-time (can cover all the natural pathologic progression period) high-dose HBO to treat the disease.OBJECTIVE: To evaluate the therapeutic effect between two kinds of high-dose hyperbaric oxygenation on super-early stage of acute permanent middle cerebral artery occlusion (MCAO) in rats.DESIGN: A randomized controlled experimental study.SETTING: Beijing Tiantan Hospital, Capital Medical University; Beijing Research Institute of Neurosurgery.MATERIALS: Seventy-four male SD rats, aged 2.5 months old, weighing (280±20) g, were provided by the Animal Institute, Chinese Academy of Medical Sciences. Hyperbaric oxygenation device was hyperbaric air cabin in which there was a self-made pure oxygen animal experimental cabin (made in China).METHODS: This experiment was carried out in the municipal laboratory of Beijing Tiantan Hospital affiliated to Capital Medical University and Beijing Research Institute of Neurosurgery. ① Experimental intervention: All the rats were developed into models of permanent MCAO by suture embolism. Then, they were randomly divided into two HBO groups (9hours and 18 hours) and control group, with 24 rats in each as well as 3-hour ultrastructure control group, with 2 rats. After being modeled for 3 hours, rats in the two HBO groups stayed in the hyperbaric cabin for 9 hours and 18 hours,separately. Rats in the 9-hour HBO group inhaled pure oxygen at hours 1, 3, 5, 7 and 9, and hyperbaric air at hours 2, 4, 6 and 8. Rats in the 18-hour HBO group inhaled pure oxygen at hours 1, 3, 5, 7, 9, 11, 13, 15 and 17, and hyperbaric air at hours 2, 4, 6, 8, 10 12, 14, 16 and 18. After being created into models, rats in the control group and 3-hour ultrastructure control group breathed room air.

  2. ANALYTICAL PERFORMANCE OF ACCELERATOR MASS SPECTROMETRY AND LIQUID SCINTILLATION COUNTING FOR DETECTION OF 14C-LABELED ATRAZINE METABOLITES IN HUMAN URINE. (R825433)

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  3. Hydrocarbons in the millipede Graphidostreptus tumuliporus (Karsch) (Myriapoda: Diplopoda)—I. In vivo incorporation of 14C-labelled precursors into the hydrocarbon fraction

    Oudejans, R.C.H.M.

    1972-01-01

    1. 1. Biosynthesis of hydrocarbons in male and female specimens of the millipede Graphidostreptus tumuliporus was investigated after injection of the following precursors: 1-14C-acetate, 16-14C- and 1-14C-palmitic acid, isoleucine-14C(U), valine-14C(U) and mevalonic-2-14C acid. 2. 2. Both sexes are

  4. Binding of /sup 14/C-labeled food mutagens (IQ, MeIQ, MeIQx) by dietary fiber in vitro

    Sjoedin, P.B.; Nyman, M.E.; Nilsson, L.; Asp, N.L.; Jaegerstad, M.

    Binding of three mutagens, known to occur in fried or broiled foods, by thirteen different types of dietary fiber was investigated in vitro. Nonspecific binding by other food polymers was minimized by using protease and amylase treatment. Water-insoluble fiber components were responsible for most of the binding capacity. Generally, a slightly larger proportion of 2-amino-3,4-dimethylimidazo (4,5-f)quinoline (MeIQ) than of 2-amino-3-methylimidazo (4,5-f)quinoline (IQ) and 2-amino-3,8-dimethylimidazo) -4,5-f)quinoxaline (MeIQx) was bound. There was a significant correlation between Klason lignin content and binding of mutagens. Optimum pH for binding was between 4 and 6. Dietary fiber from sorghum had the highest binding capacity, which could be due to the presence of a large Klason lignin fraction.

  5. Carbon transitions from either Calvin cycle or transitory starch to heteroglycans as revealed by (14) C-labeling experiments using protoplasts from Arabidopsis.

    Malinova, Irina; Steup, Martin; Fettke, Joerg

    2013-09-01

    Plants metabolize transitory starch by precisely coordinated plastidial and cytosolic processes. The latter appear to include the action of water-soluble heteroglycans (SHGin ) whose monosaccharide pattern is similar to that of apoplastic glycans (SHGex ) but, unlike SHGex , SHGin strongly interacts with glucosyl transferases. In this study, we analyzed starch metabolism using mesophyll protoplasts from wild-type plants and two knock-out mutants [deficient in the cytosolic transglucosidase, disproportionating isoenzyme 2 (DPE2) or the plastidial phosphoglucomutase (PGM1)] from Arabidopsis thaliana. Protoplasts prelabeled by photosynthetic (14) CO2 fixation were transferred to an unlabeled medium and were darkened or illuminated. Carbon transitions from the Calvin cycle or from starch to both SHGin and SHGex were analyzed. In illuminated protoplasts, starch turn-over was undetectable but darkened protoplasts continuously degraded starch. During illumination, neither the total (14) C content nor the labeling patterns of the sugar residues of SHGin were significantly altered but both the total amount and the labeling of the constituents of SHGex increased with time. In darkened protoplasts, the (14) C-content of most of the sugar residues of SHGin transiently and strongly increased and then declined. This effect was not observed in any SHGex constituent. In darkened DPE2-deficient protoplasts, none of the SHGin constituents exhibited an essential transient increase in labeling. In contrast, some residues of SHGin from the PGM1 mutant exhibited a transient increase in label but this effect significantly differed from that of the wild type. Two conclusions are reached: first, SHGin and SHGex exert different metabolic functions and second, SHGin is directly involved in starch degradation.

  6. Effects of the invasive polychaete, Marenzelleria viridis, on the fate of sediment associated pollutants – a microcosm study with 14C-labelled pyrene

    Banta, Gary Thomas; Hedman, Jenny Elisabet

    on the fate of deeply buried sediment-associated pollutants in the historically polluted Baltic Sea. We report here the results of an experimental microcosm study examining the fate of 14C radiolabelled pyrene (a 4-ring PAH) in sediment microcosms with and without Marenzelleria viridis. We also investigated...... the impact of depositing labile organic matter (seston) on the sediment surface. Worms clearly enhanced the release of pyrene and degradation metabolites from the sediment to the overlying water in all cases, mostly due to the initial flushing of sediments during burrow establishment. Surprisingly......, there was no clear effect of worms on the mineralization of pyrene to CO2, where a complicated interaction between bioturbation and the presence of labile organic matter was observed. Furthermore, the ultimate fate of the increased release of sediment-associated pyrene and its metabolites to the water is unknown....

  7. Experimental studies on tissue distribution of /sup 14/C-labelled anitimicrobic drugs in otorhinolaryngological field. Special reference to apply macro-autoradiography to these studies

    Murai, Kanetaka (Nagoya City Univ. (Japan). Faculty of Medicine)

    1981-08-01

    The distribution and concentration of antimicrobic drugs in the otorhinolaryngological field was studied together in the excised tissue by freezing macro-autoradiography in rabbits. Of the three Nalidixic acid antimicrobic analogues, i.e., pipemidic acid, AM-715 and rosoxacine, the first two accumulated remarkably in the soft palate, showing affinity for the cartilage. The concentrations of the three drugs in the paranasal sinus were higher on the medial portion of the maxilla than on the lateral portion, and the order of concentrations for ethmoidsinus were the lateral > anterior > posterior > medial portions. The present technique was thought to be a useful means for clarifying the distribution of drugs in vivo.

  8. Experimental studies on tissue distribution of /sup 14/C-labelled antimicrobial agent in otorhinolaryngological field. Application of macro-autoradiography

    Murai, K.; Baba, S. (Nagoya City Univ. (Japan). Faculty of Medicine); Morita, S.; Ishigami, M.

    1982-08-01

    The tissue distribution of nalidixic acid analog OPC-7241 was investigated. Autoradiography was performed 30 minutes after intravenous administration of /sup 14/C-OPC-7241 in 2.96 MBq(80.0 ..mu..Ci)/12.5 mg/kg to New Zealand White rabbit. Radiometry was performed 30 minutes, 1 hour and 3 hours after intravenous administration of /sup 14/C-OPC-7241 in 740 kBq(20.0 ..mu..Ci)/10.0 mg/kg to NZW rabbits. Such care was taken in filling the carboxymethyl cellulose paste into the paranasal cavity, nasal cavity, oral cavity and external ear canal not to damage mechanically. Horizontal frozen sections parallel to mandibular basis were cut in 50 ..mu..m thickness in a cryostat. Blackening of /sup 14/C-OPC-7241 was most significant in soft palate and its expanse which is apparently the same gland-like tissues as soft palate when stained with hematoxylin and eosin. Significant radioactivity was recognized in tonsils, the cartilage of external ear canal, septal cartilage, periodontal membrane, dental pulp, muscle and concha nasalis ventralis. The levels were low in ethmoid cells, mucosa of tympanic cavity, cochlea, maxillary sinus and bone. Quantitatively, the levels of /sup 14/C-OPC-7241 radioactivity were high in soft palate, mandibular gland and tonsils. Radioactivity was significant in tongue and concha nasalis ventralis. The levels were low in turbinates, ethmoid cells, maxillary sinus, septal cartilage, septal mucosa, cochlea, brain, optic nerve and lens. Thus radiometric results agreed with the above autoradiographic findings. Macro-autoradiography can be one of useful means for the evaluation chemotherapeutic agents for possible clinical application.

  9. Experimental soil warming and cooling alters the partitioning of recent assimilates: evidence from a (14)C-labelling study at the alpine treeline.

    Ferrari, A; Hagedorn, F; Niklaus, P A

    2016-05-01

    Despite concerns about climate change effects on ecosystems functioning, little is known on how plant assimilate partitioning changes with temperature. Particularly, large temperature effects might occur in cold ecosystems where critical processes are at their temperature limit. In this study, we tested temperature effects on carbon (C) assimilate partitioning in a field experiment at the alpine treeline. We warmed and cooled soils of microcosms planted with Pinus mugo or Leucanthemopsis alpina, achieving daily mean soil temperatures (3-10 cm depth) around 5.8, 12.7 and 19.2 °C in cooled, control and warmed soils. We pulse-labelled these systems with (14)CO2 for one photoperiod and traced (14)C over the successive 4 days. Plant net (14)C uptake increased steadily with soil temperature. However, (14)C amounts in fungal hyphae, soil microbial biomass, soil organic matter, and soil respiration showed a non-linear response to temperature. This non-linear pattern was particularly pronounced in P. mugo, with five times higher (14)C activities in cooled compared to control soils, but no difference between warmed and control soil. Autoradiographic analysis of the spatial distribution of (14)C in soils indicated that temperature effects on the vertical label distribution within soils depended on plant species. Our results show that plant growth, in particular root metabolism, is limited by low soil temperature. As a consequence, positive temperature effects on net C uptake may not be paralleled by similar changes in rhizodeposition. This has important implications for predictions of soil C storage, because rhizodeposits and plant biomass vary strongly in their residence times.

  10. Depletion of eugenol residues from the skin-on fillet tissue of rainbow trout exposed to 14C-labeled eugenol

    Meinertz, Jeffery R.; Schreier, Theresa M.; Porcher, Scott T.; Smerud, Justin R.; Gaikowski, Mark P.

    2014-01-01

    The U.S. is lagging in access to an approved immediate-release sedative, i.e. a compound that can be safely and effectively used to sedate fish and has no withdrawal period. AQUI-S® 20E (10% active ingredient, eugenol) is under investigation as an immediate-release sedative for freshwater finfish. Because of its investigational status, data are needed to characterize the depletion, distribution, and identity of AQUI-S® 20E residues in fillet tissue. Rainbow trout (Oncorhynchus mykiss) were exposed to uniformly ring labeled 14C-eugenol at a nominal concentration of 10 mg/L for 60 min in 18 °C water. Fish (n = 6) were sampled immediately after the exposure (0 min) then at 30, 60, 120, and 240 min. Eugenol concentrations and characterization of 14C residues in the fillet tissue were determined by high pressure liquid chromatography and flow-through liquid scintillation counting techniques. Total 14C-residue burdens in fillet tissue were determined by tissue oxidation and static liquid scintillation counting techniques. Maximum eugenol and 14C-eugenol equivalent residue concentrations in the fillet tissue were measured immediately after the exposure (44.5 and 38.8 μg/g, respectively). Eugenol was the primary 14C-residue (> 90% of all 14C-residues) in extracts from fillet tissue taken from fish sampled immediately after the exposure (0 min) and from fish sampled at 30 and 60 min after the exposure. The depletion of 14C-eugenol residues from the fillet tissue was rapid (t1/2 = 26.25 min) after transferring the exposed fish to fresh flowing water.

  11. Comparison of the efficacy of biodegradable and non-biodegradable scintillation liquids on the counting of tritium- and [14C]-labeled compounds

    Medeiros R.B.

    2003-01-01

    Full Text Available The widespread use of ³H and 14C in research has generated a large volume of waste mixed with scintillation liquid, requiring an effective control and appropriate storage of liquid radioactive waste. In the present study, we compared the efficacy of three commercially available scintillation liquids, Optiphase HiSafe 3, Ultima-Gold(TM AB (biodegradable and Insta-Gel-XF (non-biodegradable, in terms of [14C]-glucose and [³H]-thymidine counting efficiency. We also analyzed the effect of the relative amount of water (1.6 to 50%, radioisotope concentration (0.1 to 100 nCi/ml, pH (2 to 10 and color of the solutions (samples containing 0.1 to 1.0 mg/ml of Trypan blue on the counting efficiency in the presence of these scintillation liquids. There were few significant differences in the efficiency of 14C and ³H counting obtained with biodegradable or non-biodegradable scintillation liquids. However, there was an 83 and 94% reduction in the efficiency of 14C and ³H counting, respectively, in samples colored with 1 mg/ml Trypan blue, but not with 0.1 mg/ml, independent of the scintillation liquid used. Considering the low cost of biodegradable scintillation cocktails and their efficacy, these results show that traditional hazardous scintillation fluids may be replaced with the new safe biodegradable fluids without impairment of ³H and 14C counting efficiency. The use of biodegradable scintillation cocktails minimizes both human and environmental exposure to hazardous solvents. In addition, some biodegradable scintillation liquids can be 40% less expensive than the traditional hazardous cocktails.

  12. Shake-flask test for determination of biodegradation rates of 14C-labelled chemicals at low concentrations in surface water systems

    Ingerslev, F.; Nyholm, Niels

    2000-01-01

    A simple shake-flask surface water biodegradability die away test with C-14-labeled chemicals added to microgram per liter concentrations (usually 1-100 mu g/L) is described and evaluated. The aim was to provide information on biodegradation behavior and kinetic rates at environmental (low......) concentrations in surface water systems. The basic principle of measurement was to determine evolved CO2 indirectly from measurements of total organic activity in subsamples after stripping off their content of CO2, Used with surface water alone the test simulates a pelagic environment and amended with sediments...... regular reinoculation with freshly collected surface water could, however, overcome the problems of false-negative results. (C) 2000 Academic Press....

  13. Therapeutic ultrasound

    Crum, Lawrence A [Center for Industrial and Medical Ultrasound, 1013 NE 40th Street, University of Washington, Seattle, WA 98105 (United States)

    2004-01-01

    The use of ultrasound in medicine is now quite commonplace, especially with the recent introduction of small, portable and relatively inexpensive, hand-held diagnostic imaging devices. Moreover, ultrasound has expanded beyond the imaging realm, with methods and applications extending to novel therapeutic and surgical uses. These applications broadly include: tissue ablation, acoustocautery, lipoplasty, site-specific and ultrasound mediated drug activity, extracorporeal lithotripsy, and the enhancement of natural physiological functions such as wound healing and tissue regeneration. A particularly attractive aspect of this technology is that diagnostic and therapeutic systems can be combined to produce totally non-invasive, imageguided therapy. This general lecture will review a number of these exciting new applications of ultrasound and address some of the basic scientific questions and future challenges in developing these methods and technologies for general use in our society. We shall particularly emphasize the use of High Intensity Focused Ultrasound (HIFU) in the treatment of benign and malignant tumors as well as the introduction of acoustic hemostasis, especially in organs which are difficult to treat using conventional medical and surgical techniques. (amum lecture)

  14. Therapeutic efficiency of synthokine SC-55494, a human IL-3 receptor agonist, in a nonhuman primate model of HIGH dose, sublethal, radiation-induced marrow aplasia; Efficacite therapeutique d`un variant d`interleukine-3 chez des macaques irradies

    Herodin, F.; Farese, A.; Grab, L.; McKearn, J.P.; Mestries, J.C.; McVittie, T.J.

    1994-12-31

    The synthetic cytokine (Synthokine) SC-55494 is a high affinity IL-3 receptor ligand. The therapeutic administration of Synthokine to total body irradiated (TBI) monkeys (7 Gy gamma) from day 1 post TBI for 23 days, significantly enhanced platelet recovery and modulated aneutrophil nadir. (author). 6 refs.

  15. Therapeutic drug monitoring of aminoglycosides in neonates

    Touw, Daniël J; Westerman, Elsbeth M; Sprij, Arwen J

    2009-01-01

    The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to extended-in

  16. Effect of therapeutic ultrasound on endochondral ossification

    Wiltink, A.; Nijweide, P.J.; Oosterbaan, W.A.; Hekkenberg, R.T.; Helders, P.J.M.

    1995-01-01

    The effect of therapeutic doses of ultrasound was tested on endochondral ossification of in vitro developing metatarsal long bone rudiments of 16- and 17-day-old fetal mice. Bone growth, calcification and resorption following exposure to several doses of pulse-wave (PW) or continuous-wave (CW) ultra

  17. Simplified Warfarin Dose-response Pharmacodynamic Models

    Kim, Seongho; Gaweda, Adam E.; Wu, Dongfeng; Li, Lang; Shesh N Rai; Brier, Michael E.

    2015-01-01

    Warfarin is a frequently used oral anticoagulant for long-term prevention and treatment of thromboembolic events. Due to its narrow therapeutic range and large inter-individual dose-response variability, it is highly desirable to personalize warfarin dosing. However, the complexity of the conventional kinetic-pharmacodynamic (K-PD) models hampers the development of the personalized dose management. To avert this challenge, we propose simplified PD models for warfarin dose-response relationshi...

  18. Derivation of Human Lethal Doses

    2006-01-19

    Hardman, JG; Limbird, LE; Goodman Gilman , A, (editors). (2001) Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, NY: McGraw... Goodman and Gilman’s N/A No LDLo, MLD, or lethal dose for humans; no LD50 for rat or mouse NIOSH N/A No LDLo, MLD, or lethal dose for humans; no LD50...Basis of Therapeutics– Goodman and Gilman’s N/A No LDLo, MLD, or lethal dose for humans; no LD50 for rat or mouse NIOSH N/A No LDLo, MLD, or lethal

  19. Effect observation and mechanism of low - dose decitabine combined with modified CAG therapeutic regimen in the treatment of patients with myelodysplastic syndrome(MDS)%低剂量地西他滨序贯改良 CAG 方案对治疗骨髓增生异常综合征的临床疗效观察

    陈喜填; 夏维林; 林东; 王楚林; 张淳嘉; 吴桂香

    2016-01-01

    目的:探究低剂量地西他滨序贯改良 CAG 方案对治疗中高危骨髓增生异常综合征(Myelodysplastic syn-drome,MDS)的临床疗效。方法:随机抽取收治的中高危 MDS 患者96例,分为观察组46例及对照组患者50例,其中观察组患者采用低剂量地西他滨序贯 CAG 方案进行治疗,而对照组患者均采用 CAG 方案进行治疗,观察两组患者的临床疗效、不良反应的发生情况及处理结果。结果:观察组比对照组患者的疾病缓解率更高、疗效更显著,且两组比较差异具有统计学意义(P ﹤0.05)。结论:低剂量地西他滨序贯改良 CAG 方案治疗高危 MDS 比单用 CAG 方案疗效更明显、确切。%Objective The objection of the study was to investigate the clinical efficiencies and adverse reactions of treating the myelodysplastic syndrome(MDS)by using low - does decitabine combined with modified CAG therapeutic regimen. Method 96 high - risk MDS patients were randomly selected,they were divided into observation group with 46 cases and control group with 50 cases. The observation group was treated with low - dose decitabine combined with modified CAG therapeutic regimen, while the control group was treated with CAG therapeutic regimen. Clinical efficacy,adverse reactions and treatment results of each group were observed and analyzed. Results The remission rate was higher and the curative effect was more significant of ob-servation group when compared with control group,the difference between two groups has statistical significance( P ﹤ 0. 05) . Conclusion The effect of high risk MDS in treatment with low dose of decitabine combined with modified CAG therapeutic regi-ment is more significance than treated with CAG therapeutic regimen.

  20. Therapeutic and recreational methadone cardiotoxicity.

    Lusetti, Monia; Licata, Manuela; Silingardi, Enrico; Reggiani Bonetti, Luca; Palmiere, Cristian

    2016-04-01

    Several classes of drugs have been associated with an increased risk of cardiovascular disease and occurrence of arrhythmias potentially involved in sudden deaths in chronic users even at therapeutic doses. The study presented herein focuses on pathological changes involving the heart possibly due to methadone use. 60 cases were included in the study in total and were divided into three groups (therapeutic methadone users: 20 cases, recreational methadone users: 20 cases, and sudden death group in subjects who had never taken methadone: 20 cases). Autopsies, histology, biochemistry and toxicology were performed in all cases. Macroscopic and microscopic investigation results in therapeutic methadone users were similar to those observed in sudden, unexpected deaths in non-methadone users. In recreational methadone consumers, macroscopic and microscopic examination of the heart failed to provide results consistent with acute or chronic myocardial or coronary damage, thereby corroborating the hypothesis of death most likely following respiratory depression.

  1. Utilización del citrato de fentanilo oral transmucosa como rescate terapéutico en pacientes con altas dosis de opioides Use of oral transmucosal fentanyl citrate for therapeutic rescue in patients receiving high doses of opiates

    J. Cevas

    2005-07-01

    crisis de DI en pacientes oncológicos que tienen controlado su dolor basal con dosis altas de opioides. Las dosis de CFOT pueden considerarase como bajas en relación a las utilizadas para su dolor basal. Su administración y titulación es sencilla, aunque el paciente requiere de una educación previa a su uso.The management of breakthrough pain in cancer patients treated with high doses of opiates raises particular problems, such as the election of the drug to be used, the appropriate dosage and the route of administration. No clear guidelines on this issue are found in the medical literature, so each service decides its own particular way of acting. In this paper we review the cases dealt with over a one-year period in terms of the use of high doses of opiates in cancer patients taken care of in 2003 and treated with opiates. Objectives: -To study the group of patients treated with high doses of opiates. -To use OTFC as rescue drug for breakthrough pain events. -To analyze side and toxic effects. -To determine the preferences of the patients. Material and methods: A population of 280 patients with advanced cancer, 25 of which were receiving high doses of opiates. In these patients, breakthrough pain crises were managed with OTFC, starting with 400 micrograms. The satisfaction questionnaire proposed by Kornick was used. Results: -Easy adherence to treatment. -Average effective dose of OTFC: 600 micrograms, median of 627. -Dose titration on the second day. -Seventeen patients preferred OTFC, 6 preferred oral morphine and 2 were indifferent. Conclusions: Easy use of OTFC for the management of breakthrough pain, requiring low doses compared to the total daily dose of the patient. Patient education is required before its administration.

  2. Study of Therapeutic Dose Change of Thyroid Hormones of Patients with Hypothyroidism during Pregnancy%甲状腺功能减退患者妊娠期间甲状腺激素治疗剂量的变化研究

    张英霞

    2013-01-01

    目的:探讨妊娠期间甲状腺功能减退患者的甲状腺激素治疗剂量的调整规律。方法:选择于我院接受治疗的甲状腺功能减退的患者作为研究对象,将处于妊娠期间的患者作为实验组,非妊娠期间的患者作为对照组,收集两组患者的临床资料,比较两组患者甲状腺激素治疗的变化规律,并统计实验组患者在妊娠期间较妊娠期前后的甲状腺激素使用剂量变化百分比的变化。结果:实验组的患者在妊娠期间甲状腺激素的使用量显著高于对照组,其差异具有统计学意义(P<0.05);实验组患者妊娠期间甲状腺激素的使用量显著高于妊娠前及分娩后,差异具有差异。结论:甲状腺功能减退患者妊娠期间需加大甲状腺激素的治疗量,分娩后期所需量有所下降。%Objective: To discuss the regulation law of therapeutic dose change of thyroid hormones of patients with hypothyroidism during pregnancy. Method:Patients with hypothyroidism were chosen as study objects. Patients during pregnancy were marked as experiment group and patients not during pregnancy were marked as control group. Clinical data of the 2 groups were col ected. Change laws of thyroid hormones treatment of the 2 groups were compared. The percentage changes of therapeutic dose of thyroid hormones of patients with hypothyroidism during pregnancy to before and after pregnancy were counted. Result: Usage amount of thyroid hormone of experiment group during pregnancy was obviously bigger than control group and than before and after pregnancy (P<0.05). Conclusion: Patients with hypothyroidism during pregnancy should increase therapeutic dose of thyroid hormone and decrease after pregnancy.

  3. Cancer patients requiring interruption of long-term warfarin because of surgery or chemotherapy induced thrombocytopenia: the use of fixed sub-therapeutic doses of low-molecular weight heparin.

    Saccullo, Giorgia; Malato, Alessandra; Raso, Simona; Santoro, Marco; Zammit, Valentina; Casuccio, Alessandra; Siragusa, Sergio

    2012-04-01

    No data are available regarding the management of cancer patients requiring interruption of long-term vitamin-K antagonist (VKA) therapy. For this purpose, we tested the efficacy and safety of fixed doses of low-molecular weight heparin (LMWH) in substitution of VKA because of invasive procedures or chemotherapy-induced thrombocytopenia. In cancer patients on VKA, therapy was discontinued 5 ± 1 days before surgery or chemotherapy. Heparin was given at prophylactic dosage in patients at low risk and at fixed subtherapeutic doses (3,800 or 4,000 UI anti-FXa, b.i.d.) in those at high-risk for thrombosis. LMWH was reinitiated 12 hr after surgery and VKA the day after. In patients receiving chemotherapy, LMWH was reinitiated 12/24 hr after obtaining a stable platelet count ≥ 30,000 mmc(3) and VKA after a stable platelet count ≥ 50,000 mmc(3) . Thromboembolism and major bleeding events were recorded from the time of VKA suspension to 30 ± 2 days postprocedure or until the next chemotherapy. Overall, 156 patients (56.4% at low risk and 43.5% at high risk for thrombosis) were enrolled; 34.6% underwent major surgery, 40.4% nonmajor surgery, and 25% chemotherapy. Thrombotic events occurred in five patients [3.2%, 95% confidence interval (CI): 1.41-7.27], four belonging to the high-risk and one to the low-risk group. Major bleeding occurred in five patients (3.2%, 95 CI: 1.41-7.27), all belonging to the high-risk group (three during major surgery and two during chemotherapy). In conclusion, LMWH given at fixed subtherapeutic is a feasible and relatively safe approach for bridging therapy in cancer patients on long-term VKA.

  4. Therapeutical aspect of trichomoniasis

    Vukićević Jelica

    2003-01-01

    Full Text Available Trichomoniasis is frequent, parasitic and sexually transmitted infection of genitourinary tract. It is treated by metronidazole (5-nitroimidazole according to protocol recommended by Center for Disease Control (CDC formerly called: Communicable Disease Center [19]. The resistance of Trichomonas vaginalis (TV strains to metronidazole (MND was described in USA in 1960, and later on in many European countries [8, 9, 10, 11, 12, 13]. In these cases, due to persistent trichomonas infection, it is necessary to repeat MND treatment with moderate modification of dose and/or length of its application. Nevertheless, oncogenic and toxic effects of MND have to be taken into consideration. OBJECT The aim of this study was to investigate and analyze the incidence of TV in STD and lower susceptibility of certain TV strains to MND were analyzed. MATERIAL AND METHODS In three-year period (1999-2001 612 patients (244 females and 368 males suspected of STD were examined clinically and microbiologically at the Institute of Dermatovenereology in Belgrade. The patients detected for TV were treated according to CDC protocol. The affected were considered cured if there was no manifest clinical infection, and no TV verified by microbiological test. Results TV was isolated in 216 patients (35.29 % of all subjects. Trichomonas infection was found in 90 (36.88 % out of 244 tested females and in 126 (32.34 % of 368 males. Clinically manifested infection, with extensive urethral and vaginal secretion, was recorded in 161 patients, while the asymptomatic form was found in 55 subjects. This result indicates the predominance of manifested trichomonas infections (75.54 % of cases. The difference of distribution of clinical forms of trichomoniasis, in relation to sex, was not statistically significant (c2=0.854; p>0.05. The patients with verified trichomonas infection were treated by metronidazole according to CDC protocol. The recommended therapeutical scheme consisted of three

  5. DALI: Defining Antibiotic Levels in Intensive care unit patients: a multi-centre point of prevalence study to determine whether contemporary antibiotic dosing for critically ill patients is therapeutic

    Roberts Jason A

    2012-07-01

    Full Text Available Abstract Background The clinical effects of varying pharmacokinetic exposures of antibiotics (antibacterials and antifungals on outcome in infected critically ill patients are poorly described. A large-scale multi-centre study (DALI Study is currently underway describing the clinical outcomes of patients achieving pre-defined antibiotic exposures. This report describes the protocol. Methods DALI will recruit over 500 patients administered a wide range of either beta-lactam or glycopeptide antibiotics or triazole or echinocandin antifungals in a pharmacokinetic point-prevalence study. It is anticipated that over 60 European intensive care units (ICUs will participate. The primary aim will be to determine whether contemporary antibiotic dosing for critically ill patients achieves plasma concentrations associated with maximal activity. Secondary aims will compare antibiotic pharmacokinetic exposures with patient outcome and will describe the population pharmacokinetics of the antibiotics included. Various subgroup analyses will be conducted to determine patient groups that may be at risk of very low or very high concentrations of antibiotics. Discussion The DALI study should inform clinicians of the potential clinical advantages of achieving certain antibiotic pharmacokinetic exposures in infected critically ill patients.

  6. Therapeutic trial of intensified conditioning regimen with high-dose cytosine arabinoside, cyclophosphamide and either total body irradiation or busulfan followed by allogeneic bone marrow transplantation for myelodysplastic syndrome in children

    Nagatoshi, Yoshihisa; Okamura, Jun; Ikuno, Yoshiko; Akamatsu, Minoru; Tasaka, Hideko [National Kyushu Cancer Center, Fukuoka (Japan)

    1997-04-01

    Ten children with myelodysplastic syndrome underwent an allogeneic bone marrow transplantation (BMT) with an intensified conditioning regimen. The median age of the patients was 8 years (range 2-10), and included 6 males and 4 females. The subtype of the disease was refractory anemia (RA) in 4, RA with excess blasts (RAEB) in 4, RAEB in transformation (RAEB-T) in 1, and juvenile chronic myelogenous leukemia (JCML) in 1. All patients were conditioned with high-dose cytosine arabinoside (12000 mg/m{sup 2}), cyclophosphamide (120 mg/kg) and either total body irradiation (10-13.2 Gy) or busulfan (16 mg/kg or 560 mg/m{sup 2}). Cyclosporine A and/or methotrexate were used for the prophylaxis of graft-versus-host disease (GVHD). Engraftment was prompt in all but one patient. Severe acute GVHD (grade 3) (n=1), interstitial pneumonitis (n=1) and veno-occlusive disease of the liver (n=1) occurred. The disease relapsed in one patient with RAEB-T. Seven of the 10 patients were alive and disease free 2-74 months after BMT. The disease-free survival rate at 4 years was 69{+-}15%. All surviving patients were in the full performance status. The examined children with MDS tolerated this intensified conditioning regimen well. (author)

  7. 小剂量强力霉素联合甲硝唑凝胶治疗酒渣鼻疗效观察%The Therapeutic Effect of Small Doses Doxycycline Combine Metronidazole Gel for Rosacea

    郝江华; 郗宁; 唐晓琳

    2012-01-01

    Objective To observe the clinical efficacy and safety of small doses doxycycline combined with topical metronidazole gel in the treatment of rosacea. Methods Ninety cases of rosacea were divided randomly into three groups,the treatment group(n=30) were given doxycycline 20mg orally plus 0.75% metronidazole gel topically twice a day. The control group 1 (n=30)only orally took doxycycline 20mg two times per day,and the control group 2 (n=30)only applied 0.75% metronidazole gel twice a day. All groups had been given four-week courses. Results Total efficiency in the treatment group was 96.55%, which was better than that of control group 1 (75.00%)and the control group 2(76.67%) (P 0.05). Mild local desiccation occured equally in both the treatment group and the control group 2, adverse reaction rate were 10.34% in the treatment group and 13.33% in the control group 2. Adverse reaction was not be founded in the control group 1. Conclusion The combination therapy of small doses of doxycycline and topical metronidazole gel is safe and effective in the treatment of rosacea.%目的 观察小剂量强力霉素联合甲硝唑凝胶治疗酒渣鼻的临床疗效和安全性.方法 将入选的90例酒渣鼻患者随机分成3组,各30例,治疗组口服强力霉素20mg,同时外搽0.75%甲硝唑凝胶,均2次/d;对照1组仅口服强力霉素,对照2组仅外用0.75%甲硝唑凝胶,用法同治疗组,均4周为1个疗程,共治疗3个疗程.每个疗程结束后分别观察疗效.结果 治疗组有效率(96.55%)明显优于对照1组(75.00%)和对照2组(76.67%),差异均有统计学意义(P均<0.05),而对照1组有效率和对照2组比较差异无统计学意义(P>0.05).治疗组不良反应发生率为10.34%、对照2组为13.33%,该两组均表现为用药局部皮肤轻度干燥,对照1组未见不良反应.结论 小剂量强力霉素联合甲硝唑凝胶外搽治疗酒渣鼻疗效肯定,安全性好.

  8. 大剂量rhG-CSF早期单次给药对60Coγ射线照射小鼠的治疗作用%Therapeutic effects of early administration of a single high dose of rhG-CSF on mice irradiated by 60Coγ rays

    韩阿如娜; 余祖胤; 柳晓兰; 从玉文

    2011-01-01

    Objective To observe the therapeutic effects of early administration with a single high dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on mice irradiated with 60Co γ rays, and provide a reference for the treatment of acute radiation syndrome (ARS) by using cytokines. Methods Male C57 mice underwent a total body irradiation of 8. Ogy 60Co y ray, and they were treated with rhG-CSF, at 0.5h and 24h, subcutaneously in a dose of 2, 1 and 0. 5mg/kg, respectively. The 30-day survival rate and mean survival time were observed in the lethal irradiated mice. The peripheral blood cell counts and bone marrow nucleated cell counts were evaluated in the sublethally irradiated mice. Results Early administration of a high dose of rhG-CSF significantly increased 30-day survival rate and prolonged mean survival time of mice with lethal irradiation dose. A single injection of rhG-CSF (lmg/kg) at 0. 5h after irradiation was an optimal administration schedule. In addition, early administration with a single high dose of rhG-CSF improved the recovery of bone marrow nucleated cell counts and peripheral blood counts, including white blood cell (WBC), red blood cell (RBC) and platelet in mice exposed to 6. Ogy irradiation. Conclusion Early administration of a single high dose rhG-CSF may have a favorable therapeutic effect on mice irradiated with 60Co y ray.%目的 观察大剂量rhG-CSF早期单次给药对60Coγ射线照射小鼠的治疗作用,为细胞因子治疗急性放射病提供实验依据.方法 雄性C57小鼠,经8.0Gy 60Co γ射线全身照射后于0.5、24h各皮下注射一次不同剂量rhG-CSF(2、1mg/kg和0.5mg/kg),观察致死剂量照射小鼠的30d存活率及平均生存时间.小鼠经6.0Gy 60Co γ射线全身照射后,通过不同给药方案及不同剂量rhG-CSF早期干预,观察亚致死剂量照射小鼠的外周血象和骨髓有核细胞数的变化.结果 大剂量rhG-CSF早期干预明显提高致死剂量照射小鼠的30d存

  9. [Therapeutic drug monitoring of stiripentol].

    Verdier, Marie-Clémence; Tribut, Olivier; Bentué-Ferrer, Danièle

    2012-01-01

    Stiripentol is a third generation antiepileptic, marketed since 2007 under the name of Diacomit(®). It is indicated, always in combination, in the treatment of severe myoclonic epilepsy in infancy or Dravet syndrome. Its pharmacokinetics is not linear. It is a potent inhibitor of CYP3A4, 1A2 and 2C19 and increases the plasma concentrations of many other antiepileptic drugs. Without this being considered as a validated therapeutic range, the trough plasma concentrations at steady-state, corresponding to the usual doses are between 10 and 15 mg/L. The concentration-efficacy relationship is not established, but there is some evidence for a concentration-related toxicity. However, because of its non-linear kinetics, stiripentol should be a good candidate for therapeutic drug monitoring (TDM). Nonetheless, the current level of evidence for the advantage of TDM is "remains to be estimated".

  10. [Therapeutic drug monitoring of rufinamide].

    Bentué-Ferrer, Danièle; Tribut, Olivier; Verdier, Marie-Clémence

    2012-01-01

    Rufinamide is a third-generation antiepileptic drug, available since early 2010 in France. It is indicated in combination therapy in the Lennox-Gastaut syndrome from the age of 4. It has orphan drug status. The bioavailability of rufinamide is high, but decreases with the dose and increases with food intake. Rufinamide is not metabolized by cytochromes but hydrolyzed by a carboxylesterase in an inactive carboxylic derivative. Elimination is mainly renal. The half-life varies from 6 to 10h. Although established from relatively few studies, exposure efficacy and exposure toxicity relationships are argued. A plasma concentration of 15 mg/L, obtained with a standard regimen, reduces the number of seizures of 25%. Few factors of intrinsic variability are described. There are few clinically significant pharmacokinetic interactions and they concern combinations with other antiepileptic drugs, especially valproate. Although there is no validated therapeutic range, the level of evidence for this therapeutic drug monitoring has been estimated at "possibly useful".

  11. Therapeutic value of low dose L-thyroxine on patients with dialated cardiomyopathy and refractory heart failure%小剂量左旋甲状腺素治疗扩张性心肌病伴甲状腺功能正常的病态综合征疗效观察

    高红梅; 徐大文; 田巨龙; 兰建军; 周娟; 钱昌明; 唐永江; 曾晓斌; 徐颖

    2011-01-01

    目的 探讨小剂量左旋甲状腺辅助治疗扩张性心肌病合并顽固性心力衰竭的疗效及可能作用机制.方法 入选因扩张性心肌病难治性心力衰竭同时合并有甲状腺功能正常的病态综合征在本院心内科住院的患者共110例,随机分为小剂量左旋甲状腺治疗组及常规治疗组各55例,比较两组治疗效果.结果 两组心率均较治疗前减慢,治疗组减 慢更明显,较对照组减慢5次以上,差异有统计学意义;饮食、精神、6min步行距离,治疗组均较对照组改善明显、迅速:住院时间明显缩短,差异有统计学意义;12周时,左室射血分数治疗组较对照组改善明显,差异有统计学意义;28周时,左室射学分数和左室大小,治疗组较对照组均改善明显,差异有统计学意义.结论 小剂量左旋甲状腺素治疗扩张性心肌病伴甲状腺功能正常的病态综合征有效.%Objective To study the clinical therapeutic effect and mechanisms of low dose L-thyroxine on dialated cardiomyopathy accompanied by refractory heart failure. Methods llOpatients of dialated cardiomyopathy accompanied by refractory heart failure and thyroxine euthyroid sick syndromewere randomly divided into two groups, low dose L-thyroxine treated group ( 55patients) and generally treatment group( 55patients) . The treatment group used low compare the therapeutic effect . Results Heart rates decline significantly in two groups at the end of the study. Therapy groups, more obvious slow down the five above statistics, there are differences in meaning. Diet、 spirit and 6MWT improved greatly and rapidly in the low dose L-thyroxine treated group ,the duration of hospitalization were shortened significantly in the low dose L-thyroxine treated group, there are differences in meaning. LV ejection fraction( LVEF) improved significantly in two group s at the end of 12 weeks study. The treatment group improved much more( P < 0. 05) . LV ejection fraction( LVEF) and

  12. Use of microdosing and accelerator mass spectrometry to evaluate the pharmacokinetic linearity of a novel tricyclic GyrB/ParE inhibitor in rats.

    Malfatti, Michael A; Lao, Victoria; Ramos, Courtney L; Ong, Voon S; Turteltaub, Kenneth W

    2014-11-01

    Determining the pharmacokinetics (PKs) of drug candidates is essential for understanding their biological fate. The ability to obtain human PK information early in the drug development process can help determine if future development is warranted. Microdosing was developed to assess human PKs, at ultra-low doses, early in the drug development process. Microdosing has also been used in animals to confirm PK linearity across subpharmacological and pharmacological dose ranges. The current study assessed the PKs of a novel antimicrobial preclinical drug candidate (GP-4) in rats as a step toward human microdosing studies. Dose proportionality was determined at 3 proposed therapeutic doses (3, 10, and 30 mg/kg of body weight), and PK linearity between a microdose and a pharmacological dose was assessed in Sprague-Dawley rats. Plasma PKs over the 3 pharmacological doses were proportional. Over the 10-fold dose range, the maximum concentration in plasma and area under the curve (AUC) increased 9.5- and 15.8-fold, respectively. PKs from rats dosed with a (14)C-labeled microdose versus a (14)C-labeled pharmacological dose displayed dose linearity. In the animals receiving a microdose and the therapeutically dosed animals, the AUCs from time zero to infinity were 2.6 ng · h/ml and 1,336 ng · h/ml, respectively, and the terminal half-lives were 5.6 h and 1.4 h, respectively. When the AUC values were normalized to a dose of 1.0 mg/kg, the AUC values were 277.5 ng · h/ml for the microdose and 418.2 ng · h/ml for the pharmacological dose. This 1.5-fold difference in AUC following a 300-fold difference in dose is considered linear across the dose range. On the basis of the results, the PKs from the microdosed animals were considered to be predictive of the PKs from the therapeutically dosed animals.

  13. 治疗剂量下4种抗结核药物与Caco-2细胞上P-gp相互作用研究%Initial Study on Interaction between Therapeutic Doses of Four Anti-Tuberculosis Drugs and P-Glycoprotein in Caco-2 Cells

    方平飞; 高维; 李焕德; 刘艺平

    2011-01-01

    therapeutic doses of isoniazid and ethambutol decreased the accumulation of rhodamine123 in Caco-2 cells significantly compared with that of negative control group ( P < 0. 05). The therapeutic doses of isoniazid and ethambutol both up-regulated the cellular P-glycoprotein protein and MDR1 mRNA expression levels ( P <0. 05 ). Compared with the controls, the total quantity of P-glycoprotein were 3. 5 and 3.8 folds higher than that of controls, and the total levels of MDR1 mRNA expression were 11.5 and 11 folds higher than that of controls, respectively. Therapeutic doses of levofloxacin increased the accumulation of rhodamine123 in Caco-2 cells significantly higher than that of negative control group ( P < 0. 05 ). The therapeutic doses of levofloxacin down-regulated the cellular P-glycoprotein protein and MDR1 mRNA expression levels (P <0. 05 ). Compared with the controls, the total levels of P-glycoprotein and MDR1 mRNA expression were 50% and 32% of controls, respectively. Pyrazinamide showed no significant interaction with P-glycoprotein. CONCLUSION Therapeutic doses of isoniazid and ethambutol might be inducer of P-glycoprotein, levofloxacin might be inhibitors of pglycoprotein, and pyrazinamide showed no significant interaction with P-glycoprotein.

  14. Utilização da fenilefrina para controle da pressão arterial em cesarianas eletivas: dose terapêutica versus profilática Utilización de la fenilefrina para el control de la presión arterial en cesáreas electivas: dosis terapéutica versus profiláctica Phenylephrine for blood pressure control in elective cesarean section: therapeutic versus prophylactic doses

    José Francisco Nunes Pereira das Neves

    2010-08-01

    administración de fenilefrina. En el Grupo 1, se administró fenilefrina en infusión continua, con bomba de infusión en dosis de 0,15 µg.Kg-1.min-1 después de la raquianestesia. En el Grupo 2, fue administrada fenilefrina en dosis única, de forma profiláctica, en dosis de 50 µg después de la raquianestesia, y en el Grupo 3, fenilefrina en dosis única de 50 µg en el caso de hipotensión arterial definida como una caída de la PAS y/o PAD en hasta un 20% con relación al promedio de los valores basales. Se evaluó la incidencia de hipotensión arterial, náuseas, vómitos y el índice de Apgar. RESULTADOS: La incidencia de hipotensión arterial fue significativamente más elevada en el Grupo 3, acaeciendo en un 85% de las embarazadas. En los Grupos 1 y 2, ocurrió en un 17,5% y 32,5% de los casos respectivamente (p BACKGROUND AND OBJECTIVES: Spinal block is commonly used in cesarean sections and, if some prophylactic measures are not taken, the incidence of hypotension is higher than 80%. The objective of this study was to compare the efficacy of the administration of therapeutic or prophylactic doses of phenylephrine to maintain blood pressure in patients undergoing spinal block for elective cesarean section. METHODS: One hundred and twenty gravidas undergoing elective cesarean sections under spinal block, randomly divided in three equal groups according to the regimen of phenylephrine administered, were included in this study. In Group 1, continuous infusion of phenylephrine, using an infusion pump at 0.15 µg.kg-1.min-1 was administered after the spinal block. In Group 2, a single dose of prophylactic phenylephrine 50 µg was administered after the spinal block, and Group 3 received a single dose of phenylephrine 50 µg in case of hypotension, which was defined as a drop in SBP and/or DBP of up to 20% of baseline levels. The incidence of hypotension, nausea, and vomiting as well as the Apgar score were evaluated. RESULTS: The incidence of hypotension was

  15. Pharmacogenomic dosing of warfarin: ready or not?

    Lackner, Thomas E

    2008-08-01

    Warfarin is a medication with a narrow therapeutic index, nonlinear intrapatient pharmacokinetics, and high interpatient variability in its dose-response relationship. These characteristics create great difficulty in determining an appropriate dose; sub- or supratherapeutic doses can increase the risk of bleeding and venous thromboembolism complications. Algorithms based on nongenetic factors of patient age, gender, body weight, diseases, diet, smoking, and medication traditionally have been used to determine warfarin dose requirements. However, these formulas account for less than 20% of the variability in warfarin response. Following completion of the Human Genome Project, several genetic variants of CYP2C9 and VKORC1 have been identified that account for a greater proportion of the variability in patient response to warfarin than is explained by nongenetic factors. Moreover, algorithms that analyze both patient genetic and nongenetic factors, i.e., pharmacogenomics, in warfarin response account for 55% to 60% of the variability. This raises the prospect of enhancing the ability to predict warfarin dose requirements and, thereby, improving its safety, effectiveness, and therapy efficiency. This review evaluates the impact of combining genetic and nongenetic factors in accounting for the variability in warfarin response and the prospect that pharmacogenomic algorithms will improve warfarin dosing early in therapy, possibly achieving a more rapid attainment of the therapeutic dose, improving safety, and increasing effectiveness. The most comprehensive and widely available pharmacogenomic algorithms for estimating warfarin dose requirements when initiating therapy, www.WarfarinDosing.org, is reviewed.

  16. Dose Adjustment- An Important Issue in Critical Care

    Dr. M. C. Joshi

    2006-01-01

    Full Text Available There is at times marked variability in drug responsiveness especially in critically ill patients admitted in the Intensive care units. In order to obtain therapeutic effectiveness with in pharmacokinetic parameters related to therapeutic dose, it is always desirable to monitor and to maintain drug dose adjustment in such a way especially in presence of organ failure like renal failure, hepatic failure or any other clinical situation necessitating Therapeutic Drug Monitoring (TDM so that one can use safe and effective drug therapy with least toxicity due to inaccurate and invalid drug doses.

  17. Crystalline dose of interventional radiologists; Dosis en cristalino de radiologicos intervencionistas

    Hernandez Concepcion, E.; Diaz Romero, F.; Catalan Acosta, A.; Hernandez Armas, J.

    2013-07-01

    The measured dose area product in radiology equipment used in angio radiology during different diagnostic and therapeutic can be used to estimate the value of the dose in the lens of doctors or medical personnel carrying out such interventions. (Author)

  18. Therapeutic effect of different dosing regimens of rmlL-12 on acute radiation sickness in mice%白介素12不同给药方案对急性放射病小鼠的治疗作用

    王利; 王松雷; 曹务锐; 耿斌; 翟瑞仁; 逄朝霞; 张超; 余长林

    2013-01-01

    Objective: To study the therapeutic effect of different dosing regimens of recombinant murine interleu-kin 12(rmIL - 12) on the mice irradiated by γ -rays. Methods: Forty -two BALB/c mice were given 6.0Gy 60Co γ - rays total body irradiation and randomly assigned into irradiation control group,rmIL - 12 one dose and five doses treatment group. 20μg/kg of rmIL - 12 was administrated intraperitoneally 1 hour following irradiation in one dose treatment group, and was administrated every 3 days after irradiation for four times additionally in five doses treatment group. The general conditions of mice were observed twice a day, the changes in body weight, peripheral blood cell counts were examined once every three days, bone marrow cells were collected to perform colony cultivation on the 14th and 28th day after irradiation. Results: The general conditions of mice in rmIL - 12 treatment group were better than those of irradiation control group. The decline speed of platelet in rmIL - 12 one and five doses treatment group was significantly slower than that of control group. rmIL - 12 treatment significantly promoted platelet recovery, resulting in less profound nadirs(18.9% vs 8. 1% ,22.5% vs 8. 1% ,P0. 05). The white blood cell recovery speed in two treatment groups was faster than that of the irradiation control group(P<0.05) ,but there was no significant difference between two treatment groups. Semi - solid bone marrow cell culture also demonstrated that rmIL - 12 could stimulate bone marrow cells to form more CFU - Mix than those of the irradiation control group on 14th after irradiation(P <0. 01) ,and there were more CFU - GM and CFU - Mix in two rmIL - 12 treatment group than those of the irradiation control group on 28th after irradiation (P < 0.05, P< 0.01). Conclusion: 1 and 5 dosing regimens of rmIL - 12 can significantly accelerate the recovery of hematopoietic function , especially the recovery of megakaryocyte in acute radiation sickness mice.%目的:

  19. Dose-dependent galactorrhea with quetiapine

    Sethi, Sujata; Sharma, Manisha; Malik, Amit

    2010-01-01

    Quetiapine is an atypical antipsychotic agent with minimal propensity to induce hyperprolactinemia in standard therapeutic dosages. Despite that quetiapine is considered to be a prolactin-sparing atypical antipsychotic, hyperprolactinemia with related side effects may rarely be encountered in susceptible individuals. We report a case of quetiapine-induced hyperprolactinemia and galactorrhea in an adult female, which was dose-dependent.

  20. Methods of calculating radiation absorbed dose.

    Wegst, A V

    1987-01-01

    The new tumoricidal radioactive agents being developed will require a careful estimate of radiation absorbed tumor and critical organ dose for each patient. Clinical methods will need to be developed using standard imaging or counting instruments to determine cumulated organ activities with tracer amounts before the therapeutic administration of the material. Standard MIRD dosimetry methods can then be applied.

  1. Acoustic dose and acoustic dose-rate.

    Duck, Francis

    2009-10-01

    Acoustic dose is defined as the energy deposited by absorption of an acoustic wave per unit mass of the medium supporting the wave. Expressions for acoustic dose and acoustic dose-rate are given for plane-wave conditions, including temporal and frequency dependencies of energy deposition. The relationship between the acoustic dose-rate and the resulting temperature increase is explored, as is the relationship between acoustic dose-rate and radiation force. Energy transfer from the wave to the medium by means of acoustic cavitation is considered, and an approach is proposed in principle that could allow cavitation to be included within the proposed definitions of acoustic dose and acoustic dose-rate.

  2. Função renal de cães tratados com doses terapêuticas de flunixin meglumine e ketoprofen durante o trans e pós-operatório Renal function in dogs treated with therapeutic dosages of flunixin meglumine and ketoprofen during the trans and pos-operatory period

    Deila Schossler

    2001-03-01

    Full Text Available Baseando-se em relatos de casos de falência renal após a administração de flunixin meglumine em animais saudáveis, o presente trabalho foi desenvolvido visando avaliar a função renal através da medição sérica de uréia e creatinina de quatro grupos de cinco caninos submetidos a um procedimento cirúrgico, sendo os dois primeiros tratados com flunixin meglumine e os dois seguintes tratados com ketoprofen, ambos em doses terapêuticas. Os valores séricos de uréia e creatinina mantiveram-se dentro dos limites fisiológicos, permitindo concluir que não há lesão renal em consequência da utilização tanto no trans quanto no pós-operatório de animais clinicamente sadios.It has been reported in the literature several clinical cases of renal failure after the use of flunixin meglumine in normal healthy dogs. Based on these reports this study was developed to evaluate the renal function of normal healthy dogs. Blood urea nitrogen (BUN and serum creatinine were measured in four groups of 5 dogs submitted to a single surgical procedure. Two groups received flunixin meglumine and the other two ketoprofen, both in therapeutic dosages. The results showed values of BUN and serum creatinine within normal range for dogs. It is fair to conclude that flunixin meglumine and ketoprofen do not produce renal failure when administered during the peri-operative period in normal healthy dogs.

  3. Therapeutic clowning in paediatric practice.

    Finlay, Fiona; Baverstock, Anna; Lenton, Simon

    2014-10-01

    Over the past 30 years, there has been much research into the health benefits of humour and laughter. Although often viewed very positively, rigorous evaluation of the therapeutic effect of clowning is complex. Clowning is a multi-modal intervention, which may have an impact on medical conditions, procedures, family functioning and health care teams. Clowns help children to adapt to their hospital surroundings and can distract from, and demystify, painful or frightening procedures through 'doses of fun' to complement traditional clinical interventions. This paper provides a review of the paediatric literature and reveals studies looking at the effect of clown interventions on various practical procedures and individual medical conditions, and the effects of clowning within clinical teams.

  4. Therapeutic drug monitoring of amoxicillin and cloxacillin

    OTRIBUT; PTATTEVIN; MVERDIER; YLETULZO; CMICELET; HALLAIN; DBENTURE-FERRER

    2004-01-01

    AIM: Beta-lactams (BL) are broad-spectrum antibiotics currently used in number of infectious diseases and some infections need high dose of antibiotics. BL studied here are eliminated rather quickly by the kidney. A renal insufficiency involves an increase in BL concentrations. Therapeutic drug monitoring could help in adapting the target concentration. METHODS: We developed a rapid (less than 20 min), sensitive, and specific HPLC method

  5. 治疗剂量窄谱中波紫外线对B1OBR黑素细胞增殖、凋亡及黑皮素受体-1表达的影响%Effects of narrow band ultraviolet B at therapeutic doses on the proliferation of, apoptosis in and melanocortin-1 receptor (MC-1R) expression by melanocytes

    宋秀祖; 相文忠; 卢良君; 许爱娥

    2010-01-01

    Objective To investigate the mechanism of repigmentation in vitiligo induced by narrow band ultraviolet B (NB-UVB) via observing the effects of 311 nm NB-UVB on the proliferation of, apoptosis and melanogenesis in melanocytes. Methods Immortalized B10BR melanocytes were irradiated with NB-UVB at varying doses (400, 800 and 1200 mJ/cm2). Subsequently, the proliferation of and apoptosis in melanocytes were detected by MTT assay and flow cytometry, respectively, and the content of melanin was determined by NaOH assay. The expression of BCL-2 mRNA was examined by RT-PCR, and MC-1R expression of melanoeytes by immunocytochemistry and Western blotting. Results The proliferation of and apoptosis in melanocytes experienced no obvious change after irradiation with NB-UVB at the three tested doses. In B10BR melanocytes irradiated with NB-UVB at 400, 800 and 1200 mJ/cm2, the melanin content was 1.42, 1.78, 2.05 times, the mRNA expression of BCL-2 was 1.75, 2.32, 3.28 times, and the protein expression of MC-1R was 1.68, 2.35 and 3.01 times, that in unirradiated melanocytes, respectively. Conclusion NB-UVB irradiation at therapeutic doses could promote the melanogenesis in, enhance anti-oxidative stress activities of melanocytes,by upregulating the expressions of BCL-2 and MC-1R, with no marked effects on the apoptosis in melanocytes.%目的 通过观察311 nm窄谱中波紫外线(NB-UVB)对黑素细胞增殖、凋亡及黑素合成的影响,探讨NB-UVB在白癜风复色中的可能机制.方法 永生化B10BR黑素细胞,采用400、800、1200 mJ/cm2的311 nm NB-UVB照射,MTT法及流式细胞仪测定细胞增殖及凋亡变化,NaOH法测定黑素含量变化,RT-PCR方法测定B细胞淋巴瘤-2(BCL-2)表达变化,免疫细胞化学方法及Western印迹测定黑皮素受体-1(MC-1R)表达.结果 用不同剂量NB-UVB照射B10BR后,黑素细胞的增殖和凋亡没有显著变化.但随着NB-UVB照射剂量增加,黑素合成呈剂量依赖性增

  6. [Therapeutic drug monitoring of clobazam].

    Bentué-Ferrer, Danièle; Tribut, Olivier; Verdier, Marie-Clémence; Debruyne, Danièle

    2010-01-01

    Clobazam is a 1,5 benzodiazepine available in France since 1975, used in add-on with the other anticonvulsant drugs in the treatment of refractory epilepsies of child and adult and for the treatment of anxiety of adult. It is mainly metabolized in desmethylclobazam, or norclobazam, active metabolite, present in a concentration approximately eight times superior to that of the parent drug, but with an activity of the order of 20 to 40% of that of clobazam. Elimination half-life of clobazam is of 18 h while that of norclobazam is from 40 to 50 h. There is a large interindividual variability in the plasma concentrations. Furthermore, clobazam being prescribed in add-on with the other anticonvulsant drugs in resistant epilepsies, concentration-effect relationship is difficult to bring to light, since, in many studies, the patients who did not answer received the highest doses. Adverse reactions are moderated, appearing more often for the highest concentrations; also the phenomenon of tolerance seems more frequent in high concentrations. However, because of the kinetic interactions, a dosage of clobazam and norclobazam can be useful in certain cases. There is no validated therapeutic range, but the usual concentrations are in the range of 100-300 microg/L for the parent drug and about ten times more for the metabolite. The level of proof of the interest of the Therapeutic Drug Monitoring for this molecule is estimated in: rather useless.

  7. Benchmark Dose Modeling

    Finite doses are employed in experimental toxicology studies. Under the traditional methodology, the point of departure (POD) value for low dose extrapolation is identified as one of these doses. Dose spacing necessarily precludes a more accurate description of the POD value. ...

  8. Antiviral Polymer Therapeutics

    Smith, Anton Allen Abbotsford

    2014-01-01

    The field of drug delivery is in essence an exercise in engineered pharmacokinetics. Methods of doing so have been developed through the introduction of a vehicle carrying the drug, either by encapsulation or covalent attachment. The emergence of polymer therapeutics in anticancer therapy has...... the examples of polymer therapeutics being applied as an antiviral treatment are few and far in-between. This work aims to explore antiviral therapeutics, specifically in context of hepatitis virus C (HCV) and HIV. The current treatment of hepatitis C consists of a combination of drugs, of which ribavirin....... Curiously, the therapeutic window of ribavirin was vastly improved in several of these polymers suggesting altered pharmacodynamics. The applicability of liver-targeting sugar moieties is likewise tested in a similarly methodical approach. The same technique of synthesis was applied with zidovudine to make...

  9. Novel bioequivalence approach for narrow therapeutic index drugs.

    Yu, L X; Jiang, W; Zhang, X; Lionberger, R; Makhlouf, F; Schuirmann, D J; Muldowney, L; Chen, M-L; Davit, B; Conner, D; Woodcock, J

    2015-03-01

    Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products.

  10. Eficacia clínica de oxicodona: La presentación de 5 mg en el esquema terapéutico del ascensor analgésico Clinical Effectiveness of oxicodone: The 5 mg dose in the analgesic elevator therapeutic scheme

    M. A. Vidal

    2008-04-01

    ía eliminar el principal obstáculo para llevar a la práctica el "Ascensor Analgésico".Introduction. Oxicodone has been a semisynthetic opioide derived from thebaine with múltiple actions similar to morphine, used actually clinical for more than 80 years. Its main therapeutic action is the analgesia; and to a lesser extent sedative action. To dose lower than the necessary one to produce analgesia, can act on the center of the cough. The objective of this article is to make a review of the characteristics of oxicodone: its pharmacological properties, tolerability and mainly its clinical effectiveness in the different types of pain and with the different presentations that exist at the moment in the market. The reviewed articles come from the data base of Medline and Cochrane. Clinical effectiveness. Numerous studies guarantee the effectiveness of oxicodone in the treatment of the different types of pain. Nevertheless these studies have their limitations. The studies that are based on the use of oxicodone in nononcological chronic pain are positive comparative studies to placebo. As far as the oncological pain, the comparative clinical tests from morphine and hidromorphone, oxicodone has presented advantages in effectiveness, and safety. Also revisions have been carried out on the matter in which it scores at oxicodone like a good alternative to morphine. Discussion. Oxicodone is a good alternative for the treatment of the moderate-severe pain, for a program of opioids rotation of since it has an excellent balance between analgesia and toxicity. Oxicodone prolonged release 5 mg, is very useful like initial dose to titrate opioids, being climbed dose at 48 hours, with which the incidence of indirect effect is diminished and diminishes the risk of therapeutic abandonment that these entail. With this approach one would be able to eliminate the main obstacle to put in practice the "Analgesic Elevator" theory.

  11. Therapeutic effect and safety of half dose tirofiban combined PCI in patients with acute myocardial infarction complicated early renal insufficiency%半剂量替罗非班联合PCI对早期肾功能不全急性心肌梗死患者的疗效及安全性

    沈冲; 方雪花; 赵炳朕; 余清; 马飞; 张伟; 高德全; 赵雪东

    2012-01-01

    目的:观察半剂量替罗非班联合经皮冠脉介入治疗(PCI)对合并早期肾功能不全急性心肌梗死(AMI)患者的疗效及安全性.方法:选择合并早期肾功能不全的AMI患者55例作为肾功能不全组,56例肾功能正常的AMI患者作为AMI对照组,两组均应用常规抗凝、抗血小板治疗,肾功能不全组于穿刺成功后开始应用半剂量替罗非班,AMI对照组全量应用替罗非班.比较两组间住院期主要不良心血管事件(MACE),出血、血小板减少发生率及对比剂肾病发生率的差异.结果:与AMI对照组比较,肾功能不全组3支病变比例(21.1%比43.6%)、术后肌酸激酶峰值浓度[(1863.1±86.7)IU/L比(2371.5±126.3)IU/L]明显升高(P均<0.05);两组术后TIMI 3级血流率、校正的TIMI计帧数和Blush 3级率未见显著性差异(P>0.05),术后2h心电图相关导联ST段下降幅度及住院期间的MACE发生率亦无显著性差异(P>0.05),出血事件发生率和血小板减少发生率亦无显著差异(P>0.05).对比剂肾病:AMI对照组无发生,肾功能不全组有3例发生(0%比5.45%,P<0.05).结论:合并早期肾功能不全的急性心肌梗死患者三支病变比例高,半剂量替罗非班联合PCI能有效再灌注心肌,降低住院心血管事件发生,未见明显出血及血小板减少发生率增加,但需警惕对比剂肾病的发生,术后应加强监测与干预.%To investigate therapeutic effect and safety of half dose tirofiban combined percutaneous coronary intervention (PCI) on patients with acute myocardial infarction (AMI) complicated early renal insufficiency. Methods: A total of 55 AMI patients with early renal insufficiency were enrolled as renal insufficiency group and 56 AMI patients with normal renal function were regard as AMI control group. Both groups received routine anticoagulant and antiplatelet therapy, renal insufficiency group received half dose tirofiban after successful puncture while AMI control group

  12. Therapeutic applications of indium-111-octreotide for carcinoid syndrome. A case study

    Camden, B.M.; Chu, J.M.G. [Liverpool Health Service, Liverpool, NSW (Australia). Department of Nuclear Medicine and Clinical Ultrasound

    1998-06-01

    Full text: A 83 year old female presented to our department for an Indium-111 Octreotide study to evaluate her carcinoid syndrome with the view of delivering therapeutic doses of Indium-111 Octreotide. Indium-111 Octreotide uptake has been shown in tumours with high-affinity somatostatin receptor sites. In many instances a positive scintigram predicts a favourable response to treatment with Octreotide. The diagnostic scan appearance demonstrated abnormal increased focal uptake in multiple sites of both lobes of the liver and one in the right iliac fossa, her primary site. Before the therapeutic doses, both haematological and biochemical indices of her carcinoid were performed to evaluate therapeutic response. The patient was then admitted into our isolation room and underwent 3 therapeutic doses of Indium-111 Octreotide of between 180 and 350 mCi intravenously at 4 to 6 weekly intervals. A post-therapeutic total body scan with abdominal SPECT was performed after each dose to assess therapeutic uptake and response. Before the second therapeutic dose, an FDG coincidence PET study was performed. This scan corresponded with similar sites of uptake to the Octreotide scan The patient has now had 2 of her 3 therapeutic doses with the third due in late January 1998. At this point of time her biochemical indices and clinical facial flushing and diarrhoea have shown favourable response to therapy

  13. Therapeutic Drug Monitoring in the Treatment of Active Tuberculosis

    Aylin Babalik

    2011-01-01

    Full Text Available Therapeutic drug monitoring ensures optimal dosing while aiming to reduce toxicity. However, due to the high costs and complexity of testing, therapeutic drug monitoring is not routinely used in the treatment of individuals with active tuberculosis, despite the efficacy demonstrated in several randomized trials. This study reviewed data spanning five years regarding the frequency of finding low drug levels in patients with tuberculosis, the dosing adjustments that were required to achieve adequate levels and the factors associated with low drug levels.

  14. Pancreatic Pseudocyst: Therapeutic Dilemma

    A. K. Khanna

    2012-01-01

    Full Text Available Pancreatic pseudocyst develops in both acute and chronic pancreatitis. It is an entity likely to either remain asymptomatic or develop devastating complications. Despite being diagnosed easily, treatment exercise is still at crossroads whether in the form of internal or external drainage or endoscopic, laparoscopic, or open intervention with a good radiological guidance. The therapeutic dilemma whether to treat a patient with a pancreatic pseudocyst, as well as when and with what technique, is a difficult one. This paper is intended to get information about diagnostic and therapeutic exercises most appropriate for acute and chronic pancreatic pseudocyst.

  15. Therapeutic HIV Peptide Vaccine

    Fomsgaard, Anders

    2015-01-01

    Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...

  16. Lymphedema and Therapeutic Lymphangiogenesis

    Yukihiro Saito

    2013-01-01

    Full Text Available Lymphedema is a disorder of the lymphatic vascular system characterized by impaired lymphatic return and swelling of the extremities. Lymphedema is divided into primary and secondary forms based on the underlying etiology. Despite substantial advances in both surgical and conservative techniques, therapeutic options for the management of lymphedema are limited. Although rarely lethal, lymphedema is a disfiguring and disabling condition with an associated decrease in the quality of life. The recent impressive expansion of knowledge on the molecular mechanisms governing lymphangiogenesis provides new possibilities for the treatment of lymphedema. This review highlights the lymphatic biology, the pathophysiology of lymphedema, and the therapeutic lymphangiogenesis using hepatocyte growth factor.

  17. Influence of pH on the /sup 14/C-labelling pattern after photosynthesis of suspended leaf slices and isolated mesophyll cells from chenopodium album in NaH/sup 14/CO/sub 3/

    Baumann, G.; Guenther, G. (Paedagogische Hochschule Karl Liebknecht, Potsdam (German Democratic Republic). Sektion Chemie/Biologie)

    1983-01-01

    Photosynthetic fixation of /sup 14/C from solutions of NaH/sup 14/CO/sub 3/ (at constant concentrations of free CO/sub 2/) by suspended leaf slices or isolated mesophyll cells from Chenopodium album is increased with increasing pH. Above all, the incorporation of radioactivity into amino acids and malate is stimulated. A direct uptake of HCO/sub 3/ ions and its fixation by PEP carboxylase is suggested. Isolated mesophyll cells showed at pH 7.3 a higher rate of photosynthesis than at pH 5.0.

  18. Drying and rewetting of a loamy sand soil did not increase the turnover of native organic matter, but retarded the decomposition of added 14C-labelled plant material

    Magid, J.; Kjaergaard, C.; Gorissen, A.; Kuikman, P.J.

    1999-01-01

    Drying and subsequent rewetting of soils has been recognized as an important process for accelerating the decomposition of soil organic matter. This effect has been attributed to (1) increasing solubility of humic substances (molecular level) (2), microbial death during desiccation and due to osmore

  19. Synthesis and Identification of 14C Labelled Pyraoxystrobin%新型杀菌剂唑菌酯吡唑环14C标记合成和鉴定

    刘训悦; 阚登蕾; 丁兴成

    2011-01-01

    Hydrophobic FesO4 nanocrystals with superparamagnetic behavior were synthesized in an or ganic solvent. High quality water-soluble Fe3O4 nanocrystals were then prepared by a phase transfer method, in which amphiphilic oligomers (polymaleic acid aliphatic amine ester) was used as surface coating agents. The obtained aqueous Fe3O4 nanocrystals were characterized with transmission electron microscopy, Fourier transform infrared spectroscopy, thermal gravimetric analysis, and dynamic light scattering. A solution of Fe3O4 nanocrystals in water showed expected superparamagnetic behavior when subjected to an external magnetic field. We found that hydrophobic ester chain length of the amphiphilic oligomer can dramatically affect the phase transfer efficiency, which was explained by the impact of local hydrophobic environment on the stability of nanocrystals in water. A biocompatible test showed that the water-soluble Fe3Q4 were very stable in various physiological conditions without particle aggregation.%为研究新型杀菌剂唑菌酯在土壤中的代谢途径、作用机理及环境行为,以14C-对氯苯甲酸为原料,通过取代、环化、缩合三步反应合成吡唑环14C标记的唑菌酯.采用高效液相色谱-质谱联用仪(电喷雾离子源)[HPLC-MS(ESI)],质谱法(电子轰击离子源)[MS(EI)],核磁共振氢谱法(1H NMR)验证了其结构,通过HPLC外标法确定其质量纯度大于98%;液相色谱-流动液闪联用仪(HPLC-LSC)和薄层色谱-同位素成像分析法(TLC-IIA)两种方法分析表明,其放射化学纯度大于98%,比活度为(5.042±0.076)mCi/mmo1.以总反应收率计,合成反应的化学收率和放化收率均为43.93%.

  20. Studies on the percutaneous absorption of /sup 14/C-labelled flurbiprofen, (1). Absorption, distribution around the spread site, metabolism and excretion of /sup 14/C-Flurbiprofen in swine

    Sakai, Takeo; Nagao, Soshichi (Nihon Univ., Tokyo. Coll. of Agriculture and Veterinary Medicine)

    1982-03-01

    A 1% ointment of C/sup 14/-labelled 2-(2-fluoro-4-biphenylyl) propionic acid (FP) was applied onto the depilated backs of swines. A relatively large amount of C/sup 14/-FP was absorbed percutaneously. The drug concentration in the blood attained a peak of 0.097 ..mu..g/ml 12 hours after drug administration, after which it decreased rapidly to 11.3% of the peak concentration. High concentration of C/sup 14/FP was detected in the skin, its concentration being particularly high in the epidermis and corium, which shows that there were superficial dispersion and residue. The drug concentration in the muscle was low, which shows that there was little three-dimensional dispersion. The cumulative urinary excretion of the drug 120 hours after drug application was 16.7%, and the cumulative fecal excretion was 2.6%, the ratio of excretion into the urine to that into the feces being 6 : 1. The unchanged form of the drug and 3 metabolites were detected in the urine.

  1. Patient factors that influence warfarin dose response.

    White, Pamela J

    2010-06-01

    Warfarin has long been the mainstay of oral anticoagulation therapy for the treatment and prevention of venous and arterial thrombosis. The narrow therapeutic index of warfarin, and the complex number of factors that influence international normalized ratio (INR) response, makes optimization of warfarin therapy challenging. Determination of the appropriate warfarin dose during initiation and maintenance therapy requires an understanding of patient factors that influence dose response: age, body weight, nutritional status, acute and chronic disease states, and changes in concomitant drug therapy and diet. This review will examine specific clinical factors that can affect the pharmacokinetics and pharmacodynamics of warfarin, as well as the role of pharmacogenetics in optimizing warfarin therapy.

  2. Therapeutic Recombinant Monoclonal Antibodies

    Bakhtiar, Ray

    2012-01-01

    During the last two decades, the rapid growth of biotechnology-derived techniques has led to a myriad of therapeutic recombinant monoclonal antibodies with significant clinical benefits. Recombinant monoclonal antibodies can be obtained from a number of natural sources such as animal cell cultures using recombinant DNA engineering. In contrast to…

  3. Measuring Therapeutic Effectiveness.

    Callister, Sheldon L.

    In the recent past, there has been a great deal of effort directed toward developing techniques for documenting therapeutic outcome. Funding sources and the general public seem to be demanding more meaningful data which indicate, in a clear manner, whether or not the services they are paying for are of value. Mental health centers, like other…

  4. Pharmacology and therapeutics of bronchodilators.

    Cazzola, Mario; Page, Clive P; Calzetta, Luigino; Matera, M Gabriella

    2012-07-01

    Bronchodilators are central in the treatment of of airways disorders. They are the mainstay of the current management of chronic obstructive pulmonary disease (COPD) and are critical in the symptomatic management of asthma, although controversies around the use of these drugs remain. Bronchodilators work through their direct relaxation effect on airway smooth muscle cells. at present, three major classes of bronchodilators, β(2)-adrenoceptor (AR) agonists, muscarinic receptor antagonists, and xanthines are available and can be used individually or in combination. The use of the inhaled route is currently preferred to minimize systemic effects. Fast- and short-acting agents are best used for rescue of symptoms, whereas long-acting agents are best used for maintenance therapy. It has proven difficult to discover novel classes of bronchodilator drugs, although potential new targets are emerging. Consequently, the logical approach has been to improve the existing bronchodilators, although several novel broncholytic classes are under development. An important step in simplifying asthma and COPD management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence. Several once-daily β(2)-AR agonists or ultra-long-acting β(2)-AR-agonists (LABAs), such as indacaterol, olodaterol, and vilanterol, are already in the market or under development for the treatment of COPD and asthma, but current recommendations suggest the use of LABAs only in combination with an inhaled corticosteroid. In addition, some new potentially long-acting antimuscarinic agents, such as glycopyrronium bromide (NVA-237), aclidinium bromide, and umeclidinium bromide (GSK573719), are under development, as well as combinations of several classes of long-acting bronchodilator drugs, in an attempt to simplify treatment

  5. Carbohydrates in therapeutics.

    Kilcoyne, Michelle; Joshi, Lokesh

    2007-07-01

    Awareness of the importance of carbohydrates in living systems and medicine is growing due to the increasing understanding of their biological and pharmacological relevance. Carbohydrates are ubiquitous and perform a wide array of biological roles. Carbohydrate-based or -modified therapeutics are used extensively in cardiovascular and hematological treatments ranging from inflammatory diseases and anti-thrombotic treatments to wound healing. Heparin is a well-known and widely used example of a carbohydrate-based drug but will not be discussed as it has been extensively reviewed. We will detail carbohydrate-based and -modified therapeutics, both those that are currently marketed or in various stages of clinical trials and those that are potential therapeutics based on promising preclinical investigations. Carbohydrate-based therapeutics include polysaccharide and oligosaccharide anti-inflammatory, anti-coagulant and anti-thrombotic agents from natural and synthetic sources, some as an alternative to heparin and others which were designed based on known structure-functional relationships. Some of these compounds have multiple biological effects, showing anti-adhesive, anti-HIV and anti-arthrithic activities. Small molecules, derivatives or mimetics of complement inhibitors, are detailed for use in limiting ischemia/ reperfusion injuries. Monosaccharides, both natural and synthetic, have been investigated for their in vivo anti-inflammatory and cardioprotective properties. Modification by glycosylation of natural products, or glycosylation-mimicking modification, has a significant effect on the parent molecule including increased plasma half-life and refining or increasing desired functions. It is hoped that this review will highlight the vast therapeutic potential of these natural bioactive molecules.

  6. Optimizing lithium dosing in hemodialysis

    Bjarnason, N H; Munkner, R; Kampmann, J P

    2006-01-01

    We studied a 62-year-old female hemodialysis patient during initiation and maintenance of lithium carbonate therapy. Three different methods were applied to estimate the regimen: a scenario based on volume of distribution (V(d)), a scenario based on glomerular filtration rate (GFR), and a scenario...... estimates. Furthermore, the maintenance dose estimated from the central compartment (V1) led to plasma concentrations within the therapeutic range. Thus, a regimen where 12.2 mmol lithium was given after each hemodialysis session resulted in stable between-dialysis plasma lithium concentrations...... in this patient with no residual kidney function. We did not observe adverse effects related to this regimen, which was monitored from 18 days to 8 months of therapy, and the patient experienced relief from her severe depressive disorder. In conclusion, dialysis patients may be treated with lithium administrated...

  7. Strategy for stochastic dose-rate induced enhanced elimination of malignant tumour without dose escalation.

    Paul, Subhadip; Roy, Prasun Kumar

    2016-09-01

    The efficacy of radiation therapy, a primary modality of cancer treatment, depends in general upon the total radiation dose administered to the tumour during the course of therapy. Nevertheless, the delivered radiation also irradiates normal tissues and dose escalation procedure often increases the elimination of normal tissue as well. In this article, we have developed theoretical frameworks under the premise of linear-quadratic-linear (LQL) model using stochastic differential equation and Jensen's inequality for exploring the possibility of attending to the two therapeutic performance objectives in contraposition-increasing the elimination of prostate tumour cells and enhancing the relative sparing of normal tissue in fractionated radiation therapy, within a prescribed limit of total radiation dose. Our study predicts that stochastic temporal modulation in radiation dose-rate appreciably enhances prostate tumour cell elimination, without needing dose escalation in radiation therapy. However, constant higher dose-rate can also enhance the elimination of tumour cells. In this context, we have shown that the sparing of normal tissue with stochastic dose-rate is considerably more than the sparing of normal tissue with the equivalent constant higher dose-rate. Further, by contrasting the stochastic dose-rate effects under LQL and linear-quadratic (LQ) models, we have also shown that the LQ model over-estimates stochastic dose-rate effect in tumour and under-estimates the stochastic dose-rate effect in normal tissue. Our study indicates the possibility of utilizing stochastic modulation of radiation dose-rate for designing enhanced radiation therapy protocol for cancer.

  8. Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.

    Heard, Kennon; Bui, Alison; Mlynarchek, Sara L; Green, Jody L; Bond, G Randall; Clark, Richard F; Kozer, Eran; Koff, Raymond S; Dart, Richard C

    2014-01-01

    Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

  9. Dose-Effect Relationship in Chemoradiotherapy for Locally Advanced Rectal Cancer

    Jakobsen, Anders; Ploen, John; Vuong, Té

    2012-01-01

    PURPOSE: Locally advanced rectal cancer represents a major therapeutic challenge. Preoperative chemoradiation therapy is considered standard, but little is known about the dose-effect relationship. The present study represents a dose-escalation phase III trial comparing 2 doses of radiation...

  10. Speckle tracking echocardiography combined with low dose dobutamine stress in predicting therapeutic effect of percutaneous coronary intervention%超声斑点追踪技术结合小剂量多巴酚丁胺负荷试验评价经皮冠状动脉介入治疗效果

    陈军红; 李东野; 张辉; 王晓萍; 陈静; 闫艳

    2012-01-01

    Objective To evaluate the feasibility and diagnostic accuracy of speckle tracking echocardiography (STE) combined with low-dose dobutamine stress (DSE) for prediction therapeutic effect of percutaneous coronary intervention (PCI). Methods Forty patients with ischemic heart disease before PCI were included. The longitudinal peak systolic strain rate (SRs) at rest and at DSE was analyzed. Cardiac ultrasound was performed on all patients 9 months after PCI, and improvement of wall-motion score was taken as standard of evaluation. Results Among 225 segments with abnormal resting motion, functional recovery was found in 101 (44. 89%), while no recovery was found in 124 segments (55. 11%) after PCI. At baseline dobutamine echocardiography, 72 viable segments were accurately predicted by wall-motion analysis, yielding a sensitivity of 71. 29% (72/101), while 87 of 124 segments that did not recover after revascularization were accurately predicted by wall-motion analysis, yielding a specificity of 70. 16% (87/124). The area under ROC curves was 0. 76, cut-off value of SRs was -0. 49, the sensitivity was 71. 30% and specificity was 70. 20% at rest-state STE. For STE combining with DSE, the area under ROC curves was 0. 89, cut-off value of SRs was-0. 75, the sensitivity was 89. 10% and specificity was 90. 30%. SRs of the viable segments were found significantly increased than those did not recovered (P< 0. 01) when observed with STE. Conclusion Combination of STE with DSE can predict myocardial viability accurately. The presence of potential and functional viable myocardium is necessary in screening indication and forecasting the therapeutic effect of PCI.%目的 利用超声斑点追踪成像(STE)技术结合小剂量多巴酚丁胺负荷(DSE)试验预测经皮冠状动脉介入治疗的效果.方法 对40例缺血性心脏病患者,于冠状动脉介入治疗(PCI)术前分析其运动异常心肌节段静息与DSE条件下收缩期峰值应变率(SRs)变化.PCI术后9个

  11. Polymer-Based Therapeutics

    Liu, Shuang; Maheshwari, Ronak; Kiick, Kristi L.

    2009-01-01

    Polymeric materials have been applied in therapeutic applications, such as drug delivery and tissue regeneration, for decades owing to their biocompatibility and suitable mechanical properties. In addition, select polymer–drug conjugates have been used as bioactive pharmaceuticals owing to their increased drug efficacy, solubility, and target specificity compared with small-molecule drugs. Increased synthetic control of polymer properties has permitted the production of polymer assemblies for...

  12. Clinical Value of Molecular Subtypes for Breast Cancer Predicting Therapeutic Effect and Prognosis of Dose Dense Docetaxel Neoadjuvant Chemotherapy%乳腺癌分子分型在多西他赛密集新辅助化疗疗效及预后中的预测价值

    刘秋明; 曹亚丽; 吴晓波; 夏勇; 涂剑宏; 欧阳倩雯; 周平; 胡平华; 陈军

    2013-01-01

    目的 探讨不同乳腺癌分子亚型与多西他赛密集新辅助化疗疗效及预后的相关性.方法 收集2007年3月 2009年12月可手术乳腺癌患者76例,接受四周期多西他赛密集新辅助化疗,新辅助化疗前用免疫组织化学(IHC)及荧光原位杂交(FISH)法检测肿瘤病灶中ER、PR、Her-2及Ki67的表达,根据表达水平将乳腺癌分为四个分子亚型.主要研究终点包括各亚型临床有效率(RR)、3年无病生存率(DFS)和总生存率(OS).次要研究终点是化疗不良反应、病理完全缓解率(pCR).结果 76例患者中,最常见Ⅲ~Ⅳ度粒细胞缺乏(28.9%)、肝功能损害(10.5%)、皮肤毒性(9.2%)以及肌肉和关节疼痛(6.6%)等化疗不良反应.pCR为5例;Luminal A亚型、Luminal B亚型、Her-2+亚型及三阴亚型的RR分别为86.1%、82.4%、100%、100%(P=0.256),3年DFS、OS分别为94%和97%、88%和94%、70%和70%及69%和69%.对比Luminal A亚型与Her-2+亚型、Luminal A亚型与三阴亚型的3年DFS、OS,差异均有统计学意义(P<0.05).结论 75 mg/m2多西他赛密集新辅助化疗是安全的,Luminal A亚型比Her-2+亚型、三阴亚型预后更好.%Objective To investigate the correlation between different molecular subtypes for breast cancer (BO and the therapeutic effect and prognosis of dose dense docetaxel neoadjuvant chemotherapy. Methods A total of 76 patients with operable, histologically confirmed BC received 4 cycles of dose dense docetaxel neoadjuvan chemotherapy between March 2007 and December 2009. The expression of estrogen receptor (ER) progesterone receptor (PR) , Her-2 and Ki67 were detected by immunohistochemical method and fluorescence in-situ hybridization before neoadjuvan chemotherapy. The patients were classified into 4 subtypes. The primary end points were clinical response rate(RR) ,3-year disease-free survival rates(DFS) and overall survival rate(OS) for every subtypes. Secondary end points were adverse

  13. Nifedipine gastrointestinal therapeutic system versus atenolol in stable angina pectoris

    deVries, RJM; vandenHeuvel, AFM; Lok, DJA; Claessens, RJJ; Bernink, PJLM; Pasteuning, WH; Kingma, JH; Dunselman, PHJM

    1996-01-01

    The gastrointestinal therapeutic system formulation of nifedipine enables a once-daily dosing resulting in predictable, relatively constant plasma concentrations. To evaluate the efficacy and safety of this formulation and to compare this with the beta-blocker atenolol, we conducted a double-blind,

  14. Subantimicrobial dose doxycycline for acne and rosacea.

    Bikowski, Joseph B

    2003-01-01

    Acne vulgaris and rosacea present therapeutic challenges due to their chronicity, potential for disfigurement, and psychosocial impact. Although pathophysiologically distinct, both conditions have major inflammatory components. Consequently, topical and systemic antimicrobial agents are routinely prescribed for extended periods. Emergence of resistant strains of Propionibacterium acnes, adverse events, and compliance issues associated with chronic systemic tetracycline use have led to new treatment approaches. At subantimicrobial doses, tetracyclines reduce inflammation via anticollagenolytic, antimatrix-degrading metalloproteinase, and cytokine down-regulating properties. Subantimicrobial dose (SD) doxycycline (Periostat 20 mg) has clinical utility in periodontitis and has been investigated in a double-blind, placebo-controlled trial in the treatment of moderate facial acne as well as in an open label study in the treatment of rosacea. The results of subantimicrobial dose doxycycline treatment in early trials support its benefits and further investigation in acne and rosacea.

  15. Neutron absorbed dose in a pacemaker CMOS

    Borja H, C. G.; Guzman G, K. A.; Valero L, C.; Banuelos F, A.; Hernandez D, V. M.; Vega C, H. R. [Universidad Autonoma de Zacatecas, Unidad Academica de Estudios Nucleares, Cipres No. 10, Fracc. La Penuela, 98068 Zacatecas (Mexico); Paredes G, L., E-mail: fermineutron@yahoo.com [ININ, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico)

    2012-06-15

    The neutron spectrum and the absorbed dose in a Complementary Metal Oxide Semiconductor (CMOS), has been estimated using Monte Carlo methods. Eventually a person with a pacemaker becomes an oncology patient that must be treated in a linear accelerator. Pacemaker has integrated circuits as CMOS that are sensitive to intense and pulsed radiation fields. Above 7 MV therapeutic beam is contaminated with photoneutrons that could damage the CMOS. Here, the neutron spectrum and the absorbed dose in a CMOS cell was calculated, also the spectra were calculated in two point-like detectors in the room. Neutron spectrum in the CMOS cell shows a small peak between 0.1 to 1 MeV and a larger peak in the thermal region, joined by epithermal neutrons, same features were observed in the point-like detectors. The absorbed dose in the CMOS was 1.522 x 10{sup -17} Gy per neutron emitted by the source. (Author)

  16. Right dose, right now: using big data to optimize antibiotic dosing in the critically ill.

    Elbers, Paul W G; Girbes, Armand; Malbrain, Manu L N G; Bosman, Rob

    2015-01-01

    Antibiotics save lives and are essential for the practice of intensive care medicine. Adequate antibiotic treatment is closely related to outcome. However this is challenging in the critically ill, as their pharmacokinetic profile is markedly altered. Therefore, it is surprising that critical care physicians continue to rely on standard dosing regimens for every patient, regardless of the actual clinical situation. This review outlines the pharmacokinetic and pharmacodynamic principles that underlie the need for individualized and personalized drug dosing. At present, therapeutic drug monitoring may be of help, but has major disadvantages, remains unavailable for most antibiotics and has produced mixed results. We therefore propose the AutoKinetics concept, taking decision support for antibiotic dosing back to the bedside. By direct interaction with electronic patient records, this opens the way for the use of big data for providing the right dose at the right time in each patient.

  17. Frankincense--therapeutic properties.

    Al-Yasiry, Ali Ridha Mustafa; Kiczorowska, Bożena

    2016-01-04

    Recently, increasing interest in natural dietary and therapeutic preparations used as dietary supplements has been observed. One of them is frankincense. This traditional medicine of the East is believed to have anti-inflammatory, expectorant, antiseptic, and even anxiolytic and anti-neurotic effects. The present study aims to verify the reported therapeutic properties of Boswellia resin and describe its chemical composition based on available scientific studies. The main component of frankincense is oil (60%). It contains mono- (13%) and diterpenes (40%) as well as ethyl acetate (21.4%), octyl acetate (13.4%) and methylanisole (7.6%). The highest biological activity among terpenes is characteristic of 11-keto-ß-acetyl-beta-boswellic acid, acetyl-11-keto-ß-boswellic acid and acetyl-α-boswellic acid. Contemporary studies have shown that resin indeed has an analgesic, tranquilising and anti-bacterial effects. From the point of view of therapeutic properties, extracts from Boswellia serrata and Boswellia carterii are reported to be particularly useful. They reduce inflammatory conditions in the course of rheumatism by inhibiting leukocyte elastase and degrading glycosaminoglycans. Boswellia preparations inhibit 5-lipoxygenase and prevent the release of leukotrienes, thus having an anti-inflammatory effect in ulcerative colitis, irritable bowel syndrome, bronchitis and sinusitis. Inhalation and consumption of Boswellia olibanum reduces the risk of asthma. In addition, boswellic acids have an antiproliferative effect on tumours. They inhibit proliferation of tumour cells of the leukaemia and glioblastoma subset. They have an anti-tumour effect since they inhibit topoisomerase I and II-alpha and stimulate programmed cell death (apoptosis).

  18. Therapeutic approaches to cellulite.

    Green, Jeremy B; Cohen, Joel L; Kaufman, Joely; Metelitsa, Andrei I; Kaminer, Michael S

    2015-09-01

    Cellulite is a condition that affects the vast majority of women. Although it is of no danger to one's overall health, cellulite can be psychosocially debilitating. Consequently, much research has been devoted to understanding cellulite and its etiopathogenesis. With additional insights into the underlying causes of its clinical presentation, therapeutic modalities have been developed that offer hope to cellulite sufferers. This review examines evidence for topical treatments, noninvasive energy-based devices, and recently developed minimally invasive interventions that may finally provide a solution.

  19. Is it time to revise antiretrovirals dosing? a pharmacokinetic viewpoint.

    Cattaneo, Dario; Baldelli, Sara; Castoldi, Simone; Charbe, Nitin; Cozzi, Valeria; Fucile, Serena; Clementi, Emilio

    2014-10-23

    We document our experience with therapeutic drug monitoring (TDM) of antiretroviral agents (1807 determinations) carried out as day-by-day clinical practice for the optimization of drug dosing in HIV-infected patients. A significant proportion of patients had lopinavir, atazanavir and nevirapine trough concentrations exceeding the upper therapeutic threshold. Further studies are needed to identify good candidates/drugs for TDM, eventually allowing the selection of patients who may benefit from TDM-driven adjustments in antiretrovirals dosage.

  20. Rethinking Therapeutic Misconception in Biobanking

    Tupasela, Aaro; Snell, Karoliina; Cañada, Jose

    2017-01-01

    Some authors have noted that in biobank research participants may be guided by what is called therapeutic misconception, whereby participants attribute therapeutic intent to research procedures.This article argues that the notion of therapeutic misconception is increasingly less justified when ev...

  1. Doses received by organs in interventional cardiology; Les doses recues aux organes en cardiologie interventionnelle

    Maccia, C. [Centre d' Assurance de qualite des Applications Technologiques dans le domaine de la Sante, (CAATS) - 43, Bd du Marechal Joffre, 92 - Bourg-La-Reine (France)

    2009-07-01

    After a discussion of several publications about patient dosimetry in interventional cardiology, the author recalls that the in vivo assessment of the dose received by some organs is uneasy because invasive. Therefore, the assessment requires the use of physical or mathematical dosimetric phantoms which simulate patient morphology as well as the incident photon attenuation phenomenon. He evokes some characteristics and applications of these phantoms. He outlines the different sources and origins of the dose received by the patient, and discusses results obtained by collecting data from 177 patients submitted to diagnosis or therapeutic procedures

  2. Microdose study of 14C-acetaminophen with accelerator mass spectrometry to examine pharmacokinetics of parent drug and metabolites in healthy subjects.

    Tozuka, Z; Kusuhara, H; Nozawa, K; Hamabe, Y; Ikushima, I; Ikeda, T; Sugiyama, Y

    2010-12-01

    A study of the pharmacokinetics of (14)C-labeled acetaminophen (AAP) was performed in healthy Japanese subjects receiving an oral microdose of the drug. After separation by high-performance liquid chromatography (HPLC), the levels of AAP and its metabolites in the pooled plasma specimens were quantified using accelerator mass spectrometry (AMS). The total body clearance (CL(tot))/bioavailability (F) of AAP was within the variation in the reported values at therapeutic doses, indicating the linearity of AAP pharmacokinetics. AAP-glucuronide (Glu) and AAP-4-O-sulfate satisfied the criteria of safety testing of drug metabolites. AMS could detect AAP-Cys, the active metabolite of AAP conjugated with cysteine, in the urine. Probenecid prolonged the systemic elimination of total radioactivity and caused a marked decrease in AAP-Glu levels in plasma. Probenecid likely inhibited the glucuronidation of AAP and the renal elimination of AAP-4-O-sulfate. Microdosing of (14)C-labeled drug followed by AMS is a powerful tool that can be used in the early phase of drug development for pharmacokinetic analysis of drugs and their metabolites and for detecting the formation of active metabolites in humans.

  3. 间歇短程小剂量多巴胺有利于重度失代偿性心力衰竭患者的治疗%Therapeutic effects of short-term intermittent administration dopamine at low doses on patients with decompensated heart failure

    胡和生; 薛梅; 王晓军; 王晔; 穆伟; 陈明友; 闫素华

    2015-01-01

    目的:评价间歇短程应用小剂量多巴胺治疗重度失代偿性心力衰竭患者临床疗效及安全性。方法选用予利尿剂、洋地黄制剂以及神经内分泌拮抗等慢性心力衰竭失代偿期治疗2 d后NYHA心功能仍在Ⅲ~Ⅳ级的患者105例,随机分成多巴胺组(54例)和对照组(51例),对照组继续上述治疗,而多巴胺组在前述治疗基础上每日给予多巴胺注射液60~80 mg(3µg·kg-1·min-1)静脉泵入,连续5 d,观察两组疗效,同时检测治疗前后心率、血压、体重、左心室射血分数(LVEF)及血清B型钠尿肽(BNP)水平,平均住院时间,心血管事件,半年内再住院率及主要不良心脏事件。结果与对照组相比,多巴胺组显效率(59.2%vs.37.2%,P<0.05)及总有效率(81.4%vs.68.6%, P<0.05)明显提高,并且可以缩短住院时间及降低半年内再住院率(P<0.05)。同时,多巴胺更有利于心率、体重、BNP水平的控制,LVEF较对照组也有所提高[(40.3±3.4)%vs.(37.1±2.3)%, P<0.05],并且不增加住院期间的不良反应及半年内心脏事件。结论间歇短程小剂量多巴胺作用于可有效治疗重度失代偿期的慢性充血性心力衰竭,不良反应少,经济实用,值得临床推广。%Objective To evaluate clinical efficacy and safety of short-term intermittent administration dopamine at low doses on patients with severe decompensated heart failure. Methods After two days' standard treatment, patients still with NYHA classⅢ toⅣ were selected for the study. 105 patients with severe decompensated heart failure were randomly divided into dopamine group (n=54) and control group (n=51). Control group was given standard treatment such as diuretics, digitalis preparations, neuroendocrine antagonist and so on. Dopamine group was daily given intravenous dopamine (60-80 mg, 3 µg·kg-1·min-1) for 5 days besides the foregoing treatment

  4. Small computer algorithms for comparing therapeutic performances of single-plane iridium implants.

    Murphy, D J; Doss, L L

    1984-01-01

    We present a uniform method for selecting an optimum implant geometry by presenting techniques for evaluating the therapeutically significant maximum dose rate (herein referred to as the "maximum dose rate"), the reference isodose (85% of the maximum dose rate), and the area enclosed by the reference isodose contour. The therapeutic performances of planar iridium implants may be compared by evaluating their respective maximum dose rates, reference isodoses , and areas within the reference isodose contours. Because these parameters are mathematically defined, they reproducibly describe each implant geometry. We chose a small microcomputer to develop these comparison algorithms so that the radiotherapist need not have large, expensive computer facilities available to conduct his own studies. The development of these algorithms led to some significant conclusions and recommendations regarding the placement of interstitial implants. Using seeds that are centrally located in the array to evaluate the maximum dose contour avoids underestimating the array's maximum dose rate. This could occur if edge or corner seeds were used. Underestimating the maximum dose rate (and hence the reference isodose contour area) may have a serious therapeutic outcome, because the actual total treatment dosage may be excessive. As ribbon spacing is increased, there is a point beyond which the reference isodose contours become decoupled. At this point, a single relatively uniform reference isodose contour separates into several contours. This effect not only complicates the planimetry calculations, but it also adversely affects the therapeutic efficacy of the implant by producing therapeutically "cold" regions.

  5. Therapeutic Strategies in HCC: Radiation Modalities

    Gallicchio, R.; Nardelli, A.; Mainenti, P.; Nappi, A.; Capacchione, D.; Simeon, V.; Sirignano, C.; Abbruzzi, F.; Barbato, F.; Landriscina, M.

    2016-01-01

    Patients with hepatocellular carcinoma (HCC) comply with an advanced disease and are not eligible for radical therapy. In this distressed scenario new treatment options hold great promise; among them transarterial chemoembolization (TACE) and transarterial metabolic radiotherapy (TAMR) have shown efficacy in terms of both tumor shrinking and survival. External radiation therapy (RTx) by using novel three-dimensional conformal radiotherapy has also been used for HCC patients with encouraging results while its role had been limited in the past for the low tolerance of surrounding healthy liver. The rationale of TAMR derives from the idea of delivering exceptional radiation dose locally to the tumor, with cell killing intent, while preserving normal liver from undue exposition and minimizing systemic irradiation. Since the therapeutic efficacy of TACE is being continuously disputed, the TAMR with 131I Lipiodol or 90Y microspheres has gained consideration providing adequate therapeutic responses regardless of few toxicities. The implementation of novel radioisotopes and technological innovations in the field of RTx constitutes an intriguing field of research with important translational aspects. Moreover, the combination of different therapeutic approaches including chemotherapy offers captivating perspectives. We present the role of the radiation-based therapies in hepatocellular carcinoma patients who are not entitled for radical treatment. PMID:27563661

  6. Therapeutic Strategies in HCC: Radiation Modalities

    R. Gallicchio

    2016-01-01

    Full Text Available Patients with hepatocellular carcinoma (HCC comply with an advanced disease and are not eligible for radical therapy. In this distressed scenario new treatment options hold great promise; among them transarterial chemoembolization (TACE and transarterial metabolic radiotherapy (TAMR have shown efficacy in terms of both tumor shrinking and survival. External radiation therapy (RTx by using novel three-dimensional conformal radiotherapy has also been used for HCC patients with encouraging results while its role had been limited in the past for the low tolerance of surrounding healthy liver. The rationale of TAMR derives from the idea of delivering exceptional radiation dose locally to the tumor, with cell killing intent, while preserving normal liver from undue exposition and minimizing systemic irradiation. Since the therapeutic efficacy of TACE is being continuously disputed, the TAMR with 131I Lipiodol or 90Y microspheres has gained consideration providing adequate therapeutic responses regardless of few toxicities. The implementation of novel radioisotopes and technological innovations in the field of RTx constitutes an intriguing field of research with important translational aspects. Moreover, the combination of different therapeutic approaches including chemotherapy offers captivating perspectives. We present the role of the radiation-based therapies in hepatocellular carcinoma patients who are not entitled for radical treatment.

  7. Therapeutic Strategies in HCC: Radiation Modalities.

    Gallicchio, R; Nardelli, A; Mainenti, P; Nappi, A; Capacchione, D; Simeon, V; Sirignano, C; Abbruzzi, F; Barbato, F; Landriscina, M; Storto, G

    2016-01-01

    Patients with hepatocellular carcinoma (HCC) comply with an advanced disease and are not eligible for radical therapy. In this distressed scenario new treatment options hold great promise; among them transarterial chemoembolization (TACE) and transarterial metabolic radiotherapy (TAMR) have shown efficacy in terms of both tumor shrinking and survival. External radiation therapy (RTx) by using novel three-dimensional conformal radiotherapy has also been used for HCC patients with encouraging results while its role had been limited in the past for the low tolerance of surrounding healthy liver. The rationale of TAMR derives from the idea of delivering exceptional radiation dose locally to the tumor, with cell killing intent, while preserving normal liver from undue exposition and minimizing systemic irradiation. Since the therapeutic efficacy of TACE is being continuously disputed, the TAMR with (131)I Lipiodol or (90)Y microspheres has gained consideration providing adequate therapeutic responses regardless of few toxicities. The implementation of novel radioisotopes and technological innovations in the field of RTx constitutes an intriguing field of research with important translational aspects. Moreover, the combination of different therapeutic approaches including chemotherapy offers captivating perspectives. We present the role of the radiation-based therapies in hepatocellular carcinoma patients who are not entitled for radical treatment.

  8. [Therapeutic education didactic techniques].

    Valverde, Maite; Vidal, Mercè; Jansa, Margarida

    2012-10-01

    This article includes an introduction to the role of Therapeutic Education for Diabetes treatment according to the recommendations of the American Diabetes Association (ADA), the Diabetes Education Study Group (DESG) of the "European Association for Study of Diabetes (EASD) and the clinical Practice Guidelines (CPG) of the Spanish Ministry of Health. We analyze theoretical models and the differences between teaching vs. learning as well as current trends (including Internet), that can facilitate meaningful learning of people with diabetes and their families and relatives. We analyze the differences, similarities, advantages and disadvantages of individual and group education. Finally, we describe different educational techniques (metaplan, case method, brainstorming, role playing, games, seminars, autobiography, forums, chats,..) applicable to individual, group or virtual education and its application depending on the learning objective.

  9. Therapeutic and diagnostic nanomaterials

    Devasena T

    2017-01-01

    This brief highlights nanoparticles used in the diagnosis and treatment of prominent diseases and toxic conditions. Ecofriendly methods which are ideal for the synthesis of medicinally valued nanoparticles are explained and the characteristic features of these particles projected. The role of these particles in the therapeutic field, and the induced biological changes in some diseases are discussed. The main focus is on inflammation, oxidative stress and cellular membrane integrity alterations. The effect of nanoparticles on these changes produced by various agents are highlighted using in vitro and in vivo models. The mechanism of nanoparticles in ameliorating the biological changes is supported by relevant images and data. Finally, the brief demonstrates recent developments on the use of nanoparticles in diagnosis or sensing of some biological materials and biologically hazardous environmental materials.

  10. Prediction of formulation effects on dermal absorption of topically applied ectoparasiticides dosed in vitro on canine and porcine skin using a mixture-adjusted quantitative structure permeability relationship.

    Riviere, J E; Brooks, J D; Collard, W T; Deng, J; de Rose, G; Mahabir, S P; Merritt, D A; Marchiondo, A A

    2014-10-01

    Topical application of ectoparasiticides for flea and tick control is a major focus for product development in animal health. The objective of this work was to develop a quantitative structure permeability relationship (QSPeR) model sensitive to formulation effects for predicting absorption and skin deposition of five topically applied drugs administered in six vehicle combinations to porcine and canine skin in vitro. Saturated solutions (20 μL) of (14) C-labeled demiditraz, fipronil, permethrin, imidacloprid, or sisapronil were administered in single or binary (50:50 v/v) combinations of water, ethanol, and transcutol (6 formulations, n = 4-5 replicates per treatment) nonoccluded to 0.64 cm(2) disks of dermatomed pig or dog skin mounted in flow-through diffusion cells. Perfusate flux over 24 h and skin deposition at termination were determined. Permeability (logKp), absorption, and penetration endpoints were modeled using a four-term Abrahams and Martin (hydrogen-bond donor acidity and basicity, dipolarity/polarizability, and excess molar refractivity) linear free energy QSPeR equation with a mixture factor added to compensate for formulation ingredient interactions. Goodness of fit was judged by r(2) , cross-validation coefficient, coefficients (q(2) s), and Williams Plot to visualize the applicability domain. Formulation composition was the primary determinant of permeation. Compounds generally penetrated dog skin better than porcine skin. The vast majority of permeated penetrant was deposited within the dosed skin relative to transdermal flux, an attribute for ectoparasiticides. The best QSPeR logKp model for pig skin permeation (r(2) = 0.86, q(2) s = 0.85) included log octanol/water partition coefficient as the mixture factor, while for dogs (r(2) = 0.91, q(2) s = 0.90), it was log water solubility. These studies clearly showed that the permeation of topical ectoparasiticides could be well predicted using QSPeR models that account for both the physical

  11. Variability in the pharmacokinetics of mycophenolic acid: Implications for therapeutic drug monitoring

    B.C.M. de Winter (Brenda)

    2010-01-01

    textabstractMycophenolate mofetil (MMF) is an immunosuppressive drug used to prevent rejection following solid organ transplantation. MMF was introduced in 1995 with a recommended fixed-dose regimen of 1 g twice daily. Nowadays, dose individualization using therapeutic drug monitoring (TDM) of the a

  12. Controllable dose; Dosis controlable

    Alvarez R, J.T.; Anaya M, R.A. [ININ, A.P. 18-1027, 11801 Mexico D.F. (Mexico)]. E-mail: jtar@nuclear.inin.mx

    2004-07-01

    With the purpose of eliminating the controversy about the lineal hypothesis without threshold which found the systems of dose limitation of the recommendations of ICRP 26 and 60, at the end of last decade R. Clarke president of the ICRP proposed the concept of Controllable Dose: as the dose or dose sum that an individual receives from a particular source which can be reasonably controllable by means of any means; said concept proposes a change in the philosophy of the radiological protection of its concern by social approaches to an individual focus. In this work a panorama of the foundations is presented, convenient and inconveniences that this proposal has loosened in the international community of the radiological protection, with the purpose of to familiarize to our Mexican community in radiological protection with these new concepts. (Author)

  13. Corticosteroids: clinical pharmacology and therapeutic use.

    Swartz, S L; Dluhy, R G

    1978-09-01

    or total withdrawal of the steroid therapy may be associated with exacerbation of the underlying disease or with a steroid withdrawal syndrome. An additional important point to remember in any withdrawal programme is that the steroid dosage should be appropriately increased for an exacerbation of the underlying disease or for intercurrent major stress. Alternate day therapy is recommended as a steroid maintenance programme for patients requiring high dose glucocorticoid therapy over a prolonged period of time. Thus, it is usually employed to maintain a therapeutic benefit which had previously been extablished by daily steroid treatment. Complications resulting from corticosteroid therapy include: (1) proximal muscle weakness; (2) osteopenia; (3) unmasking of latent diabetes mellitus; (4) sodium retention and/or elevation of mean arterial blood pressure; (5) adverse psychiatric reactions; (6) development of glaucoma; and (7) reactivation of latent infections (such as tuberculosis).

  14. CNS pharmacology and clinical therapeutic effects of oxiracetam.

    Itil, T M; Menon, G N; Songar, A; Itil, K Z

    1986-01-01

    Oxiracetam, a new substance found to be a nootropic in experimental pharmacological studies, was tested in three clinical trials: a single rising dose tolerance and dose-finding study with quantitative pharmaco-electroencephalogram (pharmaco-EEG) and quantitative pharmacopsychology in healthy volunteers; a dose-finding study, at three dose levels for 3 months, with quantitative pharmaco-EEG in mild to moderate dementia patients; and a safety and efficacy study with increasing dosages for 12 weeks with subjective and objective tests in elderly patients with dementia. In single and repeated oral dosages up to 2,400 mg, oxiracetam is a safe compound. According to HZI Data Bank Classification Systems, oxiracetam is a vigilance-enhancing compound with some effects on spontaneous memory. The therapeutic effect of oxiracetam can be discriminated from placebo, and in comparison with piracetam, oxiracetam exhibits greater improvement in memory factor.

  15. Clinical applications of therapeutic phlebotomy.

    Kim, Kyung Hee; Oh, Ki Young

    2016-01-01

    Phlebotomy is the removal of blood from the body, and therapeutic phlebotomy is the preferred treatment for blood disorders in which the removal of red blood cells or serum iron is the most efficient method for managing the symptoms and complications. Therapeutic phlebotomy is currently indicated for the treatment of hemochromatosis, polycythemia vera, porphyria cutanea tarda, sickle cell disease, and nonalcoholic fatty liver disease with hyperferritinemia. This review discusses therapeutic phlebotomy and the related disorders and also offers guidelines for establishing a therapeutic phlebotomy program.

  16. Prostate cancer: Doses and volumes of radiotherapy; Cancer de prostate: doses et volumes cibles

    Hennequin, C.; Rivera, S.; Quero, L. [Service de cancerologie-radiotherapie, hopital Saint-Louis, AP-HP, 75 - Paris (France); Latorzeff, I. [Service de radiotherapie, groupe Oncorad-Garonne, clinique Pasteur, -l' Atrium-, 31 - Toulouse (France)

    2010-10-15

    Radiotherapy is nowadays a major therapeutic option in prostate cancer. Technological improvements allowed dose escalation without increasing late toxicity. Some randomized trials have shown that dose escalation decreases the biochemical failure rate, without any benefit in survival with the present follow-up. However, some studies indicate that the distant metastases rate is also decreased. Most of these studies have been done without hormonal treatment, and the role of dose escalation in case of long-term androgen deprivation is unknown. The target volume encompassed the whole gland: however, complete or partial focal treatment of the prostate can be done with sophisticated IMRT technique and must be evaluated. Proximal part of the seminal vesicles must be included in the target volumes. The role of nodal irradiation is another debate, but it could be logically proposed for the unfavourable group. (authors)

  17. Designing phage therapeutics.

    Goodridge, Lawrence D

    2010-01-01

    Phage therapy is the application of phages to bodies, substances, or environments to effect the biocontrol of pathogenic or nuisance bacteria. To be effective, phages, minimally, must be capable of attaching to bacteria (adsorption), killing those bacteria (usually associated with phage infection), and otherwise surviving (resisting decay) until they achieve attachment and subsequent killing. While a strength of phage therapy is that phages that possess appropriate properties can be chosen from a large diversity of naturally occurring phages, a more rational approach to phage therapy also can include post-isolation manipulation of phages genetically, phenotypically, or in terms of combining different products into a single formulation. Genetic manipulation, especially in these modern times, can involve genetic engineering, though a more traditional approach involves the selection of spontaneously occurring phage mutants during serial transfer protocols. While genetic modification typically is done to give rise to phenotypic changes in phages, phage phenotype alone can also be modified in vitro, prior to phage application for therapeutic purposes, as for the sake of improving phage lethality (such as by linking phage virions to antibacterial chemicals such as chloramphenicol) or survival capabilities (e.g., via virion PEGylation). Finally, phages, both naturally occurring isolates or otherwise modified constructs, can be combined into cocktails which provide collectively enhanced capabilities such as expanded overall host range. Generally these strategies represent different routes towards improving phage therapy formulations and thereby efficacy through informed design.

  18. Utirik Atoll Dose Assessment

    Robison, W.L.; Conrado, C.L.; Bogen, K.T

    1999-10-06

    On March 1, 1954, radioactive fallout from the nuclear test at Bikini Atoll code-named BRAVO was deposited on Utirik Atoll which lies about 187 km (300 miles) east of Bikini Atoll. The residents of Utirik were evacuated three days after the fallout started and returned to their atoll in May 1954. In this report we provide a final dose assessment for current conditions at the atoll based on extensive data generated from samples collected in 1993 and 1994. The estimated population average maximum annual effective dose using a diet including imported foods is 0.037 mSv y{sup -1} (3.7 mrem y{sup -1}). The 95% confidence limits are within a factor of three of their population average value. The population average integrated effective dose over 30-, 50-, and 70-y is 0.84 mSv (84, mrem), 1.2 mSv (120 mrem), and 1.4 mSv (140 mrem), respectively. The 95% confidence limits on the population-average value post 1998, i.e., the 30-, 50-, and 70-y integral doses, are within a factor of two of the mean value and are independent of time, t, for t > 5 y. Cesium-137 ({sup 137}Cs) is the radionuclide that contributes most of this dose, mostly through the terrestrial food chain and secondarily from external gamma exposure. The dose from weapons-related radionuclides is very low and of no consequence to the health of the population. The annual background doses in the U. S. and Europe are 3.0 mSv (300 mrem), and 2.4 mSv (240 mrem), respectively. The annual background dose in the Marshall Islands is estimated to be 1.4 mSv (140 mrem). The total estimated combined Marshall Islands background dose plus the weapons-related dose is about 1.5 mSv y{sup -1} (150 mrem y{sup -1}) which can be directly compared to the annual background effective dose of 3.0 mSv y{sup -1} (300 mrem y{sup -1}) for the U. S. and 2.4 mSv y{sup -1} (240 mrem y{sup -1}) for Europe. Moreover, the doses listed in this report are based only on the radiological decay of {sup 137}Cs (30.1 y half-life) and other

  19. Therapeutic evaluation of omeprazole.

    Adams, M H; Ostrosky, J D; Kirkwood, C F

    1988-10-01

    The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of omeprazole are reviewed. Omeprazole, a substituted benzimidazole, has a unique site and mechanism of action because it inhibits the proton pump--i.e., hydrogen, potassium adenosine triphosphatase (H+,K+-ATPase)--and consequently blocks the final common step in the gastric acid secretory pathway. Omeprazole inhibits basal and histamine-, gastrin- and pentagastrin-stimulated gastric hydrochloric acid secretion. It produces a dose-dependent reduction in gastric acidity, gastric acid output, and gastric juice volume and has variable effects on pepsin secretion. Omeprazole has no documented effect on esophageal motility or lower esophageal sphincter pressure. Omeprazole is variably absorbed from the gastrointestinal tract, and food appears to decrease the rate, but not the extent, of drug absorption. The drug is approximately 95% bound to plasma proteins and is metabolized to inactive components that are enterohepatically or renally eliminated. Omeprazole is more effective (in most studies) than H2-receptor antagonists in treating duodenal ulcer, at least as effective in treating benign gastric ulcer, and more effective in treating reflux esophagitis. Omeprazole has been used successfully in patients with Zollinger-Ellison syndrome refractory to treatment with H2-receptor antagonists. Gastrointestinal complaints (nausea and diarrhea) are the most commonly reported adverse effects associated with omeprazole therapy. The most frequently reported laboratory abnormality occurring with omeprazole use is elevation of serum aspartate aminotransferase and alanine aminotransferase concentrations. Omeprazole will serve a valuable role in the management of gastrointestinal tract ulcers and hypersecretory conditions.

  20. Mitochondrial diseases: therapeutic approaches.

    DiMauro, Salvatore; Mancuso, Michelangelo

    2007-06-01

    Therapy of mitochondrial encephalomyopathies (defined restrictively as defects of the mitochondrial respiratory chain) is woefully inadequate, despite great progress in our understanding of the molecular bases of these disorders. In this review, we consider sequentially several different therapeutic approaches. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but extends to other metabolites. Attempts to bypass blocks in the respiratory chain by administration of electron acceptors have not been successful, but this may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy and is especially important in disorders due to primary deficiencies of specific compounds, such as carnitine or coenzyme Q10. There is increasing interest in the administration of reactive oxygen species scavengers both in primary mitochondrial diseases and in neurodegenerative diseases directly or indirectly related to mitochondrial dysfunction. Aerobic exercise and physical therapy prevent or correct deconditioning and improve exercise tolerance in patients with mitochondrial myopathies due to mitochondrial DNA (mtDNA) mutations. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but interesting experimental approaches are being pursued and include, for example, decreasing the ratio of mutant to wild-type mitochondrial genomes (gene shifting), converting mutated mtDNA genes into normal nuclear DNA genes (allotopic expression), importing cognate genes from other species, or correcting mtDNA mutations with specific restriction endonucleases. Germline therapy raises ethical problems but is being considered for prevention of maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is

  1. Assessment of internal doses

    Rahola, T; Falk, R; Isaksson, M; Skuterud, L

    2002-01-01

    There is a definite need for training in dose calculation. Our first course was successful and was followed by a second, both courses were fully booked. An example of new tools for software products for bioassay analysis and internal dose assessment is the Integrated Modules for Bioassay Analysis (IMBA) were demonstrated at the second course. This suite of quality assured code modules have been adopted in the UK as the standard for regulatory assessment purposes. The intercomparison measurements are an important part of the Quality Assurance work. In what is known as the sup O utside workers ' directive it is stated that the internal dose measurements shall be included in the European Unions supervision system for radiation protection. The emergency preparedness regarding internal contamination was much improved by the training with and calibration of handheld instruments from participants' laboratories. More improvement will be gained with the handbook giving practical instructions on what to do in case of e...

  2. Cloning of thrombopoietin and its therapeutic potential.

    Miyazaki, H

    1996-01-01

    Recently, four groups reported the cloning of thrombopoietin (TPO), also called c-Mpl ligand, from various species. In this study, we examined the in vitro and in vivo biological activity of TPO and its therapeutic efficacy in experimental animal models. Recombinant human TPO (rhTPO) supported the formation of only megakaryocyte (MK) colonies from rat marrow MK progenitor cells [colony-forming units-megakaryocyte (CFU-MK)] and predominantly acted on GpIIb/IIIa+ CFU-MK at the late stage of differentiation. MKs generated from rat GpIIb/IIIa+ CFU-MK after 3 days of liquid culture in the presence of rhTPO had mature characteristics. rhTPO stimulated an increase in the size of TPO-induced cultured rat MKs and in the number of elongated cytoplasmic processes, also called proplatelets, from these MKs in a dose-dependent manner. Administration of rhTPO to normal BALB/c mice daily for 5 days caused dose-dependent thrombocytosis. Treatment with rhTPO induced an increase in the size and number of marrow MKs and an expansion of the marrow CFU-MK pool. We further examined the effects of rhTPO on chemotherapy-induced thrombocytopenia in animal models. Following treatment with mitomycin C, mice received daily injections of various doses of rhTPO. Administration of rhTPO reduced the severity of thrombocytopenia and accelerated the recovery of platelets in a dose-dependent fashion: there was a significant reduction in the decrease in numbers of marrow MKs and CFU-MK with rhTPO treatment. Treatment with rhTPO also significantly improved neutropenia in mitomycin C-treated mice. Similar therapeutic efficacy was observed in cynomolgus monkeys with thrombocytopenia induced by nimustine. In addition, there was no significant change in several serum-chemistry parameters, in C-reactive protein, an acute phase protein, or in some variables involved in the blood-coagulation system. Furthermore, platelets from mice made thrombocytotic by repeated administration of rhTPO showed normal

  3. Individualized dose prescription for hypofractionation in advanced non-small-cell lung cancer radiotherapy: an in silico trial.

    Hoffmann, A.L.; Troost, E.G.C.; Huizenga, H.; Kaanders, J.H.A.M.; Bussink, J.

    2012-01-01

    PURPOSE: Local tumor control and outcome remain poor in patients with advanced non-small-cell lung cancer (NSCLC) treated by external beam radiotherapy. We investigated the therapeutic gain of individualized dose prescription with dose escalation based on normal tissue dose constraints for various h

  4. Biotech drugs : biological therapeutic agents

    Grech, Godfrey; Fenech, Anthony

    2009-01-01

    The recent years has seen significant growth in a new therapeutic approach to the management of disease. Biological therapeutic agents, constitute a broad category of drugs, usually generated by recombinant techniques from living organisms. These therapies revolutionise the traditional approaches to drug design and development, and regulatory agencies have been swift in developing the necessary structures to ensure their optimal use.

  5. Toward Constructing the Therapeutic System.

    Andolfi, Maurizio; Angelo, Claudio

    1988-01-01

    Describes the therapist as an active participant in the construction of the therapeutic system, explaining how the therapist constructs complex relationships within the evolving therapeutic process. Reevaluates the importance of the individual in the family as an agent of change and as a mediator of triangular relational messages. (Author/NB)

  6. Dose Reduction Techniques

    WAGGONER, L.O.

    2000-05-16

    As radiation safety specialists, one of the things we are required to do is evaluate tools, equipment, materials and work practices and decide whether the use of these products or work practices will reduce radiation dose or risk to the environment. There is a tendency for many workers that work with radioactive material to accomplish radiological work the same way they have always done it rather than look for new technology or change their work practices. New technology is being developed all the time that can make radiological work easier and result in less radiation dose to the worker or reduce the possibility that contamination will be spread to the environment. As we discuss the various tools and techniques that reduce radiation dose, keep in mind that the radiological controls should be reasonable. We can not always get the dose to zero, so we must try to accomplish the work efficiently and cost-effectively. There are times we may have to accept there is only so much you can do. The goal is to do the smart things that protect the worker but do not hinder him while the task is being accomplished. In addition, we should not demand that large amounts of money be spent for equipment that has marginal value in order to save a few millirem. We have broken the handout into sections that should simplify the presentation. Time, distance, shielding, and source reduction are methods used to reduce dose and are covered in Part I on work execution. We then look at operational considerations, radiological design parameters, and discuss the characteristics of personnel who deal with ALARA. This handout should give you an overview of what it takes to have an effective dose reduction program.

  7. Bacteriophage Procurement for Therapeutic Purposes.

    Weber-Dąbrowska, Beata; Jończyk-Matysiak, Ewa; Żaczek, Maciej; Łobocka, Małgorzata; Łusiak-Szelachowska, Marzanna; Górski, Andrzej

    2016-01-01

    Bacteriophages (phages), discovered 100 years ago, are able to infect and destroy only bacterial cells. In the current crisis of antibiotic efficacy, phage therapy is considered as a supplementary or even alternative therapeutic approach. Evolution of multidrug-resistant and pandrug-resistant bacterial strains poses a real threat, so it is extremely important to have the possibility to isolate new phages for therapeutic purposes. Our phage laboratory and therapy center has extensive experience with phage isolation, characterization, and therapeutic application. In this article we present current progress in bacteriophages isolation and use for therapeutic purposes, our experience in this field and its practical implications for phage therapy. We attempt to summarize the state of the art: properties of phages, the methods for their isolation, criteria of phage selection for therapeutic purposes and limitations of their use. Perspectives for the use of genetically engineered phages to specifically target bacterial virulence-associated genes are also briefly presented.

  8. Metrics for antibody therapeutics development.

    Reichert, Janice M

    2010-01-01

    A wide variety of full-size monoclonal antibodies (mAbs) and therapeutics derived from alternative antibody formats can be produced through genetic and biological engineering techniques. These molecules are now filling the preclinical and clinical pipelines of every major pharmaceutical company and many biotechnology firms. Metrics for the development of antibody therapeutics, including averages for the number of candidates entering clinical study and development phase lengths for mAbs approved in the United States, were derived from analysis of a dataset of over 600 therapeutic mAbs that entered clinical study sponsored, at least in part, by commercial firms. The results presented provide an overview of the field and context for the evaluation of on-going and prospective mAb development programs. The expansion of therapeutic antibody use through supplemental marketing approvals and the increase in the study of therapeutics derived from alternative antibody formats are discussed.

  9. Clinical applications of therapeutic phlebotomy

    Kim KH

    2016-07-01

    Full Text Available Kyung Hee Kim,1 Ki Young Oh,2 1Department of Laboratory Medicine, Gachon University Gil Medical Center, Incheon, 2Department of Physical Medicine and Rehabilitation, Soonchunhyang University, Cheonan Hospital, Cheonan, South Korea Abstract: Phlebotomy is the removal of blood from the body, and therapeutic phlebotomy is the preferred treatment for blood disorders in which the removal of red blood cells or serum iron is the most efficient method for managing the symptoms and complications. Therapeutic phlebotomy is currently indicated for the treatment of hemochromatosis, polycythemia vera, porphyria cutanea tarda, sickle cell disease, and nonalcoholic fatty liver disease with hyperferritinemia. This review discusses therapeutic phlebotomy and the related disorders and also offers guidelines for establishing a therapeutic phlebotomy program. Keywords: therapeutic phlebotomy, hemochromatosis, polycythemia vera, porphyria cutanea tarda, sickle cell disease, nonalcoholic fatty liver disease

  10. [Flurbiprofen: therapeutic alternative in nephritic colic].

    Julián Mora, M; Extramiana, J; Navarro, F J; Arrizabalaga, M; Mañas, A; González, P; Pérez, M J; Paniagua, P

    1992-10-01

    A double blind randomized study was conducted in 52 patients with renoureteric colic to compare the therapeutic efficacy of two analgesics given in a single intramuscular dose. Following the administration of 2 gm dipirone plus 20 mg hyoscine N-butylbromide (n = 26) or 150 mg flurbiprofen (n-26), the patients were assessed for pain intensity, relief and pain status for a period of one hour. Both treatments afforded a similar analgesic effect, with pain remitting in 76.9% of the cases. No significant differences were observed for the latency periods or degree of pain at 5, 10, 30 and 60 minutes following treatment. Additional analgesic therapy was required in 34.6% of the patients who received dipirone and 26.9% of the flurbiprofen group, the difference not being statistically significant. Overall both drugs were well tolerated and only local adverse effects were observed, pain being the most frequent.

  11. Overcoming therapeutic inertia in patients with hypertension.

    Nesbitt, Shawna D

    2010-01-01

    Uncontrolled blood pressure (BP) remains a leading contributor to cardiovascular disease and mortality worldwide. Although current practice guidelines recommend treating patients with hypertension to defined BP goals, the approach is not widely implemented, and BP control in clinical practice is much worse than that attained in clinical trials. Recent and ongoing clinical trials are utilizing more aggressive approaches with combination therapy as initial treatment. This article discusses the problem of therapeutic or clinical inertia when attempting to control hypertension and highlights differences in BP control rates between clinical trials and real-world practice. Additionally, the rationale for an ongoing treat-to-goal study using a fixed-dose combination of amlodipine/olmesartan medoxomil in patients with hypertension not controlled on monotherapy is provided.

  12. [Therapeutic monitoring: analytic, pharmacokinetic and clinical aspects].

    Marquet, P

    1999-01-01

    This paper gives an overview of present aspects and future prospects of therapeutic drug monitoring (TDM). The main aims of TDM are to avoid therapeutic failures due to bad compliance or too low dose of a given drug, as well as adverse or toxic effects due to an excessive dose. The therapeutic drugs frequently monitored depend on the country, but are generally few. For some of these drugs or for others, only patients at risk or belonging to particular sub-populations for a given drug, need TDM. A pre-analytical management is necessary, comprising a correct information of the physician, concerning the nature of the sample to collect and the clinical data necessary to the interpretation, as well as their recording; the control of the sample routing and storing conditions. Nowadays, drug analyses are essentially performed using immunochemical techniques, rapid and easy to operate but limited to a small number of drugs, and chromatographic methods, more specific and adaptable to almost any therapeutic drug and financially and technically more and more accessible. The interpretation of analytical results is a most important part of TDM, which requires knowledge of clinical data, precise collection time, co-administered treatments, and to dispose of a previously defined therapeutic range or target concentration, adapted to the population to which the patient belongs; the limitations of the analytical technique used must also be considered. Clinical pharmacokinetics is a further step in the use of analytical results, allowing the prediction of an efficient dose and administration schedule in one step, using a limited number of blood samples and generally a Bayesian estimation algorithm, readily available through commercial software dedicated to a few drugs in different reference populations. The pharmacokinetic characteristics of different populations and the validation of bayesian estimation have also been published for a number of drugs, sometimes by pharmaceutical

  13. Therapeutic Applications of Monte Carlo Calculations in Nuclear Medicine

    Sgouros, George

    2003-01-01

    This book examines the applications of Monte Carlo (MC) calculations in therapeutic nuclear medicine, from basic principles to computer implementations of software packages and their applications in radiation dosimetry and treatment planning. It is written for nuclear medicine physicists and physicians as well as radiation oncologists, and can serve as a supplementary text for medical imaging, radiation dosimetry and nuclear engineering graduate courses in science, medical and engineering faculties. With chapters is written by recognised authorities in that particular field, the book covers the entire range of MC applications in therapeutic medical and health physics, from its use in imaging prior to therapy to dose distribution modelling targeted radiotherapy. The contributions discuss the fundamental concepts of radiation dosimetry, radiobiological aspects of targeted radionuclide therapy and the various components and steps required for implementing a dose calculation and treatment planning methodology in ...

  14. Exubera. Inhale therapeutic systems.

    Bindra, Sanjit; Cefalu, William T

    2002-05-01

    Inhale, in colaboration with Pfizer and Aventis Pharma (formerly Hoechst Marion Roussel; HMR), is developing an insulin formulation utilizing its pulmonary delivery technology for macromolecules for the potential treatment of type I and II diabetes. By July 2001, the phase III program had been completed and the companies had begun to assemble data for MAA and NDA filings; however, it was already clear at this time that additional data might be required for filing. By December 2001, it had been decided that the NDA should include an increased level of controlled, long-term pulmonary safety data in diabetic patients and a major study was planned to be completed in 2002, with the NDA filed thereafter (during 2002). US-05997848 was issued to Inhale Therapeutic Systems in December 1999, and corresponds to WO-09524183, filed in February 1995. Equivalent applications have appeared to date in Australia, Brazil, Canada, China, Czech Republic, Europe, Finland, Hungary, Japan, Norway, New Zealand, Poland and South Africa. This family of applications is specific to pulmonary delivery of insulin. In February 1999, Lehman Brothers gave this inhaled insulin a 60% probability of reaching market, with a possible launch date of 2001. The analysts estimated peak sales at $3 billion in 2011. In May 2000, Aventis predicted that estimated peak sales would be in excess of $1 billion. In February 2000, Merrill Lynch expected product launch in 2002 and predicted that it would be a multibillion-dollar product. Analysts Merril Lynch predicted, in September and November 2000, that the product would be launched by 2002, with sales in that year of e75 million, rising to euro 500 million in 2004. In April 2001, Merrill Lynch predicted that filing for this drug would occur in 2001. Following the report of the potential delay in regulatory filing, issued in July 2001, Deutsche Banc Alex Brown predicted a filing would take place in the fourth quarter of 2002 and launch would take place in the first

  15. Dose Reduction Techniques

    Waggoner, L O

    2000-01-01

    As radiation safety specialists, one of the things we are required to do is evaluate tools, equipment, materials and work practices and decide whether the use of these products or work practices will reduce radiation dose or risk to the environment. There is a tendency for many workers that work with radioactive material to accomplish radiological work the same way they have always done it rather than look for new technology or change their work practices. New technology is being developed all the time that can make radiological work easier and result in less radiation dose to the worker or reduce the possibility that contamination will be spread to the environment. As we discuss the various tools and techniques that reduce radiation dose, keep in mind that the radiological controls should be reasonable. We can not always get the dose to zero, so we must try to accomplish the work efficiently and cost-effectively. There are times we may have to accept there is only so much you can do. The goal is to do the sm...

  16. [The therapeutic problem of current drug addiction in Italy].

    De Caro, D

    1980-04-28

    Psicosocial factors which are of main importance for drug-dependences, especially in young people, are examined. Then the most important elements of the therapy of drug-dependences are indicated, which first of all consists in the necessary treatment in the hospital and farmacological therapy (particularly during acute and over-dose states), and also psicotherapeutic--generally speaking--and social approaches. Among those therapeutic Communities seem to be extremely significant, whose most important patterns are described.

  17. Therapeutic Potential of Adipose-Derived Therapeutic Factor Concentrate for Treating Critical Limb Ischemia.

    Procházka, Václav; Jurčíková, Jana; Laššák, Ondrej; Vítková, Kateřina; Pavliska, Lubomír; Porubová, Ludmila; Buszman, Piotr P; Krauze, Agata; Fernandez, Carlos; Jalůvka, František; Špačková, Iveta; Lochman, Ivo; Jana, Dvořáčková; Merfeld-Clauss, Stephanie; March, Keith L; Traktuev, Dmitry O; Johnstone, Brian H

    2016-01-01

    Transplantation of adipose-derived stem cells (ADSCs) is an emerging therapeutic option for addressing intractable diseases such as critical limb ischemia (CLI). Evidence suggests that therapeutic effects of ADSCs are primarily mediated through paracrine mechanisms rather than transdifferentiation. These secreted factors can be captured in conditioned medium (CM) and concentrated to prepare a therapeutic factor concentrate (TFC) composed of a cocktail of beneficial growth factors and cytokines that individually and in combination demonstrate disease-modifying effects. The ability of a TFC to promote reperfusion in a rabbit model of CLI was evaluated. A total of 27 adult female rabbits underwent surgery to induce ischemia in the left hindlimb. An additional five rabbits served as sham controls. One week after surgery, the ischemic limbs received intramuscular injections of either (1) placebo (control medium), (2) a low dose of TFC, or (3) a high dose of TFC. Limb perfusion was serially assessed with a Doppler probe. Blood samples were analyzed for growth factors and cytokines. Tissue was harvested postmortem on day 35 and assessed for capillary density by immunohistochemistry. At 1 month after treatment, tissue perfusion in ischemic limbs treated with a high dose of TFC was almost double (p < 0.05) that of the placebo group [58.8 ± 23 relative perfusion units (RPU) vs. 30.7 ± 13.6 RPU; mean ± SD]. This effect was correlated with greater capillary density in the affected tissues and with transiently higher serum levels of the angiogenic and prosurvival factors vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The conclusions from this study are that a single bolus administration of TFC demonstrated robust effects for promoting tissue reperfusion in a rabbit model of CLI and that a possible mechanism of revascularization was promotion of angiogenesis by TFC. Results of this study demonstrate that TFC represents a potent

  18. Therapeutic proteasome inhibition in experimental acute pancreatitis

    Tamás Letoha; Tamás Takács; Liliána Z Fehér; László Pecze; Csaba Somlai; Ilona Varga; József Kaszaki; Gábor Tóth; Csaba Vizier; László Tiszlavicz

    2007-01-01

    AIM: To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.METHODS: Pancreatitis was induced in rats by two hourly intraperitoneal (ip) injections of cholecystokinin octapeptide (CCK; 2 × 100 μg/kg) and the proteasome inhibitor MG132 (10 mg/kg ip) was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK.RESULTS: Administering the proteasome inhibitor MG132 (at a dose of 10 mg/kg, ip) 90 min after the onset of pancreatic inflammation induced the expression of cell-protective 72 kDa heat shock protein (HSP72) and decreased DNA-binding of nuclear factor-κB (NF-κB).Furthermore MG132 treatment resulted in milder inflammatory response and cellular damage, as revealed by improved laboratory and histological parameters of pancreatitis and associated oxidative stress.CONCLUSION: Our findings suggest that proteasome inhibition might be beneficial not only for the prevention,but also for the therapy of acute pancreatitis.

  19. Mechanisms and therapeutic effectiveness of lactobacilli

    Di Cerbo, Alessandro; Palmieri, Beniamino; Aponte, Maria; Morales-Medina, Julio Cesar; Iannitti, Tommaso

    2016-01-01

    The gut microbiome is not a silent ecosystem but exerts several physiological and immunological functions. For many decades, lactobacilli have been used as an effective therapy for treatment of several pathological conditions displaying an overall positive safety profile. This review summarises the mechanisms and clinical evidence supporting therapeutic efficacy of lactobacilli. We searched Pubmed/Medline using the keyword ‘Lactobacillus’. Selected papers from 1950 to 2015 were chosen on the basis of their content. Relevant clinical and experimental articles using lactobacilli as therapeutic agents have been included. Applications of lactobacilli include kidney support for renal insufficiency, pancreas health, management of metabolic imbalance, and cancer treatment and prevention. In vitro and in vivo investigations have shown that prolonged lactobacilli administration induces qualitative and quantitative modifications in the human gastrointestinal microbial ecosystem with encouraging perspectives in counteracting pathology-associated physiological and immunological changes. Few studies have highlighted the risk of translocation with subsequent sepsis and bacteraemia following probiotic administration but there is still a lack of investigations on the dose effect of these compounds. Great care is thus required in the choice of the proper Lactobacillus species, their genetic stability and the translocation risk, mainly related to inflammatory disease-induced gut mucosa enhanced permeability. Finally, we need to determine the adequate amount of bacteria to be delivered in order to achieve the best clinical efficacy decreasing the risk of side effects. PMID:26578541

  20. Mechanisms and therapeutic effectiveness of lactobacilli.

    Di Cerbo, Alessandro; Palmieri, Beniamino; Aponte, Maria; Morales-Medina, Julio Cesar; Iannitti, Tommaso

    2016-03-01

    The gut microbiome is not a silent ecosystem but exerts several physiological and immunological functions. For many decades, lactobacilli have been used as an effective therapy for treatment of several pathological conditions displaying an overall positive safety profile. This review summarises the mechanisms and clinical evidence supporting therapeutic efficacy of lactobacilli. We searched Pubmed/Medline using the keyword 'Lactobacillus'. Selected papers from 1950 to 2015 were chosen on the basis of their content. Relevant clinical and experimental articles using lactobacilli as therapeutic agents have been included. Applications of lactobacilli include kidney support for renal insufficiency, pancreas health, management of metabolic imbalance, and cancer treatment and prevention. In vitro and in vivo investigations have shown that prolonged lactobacilli administration induces qualitative and quantitative modifications in the human gastrointestinal microbial ecosystem with encouraging perspectives in counteracting pathology-associated physiological and immunological changes. Few studies have highlighted the risk of translocation with subsequent sepsis and bacteraemia following probiotic administration but there is still a lack of investigations on the dose effect of these compounds. Great care is thus required in the choice of the proper Lactobacillus species, their genetic stability and the translocation risk, mainly related to inflammatory disease-induced gut mucosa enhanced permeability. Finally, we need to determine the adequate amount of bacteria to be delivered in order to achieve the best clinical efficacy decreasing the risk of side effects.

  1. Clinical and economic consequences of pharmacogenetic-guided dosing of warfarin

    T.I. Verhoef (Talitha); T. Schalekamp (Talitha); W.K. Redekop (Ken); A.C. de Boer (Anthonius); A-H. Maitland-van der Zee (Anke-Hilse)

    2010-01-01

    textabstractPatients using warfarin for oral anticoagulant therapy need to be frequently monitored because of warfarins narrow therapeutic range and the large variation in dose requirements among patients. Patients receiving the wrong dose have an increased risk of bleeding or thromboembolic events.

  2. Evidence Based Digoxin Therapeutic Monitoring - A Lower and Narrower Therapeutic Range

    Amine BENLMOUDEN

    2016-06-01

    Full Text Available Cardiac glycosides have been used for congestive heart failure and certain cardiac arrhythmias for more than 200 years. Despite the introduction of a variety of new classes of drugs for the management of heart failure, specifically angiotensin-converting enzyme (ACE inhibitors, b-adrenergic antagonists (bblockers, and the aldosterone antagonist spironolactone, digoxin continues to have an important role in long-term outpatient management. However, a narrow margin exists between therapeutic and toxic doses of digoxin, resulting in a high incidence of digoxin toxicity in clinical practice.A wide variety of placebo-controlled clinical trials have unequivocally shown that treatment with digoxin can improve symptoms, quality of life, and exercise tolerance in patients with mild, moderate, or severe heart failure. The clinical relevance of digoxin therapeutic monitoring is also proved but the SDC (Serum Digoxin Conentrations required for optimal clinical efficacy and acceptable toxicity remains controversial. In the last years, international guidelines recommend 1.2 ng/mL as acceptable high level.In this bibliographic synthesis, we aim to collect pertinent informations from MedLine database about exposure-effect relationship in order to assess the evidence level scientific of new digoxin therapeutic monitoring. 

  3. Potential therapeutic uses of mecamylamine and its stereoisomers.

    Nickell, Justin R; Grinevich, Vladimir P; Siripurapu, Kiran B; Smith, Andrew M; Dwoskin, Linda P

    2013-07-01

    Mecamylamine (3-methylaminoisocamphane hydrochloride) is a nicotinic parasympathetic ganglionic blocker, originally utilized as a therapeutic agent to treat hypertension. Mecamylamine administration produces several deleterious side effects at therapeutically relevant doses. As such, mecamylamine's use as an antihypertensive agent was phased out, except in severe hypertension. Mecamylamine easily traverses the blood-brain barrier to reach the central nervous system (CNS), where it acts as a nicotinic acetylcholine receptor (nAChR) antagonist, inhibiting all known nAChR subtypes. Since nAChRs play a major role in numerous physiological and pathological processes, it is not surprising that mecamylamine has been evaluated for its potential therapeutic effects in a wide variety of CNS disorders, including addiction. Importantly, mecamylamine produces its therapeutic effects on the CNS at doses 3-fold lower than those used to treat hypertension, which diminishes the probability of peripheral side effects. This review focuses on the pharmacological properties of mecamylamine, the differential effects of its stereoisomers, S(+)- and R(-)-mecamylamine, and the potential for effectiveness in treating CNS disorders, including nicotine and alcohol addiction, mood disorders, cognitive impairment and attention deficit hyperactivity disorder.

  4. High-dose Helical Tomotherapy With Concurrent Full-dose Chemotherapy for Locally Advanced Pancreatic Cancer

    Chang, Jee Suk [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Wang, Michael L.C. [Department of Radiation Oncology, National Cancer Centre (Singapore); Koom, Woong Sub; Yoon, Hong In; Chung, Yoonsun [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Song, Si Young [Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Seong, Jinsil, E-mail: jsseong@yuhs.ac [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2012-08-01

    Purpose: To improve poor therapeutic outcome of current practice of chemoradiotherapy (CRT), high-dose helical tomotherapy (HT) with concurrent full-dose chemotherapy has been performed on patients with locally advanced pancreatic cancer (LAPC), and the results were analyzed. Methods and Materials: We retrospectively reviewed 39 patients with LAPC treated with radiotherapy using HT (median, 58.4 Gy; range, 50.8-59.9 Gy) and concomitant chemotherapy between 2006 and 2009. Radiotherapy was directed to the primary tumor with a 0.5-cm margin without prophylactic nodal coverage. Twenty-nine patients (79%) received full-dose (1000 mg/m{sup 2}) gemcitabine-based chemotherapy during HT. After completion of CRT, maintenance chemotherapy was administered to 37 patients (95%). Results: The median follow-up was 15.5 months (range, 3.4-43.9) for the entire cohort, and 22.5 months (range, 12.0-43.9) for the surviving patients. The 1- and 2-year local progression-free survival rates were 82.1% and 77.3%, respectively. Eight patients (21%) were converted to resectable status, including 1 with a pathological complete response. The median overall survival and progression-free survival were 21.2 and 14.0 months, respectively. Acute toxicities were acceptable with no gastrointestinal (GI) toxicity higher than Grade 3. Severe late GI toxicity ({>=}Grade 3) occurred in 10 patients (26%); 1 treatment-related death from GI bleeding was observed. Conclusion: High-dose helical tomotherapy with concurrent full-dose chemotherapy resulted in improved local control and long-term survival in patients with LAPC. Future studies are needed to widen the therapeutic window by minimizing late GI toxicity.

  5. Current therapeutic procedures in Dravet syndrome.

    Chiron, Catherine

    2011-04-01

    Dravet syndrome is a highly pharmaco-resistant form of epilepsy. Valproate and benzodiazepines are the first-line treatment but are usually insufficient therapeutic options. Lamotrigine, carbamazepine and high doses of intravenous phenobarbital can aggravate seizures and should be avoided. Topiramate, levetiracetam, bromide and ketogenic diet also provide substantial efficacy as adjunctive therapy and procedures. Stiripentol is the only new drug to demonstrate efficacy when combined with valproate and clobazam, as shown in two independent double-blind controlled trials dedicated to Dravet children. In order to avoid side effects (mainly loss of appetite and loss of weight) resulting from the inhibition of cytochromes P450 by stiripentol, the prescribed doses of valproate and clobazam should be reduced. Stiripentol has a proper antiepileptic effect and enhances GABAergic neurotransmission by acting on the alpha-3 subunit of GABA(A) receptors. Stiripentol was approved as an orphan drug in Europe in 2007 for adjunctive therapy in Dravet syndrome. More than 500 Dravet patients have currently been satisfactorily treated and recent experiments in Japan have confirmed stiripentol's benefit. In practice, valproate should be initiated at the first onset of complicated febrile seizure in Dravet patients. Relapses justify the addition of clobazam and stiripentol when available. Topiramate and a ketogenic diet are alternatives in pharmaco-resistant cases.

  6. Gut microbiota and tacrolimus dosing in kidney transplantation.

    John R Lee

    Full Text Available Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5 or did not require such an increase (Dose Stable Group, n=14. We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2 ± 1.1 mg/day vs. 3.8 ± 0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6 ± 2.4 mg/day vs. 3.3 ± 1.5 mg/day, respectively, P<0.001. Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses. Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01 and had a coefficient ± standard error of 1.0 ± 0.6 (P=0.08 after multivariable linear

  7. Effects of proton radiation dose, dose rate and dose fractionation on hematopoietic cells in mice

    Ware, J.H.; Rusek, A.; Sanzari, J.; Avery, S.; Sayers, C.; Krigsfeld, G.; Nuth, M.; Wan, X.S.; Kennedy, A.R.

    2010-09-01

    The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons.

  8. How to Use Equipment Therapeutically.

    Bowne, Douglas

    1986-01-01

    Shares therapeutic and economic practices surrounding equipment used in New York's Higher Horizons adventure program of therapy for troubled youth. Encourages educators, therapists, and administrators to explore relationship between equipment selection, program goals, and clients. (NEC)

  9. Entrance surface dose according to dose calculation: Head and wrist

    Sung, Ho Jin [Dept. Radiology, Chonnam National University Hospital, Gwangju (Korea, Republic of); Han, Jae Bok; Song, Jong Nam; Choi, Nam Gil [Dept. of Radiological Science, Dongshin University, Naju (Korea, Republic of)

    2016-09-15

    This study were compared with the direct measurement and indirect dose methods through various dose calculation in head and wrist. And, the modified equation was proposed considering equipment type, setting conditions, tube voltage, inherent filter, added filter and its accompanied back scatter factor. As a result, it decreased the error of the direct measurement than the existing dose calculation. Accordingly, diagnostic radiography patient dose comparison would become easier and radiographic exposure control and evaluation will become more efficient. The study findings are expected to be useful in patients' effective dose rate evaluation and dose reduction.

  10. Doses from radiation exposure

    Menzel, H G

    2012-01-01

    Practical implementation of the International Commission on Radiological Protection's (ICRP) system of protection requires the availability of appropriate methods and data. The work of Committee 2 is concerned with the development of reference data and methods for the assessment of internal and external radiation exposure of workers and members of the public. This involves the development of reference biokinetic and dosimetric models, reference anatomical models of the human body, and reference anatomical and physiological data. Following ICRP's 2007 Recommendations, Committee 2 has focused on the provision of new reference dose coefficients for external and internal exposure. As well as specifying changes to the radiation and tissue weighting factors used in the calculation of protection quantities, the 2007 Recommendations introduced the use of reference anatomical phantoms based on medical imaging data, requiring explicit sex averaging of male and female organ-equivalent doses in the calculation of effecti...

  11. Clinical and economic consequences of pharmacogenetic-guided dosing of warfarin

    2010-01-01

    textabstractPatients using warfarin for oral anticoagulant therapy need to be frequently monitored because of warfarins narrow therapeutic range and the large variation in dose requirements among patients. Patients receiving the wrong dose have an increased risk of bleeding or thromboembolic events. The required dose is influenced by environmental factors, such as gender, age, diet and concomitant medication, as well as genetic factors. Pharmacogenetic testing prior to warfarin initiation mig...

  12. [Therapeutic touch and anorexia nervosa].

    Satori, Nadine

    2016-01-01

    An innovative practice, therapeutic touch has been used for around ten years in the treatment of eating disorders. Delivered by nurse clinicians having received specific training, this approach is based on nursing diagnoses which identify the major symptoms of this pathology. The support is built around the body and its perceptions. Through the helping relationship, it mobilises the patient's resources to favour a relationship of trust, a letting-go, physical, psychological and emotional relaxation, and improves the therapeutic alliance.

  13. Antibody Engineering and Therapeutics Conference

    Larrick, James W; Parren, Paul WHI; Huston, James S; Plückthun, Andreas; Bradbury, Andrew; Tomlinson, Ian M; Chester, Kerry A.; Burton, Dennis R.; Adams, Gregory P.; Weiner, Louis M.; Scott, Jamie K.; Alfenito, Mark R; Veldman, Trudi; Reichert, Janice M.

    2013-01-01

    The Antibody Engineering and Therapeutics conference, which serves as the annual meeting of The Antibody Society, will be held in Huntington Beach, CA from Sunday December 8 through Thursday December 12, 2013. The scientific program will cover the full spectrum of challenges in antibody research and development, and provide updates on recent progress in areas from basic science through approval of antibody therapeutics. Keynote presentations will be given by Leroy Hood (Institute of System Bi...

  14. First dose in man

    2011-01-01

    Du er blevet ansat som læge i et lægemiddelfirma med ansvar for planlægning og sikkerhed i fase 1 forsøg. Firmaet har udviklet tre dopamin D2-receptor antagonister til behandling af skizofreni. Lægemidlerne har undergået et omfattende farmakologisk, toksikologisk og farmaceutisk afprøvningsprogra...... fase 1 forsøg alias »First dose in man«....

  15. Estimation of the Dose and Dose Rate Effectiveness Factor

    Chappell, L.; Cucinotta, F. A.

    2013-01-01

    Current models to estimate radiation risk use the Life Span Study (LSS) cohort that received high doses and high dose rates of radiation. Transferring risks from these high dose rates to the low doses and dose rates received by astronauts in space is a source of uncertainty in our risk calculations. The solid cancer models recommended by BEIR VII [1], UNSCEAR [2], and Preston et al [3] is fitted adequately by a linear dose response model, which implies that low doses and dose rates would be estimated the same as high doses and dose rates. However animal and cell experiments imply there should be curvature in the dose response curve for tumor induction. Furthermore animal experiments that directly compare acute to chronic exposures show lower increases in tumor induction than acute exposures. A dose and dose rate effectiveness factor (DDREF) has been estimated and applied to transfer risks from the high doses and dose rates of the LSS cohort to low doses and dose rates such as from missions in space. The BEIR VII committee [1] combined DDREF estimates using the LSS cohort and animal experiments using Bayesian methods for their recommendation for a DDREF value of 1.5 with uncertainty. We reexamined the animal data considered by BEIR VII and included more animal data and human chromosome aberration data to improve the estimate for DDREF. Several experiments chosen by BEIR VII were deemed inappropriate for application to human risk models of solid cancer risk. Animal tumor experiments performed by Ullrich et al [4], Alpen et al [5], and Grahn et al [6] were analyzed to estimate the DDREF. Human chromosome aberration experiments performed on a sample of astronauts within NASA were also available to estimate the DDREF. The LSS cohort results reported by BEIR VII were combined with the new radiobiology results using Bayesian methods.

  16. 常规剂量甲泼尼龙、泼尼松序贯疗法在原发性肾病综合征中的疗效分析%Analysis of therapeutic effect of sequential therapy in primary nephrotic syndrome with regular dose methylprednisolone and prednisone

    李晓勇; 杜娜; 张杰; 王玉路; 李方晓; 李斌

    2013-01-01

    Objective To analyze the efficacy of regular dose methylprednisolone , prednisone of sequential therapy in primary nephrotic syndrome .Methods 80 patients with primary nephrotic syndrome were divided into two groups according to pathological type , glucocorticoids group ( A) , and another group ( B) with glucocorticoid and cytotoxic drugs . Then each group was randomly divided into two groups , namely , the application of methylprednisolone group ( treatment group) and oral prednisone group ( control group) , and made a curative effect analysis .Results There was no statistical difference in the remission rate of the two groups between regular dose methylprednisolone , prednisone sequential therapy and regular prednisone therapy (P > 0 .05 ) , but the effect of the 24 - hour urinary protein excretion , serum albumin , cholesterol , edema and urinary protein clearance time in treatment group was superior to those in the control group , There was no significant statistical difference (P < 0 .05 ) .Conclusion The treatment of the regular dose of methylprednisolone , prednisone sequential therapy can more quickly relieve the patient's symptom than regular prednisone application in primary nephrotic syndrome .%目的:分析常规剂量甲泼尼龙、泼尼松序贯疗法在原发性肾病综合征中的疗效。方法80例原发性肾病综合征患者依病理类型分为2组,A 组应用糖皮质激素,B 组为应用糖皮质激素加细胞毒类药物。再将上2组各随机分为2组,即甲泼尼龙组(治疗组)、口服泼尼松组(对照组),进行疗效分析。结果常规剂量甲泼尼龙、泼尼松序贯疗法较常规泼尼松疗法在病情缓解率方面2组差异无统计学意义(P >0.05),但在24 h 尿蛋白定量、血浆白蛋白、胆固醇、水肿消退时间、尿蛋白转阴时间等方面均优于对照组,差异有统计学意义(P <0.05)。结论常规剂量甲泼尼龙、泼尼松序贯疗法在原发

  17. 个体化剂量丙种球蛋白联合地塞米松治疗儿童重症特发性血小板减少性紫癜78例疗效观察%Therapeutic effects of individual-dose intravenous immunoglobulin combined with dexamethasone on 78 children with severe idiopathic thrombocytopenic purpura

    李建厂; 贾秀红; 唐慎华; 朱淑霞; 杨华琴

    2011-01-01

    目的 观察个体化剂量静脉注射用丙种球蛋白(IVIG)联合地塞米松治疗儿童特发性血小板减少性紫癜(ITP)的疗效.方法 重症ITP患儿入院后均给地塞米松及IVIG[400 mg/(kg·d)],3 d后测外周血血小板计数,≥100×109/L停用IVIG,继用地塞米松;若<100×109/L,再继续用原剂量IVIG 2 d.结果 治疗3 d后,78例患儿中,37例外周血血小板计数升至100×109/L以上,余41例继续治疗后,31例升至100×109/L以上.结论 个体化剂量IVIG联合地塞米松是治疗儿童重症ITP的有效办法,可节省一定医疗费用.%Objective To evaluate the effect of individual-dose immunoglobulin combined with dexamethasone on 78 children with severe idiopathic thrombocytopenic purpura (ITP). Methods All the children with ITP were treated with dexamethasone and immunoglobulin (400 mg/kg · d). The platelet counts were detected after 3 day ' s treatment. The patients with platelet ≥ 100 × 109/L continued the treatment of dexamethasone. The others with platelet < 100 × 109/L added the treatment of immunoglobulin (400 mg/kg · d) for 2 days. Results The platelet counts of 37 children were elevated more than 100 ×109/L, and those of 41 children were still lower than 100 × 109/L after 3 day' s treatment. After additional treatment of dexamethasone and immunoglobulin for 2 days, 31 cases got a platelet increase of more than 100 × 109/L. Conclusions Treatment of individual-dose immunoglobulin combined with dexarnethasone is an effective way to treat children with severe ITP. It reduced a lot of medical cost for patients and their family.

  18. Clobazam single or divided dose against diazepam in anxiety neurosis.

    Channabasavanna, S M; Pinto Pereira, L M

    1986-01-01

    One-hundred-and-fifteen patients diagnosed as anxiety neurotics randomly received in a double blind study 20 mg clobazam (Frisium) as a single nightly dose (37 patients) or 10 mg b.d. (38 patients) or diazepam 5 mg b.d. (40 patients) for six weeks, followed by two weeks on placebo. Both the single and divided doses of clobazam were therapeutically equivalent to diazepam. After drug withdrawal, all three treatment groups continued to improve. Patients on clobazam showed better motor performance than the diazepam series. Patients on clobazam divided dose performed significantly better than those on diazepam. Minor side-effects occurred in all patients. From the results clobazam as a single dose of 20 mg has good anxiolysis without any hungover effect.

  19. Low dose ionizing radiation induced acoustic neuroma: A putative link?

    Sachin A Borkar

    2012-01-01

    Full Text Available Although exposure to high dose ionizing radiation (following therapeutic radiotherapy has been incriminated in the pathogenesis of many brain tumors, exposure to chronic low dose ionizing radiation has not yet been shown to be associated with tumorigenesis. The authors report a case of a 50-year-old atomic reactor scientist who received a cumulative dose of 78.9 mSv over a 10-year period and was detected to have an acoustic neuroma another 15 years later. Although there is no proof that exposure to ionizing radiation was the cause for the development of the acoustic neuroma, this case highlights the need for extended follow-up periods following exposure to low dose ionizing radiation.

  20. Phage therapy pharmacology: calculating phage dosing.

    Abedon, Stephen

    2011-01-01

    Phage therapy, which can be described as a phage-mediated biocontrol of bacteria (or, simply, biocontrol), is the application of bacterial viruses-also bacteriophages or phages-to reduce densities of nuisance or pathogenic bacteria. Predictive calculations for phage therapy dosing should be useful toward rational development of therapeutic as well as biocontrol products. Here, I consider the theoretical basis of a number of concepts relevant to phage dosing for phage therapy including minimum inhibitory concentration (but also "inundation threshold"), minimum bactericidal concentration (but also "clearance threshold"), decimal reduction time (D value), time until bacterial eradication, threshold bacterial density necessary to support phage population growth ("proliferation threshold"), and bacterial density supporting half-maximal phage population growth rates (K(B)). I also address the concepts of phage killing titers, multiplicity of infection, and phage peak densities. Though many of the presented ideas are not unique to this chapter, I nonetheless provide variations on derivations and resulting formulae, plus as appropriate discuss relative importance. The overriding goal is to present a variety of calculations that are useful toward phage therapy dosing so that they may be found in one location and presented in a manner that allows facile appreciation, comparison, and implementation. The importance of phage density as a key determinant of the phage potential to eradicate bacterial targets is stressed throughout the chapter.

  1. Biosensors and nanobiosensors for therapeutic drug and response monitoring.

    McKeating, Kristy S; Aubé, Alexandra; Masson, Jean-Francois

    2016-01-21

    Therapeutic drug monitoring (TDM) is required for pharmaceutical drugs with dosage limitations or toxicity issues where patients undergoing treatment with these drugs require frequent monitoring. This allows for the concentration of such pharmaceutical drugs in a patient's biofluid to be closely monitored in order to assess the pharmacokinetics, which could result in an adjustment of dosage or in medical intervention if the situation becomes urgent. Biosensors are a class of analytical techniques competent in the rapid quantification of therapeutic drugs and recent developments in instrumental platforms and in sensing schemes, as well as the emergence of nanobiosensors, have greatly contributed to the principal examples of these sensors for therapeutic drug monitoring. Based on initial success stories, it is clear that (nano)biosensors could pave the way for therapeutic drug monitoring of many commonly administered drugs and for new drugs that will be introduced to the market allowing for safe and optimal dosing across a wide range of pharmaceuticals. In this review, we report on the recent developments in biosensing and nanobiosensing techniques and, focussing mainly on anti-cancer agents and antibiotics, we discuss the different classes of molecules upon which therapeutic drug monitoring has already been successfully applied. The potential contributions of (nano)biosensors are also reviewed for the emerging areas of therapeutic response monitoring, where markers are monitored to ensure compliance of a patient to a treatment and in the area of cellular response to therapeutic drugs in order to identify cytotoxic effects of drugs on cells or to identify patients responding to a drug.

  2. Dose distributions around selectron applicators

    Pla, C.; Evans, M.D.; Podgorsak, E.B.

    1987-11-01

    Measured and calculated dose distributions around selectron applicators, loaded with /sup 60/Co high dose rate pellets, are presented. The effect of the stopping screw, spacers, pellets themselves and the applicator wall on the dose distribution is discussed. The measured dose distribution is in almost perfect agreement with the calculated distribution in planes perpendicular to the applicator axis and containing a source. On the applicator axis directly below the applicator the measured dose amounts to about 75% of the calculated value, when only the stopping screw attenuates the beam from a pellet. When the beam is attenuated by spacers in addition to the stopping screw, the discrepancy between the calculated and measured dose may exceed 50%. Clinically relevant source geometries are also discussed. It is shown that for most regions around the applicator the method of a simple addition of dose contributions from individual point sources is an acceptable approximation for the calculation of dose distributions around the selectron applicators.

  3. Evaluating dose response from flexible dose clinical trials

    Baron David

    2008-01-01

    Full Text Available Abstract Background The true dose effect in flexible-dose clinical trials may be obscured and even reversed because dose and outcome are related. Methods To evaluate dose effect in response on primary efficacy scales from 2 randomized, double-blind, flexible-dose trials of patients with bipolar mania who received olanzapine (N = 234, 5–20 mg/day, or patients with schizophrenia who received olanzapine (N = 172, 10–20 mg/day, we used marginal structural models, inverse probability of treatment weighting (MSM, IPTW methodology. Dose profiles for mean changes from baseline were evaluated using weighted MSM with a repeated measures model. To adjust for selection bias due to non-random dose assignment and dropouts, patient-specific time-dependent weights were determined as products of (i stable weights based on inverse probability of receiving the sequence of dose assignments that was actually received by a patient up to given time multiplied by (ii stable weights based on inverse probability of patient remaining on treatment by that time. Results were compared with those by unweighted analyses. Results While the observed difference in efficacy scores for dose groups for the unweighted analysis strongly favored lower doses, the weighted analyses showed no strong dose effects and, in some cases, reversed the apparent "negative dose effect." Conclusion While naïve comparison of groups by last or modal dose in a flexible-dose trial may result in severely biased efficacy analyses, the MSM with IPTW estimators approach may be a valuable method of removing these biases and evaluating potential dose effect, which may prove useful for planning confirmatory trials.

  4. Hanford Environmental Dose Reconstruction Project

    Finch, S.M.; McMakin, A.H. (comps.)

    1992-02-01

    The objective of the Hanford Environmental Dose Reconstruction Project is to estimate the radiation doses that individuals and populations could have received from nuclear operations at Hanford since 1944. The project is divided into the following technical tasks. These tasks correspond to the path radionuclides followed, from release to impact on humans (dose estimates): source terms; environmental transport; environmental monitoring data; demography, food consumption, and agriculture; environmental pathways and dose estimates.

  5. CLOBAZAM SINGLE OR DIVIDED DOSE AGAINST DIAZEPAM IN ANXIETY NEUROSIS

    1986-01-01

    SUMMARY One-hundred-and-fifteen patients diagnosed as anxiety neurotics randomly received in a double blind study 20 mg clobazam (Frisium) as a single nightly dose (37 patients) or 10 mg b.d. (38 patients) or diazepam 5 mg b.d. (40 patients) for six weeks, followed by two weeks on placebo. Both the single and divided doses of clobazam were therapeutically equivalent to diazepam. After drug withdrawal, all three treatment groups continued to improve. Patients on clobazam showed better motor pe...

  6. Bone-seeking therapeutic radiopharmaceuticals

    Srivastava Suresh C.

    2002-01-01

    Full Text Available Bone-seeking therapeutic radiopharmaceuticals are utilized on the basis of the radionuclide?s particulate emissions (primarily low to intermediate beta emission. The requirements therefore are different from those of bone imaging agents that consist mainly of short-lived single photon emitters. Lately, the therapeutic bone seeking radiopharmaceuticals have attained increasing importance due to their potential role in alleviating pain from osseous metastases in cancer patients, for the treatment of joint pain resulting from inflamed synovium (radiosynoviorthesis, or radiosynovectomy, or from various other forms of arthritic disease. There is, however, a paucity of published data on the bio-pharmacokinetics of these agents when used following intravenous administration for bone pain palliation. This paper will briefly review and summarize the presently available chemical and biopharmacokinetic information on the various clinically approved as well as experimental bone-localizing therapeutic radiopharmaceuticals, and make projections on their clinical application for the treatment of primary/metastatic cancer in bone.

  7. Therapeutic hypothermia for acute stroke

    Olsen, Tom Skyhøj; Weber, Uno Jakob; Kammersgaard, Lars Peter

    2003-01-01

    Experimental evidence and clinical experience show that hypothermia protects the brain from damage during ischaemia. There is a growing hope that the prevention of fever in stroke will improve outcome and that hypothermia may be a therapeutic option for the treatment of stroke. Body temperature...... is directly related to stroke severity and outcome, and fever after stroke is associated with substantial increases in morbidity and mortality. Normalisation of temperature in acute stroke by antipyretics is generally recommended, although there is no direct evidence to support this treatment. Despite its...... obvious therapeutic potential, hypothermia as a form of neuroprotection for stroke has been investigated in only a few very small studies. Therapeutic hypothermia is feasible in acute stroke but owing to serious side-effects--such as hypotension, cardiac arrhythmia, and pneumonia--it is still thought...

  8. Potential therapeutic applications of biosurfactants.

    Gudiña, Eduardo J; Rangarajan, Vivek; Sen, Ramkrishna; Rodrigues, Lígia R

    2013-12-01

    Biosurfactants have recently emerged as promising molecules for their structural novelty, versatility, and diverse properties that are potentially useful for many therapeutic applications. Mainly due to their surface activity, these molecules interact with cell membranes of several organisms and/or with the surrounding environments, and thus can be viewed as potential cancer therapeutics or as constituents of drug delivery systems. Some types of microbial surfactants, such as lipopeptides and glycolipids, have been shown to selectively inhibit the proliferation of cancer cells and to disrupt cell membranes causing their lysis through apoptosis pathways. Moreover, biosurfactants as drug delivery vehicles offer commercially attractive and scientifically novel applications. This review covers the current state-of-the-art in biosurfactant research for therapeutic purposes, providing new directions towards the discovery and development of molecules with novel structures and diverse functions for advanced applications.

  9. Computational assessment of effective dose and patient specific doses for kilovoltage stereotactic radiosurgery of wet age-related macular degeneration

    Hanlon, Justin Mitchell

    Age-related macular degeneration (AMD) is a leading cause of vision loss and a major health problem for people over the age of 50 in industrialized nations. The current standard of care, ranibizumab, is used to help slow and in some cases stabilize the process of AMD, but requires frequent invasive injections into the eye. Interest continues for stereotactic radiosurgery (SRS), an option that provides a non-invasive treatment for the wet form of AMD, through the development of the IRay(TM) (Oraya Therapeutics, Inc., Newark, CA). The goal of this modality is to destroy choroidal neovascularization beneath the pigment epithelium via delivery of three 100 kVp photon beams entering through the sclera and overlapping on the macula delivering up to 24 Gy of therapeutic dose over a span of approximately 5 minutes. The divergent x-ray beams targeting the fovea are robotically positioned and the eye is gently immobilized by a suction-enabled contact lens. Device development requires assessment of patient effective dose, reference patient mean absorbed doses to radiosensitive tissues, and patient specific doses to the lens and optic nerve. A series of head phantoms, including both reference and patient specific, was derived from CT data and employed in conjunction with the MCNPX 2.5.0 radiation transport code to simulate treatment and evaluate absorbed doses to potential tissues-at-risk. The reference phantoms were used to evaluate effective dose and mean absorbed doses to several radiosensitive tissues. The optic nerve was modeled with changeable positions based on individual patient variability seen in a review of head CT scans gathered. Patient specific phantoms were used to determine the effect of varying anatomy and gaze. The results showed that absorbed doses to the non-targeted tissues were below the threshold levels for serious complications; specifically the development of radiogenic cataracts and radiation induced optic neuropathy (RON). The effective dose

  10. Maximizing antimalarial efficacy and the importance of dosing strategies.

    Beeson, James G; Boeuf, Philippe; Fowkes, Freya J I

    2015-05-09

    Artemisinin-based combination therapies (ACTs) are the cornerstone for the treatment of malaria. However, confirmed resistance to artemisinins in South-East Asia, and reports of reduced efficacy of ACTs raise major concerns for malaria treatment and control. Without new drugs to replace artemisinins, it is essential to define dosing strategies that maximize therapeutic efficacy, limit the spread of resistance, and preserve the clinical value of ACTs. It is important to determine the extent to which reduced efficacy of ACTs reflects true resistance versus sub-optimal dosing, and quantify other factors that determine treatment failure. Pooled analyses of individual patient data from multiple clinical trials, by investigators in the Worldwide Antimalarial Resistance Network, have shown high overall efficacy for three widely used ACTs, artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine. Analyses also highlight that suboptimal dosing leads to increased risk of treatment failure, especially among children. In the most recent study, an analysis of clinical trials of artesunate-amodiaquine, widely used among children in Africa, revealed a superior efficacy for fixed-dose combination tablets compared to loose non-fixed dose combinations. This highlights the benefits of fixed-dose combinations as a practical strategy for ensuring optimal antimalarial dosing and maximizing efficacy. Please see related article: http://www.biomedcentral.com/1741-7015/13/66.

  11. Reading Philemon as therapeutic narrative

    Pierre J. Jordaan

    2010-02-01

    Full Text Available This article analysed the different narratives implied in Philemon by utilising the narrative therapeutic approach, as developed by Epston and White (1990. A dominant narrative (the harsh treatment of slaves in the early Christian environment and a challenging narrative (a more humane conduct of slaves were clearly distinguished. The article showed Paul’s attempt to bridge the gap between these two narratives by using certain pointers, possibly taken from mystery religions and Jesus’ example. In conclusion, the narrative therapeutic approach proved to be a new and unique way of looking at Philemon’s narrative world.

  12. Who needs a therapeutic phlebotomy?

    Antle, Emily Amy

    2010-12-01

    Many oncology practices treat patients with benign and malignant hematologic diagnoses. As a result, oncology nurses often are required to care for these patients. One common procedure nurses perform is therapeutic phlebotomy, where about 500 ml of blood is removed through a large-bore needle over 15-30 minutes. The procedure is ordered as a treatment for hereditary hemochromatosis, polycythemia vera, and secondary polycythemia. Before initiating the procedure, nurses must be aware of a patient's diagnosis, baseline hemoglobin, hematocrit, ferritin, and therapeutic end points. Reviewing these diagnoses will help nurses understand why phlebotomy is an important part of treatment.

  13. Effective dose and dose to crystalline lens during angiographic procedures; Dose effective et dose au cristallin lors de procedures angiographiques

    Pages, J. [QUARAD and Radiology Dept., Vvije Universiteit Brussel (Belgium)

    1998-07-01

    The highest radiation doses levels received by radiologists are observed during interventional procedures. Doses to forehead and neck received by a radiologist executing angiographic examinations at the department of radiology at the academic hospital (AZ-VUB) have been measured for a group of 34 examinations. The doses to crystalline lens and the effective doses for a period of one year have been estimated. For the crystalline lens the maximum dose approaches the ICRP limit, that indicates the necessity for the radiologist to use leaded glasses. (N.C.)

  14. Enhancing cancer therapeutics using size-optimized magnetic fluid hyperthermia.

    Khandhar, Amit P; Ferguson, R Matthew; Simon, Julian A; Krishnan, Kannan M

    2012-04-01

    Magnetic fluid hyperthermia (MFH) employs heat dissipation from magnetic nanoparticles to elicit a therapeutic outcome in tumor sites, which results in either cell death (>42 °C) or damage (<42 °C) depending on the localized rise in temperature. We investigated the therapeutic effect of MFH in immortalized T lymphocyte (Jurkat) cells using monodisperse magnetite (Fe(3)O(4)) nanoparticles (MNPs) synthesized in organic solvents and subsequently transferred to aqueous phase using a biocompatible amphiphilic polymer. Monodisperse MNPs, ∼16 nm diameter, show maximum heating efficiency, or specific loss power (watts/g Fe(3)O(4)) in a 373 kHz alternating magnetic field. Our in vitro results, for 15 min of heating, show that only 40% of cells survive for a relatively low dose (490 μg Fe/ml) of these size-optimized MNPs, compared to 80% and 90% survival fraction for 12 and 13 nm MNPs at 600 μg Fe/ml. The significant decrease in cell viability due to MNP-induced hyperthermia from only size-optimized nanoparticles demonstrates the central idea of tailoring size for a specific frequency in order to intrinsically improve the therapeutic potency of MFH by optimizing both dose and time of application.

  15. Cisplatin encapsulated nanoparticle as a therapeutic agent for anticancer treatment

    Eka Putra, Gusti Ngurah Putu; Huang, Leaf; Hsu, Yih-Chih

    2016-03-01

    The knowledge of manipulating size of biomaterials encapsulated drug into nano-scale particles has been researched and developed in treating cancer. Cancer is the second worldwide cause of death, therefore it is critical to treat cancers challenging with therapeutic modality of various mechanisms. Our preliminary investigation has studied cisplatin encapsulated into lipid-based nanoparticle and examined the therapeutic effect on xenografted animal model. We used mice with tumor volume ranging from 195 to 214 mm3 and then few mice were grouped into three groups including: control (PBS), lipid platinum chloride (LPC) nanoparticles and CDDP (cis-diamminedichloroplatinum(II) at dose of 3mg cisplatin /kg body weight. The effect of the treatment was observed for 12 days post-injection. It showed that LPC NPs demonstrated a better therapeutic effect compared to CDDP at same 3mg cisplatin/kg drug dose of tumor size reduction, 96.6% and 11.1% respectively. In addition, mouse body weight loss of LPC, CDDP and PBS treated group are 12.1%, 24.3% and 1.4%. It means that by compared to CDDP group, LPC group demonstrated less side effect as not much reduction of body weight have found. Our findings have shown to be a potential modality to further investigate as a feasible cancer therapy modality.

  16. Therapeutic apheresis in autoimmune diseases

    Bambauer R

    2013-11-01

    Full Text Available Rolf Bambauer,1 Reinhard Latza,2 Carolin Bambauer,3 Daniel Burgard,4 Ralf Schiel5 1Institute for Blood Purification, Homburg, 2Laboratorium of Medicine, St Ingbert, 3Main Hospital Darmstadt, Darmstadt, 4Herz Zentrum, Cardiology, Völklingen, 5Inselklinik Heringsdorf GmbH, Seeheilbad Heringsdorf, Germany Abstract: Systemic autoimmune diseases based on an immune pathogenesis produce autoantibodies and circulating immune complexes, which cause inflammation in the tissues of various organs. In most cases, these diseases have a bad prognosis without treatment. Therapeutic apheresis in combination with immunosuppressive therapies has led to a steady increase in survival rates over the last 35 years. Here we provide an overview of the most important pathogenic aspects indicating that therapeutic apheresis can be a supportive therapy in some systemic autoimmune diseases, such as systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, and inflammatory eye disease. With the introduction of novel and effective biologic agents, therapeutic apheresis is indicated only in severe cases, such as in rapid progression despite immunosuppressive therapy and/or biologic agents, and in patients with renal involvement, acute generalized vasculitis, thrombocytopenia, leucopenia, pulmonary, cardiac, or cerebral involvement. In mild forms of autoimmune disease, treatment with immunosuppressive therapies and/or biologic agents seems to be sufficient. The prognosis of autoimmune diseases with varying organ manifestations has improved considerably in recent years, due in part to very aggressive therapy schemes. Keywords: therapeutic apheresis, autoimmune diseases, systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, inflammatory eye disease

  17. Scenario Writing: A Therapeutic Application.

    Haddock, Billy D.

    1989-01-01

    Introduces scenario writing as useful therapeutic technique. Presents case study of woman in midst of divorce and custody fight to illustrate context in which technique was applied. Suggests additional applications. Concludes that good response is more likely for clients who possess good writing skills although other clients may use their own…

  18. Therapeutic hypothermia for acute stroke

    Olsen, Tom Skyhøj; Weber, Uno Jakob; Kammersgaard, Lars Peter

    2003-01-01

    Experimental evidence and clinical experience show that hypothermia protects the brain from damage during ischaemia. There is a growing hope that the prevention of fever in stroke will improve outcome and that hypothermia may be a therapeutic option for the treatment of stroke. Body temperature i...

  19. A method for converting dose-to-medium to dose-to-tissue in Monte Carlo studies of gold nanoparticle-enhanced radiotherapy.

    Koger, B; Kirkby, C

    2016-03-07

    Gold nanoparticles (GNPs) have shown potential in recent years as a means of therapeutic dose enhancement in radiation therapy. However, a major challenge in moving towards clinical implementation is the exact characterisation of the dose enhancement they provide. Monte Carlo studies attempt to explore this property, but they often face computational limitations when examining macroscopic scenarios. In this study, a method of converting dose from macroscopic simulations, where the medium is defined as a mixture containing both gold and tissue components, to a mean dose-to-tissue on a microscopic scale was established. Monte Carlo simulations were run for both explicitly-modeled GNPs in tissue and a homogeneous mixture of tissue and gold. A dose ratio was obtained for the conversion of dose scored in a mixture medium to dose-to-tissue in each case. Dose ratios varied from 0.69 to 1.04 for photon sources and 0.97 to 1.03 for electron sources. The dose ratio is highly dependent on the source energy as well as GNP diameter and concentration, though this effect is less pronounced for electron sources. By appropriately weighting the monoenergetic dose ratios obtained, the dose ratio for any arbitrary spectrum can be determined. This allows complex scenarios to be modeled accurately without explicitly simulating each individual GNP.

  20. Doses in sensitive organs during prostate treatment with a 60Co unit.

    Vega-Carrillo, H R; Navarro Becerra, J A; Pérez Arrieta, M L; Pérez-Landeros, L H

    2014-01-01

    Using thermoluminiscent dosimeters the absorbed dose in the bladder, rectum and thyroid have been evaluated when 200 cGy was applied to the prostate. The treatment was applied with a (60)Co unit. A water phantom was built and thermoluminiscent dosimeters were located in the position where the prostate, bladder, rectum and thyroid are located. The therapeutic beam was applied in 4 irradiations at 0, 90, 180 and 270° with the prostate at the isocenter. The TLDs readouts were used to evaluate the absorbed dose in each organ. The absorbed doses were used to estimate the effective doses and the probability of developing secondary malignacies in thyroid, rectum and bladder.

  1. PABLM. Accumulated Environment Radiation Dose

    Napier, B.A.; Kennedy, W.E.Jr.; Soldat, J.K. [Pacific Northwest Lab., Richland, WA (United States)

    1981-04-01

    PABLM calculates internal radiation doses to man from radionuclides in food products and external radiation doses from radionuclides in the environment. Radiation doses from radionuclides in the environment may be calculated from deposition on the soil or plants during an atmospheric or liquid release, or from exposure to residual radionuclides after the releases have ended. Radioactive decay is considered during the release, after deposition, and during holdup of food after harvest. The radiation dose models consider exposure to radionuclides deposited on the ground or crops from contaminated air or irrigation water, radionuclides in contaminated drinking water, aquatic foods raised in contaminated water, and radionuclides in bodies of water and sediments where people might fish, boat, or swim. For vegetation, the radiation dose model considers both direct deposition and uptake through roots. Doses may be calculated for either a maximum-exposed individual or for a population group. The program is designed to calculate accumulated radiation doses from the chronic ingestion of food products that contain radionuclides and doses from the external exposure to radionuclides in the environment. A first-year committed dose is calculated as well as an integrated dose for a selected number of years.

  2. What is the best pre-therapeutic dosimetry for successful radioiodine therapy of multifocal autonomy?

    Gotthardt, M. [Radboud Univ. Nijmegen Medical Center, Nijmegen (Netherlands). Dept. of Nuclear Medicine; Philipps Univ., Marburg (Germany). Dept. of Nuclear Medicine; Rubner, C. [Philipps Univ., Marburg (Germany). Dept. of Nuclear Medicine; Bauhofer, A. [Philipps Univ., Marburg (DE). Inst. of Theoretical Surgery] (and others)

    2006-07-01

    Purpose: Dose calculation for radioiodine therapy (RIT) of multifocal autonomies (MFA) is a problem as therapeutic outcome may be worse than in other kinds of autonomies. We compared different dosimetric concepts in our patients. Patients, methods: Data from 187 patients who had undergone RIT for MFA (Marinelli algorithm, volumetric compromise) were included in the study. For calculation, either a standard or a measured half-life had been used and the dosimetric compromise (150 Gy, total thyroid volume). Therapeutic activities were calculated by 2 alternative concepts and compared to therapeutic success achieved (concept of TcTUs-based calculation of autonomous volume with 300 Gy and TcTUs-based adaptation of target dose on total thyroid volume). Results: If a standard half-life is used, therapeutic success was achieved in 90.2% (hypothyroidism 23,1%, n=143). If a measured half-life was used the success rate was 93.1% (13,6% hypothyroidism, n=44). These differences were statistically not significant, neither for all patients together nor for subgroups eu-, hypo-, or hyperthyroid after therapy (ANOVA, all p>0.05). The alternative dosimetric concepts would have resulted either in significantly lower organ doses (TcTUs-based calculation of autonomous volume; 80.76{+-}80.6 Gy versus 125.6{+-}46.3 Gy; p<0.0001) or in systematic over-treatment with significantly higher doses (TcTUs-adapted concept; 164.2{+-}101.7 Gy versus 125.6{+-}46.3 Gy; p=0.0097). Conclusions: TcTUs-based determination of the autonomous volume should not be performed, the TcTUs-based adaptation of the target dose will only increase the rate of hypothyroidism. A standard half-life may be used in pre-therapeutic dosimetry for RIT of MFA. If so, individual therapeutic activities may be calculated based on thyroid size corrected to the 24h ITUs without using Marinelli's algorithm. (orig.)

  3. On the Toxicity of Therapeutically Used Nanoparticles: An Overview

    A. El-Ansary

    2009-01-01

    Full Text Available Human beings have been exposed to airborne nanosized particles throughout their evolutionary stages, and such exposures have increased dramatically over the last century. The rapidly developing field of nanotechnology will result in new sources of this exposure, through inhalation, ingestion, and injection. Although nanomaterials are currently being widely used in modern technology, there is a serious lack of information concerning the human health and environmental implications of manufactured nanomaterials. Since these are relatively new particles, it is necessary to investigate their toxicological behavior. The objective of this review was to trace the cellular response to nanosized particle exposure. Therapeutic application of selected nanoparticles together with their range of toxic doses was also reviewed. Effect of therapeutically used nanoparticles on cell membrane, mitochondrial function, prooxidant/antioxidant status, enzyme leakage, DNA, and other biochemical endpoints was elucidated. This paper highlights the need for caution during the use and disposal of such manufactured nanomaterials to prevent unintended environmental impacts.

  4. Acute radiation syndrome caused by accidental radiation exposure - therapeutic principles

    Dörr Harald

    2011-11-01

    Full Text Available Abstract Fortunately radiation accidents are infrequent occurrences, but since they have the potential of large scale events like the nuclear accidents of Chernobyl and Fukushima, preparatory planning of the medical management of radiation accident victims is very important. Radiation accidents can result in different types of radiation exposure for which the diagnostic and therapeutic measures, as well as the outcomes, differ. The clinical course of acute radiation syndrome depends on the absorbed radiation dose and its distribution. Multi-organ-involvement and multi-organ-failure need be taken into account. The most vulnerable organ system to radiation exposure is the hematopoietic system. In addition to hematopoietic syndrome, radiation induced damage to the skin plays an important role in diagnostics and the treatment of radiation accident victims. The most important therapeutic principles with special reference to hematopoietic syndrome and cutaneous radiation syndrome are reviewed.

  5. Newer therapeutic molecules for multiple myeloma

    Jain P

    2008-01-01

    Full Text Available Therapeutic management of multiple myeloma (MM for the last several decades has mainly involved regimens based on use of glucocorticoids and cytotoxic chemotherapeutics. Despite progress in delineating the activity of such regimens, at either conventional or high doses, MM has remained an incurable disease. This has sparked major interest in the development of novel therapies that in part capitalize on recent advances in our understanding of the biology of MM, including the molecular mechanisms by which MM cell-host bone marrow (BM interactions regulate tumor-cell growth, survival, and drug resistance in the BM milieu. Herein, we review the latest progress in the development of these novel anti-MM therapies, with major focus on therapies which have translated from preclinical evaluation to clinical application, including thalidomide and its more potent immunomodulatory derivatives (IMiD, the first-in-class proteasome inhibitor bortezomib (formerly known as PS-341. Search strategy included Medline using the terms ′Myeloma and Newer Drugs′ citations relevant to treatment guidelines issued in 1999 and 2008 were screened.

  6. Ascaris lumbricoides: an overview of therapeutic targets.

    Hagel, Isabel; Giusti, Tatiana

    2010-10-01

    A. lumbricoides is the largest of the common nematode parasites of man and has been associated with intestinal pathology, respiratory symptoms and malnutrition in children from endemic areas. Current anthelmintic treatments have proven to be safe. However, a reduced efficacy of single dose drugs has been reported. In veterinary practice, anthelmintic drug resistance is an irreversible problem. Thus, research and development of sensitive tools for early detection of drug resistance as well as new anthelmintic approaches are urgently needed. In this review, we summarized data providing information about current drug therapy against A. lumbricoides and other intestinal helminths, new drugs in experimental trials, future drugs perspectives and the identification of immunogenic parasite molecules that may be suitable vaccine targets. In addition to the WHO recommended drugs (albendazole, mebendazole, levamisole, and pyrantel pamoate), new anthelmintic alternatives such as tribendimidine and Nitazoxanide have proved to be safe and effective against A. lumbricoides and other soil-transmitted helminthiases in human trials. Also, some new drugs for veterinary use, monepantel and cyclooctadepsipeptides (e.g., PF1022A), will probably expand future drug spectrum for human treatments. The development of genomic technology has provided a great amount of available nematode DNA sequences, coupled with new gene function data that may lead to the identification of new drug targets through efficient mining of nematode genomic databases. On the other hand, the identification of nematode antigens involved in different parasite vital functions as well as immunomodulatory molecules in animals and humans may contribute to future studies of new therapeutic approaches.

  7. Therapeutic surfactant-stripped frozen micelles

    Zhang, Yumiao; Song, Wentao; Geng, Jumin; Chitgupi, Upendra; Unsal, Hande; Federizon, Jasmin; Rzayev, Javid; Sukumaran, Dinesh K.; Alexandridis, Paschalis; Lovell, Jonathan F.

    2016-05-01

    Injectable hydrophobic drugs are typically dissolved in surfactants and non-aqueous solvents which can induce negative side-effects. Alternatives like `top-down' fine milling of excipient-free injectable drug suspensions are not yet clinically viable and `bottom-up' self-assembled delivery systems usually substitute one solubilizing excipient for another, bringing new issues to consider. Here, we show that Pluronic (Poloxamer) block copolymers are amenable to low-temperature processing to strip away all free and loosely bound surfactant, leaving behind concentrated, kinetically frozen drug micelles containing minimal solubilizing excipient. This approach was validated for phylloquinone, cyclosporine, testosterone undecanoate, cabazitaxel and seven other bioactive molecules, achieving sizes between 45 and 160 nm and drug to solubilizer molar ratios 2-3 orders of magnitude higher than current formulations. Hypertonic saline or co-loaded cargo was found to prevent aggregation in some cases. Use of surfactant-stripped micelles avoided potential risks associated with other injectable formulations. Mechanistic insights are elucidated and therapeutic dose responses are demonstrated.

  8. Site-Specific PEGylation of Therapeutic Proteins

    Jonathan K. Dozier

    2015-10-01

    Full Text Available The use of proteins as therapeutics has a long history and is becoming ever more common in modern medicine. While the number of protein-based drugs is growing every year, significant problems still remain with their use. Among these problems are rapid degradation and excretion from patients, thus requiring frequent dosing, which in turn increases the chances for an immunological response as well as increasing the cost of therapy. One of the main strategies to alleviate these problems is to link a polyethylene glycol (PEG group to the protein of interest. This process, called PEGylation, has grown dramatically in recent years resulting in several approved drugs. Installing a single PEG chain at a defined site in a protein is challenging. Recently, there is has been considerable research into various methods for the site-specific PEGylation of proteins. This review seeks to summarize that work and provide background and context for how site-specific PEGylation is performed. After introducing the topic of site-specific PEGylation, recent developments using chemical methods are described. That is followed by a more extensive discussion of bioorthogonal reactions and enzymatic labeling.

  9. Recent developments in multiple sclerosis therapeutics

    Bourdette Dennis

    2009-12-01

    Full Text Available Abstract Multiple sclerosis, the most common neurologic disorder of young adults, is traditionally considered to be an inflammatory, autoimmune, demyelinating disease of the central nervous system. Based on this understanding, the initial therapeutic strategies were directed at immune modulation and inflammation control. These approaches, including high-dose corticosteroids for acute relapses and long-term use of parenteral interferon-β, glatiramer acetate or natalizumab for disease modification, are at best moderately effective. Growing evidence supports that, while an inflammatory pathology characterizes the early relapsing stage of multiple sclerosis, neurodegenerative pathology dominates the later progressive stage of the disease. Multiple sclerosis disease-modifying therapies currently in development attempt to specifically target the underlying pathology at each stage of the disease, while avoiding frequent self-injection. These include a variety of oral medications and monoclonal antibodies to reduce inflammation in relapsing multiple sclerosis and agents intended to promote neuroprotection and neurorepair in progressive multiple sclerosis. Although newer therapies for relapsing MS have the potential to be more effective and easier to administer than current therapies, they also carry greater risks. Effective treatments for progressive multiple sclerosis are still being sought.

  10. Recent developments in multiple sclerosis therapeutics.

    Spain, Rebecca I; Cameron, Michelle H; Bourdette, Dennis

    2009-12-07

    Multiple sclerosis, the most common neurologic disorder of young adults, is traditionally considered to be an inflammatory, autoimmune, demyelinating disease of the central nervous system. Based on this understanding, the initial therapeutic strategies were directed at immune modulation and inflammation control. These approaches, including high-dose corticosteroids for acute relapses and long-term use of parenteral interferon-beta, glatiramer acetate or natalizumab for disease modification, are at best moderately effective. Growing evidence supports that, while an inflammatory pathology characterizes the early relapsing stage of multiple sclerosis, neurodegenerative pathology dominates the later progressive stage of the disease. Multiple sclerosis disease-modifying therapies currently in development attempt to specifically target the underlying pathology at each stage of the disease, while avoiding frequent self-injection. These include a variety of oral medications and monoclonal antibodies to reduce inflammation in relapsing multiple sclerosis and agents intended to promote neuroprotection and neurorepair in progressive multiple sclerosis. Although newer therapies for relapsing MS have the potential to be more effective and easier to administer than current therapies, they also carry greater risks. Effective treatments for progressive multiple sclerosis are still being sought.

  11. Dose from slow negative muons.

    Siiskonen, T

    2008-01-01

    Conversion coefficients from fluence to ambient dose equivalent, from fluence to maximum dose equivalent and quality factors for slow negative muons are examined in detail. Negative muons, when stopped, produce energetic photons, electrons and a variety of high-LET particles. Contribution from each particle type to the dose equivalent is calculated. The results show that for the high-LET particles the details of energy spectra and decay yields are important for accurate dose estimates. For slow negative muons the ambient dose equivalent does not always yield a conservative estimate for the protection quantities. Especially, the skin equivalent dose is strongly underestimated if the radiation-weighting factor of unity for slow muons is used. Comparisons to earlier studies are presented.

  12. Organ Doses and Effective Doses in Pediatric Radiography: Patient-Dose Survey in Finland

    Kiljunen, T.; Tietaevaeinen, A.; Parviainen, T.; Viitala, A.; Kortesniemi, M. (Radiation Practices Regulation, Radiation and Nuclear Safety Authority, Helsinki (Finland))

    2009-01-15

    Background: Use of the effective dose in diagnostic radiology permits the radiation exposure of diverse diagnostic procedures to be quantified. Fundamental knowledge of patient doses enhances the implementation of the 'as low as reasonably achievable' (ALARA) principle. Purpose: To provide comparative information on pediatric examination protocols and patient doses in skull, sinus, chest, abdominal, and pelvic radiography examinations. Material and Methods: 24 Finnish hospitals were asked to register pediatric examination data, including patient information and examination parameters and specifications. The total number of examinations in the study was 1916 (1426 chest, 228 sinus, 96 abdominal, 94 skull, and 72 pelvic examinations). Entrance surface dose (ESD) and dose-area products (DAP) were calculated retrospectively or DAP meters were used. Organ doses and effective doses were determined using a Monte Carlo program (PCXMC). Results: There was considerable variation in examination protocols between different hospitals, indicating large variations in patient doses. Mean effective doses of different age groups ranged from 5 muSv to 14 muSv in skull and sinus examinations, from 25 muSv to 483 muSv in abdominal examinations, and from 6 muSv to 48 muSv in chest examinations. Conclusion: In chest and sinus examinations, the amount of data was extensive, allowing national pediatric diagnostic reference levels to be defined. Parameter selection in pediatric examination protocols should be harmonized in order to reduce patient doses and improve optimization

  13. [Concept of the therapeutic community].

    Eichhorn, H

    1983-08-01

    The historic development of therapeutic communities is discussed, and it is shown that the term has been neither conceptualized not operationalized. Their unclear aims are considered to be utopian, and the author stresses that previous studies on such communities have been too superficial. The following problems have not hitherto received attention: 1. micro- and macrosocial relationships, 2. the role of the supervisor (authority problems), 3. norms and valuation systems, 4. discipline and sanctions, 5. the problem of roles, 6. questions of indicants and efficacy. The introduction of therapeutic communities is superfluous as a means of improving the socialist health services: it is sufficient to implement the principles of socialist democracy by means of appropriate training programmes.

  14. Dose response problems in carcinogenesis.

    Crump, K S

    1979-03-01

    The estimation of risks from exposure to carcinogens is an important problem from the viewpoint of protection of human health. It also poses some very difficult dose-response problems. Two dose-response models may fit experimental data about equally well and yet predict responses that differ by many orders of magnitude at low doses. Mechanisms of carcinogenesis are not sufficiently understood so that the shape of the dose-response curve at low doses can be satisfactorily predicted. Mathematical theories of carcinogenesis and statistical procedures can be of use with dose-reponse problems such as this and, in addition, can lead to a better understanding of the mechanisms of carcinogenesis. In this paper, mathematical dose-response models of carcinogenesis are considered as well as various proposed dose-response procedures for estimating carcinogenic risks at low doses. Areas are suggested in which further work may be useful. These areas include experimental design problems, statistical procedures for use with time-to-occurrence data, and mathematical models that incorporate such biological features as pharmacokinetics of carcinogens, synergistic effects, DNA repair, susceptible subpopulations, and immune reactions.

  15. Yessotoxin, a Promising Therapeutic Tool

    Amparo Alfonso

    2016-01-01

    Full Text Available Yessotoxin (YTX is a polyether compound produced by dinoflagellates and accumulated in filter feeding shellfish. No records about human intoxications induced by this compound have been published, however it is considered a toxin. Modifications in second messenger levels, protein levels, immune cells, cytoskeleton or activation of different cellular death types have been published as consequence of YTX exposure. This review summarizes the main intracellular pathways modulated by YTX and their pharmacological and therapeutic implications.

  16. Therapeutic perspectives in atopic dermatitis.

    Misery, Laurent

    2011-12-01

    Therapy of atopic dermatitis should comprise emollients, topical glucocorticosteroids, or calcineurin inhibitors, phototherapies, immunosuppressants like cyclosporin A, and other treatments. All these treatments should be improved, thanks to research. But new therapeutic perspectives should be given by topical anti-inflammatory substances, selective glucocorticoid receptor agonists, probiotics, interferon γ, TNFα inhibitors, inhibition of T cells or B cells, inhibition of IgE binding, and many other possibilities.

  17. Bioengineering Beige Adipose Tissue Therapeutics.

    Tharp, Kevin M; Stahl, Andreas

    2015-01-01

    Unlocking the therapeutic potential of brown/beige adipose tissue requires technological advancements that enable the controlled expansion of this uniquely thermogenic tissue. Transplantation of brown fat in small animal model systems has confirmed the expectation that brown fat expansion could possibly provide a novel therapeutic to combat obesity and related disorders. Expansion and/or stimulation of uncoupling protein-1 (UCP1)-positive adipose tissues have repeatedly demonstrated physiologically beneficial reductions in circulating glucose and lipids. The recent discovery that brown adipose tissue (BAT)-derived secreted factors positively alter whole body metabolism further expands potential benefits of brown or beige/brite adipose expansion. Unfortunately, there are no sources of transplantable BATs for human therapeutic purposes at this time. Recent developments in bioengineering, including novel hyaluronic acid-based hydrogels, have enabled non-immunogenic, functional tissue allografts that can be used to generate large quantities of UCP1-positive adipose tissue. These sophisticated tissue-engineering systems have provided the methodology to develop metabolically active brown or beige/brite adipose tissue implants with the potential to be used as a metabolic therapy. Unlike the pharmacological browning of white adipose depots, implantation of bioengineered UCP1-positive adipose tissues offers a spatially controlled therapeutic. Moving forward, new insights into the mechanisms by which extracellular cues govern stem-cell differentiation and progenitor cell recruitment may enable cell-free matrix implant approaches, which generate a niche sufficient to recruit white adipose tissue-derived stem cells and support their differentiation into functional beige/brite adipose tissues. This review summarizes clinically relevant discoveries in tissue-engineering and biology leading toward the recent development of biomaterial supported beige adipose tissue implants and

  18. Development of new RNAi therapeutics

    LIU, G; Wong-Staal, F; Li, Q. X.

    2007-01-01

    RNAi-mediated gene inactivation has become a cornerstone of the present day gene function studies that are the foundation of mechanism and target based drug discovery and development, which could potentially shorten the otherwise long process of drug development. In particular, the coming of age of “RNAi drug” could provide new promising therapeutics bypassing traditional approaches. However, there are technological hurdles need to overcome and the biological limita...

  19. Therapeutic targeting of replicative immortality

    Yaswen, Paul; MacKenzie, Karen L.; Keith, W. Nicol; Hentosh, Patricia; Rodier, Francis; Zhu, Jiyue; Firestone, Gary L.; Matheu, Ander; Carnero, Amancio; Bilsland, Alan; Sundin, Tabetha; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G.; Amedei, Amedeo

    2015-01-01

    One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persis...

  20. Reading Judith as therapeutic narrative

    2009-01-01

    This article analysed the different narratives implied in Philemon by utilising the narrative therapeutic approach, as developed by Epston and White (1990). A dominant narrative (the harsh treatment of slaves in the early Christian environment) and a challenging narrative (a more humane conduct of slaves) were clearly distinguished. The article showed Paul’s attempt to bridge the gap between these two narratives by using certain pointers, possibly taken from mystery religions and Jesus’ examp...

  1. Reading Philemon as therapeutic narrative

    2010-01-01

    This article analysed the different narratives implied in Philemon by utilising the narrative therapeutic approach, as developed by Epston and White (1990). A dominant narrative (the harsh treatment of slaves in the early Christian environment) and a challenging narrative (a more humane conduct of slaves) were clearly distinguished. The article showed Paul’s attempt to bridge the gap between these two narratives by using certain pointers, possibly taken from mystery religions and Jesus’ examp...

  2. Development of therapeutic HPV vaccines

    Trimble, Cornelia L.; Frazer, Ian H

    2009-01-01

    At least 15% of human malignant diseases are attributable to the consequences of persistent viral or bacterial infection. Chronic infection with oncogenic human papillomavirus (HPV) types is a necessary, but insufficient, cause in the development of more cancers than any other virus. Currently available prophylactic vaccines have no therapeutic effect for established infection or for disease. Early disease is characterised by tissue sequestration. However, because a proportion of intraepithel...

  3. Avian Diagnostic and Therapeutic Antibodies

    Bradley, David Sherman [UND SMHS

    2012-12-31

    A number of infectious agents have the potential of causing significant clinical symptomology and even death, but dispite this, the number of incidence remain below the level that supports producing a vaccine. Therapeutic antibodies provide a viable treatment option for many of these diseases. We proposed that antibodies derived from West Nile Virus (WNV) immunized geese would be able to treat WNV infection in mammals and potential humans. We demonstrated that WNV specific goose antibodies are indeed successful in treating WNV infection both prophylactically and therapeutically in a golden hamster model. We demonstrated that the goose derived antibodies are non-reactogenic, i.e. do not cause an inflammatory response with multiple exposures in mammals. We also developed both a specific pathogen free facility to house the geese during the antibody production phase and a patent-pending purification process to purify the antibodies to greater than 99% purity. Therefore, the success of these study will allow a cost effective rapidly producible therapeutic toward clinical testing with the necessary infrastructure and processes developed and in place.

  4. Conotoxins that confer therapeutic possibilities

    Essack, Magbubah

    2012-06-04

    Cone snails produce a distinctive repertoire of venom peptides that are used both as a defense mechanism and also to facilitate the immobilization and digestion of prey. These peptides target a wide variety of voltage- and ligand-gated ion channels, which make them an invaluable resource for studying the properties of these ion channels in normal and diseased states, as well as being a collection of compounds of potential pharmacological use in their own right. Examples include the United States Food and Drug Administration (FDA) approved pharmaceutical drug, Ziconotide (Prialt; Elan Pharmaceuticals, Inc.) that is the synthetic equivalent of the naturally occurring ?-conotoxin MVIIA, whilst several other conotoxins are currently being used as standard research tools and screened as potential therapeutic drugs in pre-clinical or clinical trials. These developments highlight the importance of driving conotoxin-related research. A PubMed query from 1 January 2007 to 31 August 2011 combined with hand-curation of the retrieved articles allowed for the collation of 98 recently identified conotoxins with therapeutic potential which are selectively discussed in this review. Protein sequence similarity analysis tentatively assigned uncharacterized conotoxins to predicted functional classes. Furthermore, conotoxin therapeutic potential for neurodegenerative disorders (NDD) was also inferred. 2012 by the authors; licensee MDPI.

  5. Therapeutic Tools in Pancreatic Cancer

    Christopher J Hoimes

    2009-03-01

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer death in the United States and has a lower survival rate than other digestive tract tumors. It remains a therapeutic challenge with limited active agents. Honing our current understanding of markers of toxicity and response, and individualizing treatment with the prognostic and therapeutic tools available are important to make a worthy impact on a patient’s course. The authors summarize selected abstracts from the ASCO Gastrointestinal Cancers Symposium, San Francisco, CA, USA, January 15-17, 2009. The Symposium featured pancreatic cancer in 84 research abstracts, of which, seven are reviewed that focus on markers of toxicity: cytidine deaminase (Abstract #151 and haptogloin (Abstract #167 as markers of gemcitabine toxicity; markers of response: use of PET scan for prognosis (Abstract #157, and correlations with CA 19-9 to postchemo-radiation resectability (Abstract #215 and time to progression (Abstract #160; and individualized applications: characterizing the phenotypic similarities between a patient tumor and the direct xenograft (Abstract #154 and a report about the poor outcome of patients with ascites (Abstract #220. Validated clinical tools that can assist in managing patients through the narrow therapeutic window are needed.

  6. Copper complexes as therapeutic agents.

    Duncan, Clare; White, Anthony R

    2012-02-01

    The importance of transition metals in biological processes has been well established. Copper (Cu) is a transition metal that can exist in oxidised and reduced states. This allows it to participate in redox and catalytic chemistry, making it a suitable cofactor for a diverse range of enzymes and molecules. Cu deficiency or toxicity is implicated in a variety of pathological conditions; therefore inorganic complexes of Cu have been investigated for their therapeutic and diagnostic potential. These Cu complexes have been shown to be effective in cancer treatment due to their cytotoxic action on tumour cells. Alternatively, Cu complexes can also modulate Cu homeostasis in the brain, resulting in protective effects in several models of neurodegeneration. In other diseases such as coronary heart disease and skin disease, the success of Cu complexes as potential therapeutics will most likely be due to their ability to increase SOD activity, leading to relief of oxidative stress. This review seeks to provide a broad insight into some of the diverse actions of Cu complexes and demonstrate the strong future for these compounds as potential therapeutic agents.

  7. DNA as therapeutics; an update

    Saraswat P

    2009-01-01

    Full Text Available Human gene therapy is the introduction of new genetic material into the cells of an individual with the intention of producing a therapeutic benefit for the patient. Deoxyribonucleic acid and ribonucleic acid are used in gene therapy. Over time and with proper oversight, human gene therapy might become an effective weapon in modern medicine′s arsenal to help fight diseases such as cancer, acquired immunodeficiency syndrome, diabetes, high blood pressure, coronary heart disease, peripheral vascular disease, neurodegenerative diseases, cystic fibrosis, hemophilia and other genetic disorders. Gene therapy trials in humans are of two types, somatic and germ line gene therapy. There are many ethical, social, and commercial issues raised by the prospects of treating patients whose consent is impossible to obtain. This review summarizes deoxyribonucleic acid-based therapeutics and gene transfer technologies for the diseases that are known to be genetic in origin. Deoxyribonucleic acid-based therapeutics includes plasmids, oligonucleotides for antisense and antigene applications, deoxyribonucleic acid aptamers and deoxyribonucleic acidzymes. This review also includes current status of gene therapy and recent developments in gene therapy research.

  8. Therapeutic apheresis in autoimmune diseases

    Bambauer, Rolf; Latza, Reinhard; Bambauer, Carolin; Burgard, Daniel; Schiel, Ralf

    2013-01-01

    Systemic autoimmune diseases based on an immune pathogenesis produce autoantibodies and circulating immune complexes, which cause inflammation in the tissues of various organs. In most cases, these diseases have a bad prognosis without treatment. Therapeutic apheresis in combination with immunosuppressive therapies has led to a steady increase in survival rates over the last 35 years. Here we provide an overview of the most important pathogenic aspects indicating that therapeutic apheresis can be a supportive therapy in some systemic autoimmune diseases, such as systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, and inflammatory eye disease. With the introduction of novel and effective biologic agents, therapeutic apheresis is indicated only in severe cases, such as in rapid progression despite immunosuppressive therapy and/or biologic agents, and in patients with renal involvement, acute generalized vasculitis, thrombocytopenia, leucopenia, pulmonary, cardiac, or cerebral involvement. In mild forms of autoimmune disease, treatment with immunosuppressive therapies and/or biologic agents seems to be sufficient. The prognosis of autoimmune diseases with varying organ manifestations has improved considerably in recent years, due in part to very aggressive therapy schemes.

  9. Enzyme therapeutics for systemic detoxification.

    Liu, Yang; Li, Jie; Lu, Yunfeng

    2015-08-01

    Life relies on numerous biochemical processes working synergistically and correctly. Certain substances disrupt these processes, inducing living organism into an abnormal state termed intoxication. Managing intoxication usually requires interventions, which is referred as detoxification. Decades of development on detoxification reveals the potential of enzymes as ideal therapeutics and antidotes, because their high substrate specificity and catalytic efficiency are essential for clearing intoxicating substances without adverse effects. However, intrinsic shortcomings of enzymes including low stability and high immunogenicity are major hurdles, which could be overcome by delivering enzymes with specially designed nanocarriers. Extensive investigations on protein delivery indicate three types of enzyme-nanocarrier architectures that show more promise than others for systemic detoxification, including liposome-wrapped enzymes, polymer-enzyme conjugates, and polymer-encapsulated enzymes. This review highlights recent advances in these nano-architectures and discusses their applications in systemic detoxifications. Therapeutic potential of various enzymes as well as associated challenges in achieving effective delivery of therapeutic enzymes will also be discussed.

  10. Conotoxins that Confer Therapeutic Possibilities

    John A. C. Archer

    2012-06-01

    Full Text Available Cone snails produce a distinctive repertoire of venom peptides that are used both as a defense mechanism and also to facilitate the immobilization and digestion of prey. These peptides target a wide variety of voltage- and ligand-gated ion channels, which make them an invaluable resource for studying the properties of these ion channels in normal and diseased states, as well as being a collection of compounds of potential pharmacological use in their own right. Examples include the United States Food and Drug Administration (FDA approved pharmaceutical drug, Ziconotide (Prialt®; Elan Pharmaceuticals, Inc. that is the synthetic equivalent of the naturally occurring ω-conotoxin MVIIA, whilst several other conotoxins are currently being used as standard research tools and screened as potential therapeutic drugs in pre-clinical or clinical trials. These developments highlight the importance of driving conotoxin-related research. A PubMed query from 1 January 2007 to 31 August 2011 combined with hand-curation of the retrieved articles allowed for the collation of 98 recently identified conotoxins with therapeutic potential which are selectively discussed in this review. Protein sequence similarity analysis tentatively assigned uncharacterized conotoxins to predicted functional classes. Furthermore, conotoxin therapeutic potential for neurodegenerative disorders (NDD was also inferred.

  11. Conotoxins: Therapeutic Potential and Application

    Richard T. Layer

    2006-04-01

    Full Text Available The pharmacological variety of conotoxins, diverse peptides found in the venoms of marine cone snails, is well recognized. Venoms from each of the estimated 500 species of cone snails contain 50 to 200 distinct biologically active peptides. Most conotoxins characterized to date target receptors and ion channels of excitable tissues, such as ligandgated nicotinic acetylcholine, N-methyl-D-aspartate, and type 3 serotonin receptors, as well as voltage-gated calcium, sodium, and potassium channels, and G-protein-coupled receptors including α-adrenergic, neurotensin, and vasopressin receptors, and the norepinephrine transporter. Several conotoxins have shown promise in preclinical models of pain, convulsive disorders, stroke, neuromuscular block, and cardioprotection. The pharmacological selectivity of the conotoxins, coupled with the safety and efficacy demonstrated in preclinical models, has led to their investigation as human therapeutic agents. In the following review, we will survey the pharmacology and therapeutic rationale of those conotoxins with potential clinical application, and discuss the unique challenges that each will face in the course of their transition from venom component to human therapeutic.

  12. DNA as therapeutics; an update.

    Saraswat, P; Soni, R R; Bhandari, A; Nagori, B P

    2009-09-01

    Human gene therapy is the introduction of new genetic material into the cells of an individual with the intention of producing a therapeutic benefit for the patient. Deoxyribonucleic acid and ribonucleic acid are used in gene therapy. Over time and with proper oversight, human gene therapy might become an effective weapon in modern medicine's arsenal to help fight diseases such as cancer, acquired immunodeficiency syndrome, diabetes, high blood pressure, coronary heart disease, peripheral vascular disease, neurodegenerative diseases, cystic fibrosis, hemophilia and other genetic disorders. Gene therapy trials in humans are of two types, somatic and germ line gene therapy. There are many ethical, social, and commercial issues raised by the prospects of treating patients whose consent is impossible to obtain. This review summarizes deoxyribonucleic acid-based therapeutics and gene transfer technologies for the diseases that are known to be genetic in origin. Deoxyribonucleic acid-based therapeutics includes plasmids, oligonucleotides for antisense and antigene applications, deoxyribonucleic acid aptamers and deoxyribonucleic acidzymes. This review also includes current status of gene therapy and recent developments in gene therapy research.

  13. Response of SOI image sensor to therapeutic carbon ion beam

    Matsumura, Akihiko

    2015-01-01

    Carbon ion radiotherapy is known as a less invasive cancer treatment. The radiation quality is an important parameter to evaluate the biological effect and the clinical dose from the measured physical dose. The performance of SOPHIAS detector, which is the SOI image sensor having a wide dynamic range and large active area, was tested by using therapeutic carbon ion beam at Gunma University Heavy Ion Medical Center (GHMC). It was shown that the primary carbon and secondary particles can be distinguishable by SOPHIAS detector. On the other hand, a LET dependence was observed especially at the high LET region. This phenomenon will be studied by using the device simulator together with Monte Carlo simulation.

  14. Lack of Response in an Autistic Population to a Low Dose Clinical Trial of Pyridoxine Plus Magnesium.

    Tolbert, Lelland; And Others

    1993-01-01

    As some therapeutic benefits for autistic persons have been reported from combined high doses of pyridoxine and magnesium, this study evaluated long-term administration of low doses (to minimize adverse effects) to 15 subjects with autism. Findings indicated that, at this dosage level, pyridoxine and magnesium had no effect on the severity of…

  15. Special Radiation Protection Precautions in Therapeutic Nuclear Medicine

    Stefanoyiannis, A. P.; Gerogiannis, J.

    2010-01-01

    Therapeutic Nuclear Medicine concerns the administration of appropriate amounts of radioactivity of certain isotopes, in order to achieve internal localized irradiation of neoplasmatic cells. Due to the increased level and the specific isotope characteristics of administered radioactivity, special Radiation Protection precautions must be taken. This study addresses such issues, based on national as well as international legislation and guidelines. Application of the principle of optimization is of outmost importance and is based on individual dose planning. The decision about the release of Nuclear Medicine patients after therapy is determined on an individual basis, taking into account patients' pattern of contact with other people, their age and that of persons in the home environment, in addition to other factors. Estimation of the absorbed dose given to the treated organ is based on uptake measurements and other biokinetic data, as well as on the mass of the treated tissue or organ. Concerning pregnant women, the rule of thumb is that they should not be treated, unless the radionuclide therapy is required to save their lives. In that case, the potential absorbed dose and risk to the foetus should be estimated and conveyed to the patient. After radionuclide therapy, a female should be advised to avoid pregnancy for the period of time depending on the specific radionuclide. This is to ensure that the dose to a conceptus/foetus would probably not exceed 1 mGy (the member of the public dose limit). The radiation risk for relatives and caregivers is small and unlikely to exceed the legal dose constraints during the period of the patient's treatment. Solid waste from the patient's stay in hospital is a different matter, and is normally incinerated or held for a period until radioactive decay brings the activity to an acceptable level.

  16. Clinical impact of laboratory error on therapeutic drug monitoring of once-daily tobramycin in cystic fibrosis: Case series

    William A Prescott

    2014-01-01

    Full Text Available Once-daily dosing intravenous tobramycin is commonly used to treat cystic fibrosis pulmonary exacerbations. Clinicians often utilize historical therapeutic drug monitoring data to individualize the dose among patients who have been treated with tobramycin previously. This case series involves three patients with cystic fibrosis who had supra-therapeutic tobramycin levels despite use of a once-daily dosing that produced therapeutic drug levels during a previous hospital admission, raising questions about the validity of these levels. Investigation into several potential sources of error led to the discovery of an analyzer error in the laboratory. Once the laboratory’s tobramycin analyzer was recalibrated, the reported levels were comparable to historical levels. This case series emphasizes the clinical importance of critically analyzing reported levels, and specifically, the importance of utilizing past therapeutic drug monitoring data, if available, for all patients treated with intravenous tobramycin. If a patient was therapeutic on a similar dose of tobramycin during a previous admission, a dose adjustment may not be necessary, and clinicians should consider repeating levels while pursuing alternative explanations for the discrepant serum levels.

  17. Evolution of radon dose evaluation

    Fujimoto Kenzo

    2004-01-01

    Full Text Available The historical change of radon dose evaluation is reviewed based on the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR reports. Since 1955, radon has been recognized as one of the important sources of exposure of the general public. However, it was not really understood that radon is the largest dose contributor until 1977 when a new concept of effective dose equivalent was introduced by International Commission on Radiological Protection. In 1982, the dose concept was also adapted by UNSCEAR and evaluated per caput dose from natural radiation. Many researches have been carried out since then. However, lots of questions have remained open in radon problems, such as the radiation weighting factor of 20 for alpha rays and the large discrepancy of risk estimation among dosimetric and epidemiological approaches.

  18. Measurement of neutron dose equivalent to proton therapy patients outside of the proton radiation field

    Yan, X; Köhler, A; Newhauser, W D

    2002-01-01

    Measurements of neutron dose equivalent values and neutron spectral fluences close to but outside of the therapeutic proton radiation field are presented. The neutron spectral fluences were determined at five locations with Bonner sphere measurements and established by unfolding techniques. More than 50 additional neutron dose equivalent values were measured with LiI and BF sub 3 thermal neutron detectors surrounded by a 25 cm polyethylene moderating sphere. For a large-field treatment, typical values of neutron dose equivalent per therapeutic proton absorbed dose, H/D, at 50 cm distance from isocenter, range from 1 mSv/Gy (at 0 deg.with respect to the proton beam axis) to 5 mSv/Gy (at 90 deg.). Experiments reveal that H/D varies significantly with the treatment technique, e.g., patient orientation, proton beam energy, and range-modulation. The relative uncertainty in H/D values is approximately 40% (one standard deviation).

  19. A case of resistant schizophrenia responding at a higher than recommended dose of risperidone without significant side effects

    Anirban Ray

    2013-01-01

    Full Text Available A patient, diagnosed with schizophrenia, non-responsive to two atypical antipsychotics and partially responsive to the third (risperidone in therapeutic dose, ultimately showed complete response without any unacceptable side-effect in a dose (20mg that was untried previously. This case makes an important observation that high dose of risperidone can be tried in a patient with good results if his clinical condition permits.

  20. Pharmacokinetic enhancers in HIV therapeutics.

    Larson, Kajal B; Wang, Kun; Delille, Cecile; Otofokun, Igho; Acosta, Edward P

    2014-10-01

    Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed.

  1. Clinical and economic consequences of pharmacogenetic-guided dosing of warfarin.

    Verhoef, Talitha I; Schalekamp, Tom; Redekop, William K; de Boer, Anthonius; Maitland-van der Zee, Anke-Hilse

    2010-08-01

    Patients using warfarin for oral anticoagulant therapy need to be frequently monitored because of warfarin's narrow therapeutic range and the large variation in dose requirements among patients. Patients receiving the wrong dose have an increased risk of bleeding or thromboembolic events. The required dose is influenced by environmental factors, such as gender, age, diet and concomitant medication, as well as genetic factors. Pharmacogenetic testing prior to warfarin initiation might improve dosing accuracy and, therefore, safety and efficacy of warfarin treatment. Meckley et al. studied the clinical consequences and costs of genotyping before warfarin treatment. The results of their study suggest that pharmacogenetic-guided dosing of patients initiating warfarin could improve health (quality-adjusted life-years) but at a high cost per quality-adjusted life-year gained. Owing to the inevitable assumptions that have to be made in all cost-effectiveness models, great uncertainty remains regarding the cost-effectiveness of pharmacogenetic-guided warfarin dosing.

  2. The History of Therapeutic Aerosols: A Chronological Review

    Thiel, Charles G.

    2017-01-01

    Abstract In 1956, Riker Laboratories, Inc., (now 3 M Drug Delivery Systems) introduced the first pressurized metered dose inhaler (MDI). In many respects, the introduction of the MDI marked the beginning of the modern pharmaceutical aerosol industry. The MDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern MDIs, dry powder inhalers, and nebulizer systems. The innovative inhalers and drugs discovered by the pharmaceutical aerosol industry, particularly since 1956, have improved the quality of life of literally hundreds of millions of people. Yet, the delivery of therapeutic aerosols has a surprisingly rich history dating back more than 3500 years to ancient Egypt. The delivery of atropine and related compounds has been a crucial inhalation therapy throughout this period and the delivery of associated structural analogs remains an important therapy today. Over the centuries, discoveries from many cultures have advanced the delivery of therapeutic aerosols. For thousands of years, therapeutic aerosols were prepared by the patient or a physician with direct oversight of the patient using custom-made delivery systems. However, starting with the Industrial Revolution, advancements in manufacturing resulted in the bulk production of therapeutic aerosol delivery systems produced by people completely disconnected from contact with the patient. This trend continued and accelerated in the 20th century with the mass commercialization of modern pharmaceutical inhaler products. In this article, we will provide a summary of therapeutic aerosol delivery from ancient times to the present along with a look to the

  3. The selective therapeutic apheresis procedures.

    Sanchez, Amber P; Cunard, Robyn; Ward, David M

    2013-02-01

    Selective apheresis procedures have been developed to target specific molecules, antibodies, or cellular elements in a variety of diseases. The advantage of the selective apheresis procedures over conventional therapeutic plasmapheresis is preservation of other essential plasma components such as albumin, immunoglobulins, and clotting factors. These procedures are more commonly employed in Europe and Japan, and few are available in the USA. Apheresis procedures discussed in this review include the various technologies available for low-density lipoprotein (LDL) apheresis, double filtration plasmapheresis (DFPP), cryofiltration, immunoadsorption procedures, adsorption resins that process plasma, extracorporeal photopheresis, and leukocyte apheresis.

  4. Peptide-Based Polymer Therapeutics

    Aroa Duro-Castano

    2014-02-01

    Full Text Available Polypeptides are envisaged to achieve a major impact on a number of different relevant areas such as biomedicine and biotechnology. Acquired knowledge and the increasing interest on amino acids, peptides and proteins is establishing a large panel of these biopolymers whose physical, chemical and biological properties are ruled by their controlled sequences and composition. Polymer therapeutics has helped to establish these polypeptide-based constructs as polymeric nanomedicines for different applications, such as disease treatment and diagnostics. Herein, we provide an overview of the advantages of these systems and the main methodologies for their synthesis, highlighting the different polypeptide architectures and the current research towards clinical applications.

  5. Exploring breast with therapeutic ductoscopy.

    Balci, Fatih Levent; Feldman, Sheldon Marc

    2014-05-01

    Breast lesions are thought to arise mostly from the epithelium of ductal lining. Conventional imaging could only show indirect images of suspected lesions which are confirmed by percutaneous biopsies. However, ductoscopy provides direct images of the ductal epithelium which is the source of most malignant and papillary lesions. As an advance of current ductoscopy systems, pathologic nipple discharge (PND) could be treated ductoscopically by miniaturized endo-baskets or wires. Our goal is to discuss current intraductal technology which enables diagnostic and therapeutic advance for breast lesions that cause nipple discharge.

  6. Bioengineering lantibiotics for therapeutic success

    Des eField

    2015-11-01

    Full Text Available Several examples of highly modified antimicrobial peptides have been described. While many such peptides are non-ribosomally synthesized, ribosomally synthesised equivalents are being discovered with increased frequency. Of the latter group, the lantibiotics continue to attract most attention. In the present review, we discuss the implementation of in vivo and in vitro engineering systems to alter, and even enhance, the antimicrobial activity, antibacterial spectrum and physico-chemical properties, including heat stability, solubility, diffusion and protease resistance, of these compounds. Additionally, we discuss the potential applications of these lantibiotics for use as therapeutics.

  7. Dose calculation and in-phantom measurement in BNCT using response matrix method.

    Rahmani, Faezeh; Shahriari, Majid

    2011-12-01

    In-phantom measurement of physical dose distribution is very important for Boron Neutron Capture Therapy (BNCT) planning validation. If any changes take place in therapeutic neutron beam due to the beam shaping assembly (BSA) change, the dose will be changed so another group of simulations should be carried out for dose calculation. To avoid this time consuming procedure and speed up the dose calculation to help patients not wait for a long time, response matrix method was used. This procedure was performed for neutron beam of the optimized BSA as a reference beam. These calculations were carried out using the MCNPX, Monte Carlo code. The calculated beam parameters were measured for a SNYDER head phantom placed 10 cm away from beam the exit of the BSA. The head phantom can be assumed as a linear system and neutron beam and dose distribution can be assumed as an input and a response of this system (head phantom), respectively. Neutron spectrum energy was digitized into 27 groups. Dose response of each group was calculated. Summation of these dose responses is equal to a total dose of the whole neutron/gamma spectrum. Response matrix is the double dimension matrix (energy/dose) in which each parameter represents a depth-dose resulted from specific energy. If the spectrum is changed, response of each energy group may be differed. By considering response matrix and energy vector, dose response can be calculated. This method was tested for some BSA, and calculations show statistical errors less than 10%.

  8. Nonlinear Effects of Nanoparticles: Biological Variability From Hormetic Doses, Small Particle Sizes, and Dynamic Adaptive Interactions

    Bell, Iris R.; Ives, John A.; Wayne B. Jonas

    2013-01-01

    Researchers are increasingly focused on the nanoscale level of organization where biological processes take place in living systems. Nanoparticles (NPs, e.g., 1–100 nm diameter) are small forms of natural or manufactured source material whose properties differ markedly from those of the respective bulk forms of the “same” material. Certain NPs have diagnostic and therapeutic uses; some NPs exhibit low-dose toxicity; other NPs show ability to stimulate low-dose adaptive responses (hormesis). B...

  9. A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

    2013-06-01

    Nonidet P - 40 lysis buffer containing 1 mM NaO3VO4 and 1X Complete protease inhibitor tablet (Roche). Whole cell...30 40 50 60 70 R el a ti v e p S 2 l ev el s R el a ti v e P R le v el s ** ** 0 2 4 6 8 10 12 14 16 ** ** ERα β-actin PP2 - + 0 0.2 0.4 0.6...1 l ev el s ** 0 5 10 15 20 25 30 35 40 45 50 R el a ti v e T P 6 3 le v el s **

  10. A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

    2011-06-01

    followed by 1-D PAGE (polyacrylamide gel electrophoresis), and MS (mass spectrophotometry ) identification of proteins. Immunoprecipitation of... Infrared Imaging System (Li-Cor Biosciences). Protein units in figures reflect the relative level of the target protein normalized to the endogenous...cyclin B1 (D-11; Santa Cruz Biotechnology), and β-actin (AC-15; Sigma-Aldrich). Membranes were visual- ized using the Odyssey Infrared Imaging

  11. Intravenously administered lidocaine in therapeutic doses increases the intraspinal release of acetylcholine in rats

    Abelson, Klas S P; Höglund, A Urban

    2002-01-01

    of acetylcholine. Ten and 30 mg/kg lidocaine injected intravenously significantly increased the intraspinal release of acetylcholine. The effect of lidocaine could be reduced by pretreatment with intraspinally administered atropine or mecamylamine. Our results suggest that the antinociceptive effect produced...

  12. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats

    Cornelissen, J.B.W.J.; Giessen, van der J.W.B.; Takumi, K.; Teunis, P.F.M.; Wisselink, H.J.

    2014-01-01

    High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Prev

  13. A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induce Apoptosis

    2008-09-01

    various species (rat, mouse, mon- key, and dog ). Themajor route of excretion of radioactivitywas in the feces. The rat and dog were used to show that...identified in the dog [40]. This phenolic metabolite without the dimethylaminoethyl side chain is a full estrogen [47,49]. The dimethylaminoethoxy side...The American journal of Cardiology . 94, Bolognesi, A , Aldrighetti, D. and 19 1205 1208. Farris, A. (2000) Cyclophosphamide, 20 374 Verhoeven, M.O

  14. A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

    2009-09-01

    18, 19). Several studies have characterized the in vivo hemato - poietic system response to proton TBI (11, 20–22). To our knowledge, none of the... hemato - poietic effects of 7.2 Gy of proton TBI. Supplementa- tion with antioxidants prior to TBI also significantly limited radiation-induced bone...Oncol. Biol. Phys. 25, 49–60 (1993). 4. C. Vargas, A. Fryer, C. Mahajan, D. Indelicato, D. Horne, A. Chellini, C. McKenzie , P. Lawlor, R. Henderson

  15. A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

    2014-08-01

    ATCC, Manassas, VA). Results Analysis of endometrial cancer cell lines Endometrial carcinomas are derived from glandular epithelium and are typically...responsive linewith a pheno- type characteristic of luminal surface epithelium , distinct from Ishikawa cells, which expressed markers of glandular endometrial...Washington, DC, April 17-21, 2010. Loss of pigment epithelium derived-factor (PEDF) is associated with breast cancer progression and antihormone drug

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

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

    2011-01-01

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

  17. A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

    2012-06-01

    Jacksonville, FL. Pauline M. Maki, PhDVAssociate Professor of Psychiatry and Psychology , Director, Women’s Mental Health Research, University of Illinois...FL. Pauline M. Maki, PhD (Secretary)V Associate Professor of Psychiatry and Psychology , Director, Women’s Mental Health Research, University of...Laboratory The Translational Genomics Research Institute, Phoenix, AZ 85004. Email: yoga @tgen.org ABSTRACT RNA interference has been widely used to

  18. A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induce Apoptosis

    2007-09-01

    WNT signaling pathway. Part 1. Degradation of beta-catenin iabsence WNT i li 4.79E-01 2 28 * Leptin signaling via JAK/STAT and MAPK cascades...Diabetes and Digestive and Kidney Diseases, and Nuclear Receptor Signaling Atlas (B.W.O.). Views and opinions of, and endorse- ments by the author(s) do

  19. Penicillin G Treatment in Infective Endocarditis Patients - Does Standard Dosing Result in Therapeutic Plasma Concentrations?

    Öbrink-Hansen, Kristina; Wiggers, Henrik; Bibby, Bo Martin;

    2016-01-01

    Penicillin G is frequently used to treat infective endocarditis (IE) caused by streptococci, penicillin-susceptible staphylococci and enterococci. Appropriate antibiotic exposure is essential for survival and reduces the risk of complications and drug resistance development. We determined...

  20. Radiation dose estimates for radiopharmaceuticals

    Stabin, M.G.; Stubbs, J.B.; Toohey, R.E. [Oak Ridge Inst. of Science and Education, TN (United States). Radiation Internal Dose Information Center

    1996-04-01

    Tables of radiation dose estimates based on the Cristy-Eckerman adult male phantom are provided for a number of radiopharmaceuticals commonly used in nuclear medicine. Radiation dose estimates are listed for all major source organs, and several other organs of interest. The dose estimates were calculated using the MIRD Technique as implemented in the MIRDOSE3 computer code, developed by the Oak Ridge Institute for Science and Education, Radiation Internal Dose Information Center. In this code, residence times for source organs are used with decay data from the MIRD Radionuclide Data and Decay Schemes to produce estimates of radiation dose to organs of standardized phantoms representing individuals of different ages. The adult male phantom of the Cristy-Eckerman phantom series is different from the MIRD 5, or Reference Man phantom in several aspects, the most important of which is the difference in the masses and absorbed fractions for the active (red) marrow. The absorbed fractions for flow energy photons striking the marrow are also different. Other minor differences exist, but are not likely to significantly affect dose estimates calculated with the two phantoms. Assumptions which support each of the dose estimates appears at the bottom of the table of estimates for a given radiopharmaceutical. In most cases, the model kinetics or organ residence times are explicitly given. The results presented here can easily be extended to include other radiopharmaceuticals or phantoms.

  1. Therapeutic mechanism of ginkgo biloba exocarp polysaccharides on gastric cancer

    Ai-Hua Xu; Hua-Sheng Chen; Bu-Chan Sun; Xiao-Ren Xiang; Yun-Fei Chu; Fan Zhai; Ling-Chang Jia

    2003-01-01

    AIM: To study the therapeutic mechanism of Ginkgo biloba exocarp polysaccharides (GBEP) on gastric cancer.METHODS: Thirty patients with gastric cancer were treated with oral GBEP capsules. The area of tumors was measured by electron gastroscope before and after treatment, then the inhibitory and effective rates were calculated. The ultrastructures of tumor cells were examined by transmissional electron microscope. Cell culture, MTT, flow cytometry were performed to observe proliferation, apoptosis and changes of relevant gene expression of human gastric cancer SGC-7901 cells.RESULTS: Compared with the statement before treatment,GBEP capsules could reduce the area of tumors, and the effective rate was 73.4 %. Ultrastructural changes of the cells indicated that GBEP could induce apoptosis and differentiation in tumor cells of patients with gastric cancer.GBEP could inhibit the growth of human gastric cancer SGC7901 cells following 24-72 h treatment in vitro at 10-320 mg/L,which was dose- and time-dependent. GBEP was able to elevate the apoptosis rate and expression of c-los gene,but reduce the expression of c-myc and bcl-2 genes also in a dose-dependent manner.CONCLUSION: The therapeutic mechanism of GBEP on human gastric cancer may relate to its effects on the expression of c-myc, bcl-2 and c-los genes, which can inhibit proliferation and induce apoptosis and differentiation of tumor cells.

  2. Effects of low doses; Effet des faibles doses

    Le Guen, B. [Electricite de France (EDF-LAM-SCAST), 93 - Saint-Denis (France)

    2001-07-01

    Actually, even though it is comfortable for the risk management, the hypothesis of the dose-effect relationship linearity is not confirmed for any model. In particular, in the area of low dose rate delivered by low let emitters. this hypothesis is debated at the light of recent observations, notably these ones relative to the mechanisms leading to genetic instability and induction eventuality of DNA repair. The problem of strong let emitters is still to solve. (N.C.)

  3. [Vasculitis - diagnostic and therapeutic advances].

    De Albuquerque, R; Machado, Filipa

    2014-01-01

    Vasculitis is characterized by inflammation and necrosis of blood vessels walls. It represents a heterogeneous group of conditions, whose etiopathogenic mechanisms remain unclear. Although uncommon, with an annual incidence of 40-54 cases per 1.000.000 persons, this is an important cause of multiorganic dysfunction and premature mortality. Depending on the affected vessels, it can cause diverse clinical presentations, which makes difficult its recognition. It is therefore a challenge for any clinician. This paper reviews the diagnostic and therapeutic advances of the most common forms of vasculitis, in order to optimize the approach and management of this clinical entity. We have conducted a search in Medline database on articles written in English, published for the last 10 years using the keywords: vasculitis, epidemiology, classification, diagnosis and treatment. To minimize the impact of vasculitis it is essential an early diagnosis, allowing a timely institution of the appropriate treatment. The diagnosis depends on the integration of clinical, laboratory, imaging and histopathologic data. According to the clinical condition, it may be indicated the removal of the offending antigen, the treatment of the underlying disease or specific treatment of the primary vasculitis. The introduction of immunosuppressive therapy with glucocorticoids and cyclophosphamide has revolutionized the prognosis of these patients but, despite its efficacy, it is associated with frequent relapses and significant toxicity. The study of the pathogenesis has been providing more effective and safer diagnostic and therapeutic options, for example B-cell depleting agents, but additional studies are needed to confirm the potential of these alternatives.

  4. Therapeutics in duchenne muscular dystrophy.

    Strober, Jonathan B

    2006-04-01

    Duchenne muscular dystrophy (DMD) is a fatal disorder affecting approximately 1 in 3,500 live born males, characterized by progressive muscle weakness. Several different strategies are being investigated in developing a cure for this disorder. Until a cure is found, therapeutic and supportive care is essential in preventing complications and improving the afflicted child's quality of life. Currently, corticosteroids are the only class of drug that has been extensively studied in this condition, with controversy existing over the use of these drugs, especially in light of the multiple side effects that may occur. The use of nutritional supplements has expanded in recent years as researchers improve our abilities to use gene and stem cell therapies, which will hopefully lead to a cure soon. This article discusses the importance of therapeutic interventions in children with DMD, the current debate over the use of corticosteroids to treat this disease, the growing use of natural supplements as a new means of treating these boys and provides an update on the current state of gene and stem cell therapies.

  5. Neuroinflammation: a potential therapeutic target.

    Craft, Jeffrey M; Watterson, D Martin; Van Eldik, Linda J

    2005-10-01

    The increased appreciation of the importance of glial cell-propagated inflammation (termed 'neuroinflammation') in the progression of pathophysiology for diverse neurodegenerative diseases, has heightened interest in the rapid discovery of neuroinflammation-targeted therapeutics. Efforts include searches among existing drugs approved for other uses, as well as development of novel synthetic compounds that selectively downregulate neuroinflammatory responses. The use of existing drugs to target neuroinflammation has largely met with failure due to lack of efficacy or untoward side effects. However, the de novo development of new classes of therapeutics based on targeting selective aspects of glia activation pathways and glia-mediated pathophysiologies, versus targeting pathways of quantitative importance in non-CNS inflammatory responses, is yielding promising results in preclinical animal models. The authors briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to onset or progression of neurodegenerative diseases. The authors conclude with opinions based on recent experimental proofs of concept using preclinical animal models of pathophysiology. The focus is on Alzheimer's disease, but the concepts are transferrable to other neurodegenerative disorders with an inflammatory component.

  6. Broad-spectrum antiviral therapeutics.

    Todd H Rider

    Full Text Available Currently there are relatively few antiviral therapeutics, and most which do exist are highly pathogen-specific or have other disadvantages. We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA Activated Caspase Oligomerizer (DRACO that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.

  7. Hydrogels for therapeutic cardiovascular angiogenesis.

    Rufaihah, Abdul Jalil; Seliktar, Dror

    2016-01-15

    Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor or cell therapy is promising, the retention of bioactive agents in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Various types of biomaterials with different physical and chemical properties have been developed to improve the localized delivery of growth factor and/or cells for therapeutic angiogenesis in ischemic tissues. Hydrogels are particularly advantageous as carrier systems because they are structurally similar to the tissue extracellular matrix (ECM), they can be processed under relatively mild conditions and can be delivered in a minimally invasive manner. Moreover, hydrogels can be designed to degrade in a timely fashion that coincides with the angiogenic process. For these reasons, hydrogels have shown great potential as pro-angiogenic matrices. This paper reviews a few of the hydrogel systems currently being applied together with growth factor delivery and/or cell therapy to promote therapeutic angiogenesis in ischemic tissues, with emphasis on myocardial applications.

  8. Influence of therapeutic radiation on polycaprolactone and polyurethane biomaterials

    Cooke, Shelley L. [Department of Materials Science and Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061 (United States); Whittington, Abby R., E-mail: awhit@mse.vt.edu [Department of Materials Science and Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061 (United States); Department of Chemical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061 (United States)

    2016-03-01

    ABSTRACT: Biomedical polymers are exposed in vivo to ionizing radiation as implants, coatings and bystander materials. High levels of ionizing radiation (e.g. X-ray and gamma) have been reported to cause degradation and/or cross-linking in many polymers. This pilot study sought to determine causes of failure, by investigating how therapeutic radiation affects two different porous polymeric scaffolds: polycaprolactone (PCL) and polyurethane (PU). PCL is a bioresorbable material used in biomedical devices (e.g., dentistry, internal fixation devices and targeted drug delivery capsules). PU is commonly used in medical applications (e.g., coatings for pacemakers, tissue expanders, catheter tubing and wound dressings). PU was specifically fabricated to be a non-degradable polymer in this study. Porous scaffolds, fabricated using solvent casting and/or salt leeching techniques, were placed in phosphate buffered saline (PBS, pH = 7.4) and exposed to typical cancer radiotherapy. A total dose of 50 Gy was broken into 25 doses over an eleven-week period. Collected PBS was tested for polymer leachants and degradation products using Gas Chromatography Mass Spectroscopy (GC–MS), results revealed no analyzable leachants from either polymer. Scaffolds were characterized using Environmental Scanning Electron Microscopy, Size-exclusion chromatography (SEC), Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared Spectroscopy (FTIR). No gross visual changes were observed in either polymer, however PU exhibited microstructure changes after irradiation. Increased number average molecular weight and weight average molecular weight in PCL and PU were observed after irradiation, indicating crosslinking. PU displayed an increase in intrinsic viscosity that further confirms increased crosslinking. PCL and PU showed decreases in crystallinity after irradiation, and PU crystallinity shifted from long-range-order hard segments to short-range-order hard segments after

  9. Structurally Based Therapeutic Evaluation: A Therapeutic and Practical Approach to Teaching Medicinal Chemistry.

    Alsharif, Naser Z.; And Others

    1997-01-01

    Explains structurally based therapeutic evaluation of drugs, which uses seven therapeutic criteria in translating chemical and structural knowledge into therapeutic decision making in pharmaceutical care. In a Creighton University (Nebraska) medicinal chemistry course, students apply the approach to solve patient-related therapeutic problems in…

  10. The therapeutic relationship after psychiatric admission.

    Roche, Eric

    2014-03-01

    The therapeutic relationship is one of the most central and important factors in the treatment of mental health disorders. A better therapeutic relationship is associated with service engagement, medication adherence, and satisfaction with services. This study aimed to compare the demographic and clinical factors associated with the therapeutic relationship in voluntarily and involuntarily admitted psychiatric service users. We found that individuals who had been admitted involuntarily, who had a diagnosis of a psychotic disorder, and who reported higher levels of perceived pressures on admission were more likely to have a poorer therapeutic relationship with their consultant psychiatrist. Greater levels of insight and treatment satisfaction, together with higher levels of procedural justice experienced on admission, were associated with a better therapeutic relationship. We found that the level of perceived coercion on admission was not related to the therapeutic relationship. Targeted interventions to improve the therapeutic relationship, particularly for involuntarily admitted service users, are discussed.

  11. An Approach to Optimise Therapeutic Vancomycin Dosage in a Haemodialysis Population

    Gunning, H

    2016-10-01

    Haemodialysis patients are at risk of gram-positive bacteraemia and commonly require intravenous vancomycin. Intravenously administered vancomycin is primarily excreted by the kidney and exhibits complex pharmacokinetics in haemodialysis patients; achieving therapeutic levels can be challenging. An audit in our unit showed current practises of vancomycin administration resulted in a high proportion of sub-therapeutic levels. A new protocol was developed with fixed weight-based loading and subsequent dosing guided by pre-dialysis levels, target levels were 10-20mg\\/L. Its effectiveness was prospectively evaluated between 24th September 2012, and 8th February 2013. During this period 25 patients commenced vancomycin, 15 were included. In total, 112 vancomycin levels were taken, 94 (84%) were therapeutic, this was a significant improvement compared to previous practise (odds ratio 5.4, CI 3.1-9.4, p < 0.0001). In conclusion, our study shows this protocol can consistently and reliably achieve therapeutic vancomycin levels

  12. Description of dose response curve

    Al-Samarai, Firas

    2011-01-01

    The book included several methods to estimate LD50, in addition to explain how to use several programs to estimate LD50. Moreover the book illustrate the description of the dose response curves. Firas Al-Samarai

  13. Hanford Environmental Dose Reconstruction Project

    Finch, S.M.; McMakin, A.H. (comps.)

    1991-01-01

    The objective of the Hanford Environmental Dose Reconstruction Project is to estimate the radiation doses that individuals and populations could have received from nuclear operations at Hanford since 1944. The project is being managed and conducted by the Pacific Northwest Laboratory (PNL) under the direction of an independent Technical Steering Panel (TSP). The TSP consists of experts in environmental pathways, epidemiology, surface-water transport, ground-water transport, statistics, demography, agriculture, meteorology, nuclear engineering, radiation dosimetry, and cultural anthropology. Included are appointed technical members representing the states of Oregon and Washington, a representative of Native American tribes, and an individual representing the public. The project is divided into the following technical tasks. These tasks correspond to the path radionuclides followed, from release to impact on human (dose estimates): Source Terms; Environmental Transport; Environmental Monitoring Data; Demographics, Agriculture, Food Habits and; Environmental Pathways and Dose Estimates.

  14. One-compartment model with Michaelis-Menten elimination kinetics and therapeutic window: an analytical approach.

    Tang, Sanyi; Xiao, Yanni

    2007-12-01

    The purpose of this article is to provide the analytical solutions of one-compartment models with Michaelis-Menten elimination kinetics for three different inputs (single intravenous dose, multiple-dose bolus injection and constant). All analytical solutions obtained in present paper can be described by the well defined Lambert W function which can be easily implemented in most mathematical softwares such as Matlab and Maple. These results will play an important role in fitting the Michaelis-Menten parameters and in designing a dosing regimen to maintain steady-state plasma concentrations. In particular, the analytical periodic solution for multi-dose inputs is also given, and we note that the maximum and minimum values of the periodic solution depends on the Michaelis-Menten parameters, dose and time interval of drug administration. In practice, it is important to maintain a concentration above the minimum therapeutic level at all times without exceeding the minimum toxic concentration. Therefore, the one-compartment model with therapeutic window is proposed, and further the existence of periodic solution, analytical expression and its period are analyzed. The analytical formula of period plays a key role in designing a dose regimen to maintain the plasma concentration within a specified range over long periods of therapy. Finally, the completely analytical solution for the constant input rate is derived and discussed which depends on the relations between constant input rate and maximum rate of change of concentration.

  15. Juvenile rheumatoid arthritis: therapeutic perspectives.

    Chikanza, Ian C

    2002-01-01

    Juvenile rheumatoid arthritis (JRA) is the most common childhood chronic systemic autoimmune inflammatory disease. The therapeutic approach to JRA has, to date, been casual and based on extensions of clinical experiences gained in the management of adult rheumatoid arthritis (RA). The physiology of inflammation has been systemically studied and this has led to the identification of specific therapeutic targets and the development of novel approaches to the management of JRA. The classical treatments of the disease such as methotrexate, sodium aurothiomalate and sulfasalazine, are not always effective in controlling RA and JRA. This has necessitated the development of novel agents for treating RA, most of which are biological in nature and are targeted at specific sites of the inflammatory cascades. These biological therapeutic strategies in RA have proved successful and are being applied in the management of JRA. These developments have been facilitated by the advances in molecular biology which have heralded the advent of biodrugs (recombinant proteins) and gene therapy, in which specific genes can be introduced locally to enhance in vivo gene expression or suppress gene(s) of interest with a view to down-regulating inflammation. Some of these biodrugs, such as anti-tumor necrosis factor alpha (anti-TNFalpha), monoclonal antibodies (infliximab, adalimumab), TNF soluble receptor constructs (etanercept) and interleukin-1 receptor antagonist (IL-1Ra) have been tested and shown to be effective in RA. Etanercept has now been licensed for JRA. Clinical trials of infliximab in JRA are planned. Studies show that the clinical effects are transient, necessitating repeated treatments and the risk of vaccination effects. Anti-inflammatory cytokines such as IL-4, IL-10, transforming growth factor-beta and interferon-beta (IFN-beta) are undergoing clinical trials. Many of these agents have to be administered parenterally and production costs are very high; thus, there is a need

  16. Curious cases: Altered dose-response relationships in addiction genetics.

    Uhl, George R; Drgonova, Jana; Hall, F Scott

    2014-03-01

    Dose-response relationships for most addictive substances are "inverted U"-shaped. Addictive substances produce both positive features that include reward, euphoria, anxiolysis, withdrawal-relief, and negative features that include aversion, dysphoria, anxiety and withdrawal symptoms. A simple model differentially associates ascending and descending limbs of dose-response curves with rewarding and aversive influences, respectively. However, Diagnostic and Statistical Manual (DSM) diagnoses of substance dependence fail to incorporate dose-response criteria and don't directly consider balances between euphoric and dysphoric drug effects. Classical genetic studies document substantial heritable influences on DSM substance dependence. Linkage and genome-wide association studies identify modest-sized effects at any locus. Nevertheless, clusters of SNPs within selected genes display 10(-2)>p>10(-8) associations with dependence in many independent samples. For several of these genes, evidence for cis-regulatory, level-of-expression differences supports the validity of mouse models in which levels of expression are also altered. This review documents surprising, recently defined cases in which convergent evidence from humans and mouse models supports central influences of altered dose-response relationships in mediating the impact of relevant genomic variation on addiction phenotypes. For variation at loci for the α5 nicotinic acetylcholine receptor, cadherin 13, receptor type protein tyrosine phosphatase Δ and neuronal cell adhesion molecule genes, changed dose-response relationships conferred by gene knockouts in mice are accompanied by supporting human data. These observations emphasize desirability of carefully elucidating dose-response relationships for both rewarding and aversive features of abused substances wherever possible. They motivate consideration of individual differences in dose-response relationships in addiction nosology and therapeutics.

  17. Curcumin: therapeutical potential in ophthalmology.

    Pescosolido, Nicola; Giannotti, Rossella; Plateroti, Andrea Maria; Pascarella, Antonia; Nebbioso, Marcella

    2014-03-01

    Curcumin (diferuloylmethane) is the main curcuminoid of the popular Indian spice turmeric (Curcuma longa). In the last 50 years, in vitro and in vivo experiments supported the main role of polyphenols and curcumin for the prevention and treatment of many different inflammatory diseases and tumors.The anti-inflammatory, antioxidant, and antitumor properties of curcumin are due to different cellular mechanisms: this compound, in fact, produces different responses in different cell types. Unfortunately, because of its low solubility and oral bioavailability, the biomedical potential of curcumin is not easy to exploit; for this reason more attention has been given to nanoparticles and liposomes, which are able to improve curcumin's bioavailability. Pharmacologically, curcumin does not show any dose-limiting toxicity when it is administered at doses of up to 8 g/day for three months. It has been demonstrated that curcumin has beneficial effects on several ocular diseases, such as chronic anterior uveitis, diabetic retinopathy, glaucoma, age-related macular degeneration, and dry eye syndrome. The purpose of this review is to report what has so far been elucidated about curcumin properties and its potential use in ophthalmology.

  18. Therapeutic Audit Of Dermatological Prescriptions

    Thawani V.R

    1995-01-01

    Full Text Available Dermatological prescribing trends in outdoor patients attending Dermatology Clinic of Govt. Medical College Hospital, Nagpur were studied. In all 190 prescriptions were audited to find number of drugs per prescription, use of generic/brand names, dosage forms, frequency, duration of treatment, dose and categorywise drug consumption. The age and sex distributions of patients and disease distribution were also studied. Polypharmacy was found to be widely prevalent. More drugs were prescribed by brand names than generic. Dosage form, frequency and duration were mentioned in most of the prescriptions; however, doses of the drugs were not, in majority. The major drugs in the prescriptions were antihistaminics followed by antimicrobials , steroids and vitamins. Not much difference was found in sexes attending the Clinic. There were more female patients of acne vulgaris, disseminated lupus erythematosus and Hansen’s disease. More males suffered from scables and tinea infections. There were 4 patients who were prescribed drugs without diagnosis. Except in some cases, the prescribing was relational.

  19. Dose variation during solar minimum

    Gussenhoven, M.S.; Mullen, E.G.; Brautigam, D.H. (Phillips Lab., Geophysics Directorate, Hanscom Air Force Base, MA (US)); Holeman, E. (Boston Univ., MA (United States). Dept. of Physics)

    1991-12-01

    In this paper, the authors use direct measurement of dose to show the variation in inner and outer radiation belt populations at low altitude from 1984 to 1987. This period includes the recent solar minimum that occurred in September 1986. The dose is measured behind four thicknesses of aluminum shielding and for two thresholds of energy deposition, designated HILET and LOLET. The authors calculate an average dose per day for each month of satellite operation. The authors find that the average proton (HILET) dose per day (obtained primarily in the inner belt) increased systematically from 1984 to 1987, and has a high anticorrelation with sunspot number when offset by 13 months. The average LOLET dose per day behind the thinnest shielding is produced almost entirely by outer zone electrons and varies greatly over the period of interest. If any trend can be discerned over the 4 year period it is a decreasing one. For shielding of 1.55 gm/cm{sup 2} (227 mil) Al or more, the LOLET dose is complicated by contributions from {gt} 100 MeV protons and bremsstrahlung.

  20. Weldon Spring historical dose estimate

    Meshkov, N.; Benioff, P.; Wang, J.; Yuan, Y.

    1986-07-01

    This study was conducted to determine the estimated radiation doses that individuals in five nearby population groups and the general population in the surrounding area may have received as a consequence of activities at a uranium processing plant in Weldon Spring, Missouri. The study is retrospective and encompasses plant operations (1957-1966), cleanup (1967-1969), and maintenance (1969-1982). The dose estimates for members of the nearby population groups are as follows. Of the three periods considered, the largest doses to the general population in the surrounding area would have occurred during the plant operations period (1957-1966). Dose estimates for the cleanup (1967-1969) and maintenance (1969-1982) periods are negligible in comparison. Based on the monitoring data, if there was a person residing continually in a dwelling 1.2 km (0.75 mi) north of the plant, this person is estimated to have received an average of about 96 mrem/yr (ranging from 50 to 160 mrem/yr) above background during plant operations, whereas the dose to a nearby resident during later years is estimated to have been about 0.4 mrem/yr during cleanup and about 0.2 mrem/yr during the maintenance period. These values may be compared with the background dose in Missouri of 120 mrem/yr.

  1. Therapeutic target for protozoal diseases

    Rathore, Dharmendar; Jani, Dewal; Nagarkatti, Rana

    2008-10-21

    A novel Fasciclin Related Adhesive Protein (FRAP) from Plasmodium and related parasites is provided as a target for therapeutic intervention in diseases caused by the parasites. FRAP has been shown to play a critical role in adhesion to, or invasion into, host cells by the parasite. Furthermore, FRAP catalyzes the neutralization of heme by the parasite, by promoting its polymerization into hemozoin. This invention provides methods and compositions for therapies based on the administration of protein, DNA or cell-based vaccines and/or antibodies based on FRAP, or antigenic epitopes of FRAP, either alone or in combination with other parasite antigens. Methods for the development of compounds that inhibit the catalytic activity of FRAP, and diagnostic and laboratory methods utilizing FRAP are also provided.

  2. Host modulation by therapeutic agents

    Sugumari Elavarasu

    2012-01-01

    Full Text Available Periodontal disease susceptible group present advanced periodontal breakdown even though they achieve a high standard of oral hygiene. Various destructive enzymes and inflammatory mediators are involved in destruction. These are elevated in case of periodontal destruction. Host modulation aims at bringing these enzymes and mediators to normal level. Doxycycline, nonsteroidal anti-inflammatory drugs (NSAIDs, bisphosphonates, nitrous oxide (NO synthase inhibitors, recombinant human interleukin-11 (rhIL-11, omega-3 fatty acid, mouse anti-human interleukin-6 receptor antibody (MRA, mitogen-activated protein kinase (MAPK inhibitors, nuclear factor-kappa B (NF-kb inhibitors, osteoprotegerin, and tumor necrosis factor antagonist (TNF-α are some of the therapeutic agents that have host modulation properties.

  3. Therapeutic options for lip augmentation.

    Segall, Lorne; Ellis, David A F

    2007-11-01

    Aesthetic ideals vary with emerging fashion trends and within different cultures. However, over the past few decades, fuller lips have been considered a desirable trait. Many younger patients are presenting for lip augmentation to achieve the sought-after look commonly seen in many fashion magazines. In addition, as individuals age, they lose lip volume, with a thinning of the red lip, some effacement of the vermillion border, and elongation and flattening of the white portion of the lip. Rejuvenation of the lips plays a key role in restoring a more youthful appearance. As a result, lip augmentation appeals to a wide spectrum of patients who present with various different aesthetic goals and expectations. Numerous therapeutic options exist for aesthetic lip augmentation, ranging from temporary and permanent injectable fillers to implants and other surgical techniques.

  4. Angiogenesis and Its Therapeutic Opportunities

    So Young Yoo

    2013-01-01

    Full Text Available Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by “on-off switch signals” between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies. Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.

  5. Therapeutic strategies for xenograft rejection.

    Lin, S S

    2001-01-01

    The increasing demand for transplantable organs over the past several decades has stimulated the idea of using animal organs in lieu of cadaveric organs in clinical transplantation. Pigs are now considered to be the most suitable source of organs for transplantation because of their abundant availability, their appropriate size, their relatively short gestation period, and the recent development in the technology to genetically manipulate them. In the past few years, some of the seemingly complex immunologic responses in pig-to-primate transplantation have been elucidated. This progress has allowed us to focus our efforts on devising specific therapeutic strategies to overcome or prevent some of the responses that contribute to rejection of the xenograft. In this article, we review the various approaches that might allow clinical xenotransplantation to come to fruition.

  6. Therapeutic Drug Monitoring of Lithium

    Mose, Tina; Damkier, Per; Petersen, Magnus

    2015-01-01

    BACKGROUND: Serum lithium is monitored to ensure levels within the narrow therapeutic window. This study examines the interlaboratory variation and inaccuracy of lithium monitoring in Denmark. METHODS: In 16 samples consisting of (1) control materials (n = 4), (2) pooled patient serum (n = 5......), and (3) serum from individual patients (n = 7), lithium was measured in 19 laboratories using 20 different instruments. The lithium concentrations were targeted by a reference laboratory. Ion-selective electrode (n = 5), reflective spectrophotometric (RSM, n = 5), and spectrophotometric (n = 10) methods...... of >12%. Seven of these instruments had a systematic positive or negative bias and more so at lower lithium concentrations. Three poorly calibrated instruments were found in the ion-selective electrode group, 3 in the spectrophotometric group, and 2 in the RSM group. The instruments using reflectance...

  7. Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans

    Carter, Lawrence P.; Reissig, Chad J.; Johnson, Matthew W.; Klinedinst, Margaret A.; Griffiths, Roland R.

    2012-01-01

    BACKGROUND Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. METHODS Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg /70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 hours. RESULTS Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM. CONCLUSION The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse. PMID:22989498

  8. Dose assessments for SFR 1

    Bergstroem, Ulla (Swedish Nuclear Fuel and Waste Management Co., Stockholm (Sweden)); Avila, Rodolfo; Ekstroem, Per-Anders; Cruz, Idalmis de la (Facilia AB, Bromma (Sweden))

    2008-06-15

    Following a review by the Swedish regulatory authorities of the safety analysis of the SFR 1 disposal facility for low and intermediate level waste, SKB has prepared an updated safety analysis, SAR-08. This report presents estimations of annual doses to the most exposed groups from potential radionuclide releases from the SFR 1 repository for a number of calculation cases, selected using a systematic approach for identifying relevant scenarios for the safety analysis. The dose estimates can be used for demonstrating that the long term safety of the repository is in compliance with the regulatory requirements. In particular, the mean values of the annual doses can be used to estimate the expected risks to the most exposed individuals, which can then be compared with the regulatory risk criteria for human health. The conversion from doses to risks is performed in the main report. For one scenario however, where the effects of an earthquake taking place close to the repository are analysed, risk calculations are presented in this report. In addition, prediction of concentrations of radionuclides in environmental media, such as water and soil, are compared with concentration limits suggested by the Erica-project as a base for estimating potential effects on the environment. The assessment of the impact on non-human biota showed that the potential impact is negligible. Committed collective dose for an integration period of 10,000 years for releases occurring during the first thousand years after closure are also calculated. The collective dose commitment was estimated to be 8 manSv. The dose calculations were carried out for a period of 100,000 years, which was sufficient to observe peak doses in all scenarios considered. Releases to the landscape and to a well were considered. The peaks of the mean annual doses from releases to the landscape are associated with C-14 releases to a future lake around year 5,000 AD. In the case of releases to a well, the peak annual doses

  9. Therapeutic drug management of linezolid: a missed opportunity for clinicians?

    Cattaneo, Dario; Gervasoni, Cristina; Cozzi, Valeria; Castoldi, Simone; Baldelli, Sara; Clementi, Emilio

    2016-12-01

    Some studies have shown that adjustments to the linezolid dose guided by therapeutic drug monitoring (TDM) can reduce interindividual variability in drug exposure and improve linezolid tolerability. In this study, 6 years of linezolid TDM, a diagnostic service for our hospital and others in the Milan (Italy) area, is described. Samples were collected immediately before the morning dose intake (trough concentrations) in steady-state conditions. Linezolid concentrations were quantified by a validated high-performance liquid chromatography (HPLC) method. Four hundred linezolid trough concentrations from 220 patients were collected. A 20-fold variability in linezolid levels was observed. Positive and significant correlations between linezolid trough concentrations and patient age (r = 0.325, P 80 years and with impaired renal function, are at a higher risk of overexposure to linezolid. Despite the observed progressive increase in linezolid concentrations over time, most physicians did not change the drug dose according to the TDM results, even in the presence of frank overexposure to linezolid.

  10. PET/CT Based Dose Planning in Radiotherapy

    Berthelsen, Anne Kiil; Jakobsen, Annika Loft; Sapru, Wendy;

    2011-01-01

    This mini-review describes how to perform PET/CT based radiotherapy dose planning and the advantages and possibilities obtained with the technique for radiation therapy. Our own experience since 2002 is briefly summarized from more than 2,500 patients with various malignant diseases undergoing...... radiotherapy planning with PET/CT prior to the treatment. The PET/CT, including the radiotherapy planning process as well as the radiotherapy process, is outlined in detail. The demanding collaboration between mould technicians, nuclear medicine physicians and technologists, radiologists and radiology...... technologists, radiation oncologists, physicists, and dosimetrists is emphasized. We strongly believe that PET/CT based radiotherapy planning will improve the therapeutic output in terms of target definition and non-target avoidance and will play an important role in future therapeutic interventions in many...

  11. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine : efficacy, safety and dosing

    van den Broek, Marcel P. H.; Rademaker, Carin M. A.; van Straaten, Henrica L. M.; Huitema, Alwin D. R.; Toet, Mona C.; de Vries, Linda S.; Egberts, Antoine C. G.; Groenendaal, Floris

    2013-01-01

    BACKGROUND: Lidocaine is an antiarrythmicum used as an anticonvulsant for neonatal seizures, also during therapeutic hypothermia following (perinatal) asphyxia. Hypothermia may affect the efficacy, safety and dosing of lidocaine in these patients. OBJECTIVE: To study the efficacy and safety of lidoc

  12. Pharmacogenetic-guided dosing of coumarin anticoagulants : Algorithms for warfarin, acenocoumarol and phenprocoumon

    Verhoef, Talitha I.; Redekop, William K.; Daly, Ann K.; Van Schie, Rianne M F; De Boer, Anthonius; Maitland-Van Der Zee, Anke Hilse

    2014-01-01

    Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with couma

  13. [Therapeutic principles in gastroesophageal reflux].

    Chassany, O; Elkharrat, D; Bergmann, J F; Segrestaa, J M

    1995-01-01

    Gastroesophageal reflux is a common disease. Its chronic course, even if mild, is sometimes complicated by erosive oesophagitis. Drug therapy acts against gastric acidity and motility disorders. Treatment of gastroesophageal reflux disease has three aims: improvement of symptoms and quality of life, healing erosive lesions and prevention of symptomatic and endoscopic relapses. Non-drug measures are always useful, even if their efficacy is not well established. Initial therapy of a symptomatic reflux or mild oesophagitis is most of the time effective (antacids, prokinetics, H2 receptor antagonists). Proton-pump inhibitors are also effective in healing and preventing severe oesophagitis. Questions about long-term treatment adverse events with powerful acid inhibitors, such as hypergastrinemia and the risk of gastric carcinoid tumours seem to be resolved. Studies are requested to define the optimal long-term maintenance treatment with cisapride, H2 receptor antagonists or proton-pump inhibitors at low doses in prevention of symptomatic and mild oesophagitis relapses.

  14. Design of clinical trials for therapeutic cancer vaccines development.

    Mackiewicz, Jacek; Mackiewicz, Andrzej

    2009-12-25

    Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.

  15. [High-dose chemotherapy as a strategy to overcome drug resistance in solid tumors].

    Selle, Frédéric; Gligorov, Joseph; Soares, Daniele G; Lotz, Jean-Pierre

    2016-10-01

    The concept of high-doses chemotherapy was developed in the 1980s based on in vitro scientific observations. Exposure of tumor cells to increasing concentrations of alkylating agents resulted in increased cell death in a strong dose-response manner. Moreover, the acquired resistance of tumor cells could be overcome by dose intensification. In clinic, dose intensification of alkylating agents resulted in increased therapeutic responses, however associated with significant hematological toxicity. Following the development of autologous stem cells transplantation harvesting from peripheral blood, the high-doses of chemotherapy, initially associated with marked toxic effects, could be more easily tolerated. As a result, the approach was evaluated in different types of solid tumors, including breast, ovarian and germ cell tumors, small cell lung carcinoma, soft tissue sarcomas and Ewing sarcoma. To date, high-doses chemotherapy with hematopoietic stem cells support is only used as a salvage therapy to treat poor prognosis germ cell tumors patients with chemo-sensitive disease. Regarding breast and ovarian cancer, high-doses chemotherapy should be considered only in the context of clinical trials. However, intensive therapy as an approach to overcome resistance to standard treatments is still relevant. Numerous efforts are still ongoing to identify novel therapeutic combinations and active treatments to improve patients' responses.

  16. Dose assessments for SFR 1

    Bergstroem, Ulla (Swedish Nuclear Fuel and Waste Management Co., Stockholm (Sweden)); Avila, Rodolfo; Ekstroem, Per-Anders; Cruz, Idalmis de la (Facilia AB, Bromma (Sweden))

    2008-06-15

    Following a review by the Swedish regulatory authorities of the safety analysis of the SFR 1 disposal facility for low and intermediate level waste, SKB has prepared an updated safety analysis, SAR-08. This report presents estimations of annual doses to the most exposed groups from potential radionuclide releases from the SFR 1 repository for a number of calculation cases, selected using a systematic approach for identifying relevant scenarios for the safety analysis. The dose estimates can be used for demonstrating that the long term safety of the repository is in compliance with the regulatory requirements. In particular, the mean values of the annual doses can be used to estimate the expected risks to the most exposed individuals, which can then be compared with the regulatory risk criteria for human health. The conversion from doses to risks is performed in the main report. For one scenario however, where the effects of an earthquake taking place close to the repository are analysed, risk calculations are presented in this report. In addition, prediction of concentrations of radionuclides in environmental media, such as water and soil, are compared with concentration limits suggested by the Erica-project as a base for estimating potential effects on the environment. The assessment of the impact on non-human biota showed that the potential impact is negligible. Committed collective dose for an integration period of 10,000 years for releases occurring during the first thousand years after closure are also calculated. The collective dose commitment was estimated to be 8 manSv. The dose calculations were carried out for a period of 100,000 years, which was sufficient to observe peak doses in all scenarios considered. Releases to the landscape and to a well were considered. The peaks of the mean annual doses from releases to the landscape are associated with C-14 releases to a future lake around year 5,000 AD. In the case of releases to a well, the peak annual doses

  17. Editorial: advances in therapeutic glycopeptides.

    Zeng, Wenbin; Chen, Yue-Lei

    2014-01-01

    Glycopeptides, peptides containing sugar β-amino acids, have significant impact on medicinal chemistry research and pharmaceutical industr. In 1956, the discovery of one classic glycopeptide, vancomycin, broke the dawn of a new age for antibacterial research. Employing glycopeptides for the therapeutic purposes used to be regarded as proposals. Owing largely to the recent improvements in separation practices, characterization techniques, synthetic methods, and biological research, these proposals have been transformed into ongoing research projects in many laboratories around the world. Previously known as antibiotics, glycopeptides have been used as chemotherapeutic, antiviral, antitubercular, antifungal, antiproliferative and apoptotic agents. Nowadays they are even considered for the development of HIV and cancer vaccines. While several of them are in clinical trials, it could be expected that in the near future, treatment regimen of such difficult diseases might be reformed accordingly. Many interesting preliminary results are being produced in this emerging area. As witnesses and practitioners in this exciting area, however, we notice that the related communication in public domain is still limited due to the relatively small number of researchers involved. Thus, we feel the necessity to compile a timely issue about the special topic "Advances in Therapeutic Glycopeptides", covering state-of-the-art research papers and expert reviews from this area. We are glad that Protein & Peptide Letters is willing to realize the idea with us. The opening paper of this issue by Dr. Voglmeir and coauthor discusses three types of PNGases in respect of their general properties and applications of the commercially available PNGases in glycopeptide and glycoprotein analysis. Dr. Liu and coauthors describe current techniques such as high-performance liquid chromatography (HPLC), capillary electrophoresis (CE), and mass spectrometry (MS), for the characterization of

  18. Radiological dose assessment for vault storage concepts

    Richard, R.F.

    1997-02-25

    This radiological dose assessment presents neutron and photon dose rates in support of project W-460. Dose rates are provided for a single 3013 container, the ``infloor`` storage vault concept, and the ``cubicle`` storage vault concept.

  19. Translational nanomedicine--through the therapeutic window.

    Pierce, Robin L

    2015-01-01

    Translational nanomedicine occurs only through the successful integration of multiple inputs and iterative modifications. The therapeutic window plays a pivotal role in the trajectory of translational nanomedicine. Often defined in terms of the range of dosage for safe and effective therapeutic effect, a second definition of the therapeutic window refers to the often narrow temporal window in which a therapeutic effect can be obtained. Expanding the second definition to explicitly include the spatial dimension, this article explores aspects of the therapeutic spaces created by nanomedicine that shift the traditional dimensions of symptom, sign and pathology. This article analyzes three aspects of the therapeutic window in nanomedicine - temporal, spatial and manner of construction and their impact on the dimensions of modern medicine.

  20. Three dimensional conformal radiation therapy may improve the therapeutic ratio of radiation therapy after pneumonectomy for lung cancer

    Trouette, R.; Causse, N.; Elkhadri, M.; Caudry, M.; Maire, J.P.; Houlard, J.P.; Racaldini, L.; Demeaux, H.

    1995-12-01

    Three dimensional conformal radiation therapy would allow to decrease the normal tissue dose while maintaining the same target dose as standard treatment. To evaluate the feasibility of normal tissue dose reduction for ten patients with pneumonectomy for lung cancer, we determined the dose distribution to the normal tissue with 3-dimensional conformal radiation therapy (3-DCRT) and conventional treatment planning (CTP). Dose-volume histograms for target and normal tissue (lung, heart) were used for comparison of the different treatment planning. The mean percentages of lung and heart volumes which received 40 Gy with 3-DCRT were respectively 63% and 37% of the mean percentage of lung and volumes which received the same dose with CTP. These preliminary results suggest that conformal therapy may improve the therapeutic ratio by reducing risk to normal tissue.

  1. Lack of correlation between MMF dose and MPA level in pediatric and young adult cardiac transplant patients: does the MPA level matter?

    Gajarski, Robert J; Crowley, Dennis C; Zamberlan, Mary C; Lake, Kathleen D

    2004-09-01

    To determine the correlation between mycophenolate mofetil (MMF) dose and mycophenolic acid (MPA) level as well as its impact on rejection among young cardiac transplant recipients (OHT), trough concentrations of MPA and its metabolite, mycophenolic acid glucuronide (MPAG), were measured following MMF doses of 1200 mg/m2/d (max 3000 mg/d). Corresponding endomyocardial biopsy (EMB) grades and calcineurin inhibitor levels were recorded with simultaneous MPA/MPAG levels. Correlation coefficients were derived between MMF dose and MPA/MPAG levels. Contingency analysis evaluated the relation between MPA level and EMB score. Twenty-six patients (median age 15.4 years) had 120 MPA/MPAG levels measured. Average MMF dose was 1208.8 mg/m2/d with median MPA and MPAG concentrations: 2.1 (therapeutic: 1.0-3.5 microg/mL) and 48 microg/mL (reference range: 35-100 microg/mL), respectively. Only 50% of patients consistently achieved therapeutic levels with standard dosing. No correlation was found between MMF dose and MPA/MPAG levels. In the presence of therapeutic calcineurin inhibition, EMB grade > or = 2 occurred more with MPA concentrations MMF dose does not correlate with MPA/MPAG levels, and standard MMF dosing fails to consistently achieve 'therapeutic' MPA concentrations. An MPA trough level or = 2. Concentration rather than dose-driven management is a more prudent strategy when using MMF.

  2. Therapeutic window of serum haloperidol concentration in acute schizophrenia and schizoaffective disorder.

    Ulrich, S; Neuhof, S; Braun, V; Meyer, F P

    1998-09-01

    Although several studies have been performed on the serum level-therapeutic effect relationship of neuroleptic drugs, the application of therapeutic drug-monitoring of neuroleptics is still a matter of controversy. Until now, haloperidol provided the most promising results. For this reason, an investigation of the dependence of clinical improvement on haloperidol serum levels was conducted in an acute psychiatric ward (Landeskrankenhaus Bernburg). In an open clinical trial haloperidol serum levels were measured in 57 acute schizophrenic patients for at least three weeks and correlated with clinical outcome (percent change of Brief Psychiatric Rating Scale, BPRS). A bisigmoidal model was used for data analysis. After three weeks of treatment, the major result proved to be a significant relationship between haloperidol serum level and therapeutic effect with pseudo-r2=0.316 and p=0.0031. Clinical improvement is enhanced by increasing haloperidol concentration up to about 10 ng/ml. It attains a maximum at about 10 ng/ml and decreases at haloperidol serum levels in a range of 10 ng/ml to 50 ng/ml. A simulation of this dependence of clinical improvement on serum levels, mediated by the variable dose design, can be excluded because of the results of a retrospective analysis of dosing behavior. Further evidence is thus provided for the dependence of therapeutic effect on the serum haloperidol concentration in acute schizophrenia. For practical application the position of a therapeutic window can be defined by a lower threshold level of about 5 ng/ml and an upper threshold of about 17 ng/ml. However, a maximal therapeutic effect is assured at 10 ng/ml. This should be the target value in serum level-guided dose adjustments.

  3. Influence of dose calculation algorithms on the predicted dose distribution and NTCP values for NSCLC patients

    Nielsen, Tine B; Wieslander, Elinore; Fogliata, Antonella;

    2011-01-01

    To investigate differences in calculated doses and normal tissue complication probability (NTCP) values between different dose algorithms.......To investigate differences in calculated doses and normal tissue complication probability (NTCP) values between different dose algorithms....

  4. Hanford Environmental Dose Reconstruction Project

    Finch, S.M. (comp.)

    1990-01-01

    The objective of the Hanford Environmental Dose Reconstruction Project is to estimate the radiation doses that populations could have received from nuclear operations at Hanford since 1944. The project is being managed and conducted by the Pacific Northwest Laboratory (PNL) under the direction of an independent Technical Steering Panel (TSP). The project is divided into the following technical tasks. These tasks correspond to the path radionuclides followed, from release to impact on humans (dose estimates). The Source Terms Task develops estimates of radioactive emissions from Hanford facilities since 1944. The Environmental Transport Task reconstructs the movement of radioactive materials from the areas of release to populations. The Environmental Monitoring Data Task assembles, evaluates, and reports historical environmental monitoring data. The Demographics, Agriculture, Food Habits Task develops the data needed to identify the populations that could have been affected by the releases. In addition to population and demographic data, the food and water resources and consumption patterns for populations are estimated because they provide a primary pathway for the intake of radionuclides. The Environmental Pathways and Dose Estimates Task use the information produced by the other tasks to estimate the radiation doses populations could have received from Hanford radiation. Project progress is documented in this monthly report, which is available to the public. 3 figs., 3 tabs.

  5. A proposed new therapeutic protocol for the treatment of canine mange with ivermectin.

    Mueller, R S; Bettenay, S V

    1999-01-01

    Ivermectin was used orally for the treatment of generalized demodicosis or scabies in 222 dogs. The dose was increased gradually from 50 microg/kg body weight on day one, 100 microg/kg body weight on day two, 150 microg/kg body weight on day three, 200 microg/kg body weight on day four, to the final dose of 300 microg/kg body weight on day five. This dose was continued daily until resolution for demodicosis and given four times at seven-day intervals for scabies. Two patients developed clinical ivermectin toxicity after two and 10 days, respectively, and recovered once the drug was discontinued. A gradual increase of the ivermectin dose into the therapeutic range and thorough monitoring of patients during treatment are recommended when using this drug to treat patients with generalized demodicosis or scabies.

  6. Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns

    Gao CH

    2014-03-01

    Full Text Available Chu-Han Gao,1 Lu-Shan Yu,2 Su Zeng,2 Yu-Wen Huang,1 Quan Zhou11Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, 2Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of ChinaBackground: Personalized medicine should be encouraged because patients are complex, and this complexity results from biological, medical (eg, demographics, genetics, polypharmacy, and multimorbidities, socioeconomic, and cultural factors. Levofloxacin (LVX is a broad-spectrum fluoroquinolone antibiotic. Awareness of personalized therapeutics for LVX seems to be poor in clinical practice, and is reflected in prescribing patterns. Pharmacokinetic–pharmacodynamic studies have raised concerns about suboptimal patient outcomes with the use of LVX for some Gram-negative infections. Meanwhile, new findings in LVX therapeutics have only been sporadically reported in recent years. Therefore, an updated review on personalized LVX treatment with a focus on pharmacokinetic concerns is necessary.Methods: Relevant literature was identified by performing a PubMed search covering the period from January 1993 to December 2013. We included studies describing dosage adjustment and factors determining LVX pharmacokinetics, or pharmacokinetic–pharmacodynamic studies exploring how best to prevent the emergence of resistance to LVX. The full text of each included article was critically reviewed, and data interpretation was performed.Results: In addition to limiting the use of fluoroquinolones, measures such as reducing the breakpoints for antimicrobial susceptibility testing, choice of high-dose short-course of once-daily LVX regimen, and tailoring LVX dose in special patient populations help to achieve the validated pharmacokinetic–pharmacodynamic target and combat the increasing LVX resistance. Obese individuals with normal renal function cleared LVX

  7. Clinical Pharmacology & Therapeutics: Past, Present, and Future.

    Waldman, S A; Terzic, A

    2017-03-01

    Clinical Pharmacology & Therapeutics (CPT), the definitive and timely source for advances in human therapeutics, transcends the drug discovery, development, regulation, and utilization continuum to catalyze, evolve, and disseminate discipline-transformative knowledge. Prioritized themes and multidisciplinary content drive the science and practice of clinical pharmacology, offering a trusted point of reference. An authoritative herald across global communities, CPT is a timeless information vehicle at the vanguard of discovery, translation, and application ushering therapeutic innovation into modern healthcare.

  8. Therapeutic use of prebiotics, probiotics, and postbiotics to prevent necrotizing enterocolitis: what is the current evidence?

    Patel, Ravi Mangal; Denning, Patricia Wei

    2013-03-01

    Necrotizing enterocolitis (NEC) is a leading cause of neonatal morbidity and mortality, and preventive therapies that are both effective and safe are urgently needed. Current evidence from therapeutic trials suggests that probiotics are effective in decreasing NEC in preterm infants, and probiotics are currently the most promising therapy for this devastating disease. However, concerns regarding safety and optimal dosing have limited the widespread adoption of routine clinical use of probiotics in preterm infants. This article summarizes the current evidence regarding the use of probiotics, prebiotics, and postbiotics in the preterm infant, including their therapeutic role in preventing NEC.

  9. Therapeutic communities, old and new.

    Jones, M

    1979-01-01

    The author attempts to clarify two largely different uses of term, Therapeutic Community (TC). By "old" TC he describes a movement which originated in psychiatry in the United Kingdom at the end of World War II. This was an attempt to establish a democratic system in hospitals where the domination of the doctors was replaced by open communication of content and feeling, information sharing, shared decision making, and problem solving shared as far as possible with all patients and staff. Daily meetings of all patients and staff formed the nucleus of this process. In recent years developments in the areas of systems theory, learning theory, and organization development have contributed to a better understanding of social organization and change. The "new" TCs derive from the more recent developments in the treatment of substance abuse. Central to this movement is Synanon and its many modification which use the clients' peer group to solve their own problems, largely eliminating mental health professionals. Linked with these "new" TCs is the development of Asklepieion units in prisons, which use Synanon "games" along with transactional analysis. An attempt is made to distinguish the methodologies used in TCs, "old" and "new".

  10. [Glucomannan: properties and therapeutic applications].

    González Canga, A; Fernández Martínez, N; Sahagún, A M; García Vieitez, J J; Díez Liébana, M J; Calle Pardo, A P; Castro Robles, L J; Sierra Vega, M

    2004-01-01

    Glucomannan is a dietary fiber employed quite frequently in the western countries since two decades now, as its ingestion plays an important role in human health. However, eastern people have used this fiber for more than a thousand years. This dietary fiber is the main polysaccharide obtain from the tubers of the Amorphophallus konjac plant, a member of the family Araceae found in east Asia. The chemical structure of glucomannan consists, mainly, in mannose and glucose in the ratio 8:5 linked by beta (1-->4) glycosidic bonds. This soluble fiber has a extraordinarily high waterholding capacity, forming highly viscous solutions when dissolved in water. It has the highest molecular weight and viscosity of any known dietary fiber. It has been demonstrated that this product is highly effective in the treatment of obesity due to the satiety sensation that it produces; as a remedy for constipation, because it increases the faeces volume; as hypocholesterolemic agent, interfering in the transport of cholesterol and of bile acids and as hypoglycemic and hypoinsulinemic agent, probably, by delaying gastric emptying and slowering glucose delivery to the intestinal mucosa. To the beneficial properties of this fiber, several disadvantages can be added as the production of flatulence, abdominal pain, esophageal obstruction, lower gastrointestinal obstruction or even the possible modification of the bioavailability of other drugs. This paper reviews the main characteristics of glucomannan, as well as its properties, physiologic effects and therapeutic uses.

  11. Therapeutical approach to rheumatoid arthritis

    Paraskevi Gourni

    2008-10-01

    Full Text Available Rheumatoid arthritis (RA is a chronic disease characterized by inflammation of the synovial joints, and loss of the function leading to disability. The ultimate goal in managing RA is to prevent joint damage and to maintain functional ability. Although, οver the past decade, major advances have been made in our understanding of the factors that are crucial in regulating this disease, still the managment of the disease remains difficult.Aim : Τhe aim of the present study was the evaluation of the therapeutical approch on rheumatoid arthritis. The method οf this study included bibliography research from both the review and the research literature which referred to the relation between therapy and rheumatoid arthritis.Results : The majority of research studies showed thatthe main therapy on rheumatoid arthritis included medication therapy, modification of everyday living ensuring rest, physical exercise and finally surgical procedure. Individuals suffering from rheumatoid arthritis, apart from physical problems usually cope with mental disorders, that exert a negative indluence on their quality of life.Conclusively :Information and early screening of high risk may decrease the long-term consequnences on health. Monitoring from a group of specialists should serve as a cornerstone when planning a program of intervention.

  12. Statins: perspectives in cancer therapeutics.

    Corcos, Laurent; Le Jossic-Corcos, Catherine

    2013-10-01

    Virtually any cell type in a mammalian organism uses Acetyl CoA to yield mevalonate, through the activity of the 3-hydroxy-3-methyl-glutaryl-CoA reductase enzyme and, ultimately, cholesterol. Statins have long and quite successfully been used as cholesterol lowering drugs. They reversibly inhibit the 3-hydroxy-3-methyl-glutaryl-CoA reductase activity, which is rate limiting in the early steps of the cholesterol synthesis pathway. In addition to these effects, it has also been amply shown that statins may efficiently trigger cancer cell apoptosis, making them a plausible therapeutic option for the treatment of cancer. Whether statins may prevent cancer occurrence is a matter of debate and an unanswered question; undoubtedly experimental models have clearly demonstrated the potential of statins as direct cytotoxic agents, which can reduce tumour development or metastasis spread, even more so when combined with cytotoxic drugs. Until now, however, only few data in humans support the idea that statins could rightfully belong to the group of anticancer drugs. Nevertheless, as cancer cell metabolism is being thoroughly revisited, the mevalonate pathway has recently been reported as truly oncogenic, presenting the attractive possibility that mevalonate pathway inhibitors, such as statins, may join the ranks of anticancer drugs.

  13. Molecular therapeutics in pancreas cancer

    Vignesh Narayanan; Colin D Weekes

    2016-01-01

    The emergence of the "precision-medicine" paradigm in oncology has ushered in tremendous improvements in patient outcomes in a wide variety of malignancies. However, pancreas ductal adenocarcinoma(PDAC) has remained an obstinate challenge to the oncology community and continues to be associated with a dismal prognosis with 5-year survival rates consistently less than 5%. Cytotoxic chemotherapy with gemcitabine-based regimens has been the cornerstone of treatment in PDAC especially because most patients present with inoperable disease. But in recent years remarkable basic science research has improved our understanding of the molecular and genetic basis of PDAC. Whole genomic analysis has exemplified the genetic heterogeneity of pancreas cancer and has led to ingenious efforts to target oncogenes and their downstream signaling cascades. Novel stromal depletion strategies have been devised based on our enhanced recognition of the complex architecture of the tumor stroma and the various mechanisms in the tumor microenvironment that sustain tumorigenesis. Immunotherapy using vaccines and immune checkpoint inhibitors has also risen to the forefront of therapeutic strategies against PDAC. Furthermore, adoptive T cell transfer and strategies to target epigenetic regulators are being explored with enthusiasm. This review will focus on the recent advances in molecularly targeted therapies in PDAC and offer future perspectives to tackle this lethal disease.

  14. Therapeutic approach to epileptic encephalopathies.

    Vigevano, Federico; Arzimanoglou, Alexis; Plouin, Perrine; Specchio, Nicola

    2013-11-01

    Epileptic encephalopathies (EEs) are electroclinical entities with a peculiar course of disease; seizures and electroencephalographic (EEG) epileptiform abnormalities, ictal and interictal, contribute to progressive disturbance of cerebral functions. Frequently EEs are drug resistant, and consequences may be catastrophic. The main goal of treatment is to stop the peculiar course of epilepsy, operating on three parameters: seizure control, reduction of EEG abnormalities, and developmental outcome. For a correct therapeutic approach it is mandatory to have an as accurate as possible syndromic and etiologic diagnosis. Given the poor efficacy of conventional antiepileptic drugs (AEDs), the use of specific drugs for EEs, such as adrenocorticotropic hormone (ACTH) and corticosteroids or stiripentol is suggested. In some cases the choice of treatment is strictly related to the etiology: vigabatrin in tuberous sclerosis, ketogenic diet in glucose transporter type 1 (GLUT-1) deficiency, and pyridoxine in pyridoxine deficiency. Some AEDs combinations, such as sodium valproate with lamotrigine, have also provided interesting results, for example, in Lennox-Gastaut syndrome, although controlled studies are lacking. Finally, early surgery can be an option in children with focal structural abnormalities responsible for EEs preferably before irreversible damage on developmental outcome. Multispecialist support is recommended in EE. Management should be global from the onset, integrating not only seizure control but also all issues related to comorbidities, particularly neuropsychological and psychiatric.

  15. Our experiences with therapeutic hypothermia

    Petrović Milovan

    2007-01-01

    Full Text Available Introduction. The single most important clinically relevant cause of global cerebral ischemia is cardiac arrest. The estimated rate of sudden cardiac arrest is between 40 and 130 cases per 100.000 people per year. Almost 80% of patients initially resuscitated from cardiac arrest remain comatose for more than one hour. One year after cardiac arrest only 10-30% of these patients survive with good neurological outcome. The ability to survive anoxic no-flow states is dramatically increased with protective and preservative hypothermia. The results of clinical studies show a marked neuroprotective effect of mild hypothermia in resuscitation. Material and Methods. In our clinic, 12 patients were treated with therapeutic hypothermia. A combination of intravascular and external method of cooling was used according to the ILCOR (International Liaison Committee on Resuscitation guidelines. The target temperature was 33oC, while the duration of cooling was 24 hours. After that, passive rewarming was allowed. All patients also received other necessary therapy. Results. Six patients (50% had a complete neurological recovery. Two patients (16.6% had partial neurological recovery. Four patients (33.3% remained comatose. Five patients (41.66% survived, while 7 (58.33% patients died. The main cause of cardiac arrest was acute myocardial infarction (91.6%. One patient had acute myocarditis. Conclusion. Mild resuscitative hypothermia after cardiac arrest improves neurological outcome and reduces mortality in comatose survivors. .

  16. Therapeutics for multiple sclerosis symptoms.

    Ben-Zacharia, Aliza Bitton

    2011-01-01

    Symptoms management in multiple sclerosis is an integral part of its care. Accurate assessment and addressing the different symptoms provides increased quality of life among patients with multiple sclerosis. Multiple sclerosis symptoms may be identified as primary, secondary, or tertiary symptoms. Primary symptoms, such as weakness, sensory loss, and ataxia, are directly related to demyelination and axonal loss. Secondary symptoms, such as urinary tract infections as a result of urinary retention, are a result of the primary symptoms. Tertiary symptoms, such as reactive depression or social isolation, are a result of the social and psychological consequences of the disease. Common multiple sclerosis symptoms include fatigue and weakness; decreased balance, spasticity and gait problems; depression and cognitive issues; bladder, bowel, and sexual deficits; visual and sensory loss; and neuropathic pain. Less-common symptoms include dysarthria and dysphagia, vertigo, and tremors. Rare symptoms in multiple sclerosis include seizures, hearing loss, and paralysis. Symptom management includes nonpharmacological methods, such as rehabilitation and psychosocial support, and pharmacological methods, ie, medications and surgical procedures. The keys to symptom management are awareness, knowledge, and coordination of care. Symptoms have to be recognized and management needs to be individualized. Multiple sclerosis therapeutics include nonpharmacological strategies that consist of lifestyle modifications, rehabilitation, social support, counseling, and pharmacological agents or surgical procedures. The goal is vigilant management to improve quality of life and promote realistic expectations and hope.

  17. [Therapeutic use of stem cells].

    Uzan, Georges

    2004-09-15

    Stem cells display important capacities of self renewing, proliferation and differentiation. Because those present in the embryo have the more remarkable properties, their potential use in the therapy of until now incurable degenerative diseases have been envisioned. Embryonic stem (ES) cells are located in the inner mass of the balstocyst at early stages of the development. Even in long-term cultures they still retain their undifferentiated features. Under specific culture conditions, ES cells can be committed into a variety of differentiation pathways, giving rise to large amounts of cells corresponding to different tissues (neurones, cardiomyocytes, skeletal muscle, etc.). However, producing these tissues from already established ES cell lines would lead to immune rejection when transplanted to patients. To prevent this pitfall and using the expertise accumulated by animal cloning by nucleus transfer, it has been proposed to adapt this technique to human ES cells. The therapeutic cloning consists in transferring the nucleus of somatic stem cells isolated from the patient into an enucleated oocyte, to allow blastocyst development from which ES cells will be derived. From these stem cells, compatible tissues will be then produced. The problem is that it is in theoretically possible to reimplant the cloned blastocyst into a surrogate mother for obtaining a baby genetically identical to the donor. This is called reproductive cloning. This worrying risk raises important ethic and legal questions.

  18. In-phantom neutron dose distribution for bladder cancer cases treated with high-energy photons

    Khaled, N. E.; Attalla, E. M.; Ammar, H.; Khalil, W.

    2011-06-01

    This work presents an estimation of the neutron dose distribution for common bladder cancer cases treated with high-energy photons of 15 MV therapy accelerators. Neutron doses were measured in an Alderson phantom, using TLD 700 and 600 thermoluminescence dosimeters, resembling bladder cancer cases treated with high-energy photons from 15 MV LINAC and having a treatment plan using the four-field pelvic box technique. Thermal neutron dose distribution in the target area and the surrounding tissue was estimated. The sensitivity of all detectors for both gamma and neutrons was estimated and used for correction of the TL reading. TLD detectors were irradiated with a Co60 gamma standard source and thermal neutrons at the irradiation facility of the National Institute for Standards (NIS). The TL to dose conversion factor was estimated in terms of both Co60 neutron equivalent dose and thermal neutron dose. The dose distribution of photo-neutrons throughout each target was estimated and presented in three-dimensional charts and isodose curves. The distribution was found to be non-isotropic through the target. It varied from a minimum of 0.23 mSv/h to a maximum of 2.07 mSv/h at 6 cm off-axis. The mean neutron dose equivalent was found to be 0.63 mSv/h, which agrees with other published literature. The estimated average neutron equivalent to the bladder per administered therapeutic dose was found to be 0.39 mSv Gy-1, which is also in good agreement with published literature. As a consequence of a complete therapeutic treatment of 50 Gy high-energy photons at 15 MV, the total thermal neutron equivalent dose to the abdomen was found to be about 0.012 Sv.

  19. Calibration and intercomparison methods of dose calibrators used in nuclear medicine facilities; Metodos de calibracao e de intercomparacao de calibradores de dose utilizados em servicos de medicina nuclear

    Costa, Alessandro Martins da

    1999-07-01

    Dose calibrators are used in most of the nuclear medicine facilities to determine the amount of radioactivity administered to a patient in a particular investigation or therapeutic procedure. It is therefore of vital importance that the equipment used presents good performance and is regular;y calibrated at a authorized laboratory. This occurs of adequate quality assurance procedures are carried out. Such quality control tests should be performed daily, other biannually or yearly, testing, for example, its accuracy and precision, the reproducibility and response linearity. In this work a commercial dose calibrator was calibrated with solution of radionuclides used in nuclear medicine. Simple instrument tests, such as response linearity and the response variation of the source volume increase at a constant source activity concentration, were performed. This instrument can now be used as a working standard for calibration of other dose calibrators/ An intercomparison procedure was proposed as a method of quality control of dose calibrators used in nuclear medicine facilities. (author)

  20. Effect of age and sex on warfarin dosing

    Khoury G

    2014-07-01

    Full Text Available Ghada Khoury,1 Marwan Sheikh-Taha2 1School of Pharmacy, 2Department of Pharmacy Practice, Lebanese American University, Byblos, Lebanon Objective: We examined the potential effect of sex and age on warfarin dosing in ambulatory adult patients. Methods: We conducted a retrospective chart review of patients attending an anticoagulation clinic. We included patients anticoagulated with warfarin for atrial fibrillation or venous thromboembolism who had a therapeutic international normalized ratio of 2–3 for 2 consecutive months. We excluded patients who had been on any drug that is known to have a major interaction with warfarin, smokers, and heavy alcohol consumers. Out of 340 screened medical records, 96 met the predetermined inclusion criteria. The primary outcome assessed was warfarin total weekly dose (TWD. Results: There was a statistically significant difference in the TWD among the ages (P<0.01; older patients required lower doses. However there was no statistically significant difference in the TWD between sexes (P=0.281. Conclusion: Age was found to have a significant effect on warfarin dosing. Even though women did require a lower TWD than men, this observation was not statistically significant. Keywords: warfarin, INR, anticoagulation, vitamin K antagonists, age

  1. Performance standard for dose Calibrator

    Darmawati, S

    2002-01-01

    Dose calibrator is an instrument used in hospitals to determine the activity of radionuclide for nuclear medicine purposes. International Electrotechnical Commission (IEC) has published IEC 1303:1994 standard that can be used as guidance to test the performance of the instrument. This paper briefly describes content of the document,as well as explains the assessment that had been carried out to test the instrument accuracy in Indonesia through intercomparison measurement.Its is suggested that hospitals acquire a medical physicist to perform the test for its dose calibrator. The need for performance standard in the form of Indonesia Standard is also touched.

  2. Therapeutic uses of gastrointestinal peptides.

    Redfern, J S; O'Dorisio, T M

    1993-12-01

    encouraging, further progress will require the development of standardized experimental models and a more rigorous approach to experimental design. Many of the studies reported here suffered from small patient numbers, a narrow or nonexistent range of doses, or the use of only one or two dosing regimens. Lack of objective criteria for determining the level of response, e.g., in studies of mental illness or degenerative diseases, and the ethical problems of withholding treatment from some patients to establish proper controls further hamper research in this area. If the questions of efficacy and safety are to be resolved, thorough, well-planned trials will be required.

  3. Pretreatment with low doses of acenocoumarol inhibits the development of acute ischemia/reperfusion-induced pancreatitis.

    Warzecha, Z; Sendur, P; Ceranowicz, P; Dembinski, M; Cieszkowski, J; Kusnierz-Cabala, B; Tomaszewska, R; Dembinski, A

    2015-10-01

    Coagulative disorders are known to occur in acute pancreatitis and are related to the severity of this disease. Various experimental and clinical studies have shown protective and therapeutic effect of heparin in acute pancreatitis. Aim of the present study was to determine the influence of acenocoumarol, a vitamin K antagonist, on the development of acute pancreatitis. Studies were performed on male Wistar rats weighing 250 - 270 g. Acenocoumarol at the dose of 50, 100 or 150 μg/kg/dose or vehicle were administered once a day for 7 days before induction of acute pancreatitis. Acute pancreatitis was induced in rats by pancreatic ischemia followed by reperfusion. The severity of acute pancreatitis was assessed after 5-h reperfusion. Pretreatment with acenocoumarol given at the dose of 50 or 100 μg/kg/dose reduced morphological signs of acute pancreatitis. These effects were accompanied with a decrease in the pancreatitis-evoked increase in serum activity of lipase and serum concentration of pro-inflammatory interleukin-1β. Moreover, the pancreatitis-evoked reductions in pancreatic DNA synthesis and pancreatic blood flow were partially reversed by pretreatment with acenocoumarol given at the dose of 50 and 100 μg/kg/dose. Administration of acenocoumarol at the dose of 150 μg/kg/dose did not exhibit any protective effect against ischemia/reperfusion-induced pancreatitis. We concluded that pretreatment with low doses of acenocoumarol reduces the severity of ischemia/reperfusion-induced acute pancreatitis.

  4. Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products.

    García-Arieta, Alfredo; Morales-Alcelay, Susana; Herranz, Marta; de la Torre-Alvarado, José María; Blázquez-Pérez, Antonio; Suárez-Gea, Ma Luisa; Alvarez, Covadonga

    2012-02-28

    In the European Union multiple dose bioequivalence studies are required for the approval of generic prolonged-release products, but they are not required by the US-FDA. In order to investigate if the multiple dose bioequivalence studies are necessary, the bioequivalence studies assessed in the Spanish Agency for Medicines and Health Care Products in the last 10 years were searched to find all reasons for rejection and identify those cases where the multiple dose study had failed to show bioequivalence and the single dose study had shown bioequivalence. In these latter cases, the plasma concentration at the end of the dosing interval (C(τ)) in the single dose study was assessed to investigate its sensitivity to predict non-bioequivalence in the steady state. The search identified six cases where the non-equivalence in the multiple dose study was not detected by the corresponding single dose study. C(τ) was not able to detect the difference in five cases and in general it was more variable than conventional metrics. In conclusion, the multiple dose bioequivalence study is necessary to ensure therapeutic equivalence and the use of C(τ) would be counterproductive, increasing the sample size of the studies without enough sensitivity to detect differences in the steady state.

  5. Implementation of an Analytical Model for Leakage Neutron Equivalent Dose in a Proton Radiotherapy Planning System

    Eley, John [Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (United States); Graduate School of Biomedical Sciences, The University of Texas, 6767 Bertner Ave., Houston, TX 77030 (United States); Newhauser, Wayne, E-mail: newhauser@lsu.edu [Department of Physics and Astronomy, Louisiana State University and Agricultural and Mechanical College, 202 Nicholson Hall, Tower Drive, Baton Rouge, LA 70803 (United States); Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, LA 70809 (United States); Homann, Kenneth; Howell, Rebecca [Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (United States); Graduate School of Biomedical Sciences, The University of Texas, 6767 Bertner Ave., Houston, TX 77030 (United States); Schneider, Christopher [Department of Physics and Astronomy, Louisiana State University and Agricultural and Mechanical College, 202 Nicholson Hall, Tower Drive, Baton Rouge, LA 70803 (United States); Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, LA 70809 (United States); Durante, Marco; Bert, Christoph [GSI Helmholtzzentrum für Schwerionenforschung, Planckstr. 1, Darmstadt 64291 (Germany)

    2015-03-11

    Equivalent dose from neutrons produced during proton radiotherapy increases the predicted risk of radiogenic late effects. However, out-of-field neutron dose is not taken into account by commercial proton radiotherapy treatment planning systems. The purpose of this study was to demonstrate the feasibility of implementing an analytical model to calculate leakage neutron equivalent dose in a treatment planning system. Passive scattering proton treatment plans were created for a water phantom and for a patient. For both the phantom and patient, the neutron equivalent doses were small but non-negligible and extended far beyond the therapeutic field. The time required for neutron equivalent dose calculation was 1.6 times longer than that required for proton dose calculation, with a total calculation time of less than 1 h on one processor for both treatment plans. Our results demonstrate that it is feasible to predict neutron equivalent dose distributions using an analytical dose algorithm for individual patients with irregular surfaces and internal tissue heterogeneities. Eventually, personalized estimates of neutron equivalent dose to organs far from the treatment field may guide clinicians to create treatment plans that reduce the risk of late effects.

  6. Magnetic Microspheres for Therapeutical Applications

    Mazuruk, K.; Ramachandran, N.; Curreri, Peter A. (Technical Monitor)

    2002-01-01

    Hyperthermia is a well known cancer therapy and consists of heating a tumor region to the elevated temperatures in the range of 40-45 C for an extended period of time (2-8 hours). This leads to thermal inactivation of cell regulatory and growth processes with resulting widespread necrosis, carbonization and coagulation. Moreover, heat boosts the tumor response to other treatments such as radiation, chemotherapy or immunotherapy. Of particular importance is careful control of generated heat in the treated region and keeping it localized. Higher heating, to about 56 C can lead to tissue thermo-ablation. With accurate temperature control, hyperthermia has the advantage of having minimal side effects. Several heating techniques are utilized for this purpose, such as whole body hyperthermia, radio-frequency (RF) hyperthermia, ultrasound technique, inductive microwave antenna hyperthermia, inductive needles (thermoseeds), and magnetic fluid hyperthermia (MFH).MFH offers many advantages as targeting capability by applying magnets. However, this technology still suffers significant inefficiencies due to lack of thermal control. This paper will provide a review of the topic and outline the ongoing work in this area. The main emphasis is in devising ways to overcome the technical difficulty in hyperthermia therapy of achieving a uniform therapeutic temperature over the required region of the body and holding it steady. The basic obstacle of the present heating methods are non-uniform thermal properties of the tissue. Our approach is to develop a novel class of magnetic fluids which have inherent thermoregulating properties. We have identified a few magnetic alloys which can serve as a suitable nano-particle material. The objective is to synthesize, characterize and evaluate the efficacy of TRMF for hyperthermia therapy.

  7. Therapeutic monoclonal antibody for Sporotrichosis

    Sandro eAlmeida

    2012-11-01

    therapeutic vaccine against

  8. Pediatric health, medicine, and therapeutics

    Claire E Wainwright

    2011-03-01

    Full Text Available Claire E Wainwright1,21Royal Children’s Hospital, Brisbane and Queensland, Queensland, Australia; 2Queensland Children’s Medical Research Institute, The University of Queensland, Brisbane, AustraliaThe idea of children as small adults with health care needs that can be managed by extrapolation from adult studies has now largely been abandoned. We now recognize that adult health and disease are closely linked to childhood factors and the critical and ethical importance of clinical research in pediatrics is increasingly being recognized.  While funding and output from pediatric clinical research continues to lag behind health research in adults, particularly in the area of therapeutics, the last decade has thankfully seen a dramatic increase in the number of pediatric studies and particularly randomized controlled clinical trials (RCTs. Since the 1997 Food and Drug Administration (FDA Modernization Act in the United States (US and the subsequent changes in drug registration regulatory systems in the US and Europe, there has been a huge increase in the number of pediatric studies sponsored by pharmaceutical companies. In the United Kingdom, the Medicine for Children’s Research Network was established in 2005 to address the lack of clinical studies in pediatrics. Over the first five years they reported an exciting increase in the number of high quality clinical studies and on their website they have a current portfolio of over 200 pediatric studies, half of which are RCTs and half are sponsored by pharmaceutical companies. Other countries particularly across Europe are also establishing similar programs. 

  9. Therapeutic strategies in pulmonary hypertension

    Leonello eFuso

    2011-04-01

    Full Text Available Pulmonary hypertension (PH is a life-threatening condition characterized by elevated pulmonary arterial pressure. It is clinically classified into five groups: patients in the first group are considered to have pulmonary arterial hypertension (PAH whereas patients of the other groups have PH that is due to cardiopulmonary or other systemic diseases. The management of patients with PH has advanced rapidly over the last decade and the introduction of specific treatments especially for PAH has lead to an improved outcome. However, despite the progress in the treatment, the functional limitation and the survival of these patients remain unsatisfactory and there is no cure for PAH. Therefore the search for an ideal therapy still goes on. At present, two levels of treatment can be identified: primary and specific therapy. Primary therapy is directed at the underlying cause of the PH. It also includes a supportive therapy consisting in oxygen supplementation, diuretics, and anticoagulation which should be considered in all patients with PH. Specific therapy is directed at the PH itself and includes treatment with vasodilatators such as calcium channel blockers and with vasodilatator and pathogenetic drugs such as prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors. These drugs act in several pathogenetic mechanisms of the PH and are specific for PAH although they might be used also in the other groups of PH. Finally, atrial septostomy and lung transplantation are reserved for patients refractory to medical therapy. Different therapeutic approaches can be considered in the management of patients with PH. Therapy can be established on the basis of both the clinical classification and the functional class. It is also possible to adopt a goal-oriented therapy in which the timing of treatment escalation is determined by inadequate response to known prognostic indicators.

  10. [Therapeutic education for recurrent depressive disorder].

    Carde, Soufiane; Hatif, Séverine; Samama, Diane; Charbonnel, Patricia; Jouvent, Roland

    2016-01-01

    Depression is a serious and recurrent condition which can become chronic. As a complement to other therapeutic approaches, therapeutic patient education (TPE) or psychoeducation is effective. TPE groups led by a multidisciplinary hospitalisation team in a psychiatric department are thereby integrated into the global care in order to reduce relapses and improve patients' quality of life.

  11. Ethics Audit of a Therapeutic Recreation Course

    Nisbett, Nancy; Hinton, Jennifer

    2008-01-01

    The purpose of this study was to enhance awareness of the presence of ethics education within the allied health discipline of therapeutic recreation. To achieve this end, a curriculum audit was conducted in a therapeutic recreation course to determine the existence of ethics education within the course. Included topics, methods of delivery, and…

  12. Aquatic Therapy. Making Waves in Therapeutic Recreation.

    Broach, Ellen; Dattilo, John

    1996-01-01

    Therapeutic recreation professionals often use aquatic therapy to improve physiological and psychological functioning, and they have reported improvements for people with many different types of disabilities. The paper discusses aquatic therapy methods, water as a therapeutic environment, professional training and development, and lifestyle…

  13. AMS method validation for quantitation in pharmacokinetic studies with concomitant extravascular and intravenous administration.

    Lappin, Graham; Seymour, Mark; Young, Graeme; Higton, David; Hill, Howard M

    2011-02-01

    A technique has emerged in the past few years that has enabled a drug's intravenous pharmacokinetics to be readily obtained in humans without having to conduct extensive toxicology studies by this route of administration or expand protracted effort in formulation. The technique involves the intravenous administration of a low dose of (14)C-labelled drug (termed a tracer dose) concomitantly with a non-labelled extravascular dose given at therapeutically levels. Plasma samples collected over time are analysed to determine the total parent drug concentration by LC-MS (which essentially measures that arising from the oral dose) and by LC followed by accelerator mass spectrometry (AMS) to determine the (14)C-drug concentration (i.e., that arising from the intravenous dose). There are currently no published accounts of how the principles of bioanalytical validation might be applied to intravenous studies using AMS as an analytical technique. The authors describe the primary elements of AMS when used with LC separation and how this off-line technique differs from LC-MS. They then discuss how the principles of bioanalytical validation might be applied to determine selectivity, accuracy, precision and stability of methods involving LC followed by AMS analysis.

  14. [Absorbed doses in dental radiology].

    Bianchi, S D; Roccuzzo, M; Albrito, F; Ragona, R; Anglesio, S

    1996-01-01

    The growing use of dento-maxillo-facial radiographic examinations has been accompanied by the publication of a large number of studies on dosimetry. A thorough review of the literature is presented in this article. Most studies were carried out on tissue equivalent skull phantoms, while only a few were in vivo. The aim of the present study was to evaluate in vivo absorbed doses during Orthopantomography (OPT). Full Mouth Periapical Examination (FMPE) and Intraoral Tube Panoramic Radiography (ITPR). Measurements were made on 30 patients, reproducing clinical conditions, in 46 anatomical sites, with 24 intra- and 22 extra-oral thermoluminiscent dosimeters (TLDS). The highest doses were measured, in orthopantomography, at the right mandibular angle (1899 mu Gy) in FMPE on the right naso-labial fold (5640 mu Gy and in ITPR on the palatal surface of the left second upper molar (1936 mu Gy). Intraoral doses ranged from 21 mu Gy, in orthopantomography, to 4494 mu Gy in FMPE. Standard errors ranged from 142% in ITPR to 5% in orthopantomography. The highest rate of standard errors was found in FMPE and ITPR. The data collected in this trial are in agreement with others in major literature reports. Disagreements are probably due to different exam acquisition and data collections. Such differences, presented comparison in several sites, justify lower doses in FMPE and ITPR. Advantages and disadvantages of in vivo dosimetry of the maxillary region are discussed, the former being a close resemblance to clinical conditions of examination and the latter the impossibility of collecting values in depth of tissues. Finally, both ITPR and FMPE required lower doses than expected, and can be therefore reconsidered relative to their radiation risk.

  15. Dose rate mapping of VMAT treatments

    Podesta, Mark; Antoniu Popescu, I.; Verhaegen, Frank

    2016-06-01

    Human tissues exhibit a varying response to radiation dose depending on the dose rate and fractionation scheme used. Dose rate effects have been reported for different radiations, and tissue types. The literature indicates that there is not a significant difference in response for low-LET radiation when using dose rates between 1 Gy min-1 and 12 Gy min-1 but lower dose rates have an observable sparing effect on tissues and a differential effect between tissues. In intensity-modulated radiotherapy such as volumetric modulated arc therapy (VMAT) the dose can be delivered with a wide range of dose rates. In this work we developed a method based on time-resolved Monte Carlo simulations to quantify the dose rate frequency distribution for clinical VMAT treatments for three cancer sites, head and neck, lung, and pelvis within both planning target volumes (PTV) and normal tissues. The results show a wide range of dose rates are used to deliver dose in VMAT and up to 75% of the PTV can have its dose delivered with dose rates  organs at risk. Two VMAT plans that fulfil the same dose objectives and constraints may be delivered with different dose rate distributions, particularly when comparing single arcs to multiple arc plans. It is concluded that for dynamic plans, the dose rate range used varies to a larger degree than previously assumed. The effect of the dose rate range in VMAT on clinical outcome is unknown.

  16. Levothyroxine: therapeutic use and regulatory issues related to bioequivalence.

    Wartofsky, Leonard

    2002-06-01

    Levothyroxine is the overwhelming choice of clinicians for the treatment of hypothyroidism and for the suppression of goitre and thyroid nodules in selected cases. The monitoring of serum levels of thyroid stimulating hormone is necessary for appropriate dosage adjustment of levothyroxine. Levothyroxine has a narrow therapeutic index: both underdosage (subclinical hypothyroidism) and excessive dosage (subclinical hyperthyroidism) are associated with adverse symptoms and pathophysiological effects and are to be avoided. The consequent necessity for careful titration of doses has had an impact on the issue of switchability, or bioequivalence, of the various marketed levothyroxine products. In this article, the basis for concern about currently accepted standards of the FDA for pharmacological bioequivalence are examined in the context of levothyroxine. The history and status of the recent request by the FDA for a new drug application for all levothyroxine products, and its impact on the market leader Synthroid, is also discussed.

  17. Therapeutic Potential of Curcumin for the Treatment of Brain Tumors

    Klinger, Neil V.

    2016-01-01

    Brain malignancies currently carry a poor prognosis despite the current multimodal standard of care that includes surgical resection and adjuvant chemotherapy and radiation. As new therapies are desperately needed, naturally occurring chemical compounds have been studied for their potential chemotherapeutic benefits and low toxicity profile. Curcumin, found in the rhizome of turmeric, has extensive therapeutic promise via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown it to be an effective treatment for brain tumors including glioblastoma multiforme. These effects are potentiated by curcumin's ability to induce G2/M cell cycle arrest, activation of apoptotic pathways, induction of autophagy, disruption of molecular signaling, inhibition of invasion, and metastasis and by increasing the efficacy of existing chemotherapeutics. Further, clinical data suggest that it has low toxicity in humans even at large doses. Curcumin is a promising nutraceutical compound that should be evaluated in clinical trials for the treatment of human brain tumors.

  18. Therapeutic effect of carbonate buffer mixture on gastrointestinal atony in cattle

    Yu Yi Li; Nai Sheng Zhang; Ze Wang; Zi Jun Yang

    2000-01-01

    AIM To substantiate the therapeutic effects of carbonate buffer mixture on naturally occurringgastrointestinal atony in cattle.METHODS Therapeutic effects of carbonate buffer mixture (Na2CO350 g, NaHCO3420 g, KCI 20 g, NaC1100 g, water 10 L) were observed in 120 cases of gastrointestinal atony including forestomach atony, rumenimpaction, rumen acidosis, omasum impaction and intestinal constipation. Judgement of curative effects ascure: after treated, the cases become clinically normal in general conditions, appetite, rumination, ruminalperistalsis and defecation; uncure: after giving two doses, the gasto-intestinal atony has not been eliminated.RESULTS Average cure rate of carbonate buffer mixture on above-mentioned diseases were 95%, andaverage dose was 1.4±0.5.CONCLUSION Being a new approach for treatment of gastrointestinal atony in ruminants, the carbonatebuffer mixture can eliminate the gastrointestinal atony originated from the over acidity in gastrointestinalcanal.

  19. Association between number of doses per day, number of medications and patient's non-compliance, and frequency of readmissions in a multi-ethnic Asian population

    Ming Ren Toh

    2014-01-01

    Conclusion: Complex medication regimen (i.e. multiple medications and multiple doses per day is a statistically significant predictor of number of readmissions. Simplifying therapeutic regimens with alternatives such as longer-acting or fixed-dose combination drugs may facilitate better patient adherence and reduce costly readmissions.

  20. Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers.

    Aarnoutse, R.E.; Kleinnijenhuis, J.; Koopmans, P.P.; Touw, D.J.; Wieling, J.; Hekster, Y.A.; Burger, D.M.

    2005-01-01

    OBJECTIVE: In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose

  1. Effect of low-dose ritonavir (100 mg twice daily) on the activity of cytochrome P450 2D6 in healthy volunteers

    Aarnoutse, Rob E; Kleinnijenhuis, Johanneke; Koopmans, Peter P; Touw, Daan J; Wieling, Jaap; Hekster, Yechiel A; Burger, David M

    2005-01-01

    OBJECTIVE: In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose

  2. Entrance surface dose in cerebral interventional radiology procedures

    Barrera-Rico, M.; Lopez-Rendon, X.; Rivera-Ordonez, C. E.; Gamboa-deBuen, I. [Instituto de Ciencias Nucleares, Universidad Nacional Autonoma de Mexico, 04510 DF (Mexico); Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez, 14269 DF (Mexico); Instituto de Ciencias Nucleares, Universidad Nacional Autonoma de Mexico, 04510 DF (Mexico)

    2012-10-23

    At the Instituto Nacional de Neurologia y Neurocirugia (INNN) diagnostic as well as therapeutic procedures of interventional radiology are carried out. Since the procedures can last from some minutes to several hours, the absorbed dose for the patient could increase dangerously. An investigation had begun in order to determine the entrance surface dose (ESD) using 25 thermoluminiscent dosimeters TLD-100 and 8 strips of 15 Multiplication-Sign 1 cm{sup 2} of Gafchromic XR-QA2 film bound in a holder of 15 Multiplication-Sign 15 cm{sup 2} in the posteroanterior (PA) and lateral (LAT) positions during all the procedure. The results show that maximum ESD could be from 0.9 to 2.9 Gy for the PA position and between 1.6 and 2.5 Gy for the lateral position. The average ESD was between 0.7 and 1.3 Gy for the PA position, and from 0.44 to 1.1 Gy for the lateral position in a therapeutic procedure.

  3. Locoregional IL-2 low dose applications for gastrointestinal tumors

    Zachary Krastev; Willem Den Otter; V Koltchakov; R Tomova; S Deredjian; A Alexiev; D Popov; B Tomov; Jan-Willem Koten; John Jacobs

    2005-01-01

    AIM: To explore the feasibility of local interleukin 2 (IL-2)in patients with different forms of abdominal cancer. This required experimentation with the time interval between IL-2 applications and the methods of application.METHODS: Sixteen patients with stages Ⅲ and Ⅳ of gastrointestinal malignancies (primary or metastatic) who were admitted to our Department of Gastroenterology were treated with locoregionally applied IL-2 in low doses.RESULTS: No major problems applying locoregional IL-2 were encountered. In 6 out of 16 patients, a modest but clinically worthwhile improvement was obtained. Adverse effects were minimal, The therapeutic scheme was well tolerated, even in patients in a poor condition.CONCLUSION: This study demonstrates the feasibility of low dose locoregional IL-2 application in advanced abdominal cancer. Local IL-2 therapy gives only negligible adverse effects. The results suggest that it is important to apply intratumorally. Local IL-2 may be given adjunct to standard therapeutic regimes and does not imply complex surgical interventions. These initial results are encouraging.

  4. Paradoxical Roles of Nanoparticles in Cancer Therapeutics and Carcinogenesis

    Despeaux, Emily

    Nanoparticles (NPs) are becoming increasingly common in consumer goods and are under investigation for a variety of industrial and biomedical applications. However, challenges in determining NP toxicity may prevent them from reaching their full potential. NPs cannot be treated as single class for toxicity evaluations. Even among particles made from the same material, particle-specific physical properties, including size, shape, surface charge, agglomeration state, and surface modifications have a strong effect on the toxicity. Even so, the obstacles to conclusively and reproducibly evaluating toxicity span all NP classes. NP literature is riddled with confusing and often contradictory reports regarding the biocompatibility of both engineered NPs, designed with biocompatibility as a priority, and NPs from occupational or environmental exposures. Incomplete NP characterization and sample inhomogeneity represent major confounding factors in disparate results from seemingly comparable study setups. Additionally, NPs can interfere with many conventional toxicity screening methods. Inappropriate doses, exposure routes, and toxicity endpoints further diminish the utility of many published studies. Given the burgeoning interest in NP-based therapeutic agents, consistent, reliable standards are needed to ensure the biocompatibility of new formulations. To those ends, the synthesis, characterization, and in vitro toxicity of a multi-functional NP therapeutic were investigated (Chapter 2). Specifically, superparamagnetic iron oxide nanoparticles (SPIONs) were coated with amphiphilic polymer and functionalized with antisense oligonucleotides targeting survivin, an anti-apoptotic protein that is highly overexpressed in cancer. SPION physical properties, including particle size and composition, were characterized at each step of synthesis. Our results showed that the SPION platform is biocompatible and capable of delivering functional antisense oligonucleotides to regulate

  5. Therapeutic Use of Prebiotics, Probiotics, and Postbiotics to Prevent Necrotizing Enterocolitis: What is the Current Evidence?

    2013-01-01

    Necrotizing enterocolitis (NEC) is a leading cause of neonatal morbidity and mortality and preventative therapies that are both effective and safe are urgently needed. Current evidence from therapeutic trials suggests that probiotics are effective in decreasing NEC in preterm infants and probiotics are currently the most promising therapy on the horizon for this devastating disease. However, concerns regarding safety and optimal dosing have limited the widespread adoption of routine clinical ...

  6. Dose of selective serotonin uptake inhibitors across pregnancy: clinical implications.

    Hostetter, A; Stowe, Z N; Strader, J R; McLaughlin, E; Llewellyn, A

    2000-01-01

    The use of antidepressants during pregnancy has undergone considerable scrutiny with respect to safety issues, though limited data with respect to dose management and symptom resolution is available. Previous reports on tricyclic antidepressants (TCAs) have demonstrated the need to adjust maternal dose later in pregnancy to maintain therapeutic serum concentrations. However, there is no data on the dosage of selective serotonin uptake inhibitors (SSRIs) required to maintain symptom resolution in women treated for major depression during pregnancy. The purpose of this study, then, was to assess the medication dosage requirements of SSRIs during this time. In this naturalistic study, pregnant women with a primary diagnosis of major depression were followed prospectively through pregnancy at monthly intervals with symptom assessment. Subjects were included in data analysis if they presented prior to 28 weeks gestation, were treated with SSRI monotherapy, received all psychiatric treatment during the pregnancy at the Emory Pregnancy and Postpartum Mood Disorders Program, and achieved euthymia after initial treatment intervention (CGI = 1 and Beck Depression Inventory (BDI) < 9) during pregnancy or failed to respond after eight weeks of treatment. Medication selection was based on personal treatment history or family treatment history (if any), and the published data on SSRIs in pregnancy. All medication dose adjustments were based on depressive symptoms as measured by the BDI and a psychiatric interview (ZNS). Thirty-four pregnant women were included in final analysis. Two thirds of the subjects (n = 22) required an increase in their daily dose of medication to maintain euthymia. The dose increases occurred at 27.1 +/- 7.1 weeks gestation, with mean BDI scores of 16.4 +/- 9.6, compared to a mean treatment response BDI of 6.9 +/- 5.4. Subject's age, education, past personal and familial psychiatric history were not significantly associated with dose adjustment. These

  7. Methotrexate Dosing Regimen for Plaque-type Psoriasis: A Systematic Review of the Use of Test-dose, Start-dose, Dosing Scheme, Dose Adjustments, Maximum Dose and Folic Acid Supplementation.

    Menting, Stef P; Dekker, Paul M; Limpens, Jacqueline; Hooft, Lotty; Spuls, Phyllis I

    2016-01-01

    There is a range of methotrexate dosing regimens for psoriasis. This review summarizes the evidence for test-dose, start-dose, dosing scheme, dose adjustments, maximum dose and use of folic acid. A literature search for randomized controlled trials and guidelines was performed. Twenty-three randomized controlled trials (29 treatment groups) and 10 guidelines were included. Two treatment groups used a test-dose, 5 guidelines recommend it. The methotrexate start-dose in randomized controlled trials varied from 5 to 25 mg/week, most commonly being either 7.5 mg or 15 mg. Guidelines vary from 5 to 15 mg/week. Methotrexate was administered as a single dose or in a Weinstein schedule in 15 and 11 treatment-groups, respectively; both recommended equally in guidelines. A fixed dose (n = 18), predefined dose (n = 3), or dose adjusted on clinical improvement (n = 8) was used, the last also being recommended in guidelines. Ten treatment groups used folic acid; in 2 it was allowed, in 14 not mentioned, and in 3 no folic acid was used. Most guidelines recommend the use of folic acid. Authors' suggestions for methotrexate dosing are given.

  8. Developing a Therapeutic Range of Adalimumab Serum Concentrations in Management of Psoriasis: A Step Toward Personalized Treatment

    Menting, S.P.; Coussens, E.; Pouw, M.F.; Reek, J.M.P.A. van den; Temmerman, L.; Boonen, H.; Jong, E.M.G.J. de; Spuls, P.I.; Lambert, J.

    2015-01-01

    IMPORTANCE: Adalimumab has proven to be effective in suppressing psoriasis disease activity and is administered in a standard dose. OBJECTIVE: To establish a therapeutic range for adalimumab trough levels in the treatment of plaque-type psoriasis, leading to a more personalized treatment. DESIGN, SE

  9. Therapeutic drug monitoring of monoclonal antibodies in inflammatory and malignant disease: translating TNF-ɑ experience to oncology

    Oude Munnink, T.H.; Henstra, M.J.; Segerink, L.I.; Movig, K.L.L.; Brummelhuis-Visser, P.

    2016-01-01

    Lack of response to monoclonal antibodies (mAbs) has been associated with inadequate mAb serum concentrations. Therapeutic drug monitoring (TDM) of mAbs has the potential to guide to more effective dosing in individual patients. This review discusses the mechanisms responsible for interpatient varia

  10. Multiple sclerosis: Therapeutic applications of advancing drug delivery systems.

    Dolati, Sanam; Babaloo, Zohreh; Jadidi-Niaragh, Farhad; Ayromlou, Hormoz; Sadreddini, Sanam; Yousefi, Mehdi

    2017-02-01

    Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, which is accompanying with demyelination, neurodegeneration and sensibility to oxidative stress. In MS, auto-reactive lymphocytes cross the blood-brain barrier (BBB) and reside in the perivenous demyelinating lesions which create various distinct inflammatory demyelinated plaques situated predominantly in the white matter. The current MS-related therapeutic approaches can be classified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs suppress circulating immune cells, inhibit passing the BBB and decrease the inflammatory responses. Recent advances have remarkably delayed disease development and improved the quality of life for numerous patients. In spite of major improvements in therapeutic options, there are some limitations regarding the routes of administration and the necessity for repeated and long-term dosing in which cause to systemic disadvantageous consequences and patient non-compliance. Nanotechnology presents promising approaches to improve autoimmune disease treatment with the capability to overcome many of the limitations common to the current immunosuppressive and biological therapies. Here we emphasis on nanomedicine-based drug delivery approaches of biological immunomodulatory mediators for the treatment of multiple sclerosis. This comprehensive review details the most successful drugs in MS therapy and also focuses on conceptions and clinical potential of novel nanomedicine attitudes for inducing immunosuppression and immunological tolerance in MS to modulate abnormal and pathologic immune responses.

  11. Therapeutic enhancement of protective immunity during experimental leishmaniasis.

    Senad Divanovic

    2011-09-01

    Full Text Available BACKGROUND: Leishmaniasis remains a significant cause of morbidity and mortality in the tropics. Available therapies are problematic due to toxicity, treatment duration and emerging drug resistance. Mouse models of leishmaniasis have demonstrated that disease outcome depends critically on the balance between effector and regulatory CD4(+ T cell responses, something mirrored in descriptive studies of human disease. Recombinant IL-2/diphtheria toxin fusion protein (rIL-2/DTx, a drug that is FDA-approved for the treatment of cutaneous T cell lymphoma, has been reported to deplete regulatory CD4(+ T cells. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the potential efficacy of rIL-2/DTx as adjunctive therapy for experimental infection with Leishmania major. Treatment with rIL-2/DTx suppressed lesional regulatory T cell numbers and was associated with significantly increased antigen-specific IFN-γ production, enhanced lesion resolution and decreased parasite burden. Combined administration of rIL-2/DTx and sodium stibogluconate had additive biological and therapeutic effects, allowing for reduced duration or dose of sodium stibogluconate therapy. CONCLUSIONS/SIGNIFICANCE: These data suggest that pharmacological suppression of immune counterregulation using a commercially available drug originally developed for cancer therapy may have practical therapeutic utility in leishmaniasis. Rational reinvestigation of the efficacy of drugs approved for other indications in experimental models of neglected tropical diseases has promise in providing new candidates to the drug discovery pipeline.

  12. Therapeutic Use of Cannabis in Inflammatory Bowel Disease

    Katz, Seymour

    2016-01-01

    The marijuana plant Cannabis sativa and its derivatives, cannabinoids, have grown increasingly popular as a potential therapy for inflammatory bowel disease (IBD). Studies have shown that modulation of the endocannabinoid system, which regulates various functions in the body and has been shown to play a key role in the pathogenesis of IBD, has a therapeutic effect in mouse colitis. Epidemiologic data and human therapy studies reveal a possible role for cannabinoids in the symptomatic treatment of IBD, although it has yet to be determined in human populations whether cannabinoids have therapeutic anti-inflammatory effects in IBD or are simply masking its many debilitating symptoms. Large, double-blind, randomized, placebo-controlled trials using serial inflammatory markers, biopsy findings, and endoscopic disease severity to demonstrate objective improvement in IBD are necessary before cannabis can be empirically accepted and recommended as an IBD treatment option. Questions concerning its safety profile and adverse effects prompt the need for further research, particularly in regard to dosing and route of administration to maximize benefits and limit potential harms. Cannabis use should be reserved for symptomatic control in patients with severe IBD refractory to the currently available standard-of-care and complementary and alternative medicines. PMID:28035196

  13. Oncolytic Viruses: Therapeutics With an Identity Crisis.

    Breitbach, Caroline J; Lichty, Brian D; Bell, John C

    2016-07-01

    Oncolytic viruses (OV) are replicating viral therapeutics for the treatment of cancer and have been in laboratory development for about twenty years. Recently, the FDA approved Imlygic, a herpes virus based therapeutic for the treatment of melanoma and thus OVs have entered a new era where they are a weapon in the armament of the oncologist. OVs are unique therapeutics with multiple mechanisms of therapeutic activity. The exact path for their development and eventual uptake by pharmaceutical companies is somewhat clouded by an uncertain identity. Are they vaccines, tumour lysing therapeutics, inducers of innate immunity, gene therapy vectors, anti-vascular agents or all of the above? Should they be developed as stand-alone loco-regional therapeutics, systemically delivered tumour hunters or immune modulators best tested as combination therapeutics? We summarize data here supporting the idea, depending upon the virus, that OVs can be any or all of these things. Pursuing a "one-size fits all" approach is counter-productive to their clinical development and instead as a field we should build on the strengths of individual virus platforms.

  14. Oncolytic Viruses: Therapeutics With an Identity Crisis

    Caroline J. Breitbach

    2016-07-01

    Full Text Available Oncolytic viruses (OV are replicating viral therapeutics for the treatment of cancer and have been in laboratory development for about twenty years. Recently, the FDA approved Imlygic, a herpes virus based therapeutic for the treatment of melanoma and thus OVs have entered a new era where they are a weapon in the armament of the oncologist. OVs are unique therapeutics with multiple mechanisms of therapeutic activity. The exact path for their development and eventual uptake by pharmaceutical companies is somewhat clouded by an uncertain identity. Are they vaccines, tumour lysing therapeutics, inducers of innate immunity, gene therapy vectors, anti-vascular agents or all of the above? Should they be developed as stand-alone loco-regional therapeutics, systemically delivered tumour hunters or immune modulators best tested as combination therapeutics? We summarize data here supporting the idea, depending upon the virus, that OVs can be any or all of these things. Pursuing a “one-size fits all” approach is counter-productive to their clinical development and instead as a field we should build on the strengths of individual virus platforms.

  15. Therapeutic effect of ursolic acid in experimental visceral leishmaniasis

    Jéssica A. Jesus

    2017-04-01

    Full Text Available Leishmaniasis is an important neglected tropical disease, affecting more than 12 million people worldwide. The available treatments are not well tolerated and present diverse side effects in patients, justifying the search for new therapeutic compounds. In the present study, the therapeutic potential and toxicity of ursolic acid (UA, isolated from the leaves of Baccharis uncinella C. DC. (Asteraceae, were evaluated in experimental visceral leishmaniasis. To evaluate the therapeutic potential of UA, hamsters infected with L. (L. infantum were treated daily during 15 days with 1.0 or 2.0 mg UA/kg body weight, or with 5.0 mg amphotericin B/kg body weight by intraperitoneal route. Fifteen days after the last dose, the parasitism of the spleen and liver was stimated and the main histopathological alterations were recorded. The proliferation of splenic mononuclear cells was evaluated and IFN-γ, IL-4, and IL-10 gene expressions were analyzed in spleen fragments. The toxicity of UA and amphotericin B were evaluated in healthy golden hamsters by histological analysis and biochemical parameters. Animals treated with UA had less parasites in the spleen and liver when compared with the infected control group, and they also showed preservation of white and red pulps, which correlate with a high rate of proliferation of splenic mononuclear cells, IFN-γ mRNA and iNOS production. Moreover, animals treated with UA did not present alterations in the levels of AST, ALT, creatinine and urea. Taken together, these findings indicate that UA is an interesting natural compound that should be considered for the development of prototype drugs against visceral leishmaniasis.

  16. Clinical, immunopathologic, and therapeutic considerations of inflammatory myopathies.

    Dalakas, M C

    1992-10-01

    The inflammatory myopathies encompass a group of heterogenous muscle diseases which have in common an acquired myopathy with histological signs of endomysial inflammation. We present evidence based on recently emerged clinical, histologic, immunopathologic, demographic and therapeutic observations that these myopathies comprise three major and distinct groups: polymyositis (PM), dermatomyositis (DM), and inclusion-body myositis (IBM). Immune-mediated mechanisms characteristic for each group appear to play a primary role in the pathogenesis of these diseases. In DM there is an intramuscular microangiopathy mediated by the C5b-9 membranolytic attack complex, leading sequentially to loss of capillaries, muscle ischemia, muscle fiber necrosis and perifascicular atrophy. In contrast, in PM and IBM the muscle fiber injury is initiated by sensitized CD8+ cytotoxic T cells that recognize MHC-I restricted muscle antigens, leading to phagocytosis and fiber necrosis. Among the viruses implicated in the cause of inflammatory myopathies, only the retroviruses, HIV, HTLV-1 and simian retroviruses, have been convincingly associated with PM. Retroviruses, therefore, appear to be the leading group of viruses capable of triggering these diseases. The treatment of inflammatory myopathies has been largely empirical. A detailed therapeutic plan based on our experience with a large number of patients is presented. Patients with bona fide PM or DM respond to steroids to some degree and for some period of time. In contrast, patients with IBM do not respond to any therapy and the disease should be suspected when a patient with presumed PM has failed treatment. Methotrexate and cyclophosphamide are disappointing. Cyclosporine and Azathioprine are commonly used but they are of uncertain benefit. Plasmapheresis is ineffective. High-dose intravenous immunoglobulin is a promising new therapeutic modality.

  17. Rivaroxaban – a safe therapeutic option in patients with antiphospholipid syndrome? Our experience in 23 cases

    Olesińska, Marzena

    2016-01-01

    In the therapeutic approach to patients with antiphospholipid syndrome (APS) with thrombotic manifestations, oral vitamin K antagonists (VKA) remain the standard of care. However, the use of VKA is very often associated with inability to achieve a therapeutic dose even in patients maintaining nutritional and therapeutic restrictions. The non-vitamin-K oral anticoagulants (NOAC) have a lot of advantages, but their efficacy and safety in APS have not been proven. We present 23 patients with APS treated with rivaroxaban in our department. Recurrence of thrombosis was observed only in 1 patient. No major or minor bleeding occurred. It proves the efficacy of treatment with rivaroxaban, but our observations require further prospective, randomized studies. PMID:27504026

  18. Rivaroxaban - a safe therapeutic option in patients with antiphospholipid syndrome? Our experience in 23 cases.

    Haładyj, Ewa; Olesińska, Marzena

    2016-01-01

    In the therapeutic approach to patients with antiphospholipid syndrome (APS) with thrombotic manifestations, oral vitamin K antagonists (VKA) remain the standard of care. However, the use of VKA is very often associated with inability to achieve a therapeutic dose even in patients maintaining nutritional and therapeutic restrictions. The non-vitamin-K oral anticoagulants (NOAC) have a lot of advantages, but their efficacy and safety in APS have not been proven. We present 23 patients with APS treated with rivaroxaban in our department. Recurrence of thrombosis was observed only in 1 patient. No major or minor bleeding occurred. It proves the efficacy of treatment with rivaroxaban, but our observations require further prospective, randomized studies.

  19. Radon as a medicine. Therapeutic effectiveness, biological mechanism and comparative risk assessment

    Deetjen, Peter; Falkenbach, Albrecht; Harder, Dietrich; Joeckel, Hans; Kaul, Alexander; Philipsborn, Henning von

    2014-07-01

    Proofs of the therapeutic efficiency of balneological radon applications administered to patients suffering from rheumatic diseases, investigations into the biological action mechanism associated with the alpha particles emitted by radon and its radioactive daughter products, and the comparative risk assessment of radon treatment and medicinal pain therapy have been the research projects whose results are summarized in this book. Controlled clinical studies, if possible performed as prospective, randomized and placebo-controlled double blind studies, have given evidence that the therapeutic effects of balneological radon applications - long-lasting pain reduction and reduced consumption of medicines compared with controls - are significantly persisting over many post-treatment months. The molecular and cellular mechanism of action underlying these long-lasting therapeutic effects has been identified as the down-regulation of cellular immune responses, initiated by cellular apoptosis sequential to low alpha particle doses and by the subsequent release of anti-inflammatory cytokines. The unwanted side-effects of non-steroidal anti-rheumatic drug treatments have to be compared with the absence of side effects from the balneological radon applications which merely involve radiation doses well below the mean value and the fluctuation width of the annual doses attributable to everybody's natural radiation exposure.

  20. Prophylactic and Therapeutic Potential of Acetyl-L-carnitine against Acetaminophen-Induced Hepatotoxicity in Mice.

    Alotaibi, Salman A; Alanazi, Abdulrazaq; Bakheet, Saleh A; Alharbi, Naif O; Nagi, Mahmoud N

    2016-01-01

    Prophylactic and therapeutic effects of acetylcarnitine against acetaminophen-induced hepatotoxicity were studied in mice. To evaluate the prophylactic effects of acetylcarnitine, mice were supplemented with acetylcarnitine (2 mmol/kg/day per oral (p.o.) for 5 days) before a single dose of acetaminophen (350 mg/kg intraperitoneal (i.p.)). Animals were sacrificed 6 h after acetaminophen injection. Acetaminophen significantly increased the markers of liver injury, hepatic reactive oxygen species, and nitrate/nitrite, and decreased hepatic glutathione (GSH) and the antioxidant enzymes. Acetylcarnitine supplementation resulted in reversal of all biochemical parameters toward the control values. To explore the therapeutic effects of acetylcarnitine, mice were given a single dose of acetylcarnitine (0.5, 1, and 2 mmol/kg p.o.) 1.5 h after acetaminophen. Animals were sacrificed 6 h after acetaminophen. Acetylcarnitine administration resulted in partial reversal of liver injury only at 2 mmol/kg p.o. At equimolar doses, N-acetylcystiene was superior as therapeutic agent to acetylcarnitine. However, acetylcarnitine potentiated the effect of N-acetylcystiene in the treatment of acetaminophen toxicity.

  1. Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease

    Björn Tampe

    2015-01-01

    Retrospective analysis of patients with hypertensive nephrosclerosis revealed that circulating methylated RASAL1 promoter DNA fragments in peripheral blood decrease with Dihydralazine treatment in patients with hypertensive nephrosclerosis, and provided evidence that low-dose Dihydralazine delays decline of excretory kidney function, whereas Dihydralazine at standard doses had no protective effect. We demonstrate that the protective effect of Dihydralazine is due to induction of endogenous Tet3/Tdg-mediated DNA-de-methylation activity reversing aberrant promoter CpG island methylation, while HIF1α induction at standard doses counterbalances its protective activity. We conclude that RASAL1 promoter methylation is a therapeutic target and a biomarker of renal fibrosis. Our study suggests that therapeutic use of low-dose Dihydralazine in patients with chronic kidney disease and fibrosis deserves further consideration.

  2. Effect of Uniform and Non-uniform High-z Nanoparticles Distribution in Tumor Volume on Dose Enhancement Factor During 192Ir Brachytherapy

    M Zabihzadeh

    2013-12-01

    Conclusion: increase of atomic number and concentrations of NPs enhance the absorbed dose due to increased possibility of photoelectric phenomena. Non-uniform distribution of NPs underestimated dose compared to uniform distribution; therefore, considering accurate NPs distribution inside the tumor volume is crucial to calculation of dose enhancement. Targeted labeling of NPs for the maximum absorption by tumor and for the minimal penetration into peripheral tissues has potential to increase radiation therapeutic ratio.

  3. Atmospheric radiation flight dose rates

    Tobiska, W. K.

    2015-12-01

    Space weather's effects upon the near-Earth environment are due to dynamic changes in the energy transfer processes from the Sun's photons, particles, and fields. Of the domains that are affected by space weather, the coupling between the solar and galactic high-energy particles, the magnetosphere, and atmospheric regions can significantly affect humans and our technology as a result of radiation exposure. Space Environment Technologies (SET) has been conducting space weather observations of the atmospheric radiation environment at aviation altitudes that will eventually be transitioned into air traffic management operations. The Automated Radiation Measurements for Aerospace Safety (ARMAS) system and Upper-atmospheric Space and Earth Weather eXperiment (USEWX) both are providing dose rate measurements. Both activities are under the ARMAS goal of providing the "weather" of the radiation environment to improve aircraft crew and passenger safety. Over 5-dozen ARMAS and USEWX flights have successfully demonstrated the operation of a micro dosimeter on commercial aviation altitude aircraft that captures the real-time radiation environment resulting from Galactic Cosmic Rays and Solar Energetic Particles. The real-time radiation exposure is computed as an effective dose rate (body-averaged over the radiative-sensitive organs and tissues in units of microsieverts per hour); total ionizing dose is captured on the aircraft, downlinked in real-time, processed on the ground into effective dose rates, compared with NASA's Langley Research Center (LaRC) most recent Nowcast of Atmospheric Ionizing Radiation System (NAIRAS) global radiation climatology model runs, and then made available to end users via the web and smart phone apps. Flight altitudes now exceed 60,000 ft. and extend above commercial aviation altitudes into the stratosphere. In this presentation we describe recent ARMAS and USEWX results.

  4. Stridor in asphyxiated neonates undergoing therapeutic hypothermia.

    Orme, Judith; Kissack, Christopher; Becher, Julie-Clare

    2014-07-01

    Therapeutic hypothermia is an established standard of care in the treatment of hypoxic-ischemic encephalopathy. Application of therapeutic hypothermia in the clinical setting may reveal a wider spectrum of adverse events than previously reported. We report 5 cases of transient respiratory stridor in 51 infants, occurring at different time points in the cooling process, which appeared to be unrelated to the intubation procedure. Therapeutic hypothermia was associated with transient stridor in this case series. Formal laryngoscopy is required to determine the underlying pathologic etiology.

  5. [Therapeutic problems posed by various angiodysplasias].

    Maraval, M

    1980-01-01

    The clinical and anatomical aspects of the angiodysplasias are multiple and numerous classifications have been proposed. After review of a more simple classification put forward by Natali and Merland based on the contribution of superselective arteriography, consideration is given to a therapeutic approach for each angiodysplasia. Whereas for a long time the only therapeutic alternatives have been between surgery and no surgery, improved arteriographic understanding of these lesions has now permitted improved treatment, by surgery or by embolization or by the combination of the two methods. Finally the fields of the pure arterial dysplasias and the rares phacomatoses are considered, with a therapeutic scheme in each case.

  6. Exploratory Studies With BT-11: A Proposed Orally Active Therapeutic for Crohn's Disease.

    Bissel, Philippe; Boes, Katie; Hinckley, Jonathan; Jortner, Bernard S; Magnin-Bissel, Geraldine; Werre, Stephen R; Ehrich, Marion; Carbo, Adria; Philipson, Casandra; Hontecillas, Raquel; Philipson, Noah; Gandour, Richard D; Bassaganya-Riera, Josep

    2016-09-01

    Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn's disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/d. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days (n = 10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical, and continuous end points, including posture, in cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of the brain, kidney, liver, adrenal gland, testes, stomach, small and large intestines, duodenum, pancreas, heart, lungs, spleen, thymus, and rib found no significant differences between the groups. Plasma enzymes associated with liver function were transiently elevated 2 to 4 days after the 500 mg/kg single dose but returned to normal values by 8 days and were not observed at any time in rats given 80 mg/kg/d for 14 days. One hour after oral administration of a single dose of 80 mg/kg, BT-11 had a maximal concentration of 21 ng/mL; the half-life was 3 hours. These experimental results demonstrated that BT-11 is well tolerated in rats, and, with further testing, may hold promise as an orally active therapeutic for CD.

  7. Surface dose measurements and comparison of unflattened and flattened photon beams

    Ashokkumar Sigamani

    2016-01-01

    Full Text Available The purpose of this study was to evaluate the central axis dose in the build-up region and the surface dose of a 6 MV and 10 MV flattened photon beam (FB and flattening filter free (FFF therapeutic photon beam for different square field sizes (FSs for a Varian Truebeam linear accelerator using parallel-plate ionization chamber and Gafchromic film. Knowledge of dosimetric characteristics in the build-up region and surface dose of the FFF is essential for clinical care. The dose measurements were also obtained empirically using two different commonly used dosimeters: a p-type photon semiconductor dosimeter and a cylindrical ionization chamber. Surface dose increased linearly with FS for both FB and FFF photon beams. The surface dose values of FFF were higher than the FB FSs. The measured surface dose clearly increases with increasing FS. The FFF beams have a modestly higher surface dose in the build-up region than the FB. The dependence of source to skin distance (SSD is less significant in FFF beams when compared to the flattened beams at extended SSDs.

  8. Tolerance doses for treatment planning

    Lyman, J.T.

    1985-10-01

    Data for the tolerance of normal tissues or organs to (low-LET) radiation has been compiled from a number of sources which are referenced at the end of this document. This tolerance dose data are ostensibly for uniform irradiation of all or part of an organ, and are for either 5% (TD/sub 5/) or 50% (TD/sub 50/) complication probability. The ''size'' of the irradiated organ is variously stated in terms of the absolute volume or the fraction of the organ volume irradiated, or the area or the length of the treatment field. The accuracy of these data is questionable. Much of the data represents doses that one or several experienced therapists have estimated could be safely given rather than quantitative analyses of clinical observations. Because these data have been obtained from multiple sources with possible different criteria for the definition of a complication, there are sometimes different values for what is apparently the same endpoint. The data from some sources shows a tendancy to be quantized in 5 Gy increments. This reflects the size of possible round off errors. It is believed that all these data have been accumulated without the benefit of 3-D dose distributions and therefore the estimates of the size of the volume and/or the uniformity of the irradiation may be less accurate than is now possible. 19 refs., 4 figs.

  9. Dose Estimation in Radiation Cytogenetics

    Ainsbury, Elizabeth; Lloyd, David

    2009-04-01

    Throughout the radiation cytogenetics community, a core group of methods exists to produce an estimate of radiation dose from an observed yield of DNA damage in blood. Mathematical and statistical analysis is extremely important for accurate assessment of data and results, and a number of classical statistical methods are commonly employed. However, the large number of statistical techniques, and the complexity of the methods, can lead to errors in data analysis and misinterpretation of results. Cytogenetics dose estimation software has been developed to simplify mathematical and statistical analysis of cytogenetic data. ``Dose Estimate'' is a collection of mathematical and statistical methods based on the cytogenetics methods and programs written by Alan Edwards, David Papworth, and others. Details of the biological and mathematical techniques used in the software will be presented, including maximum likelihood estimation of yield curve coefficients for the dicentric or translocation assays. Proposals for increasing the sophistication of the software through implementation of recently published Bayesian analysis techniques for cytogenetics will also be outlined.

  10. Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins.

    Verthelyi, Daniela; Wang, Vivian

    2010-12-22

    Therapeutic proteins such as monoclonal antibodies, replacement enzymes and toxins have significantly improved the therapeutic options for multiple diseases, including cancer and inflammatory diseases as well as enzyme deficiencies and inborn errors of metabolism. However, immune responses to these products are frequent and can seriously impact their safety and efficacy. Of the many factors that can impact protein immunogenicity, this study focuses on the role of innate immune response modulating impurities (IIRMIs) that could be present despite product purification and whether these impurities can synergize to facilitate an immunogenic response to therapeutic proteins. Using lipopolysaccharide (LPS) and CpG ODN as IIRMIs we showed that trace levels of these impurities synergized to induce IgM, IFNγ, TNFα and IL-6 expression. In vivo, trace levels of these impurities synergized to increase antigen-specific IgG antibodies to ovalbumin. Further, whereas mice treated with human erythropoietin showed a transient increase in hematocrit, those that received human erythropoietin containing low levels of IIRMIs had reduced response to erythropoietin after the 1(st) dose and developed long-lasting anemia following subsequent doses. This suggests that the presence of IIRMIs facilitated a breach in tolerance to the endogenous mouse erythropoietin. Overall, these studies indicate that the risk of enhancing immunogenicity should be considered when establishing acceptance limits of IIRMIs for therapeutic proteins.

  11. Trace levels of innate immune response modulating impurities (IIRMIs synergize to break tolerance to therapeutic proteins.

    Daniela Verthelyi

    Full Text Available Therapeutic proteins such as monoclonal antibodies, replacement enzymes and toxins have significantly improved the therapeutic options for multiple diseases, including cancer and inflammatory diseases as well as enzyme deficiencies and inborn errors of metabolism. However, immune responses to these products are frequent and can seriously impact their safety and efficacy. Of the many factors that can impact protein immunogenicity, this study focuses on the role of innate immune response modulating impurities (IIRMIs that could be present despite product purification and whether these impurities can synergize to facilitate an immunogenic response to therapeutic proteins. Using lipopolysaccharide (LPS and CpG ODN as IIRMIs we showed that trace levels of these impurities synergized to induce IgM, IFNγ, TNFα and IL-6 expression. In vivo, trace levels of these impurities synergized to increase antigen-specific IgG antibodies to ovalbumin. Further, whereas mice treated with human erythropoietin showed a transient increase in hematocrit, those that received human erythropoietin containing low levels of IIRMIs had reduced response to erythropoietin after the 1(st dose and developed long-lasting anemia following subsequent doses. This suggests that the presence of IIRMIs facilitated a breach in tolerance to the endogenous mouse erythropoietin. Overall, these studies indicate that the risk of enhancing immunogenicity should be considered when establishing acceptance limits of IIRMIs for therapeutic proteins.

  12. A cross-sectional, multicentre study of the therapeutic management of multiple sclerosis relapses in Italy.

    Annovazzi, Pietro; Tomassini, Valentina; Bodini, Benedetta; Boffa, Laura; Calabrese, Massimiliano; Cocco, Eleonora; Cordioli, Cinzia; De Luca, Giovanna; Frisullo, Giovanni; Gallo, Antonio; Malucchi, Simona; Paolicelli, Damiano; Pesci, Ilaria; Radaelli, Marta; Ragonese, Paolo; Roccatagliata, Luca; Tortorella, Carla; Vercellino, Marco; Zipoli, Valentina; Gasperini, Claudio; Rodegher, Mariaemma; Solaro, Claudio

    2013-02-01

    Despite the existence of therapeutic guidelines, management of multiple sclerosis relapse remains heterogeneous. Optimisation of relapse outcome demands an improved understanding of the neurologist's therapeutic attitude towards relapse management, which is the aim of this study. Neurologists from 13 multiple sclerosis centres completed a questionnaire every time they assessed multiple sclerosis relapses. The questionnaire requested a guided description of the relapse's clinical characteristics and an indication of the prescribed therapy, supported with up to 3 out of 20 suggested reasons. Over 3 months, 368 questionnaires were collected. Median percentage (%) of 21 relapses resulting in a prescription was 88.9%. Corticosteroids represented the most frequent prescription. A short-course of high-dose intravenous methylprednisolone was the most used corticosteroid (73.7%). Treatment was administrated mainly in day case unit (80.0%) and at home (13.6%). A tapered therapy was prescribed to 28.8% of patients. Neurologists' therapeutic decisions were driven mainly by relapse severity (45.3%) and symptom evolution (24.2%). Our study confirms the therapeutic attitude of multiple sclerosis specialists in treating relapses with high-dose intravenous corticosteroids in a day hospital setting, with a tapering in a proportion of cases. The main reasons for prescription are relapse severity and symptom evolution.

  13. What level of accuracy is achievable for preclinical dose painting studies on a clinical irradiation platform?

    Trani, Daniela; Reniers, Brigitte; Persoon, Lucas; Podesta, Mark; Nalbantov, Georgi; Leijenaar, Ralph T H; Granzier, Marlies; Yaromina, Ala; Dubois, Ludwig; Verhaegen, Frank; Lambin, Philippe

    2015-05-01

    in a rat tumor model on a clinical platform, with a high accuracy achieved in the delivery of complex dose distributions. Our work demonstrates the technical feasibility of this approach and enables future investigations on the therapeutic effect of preclinical dose painting strategies using a state-of-the-art clinical platform.

  14. Early therapeutic effects of cyberknife radiosurgery on trigeminal neuralgia

    Mun, Seong Kwon; Choi, Byung Ock; Choi, Ihl Bohng; Kang, Young Nam; Jang, Ji Sun [The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of); Kang, Ki Mun [Gyeongsang National University School of Medicine, Jinju (Korea, Republic of)

    2006-06-15

    We evaluated whether Cyberknife radiosurgery is an effective and safe method of therapy for medically intractable trigeminal neuralgia (TN). We retrospectively analyzed the outcome of 26 patients, who failed to surgery or were not suitable candidates for invasive intervention and were treated by Cyberknife radiosurgery between March 2004 and May 2005. Radiosurgery doses of 60 {approx} 64 Gy were delivered to the 80% isodose line prescribed to an 6 mm length of the nerve, sparing the most proximal 3 mm away from the trigeminal nerve root entry zone (median dose: 64 Gy). Follow-up period was 3 {approx} 15 months (median follow-up period: 9 months) Preliminary results from a cohort of 26 patients undergoing Cyberknife radiosurgery for TN showed that pain relief was achieved in 50% (13/26) of patients within the first 24 hrs after treatment. At last follow-up, 96.2% (25/26) of patients reported early pain relief within 7 days. Treatment failure developed in 2 of 26. Poor response occurred in one patient and relapse was observed in the other patient. 3 patients had hypoesthesia (11.5%), which was the only complication observed with any of our patients. With these results, authors assumed that Cyberknife radiosurgery for TN could be one of safe and effective therapeutic methods.

  15. Sesamol: an efficient antioxidant with potential therapeutic benefits.

    Geetha, Thiraviam; Rohit, Bhandari; Pal, Kaur Indu

    2009-07-01

    Sesamol has been shown earlier to exhibit antimutagenic (reactive oxygen mediated) and antiageing activity in our lab and it has also been found to exert chemopreventive effect. Here we report the in vitro antioxidant activity of sesamol. As most of the antioxidants act due to their property to auto-oxidise and the pro- or antioxidant activity would depend on the concentration of the agent used and the free radical source, at least 6 dilutions in concentration range of 5-1000 nmoles of sesamol were selected for each test system. Further the antioxidant activity was compared with a water soluble antioxidant (ascorbic acid). Eventhough some preliminary studies on the antioxidant activity of sesamol have been reported in DPPH assay & inhibition of lipid peroxidation, it is not complete. We, here in report comprehensively (both in terms of the no. of doses and also a variety of test systems being employed) on the antioxidant activity of sesamol. Furthermore, since all the data has been generated by the same workers and under same laboratory conditions, hence is scientifically significant. Also the process of dose selection as discussed earlier is more scientific; and the data treatment, i.e. calculation of IC(50) values and comparisons with ascorbic acid has been statistically validated. In conclusion, sesamol was found to be an efficient scavenger of the entire range of ROS in several test systems pointing towards the potential of sesamol to be developed as a possible therapeutic.

  16. V-ATPase as an effective therapeutic target for sarcomas

    Perut, Francesca, E-mail: francesca.perut@ior.it [Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna (Italy); Avnet, Sofia; Fotia, Caterina; Baglìo, Serena Rubina; Salerno, Manuela [Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna (Italy); Hosogi, Shigekuni [Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna (Italy); Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan); Kusuzaki, Katsuyuki [Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan); Baldini, Nicola [Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, Bologna (Italy); Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna (Italy)

    2014-01-01

    Malignant tumors show intense glycolysis and, as a consequence, high lactate production and proton efflux activity. We investigated proton dynamics in osteosarcoma, rhabdomyosarcoma, and chondrosarcoma, and evaluated the effects of esomeprazole as a therapeutic agent interfering with tumor acidic microenvironment. All sarcomas were able to survive in an acidic microenvironment (up to 5.9–6.0 pH) and abundant acidic lysosomes were found in all sarcoma subtypes. V-ATPase, a proton pump that acidifies intracellular compartments and transports protons across the plasma membrane, was detected in all cell types with a histotype-specific expression pattern. Esomeprazole administration interfered with proton compartmentalization in acidic organelles and induced a significant dose-dependent toxicity. Among the different histotypes, rhabdomyosarcoma, expressing the highest levels of V-ATPase and whose lysosomes are most acidic, was mostly susceptible to ESOM treatment. - Highlights: • Osteosarcoma, rhabdomyosarcoma, and chondrosarcoma survive in acidic microenvironment. • At acidic extracellular pH, sarcoma survival is dependent on V-ATPase expression. • Esomeprazole administration induce a significant dose-dependent toxicity.

  17. Mean dose to lymphocytes during radiotherapy treatments

    Brandan, M.E.; Perez-Pastenes, M.A. [Instituto de Fisica (Mexico); Ostrosky-Wegman, P.; Gonsebatt, M.E. [Instituto de Investigaciones Biomedicas (Mexico); Diaz-Perches, R. [Hospital General de Mexico (Mexico)

    1994-10-01

    Using a probabilistic model with parameters from four radiotherapy protocols used in Mexican hospitals for the treatment of cervical cancer, the authors have calculated the distribution of dose to cells in peripheral blood of patients. Values of the mean dose to the lymphocytes during and after a {sup 60}Co treatment are compared to estimates from an in vivo chromosome aberration study performed on five patients. Calculations indicate that the mean dose to the circulating blood is about 2% of the tumor dose, while the mean dose to recirculating lymphocytes may reach up to 7% of the tumor dose. Differences up to a factor of two in the dose to the blood are predicted for different protocols delivering equal tumor doses. The data suggest mean doses higher than the predictions of the model. 10 refs., 3 figs., 2 tabs.

  18. Organ-specific external dose coefficients and protective apron transmission factors for historical dose reconstruction for medical personnel.

    Simon, Steven L

    2011-07-01

    While radiation absorbed dose (Gy) to the skin or other organs is sometimes estimated for patients from diagnostic radiologic examinations or therapeutic procedures, rarely is occupationally-received radiation absorbed dose to individual organs/tissues estimated for medical personnel; e.g., radiologic technologists or radiologists. Generally, for medical personnel, equivalent or effective radiation doses are estimated for compliance purposes. In the very few cases when organ doses to medical personnel are reconstructed, the data is usually for the purpose of epidemiologic studies; e.g., a study of historical doses and risks to a cohort of about 110,000 radiologic technologists presently underway at the U.S. National Cancer Institute. While ICRP and ICRU have published organ-specific external dose conversion coefficients (DCCs) (i.e., absorbed dose to organs and tissues per unit air kerma and dose equivalent per unit air kerma), those factors have been published primarily for mono-energetic photons at selected energies. This presents two related problems for historical dose reconstruction, both of which are addressed here. It is necessary to derive conversion factor values for (1) continuous distributions of energy typical of diagnostic medical x-rays (bremsstrahlung radiation), and (2) energies of particular radioisotopes used in medical procedures, neither of which are presented in published tables. For derivation of DCCs for bremsstrahlung radiation, combinations of x-ray tube potentials and filtrations were derived for different time periods based on a review of relevant literature. Three peak tube potentials (70 kV, 80 kV, and 90 kV) with four different amounts of beam filtration were determined to be applicable for historic dose reconstruction. The probabilities of these machine settings were assigned to each of the four time periods (earlier than 1949, 1949-1954, 1955-1968, and after 1968). Continuous functions were fit to each set of discrete values of the

  19. Therapeutic drug monitoring in clinical research

    Neef, Cees; Touw, Daniel J.; Stolk, Leo M.

    2008-01-01

    The development of a new drug is characterized by distinct developmental stages, usually described as phases I to IV. Dose tolerance and dose response exploration studies are undertaken in phase II or III. Pharmacokinetic studies are often involved in these phases, but frequently only as an objectiv

  20. Clinical study of 312 cases with matastatic differentiated thyroid cancer treated with large doses of 131 I

    ZHU Rui-sen; YU Yong-li; LU Han-kui; LUO Quan-yong; CHEN Li-bo

    2005-01-01

    @@ Patients with metastatic thyroid cancer (MTC) was routinely treated with a small dose of 131I before 1989. After that we have been switched to multiple courses of large dose 131I therapy. In this paper, the therapeutic result and its effect, in particular on bone marrow depression, pulmonary, parathyroid and salivary gland function as well as chromosome aberration1-3 were observed and reported.