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Different Doses (different + dose)
Selected AbstractsPain Sensation during Intradermal Injections of Three Different Botulinum Toxin Preparations in Different Doses and DilutionsDERMATOLOGIC SURGERY, Issue 7 2006GOTTFRIED KRANZ MD BACKGROUND Pain sensation associated with injections of botulinum neurotoxin (BoNT) is commonly reported. To date differences in pain sensation between the commercially available products containing BoNT have not been quantified. OBJECTIVES The pain sensations during injection of Dysport, Botox, Neurobloc, and pure saline (control) were compared. In addition, the nociceptive effect of different volumes used for the dilution of the same BoNT dose was investigated. METHODS In a prospective, double-blind, controlled trial, 10 healthy subjects were injected intradermally with Dysport (12 U), Botox (3 and 4 U), Neurobloc (150 and 300 U) reconstituted in 0.9% saline, and pure saline. Pain sensation was quantified during injections. RESULTS Neurobloc injections caused significantly more injection pain than Botox, Dysport, and saline. No significant differences between Dysport, Botox, and saline were found, although there was a trend toward less pain with pure saline injections. Higher pain levels with higher volumes could not be demonstrated significantly. CONCLUSION Our data demonstrate that BoNT type B injections are associated with substantial pain. There is a considerable difference between the commercially available BoNT type B compared to the two BoNT type A preparations. Therefore, considering mitigation of injection pain seems necessary when using BoNT type B. [source] Effects of Different Doses of Low Power Continuous Wave He,Ne Laser Radiation on Some Seed Thermodynamic and Germination Parameters, and Potential Enzymes Involved in Seed Germination of Sunflower (Helianthus annuus L.)PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2010Rashida Perveen In this study, water-soaked seeds of sunflower were exposed to He,Ne laser irradiation of different energies to determine whether or not He,Ne laser irradiation caused changes to seed thermodynamic and germination parameters as well as effects on the activities of germination enzymes. The experiment comprised four energy levels: 0 (control), 100, 300 and 500 mJ of laser energy and each treatment replicated four times arranged in a completely randomized design. The experimentation was performed under the greenhouse conditions in the net-house of the Department of Botany, University of Agriculture, Faisalabad. The seed thermodynamic parameters were calculated according to seed germination thermograms determined with a calorimeter at 25.8°C for 72 h. Various thermodynamic parameters of seed (,H, (,S)e, (,S)c, (,S)e/,t and (,S)c/,t) were affected significantly due to presowing laser treatment. Significant changes in seed germination parameters and enzyme activities were observed in seeds treated with He,Ne laser. The He,Ne laser seed treatment resulted in increased activities of amylase and protease. These results indicate that the low power continuous wave He,Ne laser light seed treatment has considerable biological effects on seed metabolism. This seed treatment technique can be potentially employed to enhance agricultural productivity. [source] Effect of Different Doses of Thalidomide in Experimentally Induced Inflammatory Bowel Disease in RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2008Om Prakash Adult Wistar rats of either sex were used (n = 36). Colitis was induced by a single intra-colonic application of 20 mg 2,4,6-trinitrobenzene sulfonic acid (TNBS) dissolved in 35% ethanol into the descending colon. Rats were divided into six groups (n = 6). Animals were treated with vehicle (ethanol), TNBS dissolved in 35% ethanol, thalidomide (with different doses of 50, 100 and 150 mg/kg body weight), and sulfasalazine (360 mg/kg body weight) for 14 days. After completion of 14 days of treatment, animals were killed and the following parameters were assessed: morphological score, histological score and biochemical parameters (myeloperoxidase, malondialdehyde and tumour necrosis factor-,). Results showed thalidomide with different doses provided protection against TNBS-induced colonic damage. There was significant protection with thalidomide 150 mg/kg body weight compared to controls (P < 0.001). All the biochemical parameters were highly reduced in the entire thalidomide-treated group compared to controls particularly with thalidomide 150 mg/kg body weight (P < 0.001). Treatment with thalidomide restored malondialdehyde as well as reduction of myeloperoxidase and tumour necrosis factor-, towards normal levels. Morphological and histological score were significantly reduced in all the treated groups with significant effect found with 150 mg/kg (P < 0.001). Our results indicate efficacy of thalidomide in TNBS induce experimental colitis model in rats but present findings requires further investigation to establish the real safety and efficacy in human beings. [source] The effect of hyaluronic acid on IL-1,-induced chondrocyte apoptosis in a rat model of osteoarthritisJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 12 2008Pang-Hu Zhou Abstract The purpose of this article was to study the effect of hyaluronic acid (HA) on chondrocyte apoptosis in a rat osteoarthritis in vitro model (exposure to IL-1,) and explore its mechanism. A rat in vitro model of osteoarthritis (OA) was established using 10 ng/mL IL-1, as a modulating and chondrocyte apoptosis inducing agent. Different doses of HA (10, 20, and 40 µg/mL) were added 1 h prior to the addition of IL-1, to a monolayer culture of freshly isolated juvenile rat chondrocytes. The ratio of apoptotic cell death was surveyed by Annexin V-FITC and propidium iodide double-labeling FACS analysis. The mitochondrial membrane potential of chondrocytes was evaluated by rhodamine-123 fluorescence. The mitochondrial function was evaluated through detecting the ATP production by a luciferase assay. The reverse transcription polymerase chain reaction (RT-PCR) was performed to measure mRNA expression levels of inducible oxide synthase (iNOS). HA could inhibit IL-1,-induced chondrocyte apoptosis in our cell culture model system. It was showed that addition of HA to the medium was able in a dose-dependent way to reduce the impairment of the mitochondrial membrane potential and to restore mitochondrial ATP production. This study shows that HA could suppress in a dose-dependent way chondrocyte apoptosis in our IL-1,-induced osteoarthritis model. The suppression of inflammatory cytokine activity within the joint might be one important mechanism of the clinical action of intraarticular injection of HA in the treatment of OA. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Baicalin attenuates air embolism-induced acute lung injury in rat isolated lungsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2009Min-Hui Li Background and purpose:, Baicalin has been reported to have anti-inflammatory effects and protect against various tissue injuries. However, the effect of baicalin on air embolism-induced acute lung injury has not been tested yet. Experimental approach:, Acute lung injury was induced by infusion of air at a rate of 0.25 mL·min,1 for 1 min into the pulmonary artery of rat isolated lungs. At the end of the experiment, samples were collected for assessment of lung injury, biochemical analysis and histology. Different doses of baicalin (1, 2 and 4 mg·kg,1) were given into the perfusate before air infusion. Key results:, Air embolism elicited a significant increase in microvascular permeability (Kf), lung weight gain, wet/dry weight ratio, pulmonary artery pressure and protein concentration in the bronchoalveolar lavage fluid. Levels of the cytokines, tumour necrosis factor , and cytokine-induced neutrophil chemoattractant-1 in perfusate, and malondialdehyde levels and myeloperoxidase activities in lung tissue were also significantly increased. In addition, histological examination showed increased neutrophil infiltration in lung tissues. Furthermore, nuclear factor-,B activity and degradation of I,B-, were significantly increased in lungs. Pretreatment of the lungs with baicalin (4 mg·kg,1) showed a statistically significant difference in all of the assessed parameters, except for alteration in the pulmonary artery pressure. Conclusions and implications:, Our study suggests that baicalin attenuated air embolism-induced acute lung injury and may be considered a useful adjunct drug therapy in this clinical condition. [source] Augmented suppression of androgen receptor signaling by a combination of ,-tocopheryl succinate and methylseleninic acidCANCER, Issue 12 2006Haitao Zhang PhD Abstract BACKGROUND. Previous reports showed that ,-tocopheryl succinate (,TS) and methylseleninic acid (MSA) independently reduce the abundance of androgen receptor (AR) in prostate cancer cells. The response to MSA happens quickly, whereas the response to ,TS takes much longer. The present study was designed to investigate whether a combination of ,TS and MSA would produce an additive or a greater than additive effect in suppressing AR level, AR transactivation, and prostate-specific antigen (PSA). METHODS. LNCaP cells were treated with ,TS alone for 31 hours, MSA alone for 3 hours, or ,TS first for 28 hours and ,TS/MSA together for the last 3 hours. AR and PSA mRNA levels were quantitated by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). AR transactivation was determined by the ARE-luciferase reporter assay. Both cellular and secretory PSA was also measured by the enzyme-linked immunosorbent assay (ELISA) method. RESULTS. Different doses of ,TS were evaluated in combination with MSA. Some striking results are highlighted below for ,TS alone, MSA alone, or ,TS/MSA (presented in that order). AR mRNA level was depressed by 0%, 20%, or 60%, respectively; AR transactivation was inhibited by 35%, 10%, or 60%, respectively; whereas the PSA mRNA level was decreased by 40%, 60%, or 90%, respectively. Interestingly, secretory PSA was consistently reduced to a greater extent than cellular PSA. CONCLUSIONS. A combination of ,TS/MSA produced a greater than additive effect in suppressing AR signaling compared with the single agent. Decreased AR abundance is a major factor, but not necessarily the sole factor, in diminishing the transcriptional activity of AR by ,TS or MSA. Cancer 2006. © 2006 American Cancer Society. [source] Solid dispersion of rutaecarpine improved its antihypertensive effect in spontaneously hypertensive ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2008Jin-Song Ding Abstract It was reported previously that rutaecarpine produced a hypotensive effect in phenol-induced and 2-kidney, 1-clip hypertensive rats. However, the same dose of crude rutaecarpine did not produce significant hypotensive effects when applied to spontaneously hypertensive rats (SHR). In the present study, a different dose of rutaecarpine solid dispersion was administered intragastrically to SHR. The systolic blood pressure was monitored by the tail-cuff method with an electro-sphygmomanometer. The plasma concentration of rutaecarpine, calcitonin gene-related peptide (CGRP) and the mRNA levels of CGRP in dorsal root ganglion were determined. The results showed that administration of the solid dispersion significantly increased the blood concentration of rutaecarpine, accompanied by significant hypotensive effects in SHR in a dose-dependent manner. The levels of plasma CGRP were also elevated significantly, concomitantly with the increased mRNA levels in the dorsal root ganglion in a dose-dependent manner. It was concluded that a change of the dosage from the crude drug to solid dispersion could improve significantly the efficiency of rutaecarpine absorption and increase its plasma concentration. The anti-hypertensive effect exerted by rutaecarpine solid dispersion in SHR is mediated by CGRP. Copyright © 2008 John Wiley & Sons, Ltd. [source] P30 Transparent plastic foils allow a short patch-test application timeCONTACT DERMATITIS, Issue 3 2004Bolli Bjarnason Objective:, To investigate whether application of allergic patch tests with transparent semi-occlusive adhesive plastic foils yields higher test sensitivity than when tapes are used. To study whether such foils compared to tapes allow a shorter application time of tests. Methods:, We applied different doses of budesonide printed on polyester squares and vehicle control squares to budesonide allergic subjects for 4 days. Each subject was tested with a set of tests both with a tape and a foil. We assessed all tests when they had been detached and additionally those applied with foils at earlier time points. All assessments were performed both visually and with a laser Doppler perfusion imaging technique. Results:, Test sensitivity is higher with foil applications than when tapes are used and the perfusion is higher with the foils in many cases. The foils allow detachment of visually positive tests before 48 hours in some subjects, regardless of dose. Conclusions:, Test applications with transparent semi-occlusive adhesive plastic foils is sensitive and should be considered for application of patch tests when a short application time is important as when tests are carried out with occupationally hazardous allergens or when test substances containing allergens are expected to be irritating. [source] Correlation between the residual resistivity ratio and the power-law of the normal-state resistivity in MgB2CRYSTAL RESEARCH AND TECHNOLOGY, Issue 1 2008I. M. Obaidat Abstract MgB2 polycrystalline superconducting specimens were irradiated with several doses of ,-rays up to 100 MR. An increase in the normal state resistivity and a broadening of the resistive transition to the superconducting state were observed with increasing ,-irradiation dose. Although very small changes to the superconducting transition temperature were obtained after ,-irradiation, different temperature dependence of normal-state resistivity and different residual resistivity ratios, RRR were obtained for different doses. We have found a correlation between RRR and the power law dependence of resistivity, n as the irradiation dose increases. This correlation may be an indication that the electron-phonon interaction is important in these samples. These results are attributed to the disorder caused by ,-rays. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Sensitivity and reproducibility of indirect calorimetry in measurement of resting metabolic rateDRUG DEVELOPMENT RESEARCH, Issue 8 2008Cecilia Karlsson Abstract The aim of this study was to assess indirect calorimetry measurement of resting metabolic rate (RMR) with respect to sensitivity and reproducibility in a human study population suitable for early clinical studies to evaluate new anti-obesity candidate drugs. Twenty-four overweight, but otherwise healthy males were included in this randomized, single-blind, placebo-controlled, crossover study. Three different doses of epinephrine (0.005, 0.01, 0.03,µg · kg fat-free mass (FFM),1 · min,1) were used as active treatment. There were two identical study periods, separated by a 4-week washout. Increases in RMR were seen with all tested concentrations of epinephrine when compared with placebo. Changes in RMR of ,1.8% could be detected with 90% power in this crossover study design. The RMR values measured at the two study periods revealed a highly significant correlation (Spearman correlation 0.803, P=0.0007). To conclude, indirect calorimetry is a sensitive and robust means of measuring RMR. The method can be used to assess RMR in diverse clinical settings, even when considering modest differences. Drug Dev Res 69: 2008. © 2008 Wiley-Liss, Inc. [source] Enhanced Left Ventricular Endocardial Border Delineation with an Intravenous Injection of SonoVue, a New Echocardiography Contrast Agent:ECHOCARDIOGRAPHY, Issue 8 2000A European Multicenter Study The safety and efficacy of SonoVue (also referred to as BR1), a new contrast agent for delineating endocardial border of the left ventricle after intravenous administration, was assessed. Two hundred and eighteen patients with suspected coronary artery disease undergoing fundamental echocardiography for the assessment of left ventricle were enrolled in a prospective multicenter, single blind, cross-over study with random sequence allocation of four different doses of SonoVue. Endocardial border definition in the apical and parasternal views was scored as O = not visible, 1 = barely visible, and 2 = well visualized before and after contrast enhancement. Analysis was performed by two pairs of off-site observers. Safety of SonoVue was also assessed. Results of our study indicated that the mean improvements in the endocardial border visualization score were as follows: 3.1 ± 7.8 (95% CI, 2.5 and 3.7) for 0.5 ml, 3.4 ± 8.0 (95% CI, 2.8 and 4.0) for 1 ml, 3.4 ± 7.9 (95% CI, 2.8 and 4.0) for 2 ml, and 3.7 ± 8.0 (95% CI, 3.1 and 4.3) for 4 ml (P < 0.05 for all doses from baseline). Changes from baseline in endocardial visualization scores were also seen in the apical views (P < 0.05) and they were dose-dependent (P < 0.001). Similar enhancements of endocardial visualization scores were observed in the apical views in patients with suboptimal baseline echocardiographic images. Diagnostic confidence for assigning a score and image quality also were significantly better following contrast enhancement. No significant changes in the laboratory parameters and vital signs were noted following contrast enhancement, and the side effects were minimal. It was concluded that SonoVue is safe and effective in delineating endocardial border, including in patients with suboptimal baseline images. [source] Evaluation of the radioprotective effect of Liv 52 in miceENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 7 2006Ganesh C. Jagetia Abstract Liv 52 is a mixture of botanicals that is used clinically to treat various hepatic disorders. In this study, the radioprotective activity of Liv 52 was evaluated in mice given whole-body exposure to different doses of ,-radiation. In addition, a series of studies was conducted to explore the mechanism of radioprotection. Radioprotection was evaluated by the ability of Liv 52 to reduce both the frequency of bone marrow micronucleated erythrocytes and the lethality produced by 60Co ,-radiation. Mice were treated by oral gavage once daily for seven consecutive days with 500 mg/kg body weight Liv 52 or carboxymethylcellulose vehicle prior to radiation. Micronucleated polychromatic erythrocytes (MPCEs), micronucleated normochromatic erythrocytes (MNCEs), and the PCE/NCE ratio were measured at 0.25,14 days after exposure to whole-body radiation doses of 0, 0.5, 1.5, 3.0, or 4.5 Gy; animal survival was monitored after doses of 7, 8, 9, 10, 11, or 12 Gy. Pretreatment of mice with Liv 52 significantly reduced the frequency of radiation-induced MPCEs and MNCEs. Irradiation reduced the PCE/NCE ratio in a dose-related manner for up to 7 days following irradiation; Liv 52 pretreatment significantly mitigated against these reductions. Liv 52 treatment also reduced the symptoms of radiation sickness and increased mouse survival 10 and 30 days after irradiation. Liv 52 pretreatment elevated the levels of reduced glutathione (GSH), increased the activities of glutathione transferase, GSH peroxidase, GSH reductase, superoxide dismutase, and catalase, and lowered lipid peroxidation (LPx) and the activities of alanine amino transferase and aspartate aminotransferase 30 min after exposure to 7 Gy of ,-radiation. Liv 52 pretreatment also reduced radiation-induced LPx and increased GSH concentration 31 days following the exposure. The results of this study indicate that pretreatment with Liv 52 reduces the genotoxic and lethal effects of ,-irradiation in mice and suggest that this radioprotection may be afforded by reducing the toxic effects of the oxidative products of irradiation. Environ Mol. Mutagen., 2006. © 2006 Wiley-Liss, Inc. [source] In vivo genotoxic effects of industrial waste leachates in mice following oral exposureENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 5 2006Saurabh Chandra Abstract Contamination of ground water by industrial waste poses potential health hazards for man and his environment. The improper disposal of toxic wastes could allow genotoxic chemicals to percolate into ground waters, and these contaminated ground waters may produce toxicity, including mutation and eventually cancer, in exposed individuals. In the present study, we evaluated the in vivo genotoxic potential of leachates made from three different kinds of industrial waste (tannery waste, metal-based waste, and waste containing dyes and pigments) that are disposed of in areas adjoining human habitation. Three different doses of test leachates were administered by oral gavage for 15 consecutive days to Swiss albino mice; their bone marrow cells were examined for chromosome aberrations (CAs), micronucleated polychromatic erythrocytes (MNPCEs), and DNA damage using the alkaline Comet assay. Exposure to the leachates resulted in significant (P < 0.05 or P < 0.001) dose-dependent increases in chromosome and DNA damage. Fragmented chromosomes and chromatid breaks were the major CAs observed. Chemical analysis of the leachates indicated that chromium and nickel were elevated above the limits established by health organizations. The highest levels of genotoxicity were produced by the metal-based leachate and the tannery-waste leachate, while the dye-waste leachate produced weaker genotoxic responses. The cytogenetic abnormalities and DNA damage produced by the leachates indicate that humans consuming water contaminated with these materials are at increased risk of developing adverse health consequences. Environ. Mol. Mutagen., 2006. © 2006 Wiley-Liss, Inc. [source] Malathion-induced oxidative stress in human erythrocytes and the protective effect of vitamins C and E in vitroENVIRONMENTAL TOXICOLOGY, Issue 3 2009Dilek Durak Abstract Malathion is an organophosphate (OP) pesticide that has been shown to induce oxidative stress in erythrocytes through the generation of free radicals and alteration of the cellular antioxidant defense system. We examined the effect of several different doses of malathion (25, 75, 200 ,M), or malathion in combination with vitamin C (VC; 10 ,M) or vitamin E (VE; 30 ,M), on the levels of malondialdehyde (MDA), and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in human erythrocytes in vitro. Erythrocytes were incubated under various treatment conditions (malathion alone, vitamins alone, or malathion plus vitamin) at 37°C for 60 min, and the levels of MDA, and SOD, CAT and GPx activities, were determined. Treatment with malathion alone increased the levels of MDA and decreased SOD, CAT, and GPx activities in erythrocytes (P < 0.05). There were no statistical differences among VC-treated, VE-treated, or VC + VE-treated erythrocyes, as compared with nontreated control cells. Treatment of cells with malathion + VC, malathion + VE, or a combination of all three agents prevented malathion-induced changes in antioxidant enzyme activity and lipid peroxidation. However, this effect was seen only at low concentrations of malathion (25 and 75 ,M), and the combination of VC + VE had a more protective effect than VC or VE alone. These results indicated that the presence of vitamins at concentrations that are similar to the levels found in plasma have no effect on malathion-induced toxicity in erythrocytes at a concentration of malathion (200 ,M) that is typically used in pesticides. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2009. [source] Physiological and biochemical analyses of microcystin-RR toxicity to the cyanobacterium Synechococcus elongatusENVIRONMENTAL TOXICOLOGY, Issue 6 2004Zhi-quan Hu Abstract Freshwater Microcystis may form dense blooms in eutrophic lakes. It is known to produce a family of related cyclic hepatopeptides (microcystins, MC) that constitute a threat to aquatic ecosystems. Most toxicological studies of microcystins have focused on aquatic animals and plants, with few examining the possible effects of microcystins on phytoplankton. In this study we chose the unicellular Synechococcus elongatus (one of the most studied and geographically most widely distributed cyanobacteria in the picoplankton) as the test material and investigated the biological parameters: growth, pigment (chlorophyll-a, phycocyanin), photosynthetic activity, nitrate reductase activity, and protein and carbohydrate content. The results revealed that microcystin-RR concentrations above 100 ,g · L,1 significantly inhibited the growth of Synechococcus elongatus. In addition, a change in color of the toxin-treated algae (chlorosis) was observed in the experiments. Furthermore, MC-RR markedly inhibited the synthesis of the pigments chlorophyll-a and phycocyanin. A drastic reduction in photochemical efficiency of PSII (Fv/Fm) was found after a 96-h incubation. Changes in protein and carbohydrate concentrations and in nitrate reductase activity also were observed during the exposure period. This study aimed to evaluate the mechanisms of microcystin toxicity on a cyanobacterium, according to the physiological and biochemical responses of Synechococcus elongatus to different doses of microcystin-RR. The ecological role of microcystins as an allelopathic substance also is discussed in the article. © 2004 Wiley Periodicals, Inc. Environ Toxicol 19: 571,577, 2004. [source] Protective effects of naloxone in two-hit seizure modelEPILEPSIA, Issue 3 2010Lu Yang Summary Purpose:, Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two-hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose-dependent protective effects of naloxone in kainic acid (KA),induced two-hit seizure model. Methods:, After KA-induced SE at postnatal day 15 (P15), Sprague-Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin-1, [IL-1,], S100B) was assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT-mediated dUTP nick end labeling (TUNEL) assays. Results:, Naloxone reduced IL-1, synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE. Conclusions:, Naloxone treatment immediately after early life SE could dose-dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood. [source] Vigabatrin extracellular pharmacokinetics and concurrent ,-aminobutyric acid neurotransmitter effects in rat frontal cortex and hippocampus using microdialysisEPILEPSIA, Issue 2 2009Xin Tong Summary Purpose:, To investigate the pharmacokinetic interrelationship of vigabatrin in blood and the brain (frontal cortex vs. hippocampus) and to ascertain the relationship between brain extracellular vigabatrin concentrations and concurrent ,-aminobutyric acid (GABA) concentrations. Methods:, Sprague-Dawley rats were implanted with a jugular vein catheter for blood sampling, and microdialysis probes in the frontal cortex and hippocampus for extracellular fluid (ECF) sampling. Vigabatrin was administered intraperitoneally at two different doses (500 and 1,000 mg/kg), and blood and ECF were collected at timed intervals up to 8 h. Rats were freely moving and behaving. Vigabatrin (sera and ECF) and GABA (ECF) concentrations were measured with use of high performance liquid chromatography (HPLC). Results:, Vigabatrin concentrations in blood rose linearly and dose-dependently, and vigabatrin rapidly appeared in the brain as evidenced by the detection of vigabatrin in the ECF of both the frontal cortex and hippocampus at time of first sampling (15 min). However, frontal cortex concentrations were twofold greater than those of the hippocampus. Furthermore, GABA concentrations increased five-fold in the frontal cortex but were unaffected in the hippocampus. In addition, GABA concentrations began to increase approximately 3 h after vigabatrin administration at a time when vigabatrin concentrations were in exponential decline. Conclusions:, Vigabatrin distribution in the brain is region specific, with frontal cortex concentrations substantially greater than those seen in the hippocampus. Elevation of GABA concentrations did not reflect the concentration profile of vigabatrin but reflected its regional distribution. [source] The Effects of Ascorbic Acid on Penicillin-induced Epileptiform Activity in RatsEPILEPSIA, Issue 7 2007Mustafa Ayyildiz Summary:,Purpose: Epileptic seizure results from excessive discharge in a population of hyperexcitable neurons. A number of studies help to document the effects of active oxygen free radical scavengers such as ,-tocopherol or ascorbic acid (vitamin C). In the present study, we examined the effects of ascorbic acid, at the six different doses, on penicillin-induced epileptiform activity. Methods: A single microinjection of penicillin (2.5 ,l, 500 units, intracortically) into the left sensorimotor cortex induced epileptiform activity within 2,5 min, progressing to full seizure activity lasting ,3,5 h. In the first set of experiments, 30 min after penicillin injection, six different doses of ascorbic acid (25, 50, 100, 200, 400, or 800 mg/kg) were administered intraperitoneally (IP). The other group of animals received the effective dose of ascorbic acid (100 mg/kg, IP) for 7 days. Ascorbic acid administration was stopped 24 h before penicillin treatment. Another group of rats received the effective dose of ascorbic acid (100 mg/kg, IP) 30 min before penicillin treatment. In the second set of experiments, the lipid peroxidation (MDA) and reduced glutathione (GSH) levels of brain were measured in the control, control + ascorbic acid, penicillin, and penicillin + ascorbic acid groups. Results: Ascorbic acid, at the low dose (50, 100 mg/kg, 30 min after penicillin injection), decreased both the frequency and amplitude of penicillin-induced epileptiform activity in rats. Ascorbic acid, at intermediate doses (200, 400 mg/kg, 30 min after penicillin injection), decreased the frequency of epileptiform activity without changing the amplitude. Ascorbic acid, at the lowest dose (25 mg/kg) and highest dose (800 mg/kg) (30 min after penicillin injection), did not change either the frequency or amplitude of epileptiform activity. Ascorbic acid, at the low dose (100 mg/kg) was the most effective dose in changing the frequency and amplitude of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) 30 min before penicillin treatment caused a significant delay in the onset of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) for 7 days did not change the latency of epileptiform activity. The most effective dose of ascorbic acid (100 mg/kg) prevented both the decrease in GSH level and the increase in lipid peroxidation level (MDA) occurring after penicillin-induced epileptiform activity. Conclusions: These data indicate that ascorbic acid has neuroprotective activity against penicillin-induced epileptiform electrocorticogram activity. [source] Industry sponsorship and selection of comparators in randomized clinical trialsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2010D. N. Lathyris Eur J Clin Invest 2010; 40 (2): 172,182 Abstract Background, Most clinical trials on medical interventions are sponsored by the industry. The choice of comparators shapes the accumulated evidence. We aimed to assess how often major companies sponsor trials that involve only their own products. Methods, Studies were identified by searching ClinicalTrials.gov for trials registered in 2006. We focused on randomized trials involving the 15 companies that had sponsored the largest number of registered trials in ClinicalTrials.gov in that period. Results, Overall, 577 randomized trials were eligible for analysis and 82% had a single industry sponsor [89% (166/187) of the placebo-control trials, 87% (91/105) of trials comparing different doses or ways of administration of the same intervention, and 78% (221/285) of other active control trials]. The compared intervention(s) belonged to a single company in 67% of the trials (89%, 81% and 47% in the three categories respectively). All 15 companies strongly preferred to run trials where they were the only industry sponsor or even the only owner of the assessed interventions. Co-sponsorship typically reflected co-ownership of the same intervention by both companies. Head-to-head comparison of different active interventions developed by different companies occurred in only 18 trials with two or more industry sponsors. Conclusions, Each company generates a clinical research agenda that is strongly focused on its own products, while comparisons involving different interventions from different companies are uncommon. This diminishes the ability to understand the relative merits of different interventions for the same condition. [source] Inhibition of endogenous pancreatic enzyme secretion by oral pancreatic enzyme treatmentEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2003J. Walkowiak Abstract Background ,The existence of a feedback mechanism for exocrine pancreatic secretion in humans is controversial. Exclusion of proteases from the duodenum stimulates exocrine pancreatic secretion. Conversely, addition of exogenous enzymes could reduce the enzyme secretion. Further investigation of the feedback mechanism should be performed under the most physiological conditions. In the present study we investigated exocrine pancreatic function by measuring fecal enzyme output in healthy volunteers consuming a normal diet, before and during a time course of exogenous pancreatic enzyme supplementation. Material and methods ,Twenty-five healthy subjects (HS) were given two different doses (30 and 60 FIP proteases kg,1 d,1) divided by the number of meals. In all subjects, fecal elastase-1 (E1) concentrations and chymotrypsin (ChT) activities were measured without and with enzyme supplements after 7 days of treatment. In eight subjects, E1 concentrations and ChT activities were measured daily for 10 consecutive days. The subjects were given a dose regimen of 100 FIP proteases kg,1 d,1 (divided by the number of meals) for the first 7 days. Results ,Oral pancreatic treatment dose-dependently inhibited endogenous pancreatic secretion measured with the use of E1 concentrations. In both regimen groups, the differences were statistically significant. The exogenous enzymes, which interfere with colorimetric method for ChT, dose-dependently increased ChT output. However, only the higher dose resulted in a statistically significant difference. In the subgroup of eight HS, time-dependent changes of fecal enzyme output occurred with a decrease of E1 concentrations and an increase of ChT activity from the second up to eighth or ninth day of the experiment. Conclusion ,Exogenous applied pancreatic enzymes, dose- and time-dependently inhibited endogenous pancreatic secretion. The obtained results strongly support the existence of a protease mediated feedback mechanism in humans. [source] BRIEF REPORT: Single exposure to cocaine or ecstasy induces DNA damage in brain and other organs of miceADDICTION BIOLOGY, Issue 1 2010Tathiana A. Alvarenga ABSTRACT We evaluated the overall genetic damage induced by different doses of cocaine and MDMA (3,4-Methylenedioxymethamphetamine) in several organs. One hour after intraperitoneal drug administration, mice were euthanized; peripheral blood, liver and brain were collected, and the cellular suspensions were used for the single cell gel (comet) assay. We determined that all doses of cocaine and MDMA tested were able to induce DNA damage in blood cells. Extensive genotoxic damage was induced by cocaine or MDMA at the highest doses used in liver cells. Brain cells were affected by all doses administrated. These findings demonstrate that cocaine and MDMA are potent genotoxins. [source] The role of NGF uptake in selective vulnerability to cell death in ageing sympathetic neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2004Kliment P. Gatzinsky Abstract We have examined the hypothesis that differences in nerve growth factor (NGF) uptake and transport determine vulnerability to age-related neurodegeneration. Neurons projecting to cerebral blood vessels (CV) in aged rats are more vulnerable to age-related degeneration than those projecting to the iris. Uptake of NGF was therefore examined in sympathetic neurons projecting from the superior cervical ganglion (SCG) to CV and iris in young and old rats by treating the peripheral processes of these neurons with different doses of I125 -NGF. Total uptake of I125 -NGF was reduced in old CV-projecting, but not iris-projecting, neurons. Numbers of radiolabelled neurons projecting to each target were counted in sectioned ganglia. The data showed age-related reductions in numbers of labelled neurons projecting to CV, but no change in numbers of neurons projecting to the iris. Calculation of uptake of I125 -NGF per neuron unexpectedly showed no major age-related differences in either of the two neuron populations. However, uptake per neuron was considerably lower for young and old CV-projecting, compared to iris-projecting, SCG neurons. We hypothesized that variations in NGF uptake might affect neuronal survival in old age. Counts of SCG neurons using a physical disector following retrograde tracing with Fluorogold confirmed the selective vulnerability of CV-projecting neurons by showing a significant 37% loss of these neurons in the period between 15 and 24 months. In contrast, there was no significant loss of iris-projecting neurons. We conclude that vulnerability to, or protection from, age-related neurodegeneration and neuronal cell death are associated with life-long low, or high, levels of NGF uptake, respectively. [source] Angiotensin II-based hypertension and the sympathetic nervous system: the role of dose and increased dietary salt in rabbitsEXPERIMENTAL PHYSIOLOGY, Issue 5 2007Fiona D. McBryde There is accumulating evidence that angiotensin II may exert its hypertensive effect through increasing sympathetic drive. However, this action may be dependent on the dose of angiotensin II as well as salt intake. We determined the effect of different doses of angiotensin II and different levels of salt intake on neurogenic pressor activity. We also examined the effect of renal denervation. New Zealand White rabbits were instrumented to continuously measure arterial pressure. The depressor response to the ganglionic blocker pentolinium tartrate (5 mg kg,1) was used to assess pressor sympathetic drive on days 0, 7 and 21 of a 20 or 50 ng kg,1 min,1 continuous i.v. angiotensin II infusion. A 50 ng kg,1 min,1 infusion caused an immediate increase in pressure (23 ± 5 mmHg), whereas a 20 ng kg,1 min,1 infusion caused a slow increase in pressure, peaking by day 12 (17 ± 4 mmHg). The ganglionic blockade profiles indicated sympathoinhibition in the 50 ng kg,1 min,1 group by day 7 and sympathoinhibition in the 20 ng kg,1 min,1 group at day 21, corresponding to the development of hypertension. Animals receiving increased dietary salt (0.9% NaCl in drinking water), however, showed a similar slow increase in pressure with 20 ng kg,1 min,1 angiotensin II (16 ± 5 mmHg) but no sympathoinhibition at day 21. Bilateral renal denervation delayed the onset but not the extent of hypertension in this group. We conclude that different doses of angiotensin II produce distinct profiles of hypertension and associated changes in pressor sympathetic drive and that increased dietary salt intake disrupts the normal sympathoinhibitory response to angiotensin II-based hypertension. [source] Route of Administration Differentially Affects Fevers Induced by Gram-Negative and Gram-Positive Pyrogens in RabbitsEXPERIMENTAL PHYSIOLOGY, Issue 3 2002T. Cartmell We have investigated the febrile responses of New Zealand White rabbits to a Gram-negative pyrogen (bacterial lipopolysaccharide (LPS) from Salmonella typhosa), commonly associated with systemic infection, and a Gram-positive pyrogen (Staphylococcus aureus), more frequently associated with superficial soft tissue infection, each administered via one of four different routes (intravenous, intramuscular, subcutaneous or intraperitoneal) at each of three different doses (LPS: 0.1, 1 and 10 ,g kg,1; S. aureus: 1.5 × 107, 1.5 × 108 and 1.5 × 109 cell walls kg,1). Intravenous administration of LPS evoked rapid, dose-dependent biphasic fever. Injection of LPS by the other routes also evoked dose-dependent fever. However, these fevers were monophasic, had increased latency of onset, and were of lower amplitude. It is important to note that a dose of approximately 10 and 100 times that of the standard intravenous dose was required to produce a similar peak rise in temperature when administered subcutaneously and intraperitoneally, respectively. Intravenous injection of the highest dose of S. aureus evoked dose-dependent biphasic fever, with short latency of onset, which was very similar to that induced by intravenous LPS. At lower doses, intravenous S. aureus induced monophasic fever. No fever occurred when the same doses of S. aureus were administered by any other route. We conclude that any of the four routes may be used for the study of LPS-induced fever, provided that the doses are adjusted. However, studies of S. aureus -induced fever, and detection of contamination with either pyrogen, requires intravenous injection. [source] Dose-dependent long-term effects of Tat in the rat hippocampal formation: A design-based stereological studyHIPPOCAMPUS, Issue 4 2010Sylvia Fitting Abstract The human immunodeficiency virus type 1 (HIV-1) protein transactivator of transcription (Tat) is believed to play a critical role in mediating central nervous system (CNS) pathology in pediatric HIV-1 infection. Long-term neurotoxicity was investigated in a design-based stereology study following intrahippocampal injection of Tat on postnatal day (P)10, a time period that approximates the peak in the rats' rate of brain growth and mimics clinical HIV-1 CNS infection at labor/delivery. The goal was to examine the impact of P10 intrahippocampal Tat injection on the anatomy of the adult hippocampus (5 month) to gain a better understanding about how timing of infection influences the rate of progression of pediatric HIV-1 infection [cf. Fitting et al. (2008a) Hippocampus 18:135,147]. Male P10 Sprague-Dawley rats were bilaterally injected with vehicle or one of three different doses of Tat (5, 25, or 50 ,g). Unbiased stereological estimates were used to quantify total neuron number (Nissl stain) in five major subregions of the rat hippocampus: granular layer (GL), hilus of the dentate gyrus (DGH), cornu ammonis fields (CA)2/3, CA1, and subiculum (SUB). Glial cells (astrocytes and oligodendrocytes) were quantified in the DGH and SUB. No significant reduction of neuron number was noted for any of the five hippocampal subregions, in contrast to the very prominent reductions reported when Tat was administered on P1 [Fitting et al. (2008a) Hippocampus 18:135,147]. However, for glial cells, the number of astrocytes in the DGH and SUB as well as the number of oligodendrocytes in the DGH were linear dose dependently increased as a function of dose of Tat. In conjunction with previous stereological research [Fitting et al., (2008a) Hippocampus 18:135,147], the present data suggest that variability in the progression of pediatric HIV/acquired immunodeficiency syndrome (AIDS) may be better understood with the knowledge of the factor of timing of HIV-1 CNS infection. © 2009 Wiley-Liss, Inc. [source] Disparity between prostate tumor interior versus peripheral vasculature in response to verteporfin-mediated vascular-targeting therapyINTERNATIONAL JOURNAL OF CANCER, Issue 3 2008Bin Chen Abstract Photodynamic therapy (PDT) is a light-based cancer treatment modality. Here we employed both in vivo and ex vivo fluorescence imaging to visualize vascular response and tumor cell survival after verteporfin-mediated PDT designed to target tumor vasculature. EGFP-MatLyLu prostate tumor cells, transduced with EGFP using lentivirus vectors, were implanted in athymic nude mice. Immediately after PDT with different doses of verteporfin, tumor-bearing animals were injected with a fluorochrome-labeled albumin. The extravasation of fluorescent albumin along with tumor EGFP fluorescence was monitored noninvasively with a whole-body fluorescence imaging system. Ex vivo fluorescence microscopy was performed on frozen sections of tumor tissues taken at different times after treatment. Both in vivo and ex vivo imaging demonstrated that vascular-targeting PDT with verteporfin significantly increased the extravasation of fluorochrome-labeled albumin in the tumor tissue, especially in the tumor periphery. Although PDT induced substantial vascular shutdown in interior blood vessels, some peripheral tumor vessels were able to maintain perfusion function up to 24 hr after treatment. As a result, viable tumor cells were typically detected in the tumor periphery in spite of extensive tumor cell death. Our results demonstrate that vascular-targeting PDT with verteporfin causes a dose- and time-dependent increase in vascular permeability and decrease in blood perfusion. However, compared to the interior blood vessels, peripheral tumor blood vessels were found less sensitive to PDT-induced vascular shutdown, which was associated with subsequent tumor recurrence in the tumor periphery. © 2008 Wiley-Liss, Inc. [source] Gambogic acid induces apoptosis by regulating the expression of Bax and Bcl-2 and enhancing caspase-3 activity in human malignant melanoma A375 cellsINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 2 2009Xiaoyuan Xu Objectives, To investigate the effect of a Chinese traditional medicine, gambogic acid (GA), on human malignant melanoma (MM) A375 cells and to study the mechanism of apoptosis induced by GA. Methods, A375 cells were treated with GA at different doses and for different times, and their proliferation and viability were detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis induced by GA in A375 cells was observed by annexin-V/propidium iodide doubling staining flow cytometry assay and Hoechst staining. To further determine the molecular mechanism of apoptosis induced by GA, the changes in expression of Bcl-2 and Bax were detected by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, and caspase-3 activity was measured by fluorescence resonance energy transfer (FRET) probe. Results, After incubation with GA, A375 cell proliferation was dramatically inhibited in a dose-dependent manner. After these cells had been exposed to GA for 24, 36 and 48 h, the IC50 values were 1.57 ± 0.05, 1.31 ± 0.20, and 1.12 ± 0.19 µg/mL, respectively. Treatment of A375 cells with GA (2.5,7.5 µg/mL) for 36 h resulted in an increased number of early apoptotic cells, which ranged from 27.6% to 41.9%, in a dose-dependent manner, compared with only 3.5% apoptotic cells in the non-GA-treated group. An increase in Bax and decrease in Bcl-2 expression were found by real-time RT-PCR and Western blot. Caspase-3 activity was increased in a dose-dependent manner, observed by FRET probe. Conclusion, GA can inhibit the proliferation of A375 cells and induce their apoptosis, which may be related to the up-regulation of the Bax/Bcl-2 ratio and caspase-3 activity. [source] Recovery of rat submandibular salivary gland function following removal of obstruction: a sialometrical and sialochemical studyINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 6 2006Samira M. Osailan Summary Functional recovery of the rat submandibular gland following ligation of the main excretory duct was examined. Rat submandibular glands were ligated for 1, 4 and 8 weeks using a micro-clip with a plastic tube. Micro-clips were removed and glands were allowed to recover for periods of 8, 16 and 24 weeks. Submandibular glands were stimulated with autonomimetic drugs (methacholine and isoprenaline) and salivas were collected from atrophic or de-ligated and contralateral control glands. Glands recovered almost full size (92% of control gland) following 24 weeks of de-ligation. Saliva volume secreted by ligated/de-ligated (RSM) and control (LSM) glands were similar with different doses of agonists. Protein output expressed per gram of tissue wet weight was similar from both ligated/de-ligated and control glands with all doses of agonist. Sodium and chloride levels were higher from de-ligated glands than contralateral control glands. Protein electrophoresis showed similar profiles of salivary proteins in all samples with some minor differences. Acinar cells in de-ligated glands showed a normal morphology, as indicated by light microscopy, whilst granular ductal cells were fewer and contained fewer secretory granules. Sodium potassium ATPase staining of striated ducts in de-ligated glands was similar to that of control glands. It can be concluded that rat submandibular glands can regenerate following severe atrophy and secrete normal amounts of saliva containing broadly a full profile of secretory proteins. In contrast to acinar cells, ductal cells appear not to recover full function. [source] Effect of different levels of mannan-oligosaccharide supplementation on some immunological variables in weaned pigletsJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 4 2009I. Nochta Summary The effect of different doses of mannan-oligosaccharide (MOS) on specific and non-specific immune responses was studied in piglets, weaned at 28 days. A total of 58 piglets were used in six groups. Five groups were fed 0, 1, 2, 4 g MOS product per kg diet or with growth promoting antibiotics and immunized by inactivated Aujeszky's disease virus (AyV) vaccine at week 1 and 3 of the experiment (35 and 49 days). A sixth group, receiving the same non-supplemented diets was not immunized. Blood samples for lymphocyte stimulation (LST) and AyV neutralization (VN) tests were taken from all pigs on the first day of the experiment and at weekly intervals for 5 weeks. At week 8, the immunized piglets were infected orally with transmissible gastroenteritis virus. All piglets were weighed and slaughtered at week 10, digesta from small intestine were collected and tested for the presence of secretory (s)IgA. Feeding MOS supplementation resulted in enhanced specific and non-specific immune responses, however, a regressive dose-response of MOS was observed. Both the specific cellular (LST) and humoral responses (VN) were enhanced after 2 weeks of feeding 1 g/kg MOS and significantly differed from the antibiotic positive control. The same tendency was detected in case of the non-specific LSTs, although these started some weeks later showing significant differences by the fifth week. Higher doses of MOS had no further beneficial effect on systemic immunity. In addition, 1 g/kg MOS supplementation group also showed some advantage in local immune responsiveness. Therefore, based on the studied immune variables, 1 g/kg MOS product is suggested in the diet of weaned piglets. [source] Efficacy and toxicity of orally administered anticoccidial drugs for innovative treatments of Polysporoplasma sparis (Sitja-Bobadilla and Alvarez-Pellitero 1985) infection in Sparus aurata L.JOURNAL OF APPLIED ICHTHYOLOGY, Issue 5 2004F. Athanassopoulou Summary The purpose of this study was to test experimentally different drugs and therapeutic schemes in order to find a efficient commercial treatment for fish infected with myxosporeans. Two series of land-based experiments and one experimental cage trial were performed for this purpose. In the first land-based experiment, 10 and 30 g Sparus aurata naturally infected in the kidneys with Polysporoplasma sparis were used. Initially, six different doses of Fumagillin, two doses of Toltrazuril, and one dose of Amprolium, ESB3 and Salinomycin were tested. In the second land-based experiment, 25 and 50 g fish infected with the same parasite were treated with Origanum essential oils, Toltrazuril with propylene glycol, Amprolium, and a combination of Salinomycin 12% + Amprolium (SA). In the field trials, 15 and 155 g S. aurata infected with the same parasite were treated with SA, Origanum essential oils and Fumagillin. In all trials the drugs were incorporated in food and administered according to the selected schemes, while their efficacy was evaluated in terms of mortality (acceptable level <2%), pathology and prevalence rate of P. sparis. According to our results the SA combination proved to be the most effective treatment against P. sparis infection in S. aurata: (i) the therapeutic scheme and commercial product used was not toxic and (ii) a significant reduction in percentage of prevalence was observed. [source] | ||||||||||||||||||||||||||||||||||||||||||||||