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Dose Levels (dose + level)
Kinds of Dose Levels Selected AbstractsTREATMENT OF CULTIVATED HIGHBUSH BLUEBERRIES (VACCINIUM CORYMBOSUM L.) WITH ELECTRON BEAM IRRADIATION: DOSIMETRY AND PRODUCT QUALITYJOURNAL OF FOOD PROCESS ENGINEERING, Issue 2 2008M.A. MORENO ABSTRACT We determined the dose distribution within a tray of highbush blueberries (Vaccinium corymbosum L.) exposed to electron beam irradiation at medium levels (1.0,3.2 kGy) using Monte Carlo and computer tomography scanning technology. We also evaluated the quality of irradiated and nonirradiated (control) fruits stored at 5C and 70% relative humidity during 14 days by a series of chemical analyses. Blueberries packed in plastic clamshell containers (trays) were irradiated using a 10-MeV linear accelerator with single-beam fixture (top only). Irradiation of blueberries at 1.1 kGy had no significant (P > 0.05) effect on the fruit quality with the exception of ascorbic acid, which decreased by 17% by the end of storage. Irradiation had an enhancing effect on the total phenolic and tannin content of all the irradiated fruits (10,20% increases). The calculated dose distribution in a pack of blueberries confirmed that the dose is not uniformly distributed within the pack because of density inhomogeneities (flesh, skin air). Dose levels at the bottom of the trays were 18 (±8%) higher than at the top. These results suggest that careful dose distribution examination must be conducted prior to setting up of an irradiation run for the packed fruits. Excellent agreement was found between measured and calculated doses at different electron beam conveyor speeds. PRACTICAL APPLICATIONS Little information is available on how electron beam irradiation penetrates a complex medium such as packed blueberries. This study presents unique results from a dose distribution calculation method using Monte Carlo simulation and computed tomography scanning techniques, which can be an effective tool for the development of proper irradiation treatment planning of packed fruits and other fresh produce. The suitability of using electron beam technology to preserve the quality characteristics and shelf life of packed blueberries was verified. [source] Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer,CANCER, Issue 5 2008Celestia S. Higano MD Abstract BACKGROUND This open-label, multicenter, dose-escalation study evaluated multiple dose levels of immunotherapy in patients with metastatic hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, consisted of 2 allogeneic prostate-carcinoma cell lines modified to secrete granulocyte-macrophage-colony-stimulating factor (GM-CSF). METHODS Dose levels ranged from 100 × 106 cells q28d × 6 to 500 × 106 cells prime/300 × 106 cells boost q14d × 11. Endpoints included safety, immunogenicity, overall survival, radiologic response, prostate-specific antigen (PSA) kinetics, and serum GM-CSF pharmacokinetics. RESULTS Eighty men, median age 69 years (range, 49-90 years), were treated. The most common adverse effect was injection-site erythema. Overall, the immunotherapy was well tolerated. A maximal tolerated dose was not established. The median survival time was 35.0 months in the high-dose group, 20.0 months in the mid-dose, group, and 23.1 months in the low-dose group. PSA stabilization occurred in 15 (19%) patients, and a >50% decline in PSA was seen in 1 patient. The proportion of patients who generated an antibody response to 1 or both cell lines increased with dose and included 10 of 23 (43%) in the low-dose group, 13 of 18 (72%) in the mid-dose group, and 16 of 18 (89%) in the high-dose group (P = .002; Cochran-Armitage trend test). CONCLUSIONS This immunotherapy was well tolerated. Immunogenicity and overall survival varied by dose. Two phase 3 trials in patients with metastatic HRPC are underway. Cancer 2008. © 2008 American Cancer Society. [source] Assessment of balsam of Peru patch testsCONTACT DERMATITIS, Issue 6 2000Bolli Bjarnason To find an ideal test technique for as low a dose of balsam of Peru (Myroxylon Pereirae) as possible, subjects testing positive to balsam of Peru are re-tested with a 25% concentration of balsam of Peru in petrolatum. Applications are with Finn Chambers® for 6 different application times, and directly by foils for 96 h (4 days (D)). The goals are to confirm which subjects are positive and which are not, and, using that information, to see if it is possible to distinguish between these 2 groups, tested concomitantly at much lower serial dose levels, in terms of perfusion or by visual assessments. 5 different serial doses are applied with strips for 3,96 h (4D) and with foils for 96 h (4D). The Finn Chamber® tests allow a distinction between visually positive and negative subjects supported by perfusion assessments. With the foils, a 24× lower serial dose level than with the 25% test substance is sufficient to distinguish between positive and negative subjects in terms of perfusion values. This approach requires readings up to 9 days. With this test, the visual approach yields only 3 of 10 positive subjects. This study demonstrates that a lower test dose is possible with perfusion assessments compared to visual ones. [source] Epoxiconazole causes changes in testicular histology and sperm production in the Japanese quail (Coturnix coturnix japonica)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2008Konstanze Grote Abstract The fungicide epoxiconazole (Epox), a triazole, belongs to the group of azole compounds that are extensively used as fungicides in various fruit crops. The frequent use of agricultural lands for wintering by migrating birds can be the source of their increased dietary intake of agricultural pesticides. We investigated whether exposure to Epox causes effects on avian fertility and reproduction, using the Japanese quail (Coturnix coturnix japonica) as a model species for the assessment of reproductive effects of pesticides in wild birds. Epox was administered to adult Japanese quail for three weeks at dietary levels of 10, 50, and 500 ppm, and possible effects on reproduction were investigated. Epox administration resulted in a significantly decreased number of spermatids in the 50- and 500-ppm dose groups. Histopathology showed a reduced number of testicular canaliculi with visible germ cells and a reduction in spermatid number. However, testis weight was not affected up to the highest dose level. No impact was observed on hormone levels, fertility, and reproductive outcome, as laying rate and percentage of fertile eggs were not altered. Likewise, treatment had no influence on the egg or chick parameters evaluated. A time- and dose-related transfer of Epox into the eggs was determined in all treatment groups. We conclude that dietary treatment of Japanese quail with 50 and 500 ppm of the triazole fungicide Epox resulted in a clear impact on the testis. The evaluation of the additional endpoints spermatid count and testicular histology have proven useful and are recommended for future studies on avian reproduction. [source] Significance testing of synergistic/antagonistic, dose level-dependent, or dose ratio-dependent effects in mixture dose-response analysisENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2005Martijs J. Jonker Abstract In ecotoxicology, the state of the art for effect assessment of chemical mixtures is through multiple dose,response analysis of single compounds and their combinations. Investigating whether such data deviate from the reference models of concentration addition and/or independent action to identify overall synergism or antagonism is becoming routine. However, recent data show that more complex deviation patterns, such as dose ratio,dependent deviation and dose level,dependent deviation, need to be addressed. For concentration addition, methods to detect such deviation patterns exist, but they are stand-alone methods developed separately in literature, and conclusions derived from these analyses are therefore difficult to compare. For independent action, hardly any methods to detect such deviations from this reference model exist. This paper describes how these well-established mixture toxicity principles have been incorporated in a coherent data analysis procedure enabling detection and quantification of dose level,and dose ratio,specific synergism or antagonism from both the concentration addition and the independent action models. Significance testing of which deviation pattern describes the data best is carried out through maximum likelihood analysis. This analysis procedure is demonstrated through various data sets, and its applicability and limitations in mixture research are discussed. [source] Dose-dependent stimulation of hepatic retinoic acid hydroxylation/oxidation and glucuronidation in brook trout, Salvelinus fontinalis, after exposure to 3,3,,4,4,-tetrachlorobiphenylENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2000Patrick M. Boyer Abstract Extremely low stores of vitamin A have been reported in fish and birds inhabiting regions contaminated by coplanar polychlorinated biphenyls (PCBs) and other organochlorines, suggesting many possible effects on retinoid biochemical pathways. Metabolic imbalances associated with biologically active retinoids (e.g., retinoic acid) could be associated with teratogenesis, edema, growth inhibition, reproductive impairment, immunosuppression, and susceptibility to cancer. Sexually mature brook trout were injected intraperitoneally with the coplanar PCB 3,3,,4,4,-tetrachlorobiphenyl (TCBP) and again 4 weeks later. At 8 weeks, retinoic acid metabolism was measured in liver microsomes. To our knowledge, retinoic acid conjugation by UDP-glucuronyltransferase is described here for the first time in fish. A substantial rate of glucuronidation was detected in the microsomes from control brook trout, which tended to increase over the dose range of TCBP. Glucuronidation was significantly greater in fish receiving the 10 ,g/g body weight dose level. Metabolism through the cytochrome P450 system was also dose-dependent, resulting in significantly greater production of 4-hydroxyretinoic acid at the 10 ,g/g dose level. In contrast, subsequent oxidation to 4- oxo -retinoic acid was greatest at the 1 ,g/g dose level and did not increase further at higher doses. Liver stores of dehydroretinyl palmitate/oleate were significantly decreased at the 5 and 10 ,g/g dose levels. [source] A review of the acute subjective effects of MDMA/ecstasyADDICTION, Issue 7 2006Chelsea A. Baylen ABSTRACT Aim Although several relatively recent reviews have summarized the neuropsychiatric effects associated with chronic ecstasy use, there is no published comprehensive review of studies on the acute subjective effects (ASEs) of MDMA/ecstasy. Design The present study reviewed the prevalence, intensity and duration of ASEs collected from 24 studies that provided frequency data on the prevalence of self-reported ecstasy effects and/or provided data on the intensity of ecstasy effects. Findings Although hundreds of ASEs have been reported following MDMA consumption, we identified a subset of effects reported repeatedly by meaningful proportions and large numbers of participants across multiple investigations, most of which were either emotional (e.g. anxiety, depression, closeness, fear, euphoria, calmness) or somatic (e.g. nausea/vomiting, bruxism, muscle aches/headache, sweating, numbness, body temperature changes, fatigue, dizziness, dry mouth, increased energy). Only one sexual ASE (sexual arousal/increased sensual awareness), one cognitive ASE (confused thought), one sensory,perceptual ASE (visual effects/changes in visual perception), one sleep-related ASE (sleeplessness) and one appetite-related ASE (decreased appetite) were reported across five or more investigations. Three factors,number of hours between ingestion and assessment, dose level, and gender,have been associated with the acute subjective experience of MDMA/ecstasy., Conclusions This review provides useful information for clinicians and researchers who want to understand the desirable and undesirable ASEs that may motivate and restrain ecstasy use, for public health advocates who seek to reduce biomedical harms (e.g. fainting, dehydration, shortness of breath, bruxism) associated with recreational use of MDMA/ecstasy, and for educators who wish to design credible prevention messages that neither underestimate nor exaggerate users' experiences of this drug. [source] Statistical issues on the determination of the no-observed-adverse-effect levels in toxicologyENVIRONMETRICS, Issue 4 2001Takashi Yanagawa Abstract The determination of a safe exposure level for toxic agents, often defined as the highest dose level with no toxic effect and termed the no-observed-adverse-effect level (NOAEL) is reviewed. The conventional methods based on statistical tests are criticized, particularly when the sample size is small, and an alternative method, which is based on the Akaike information criterion (AIC), is discussed. The method is extended to the estimation of the NOAEL for continuous data. Computer programs for Windows 95/NT for determining the NOAEL by the AIC approach are developed and its application to practical data is illustrated with examples. Copyright © 2001 John Wiley & Sons, Ltd. [source] REVIEW: Human and laboratory rodent low response to alcohol: is better consilience possible?ADDICTION BIOLOGY, Issue 2 2010John C. Crabbe ABSTRACT If people are brought into the laboratory and given alcohol, there are pronounced differences among individuals in many responses to the drug. Some participants in alcohol challenge protocols show a cluster of ,low level of responses to alcohol' determined by observing post-drinking-related changes in subjective, motor and physiological effects at a given dose level. Those individuals characterized as having low level of response (LR) to alcohol have been shown to be at increased risk for a lifetime diagnosis of alcohol dependence (AD), and this relationship between low LR and AD appears to be in part genetic. LR to alcohol is an area where achieving greater consilience between the human and the rodent phenotypes would seem to be highly likely. However, despite extensive data from both human and rodent studies, few attempts have been made to evaluate the human and animal data systematically in order to understand which aspects of LR appear to be most directly comparable across species and thus the most promising for further study. We review four general aspects of LR that could be compared between humans and laboratory animals: (1) behavioral measures of subjective intoxication; (2) body sway; (3) endocrine responses; and (4) stimulant, autonomic and electrophysiological responses. None of these aspects of LR provide completely face-valid direct comparisons across species. Nevertheless, one of the most replicated findings in humans is the low subjective response, but, as it may reflect either aversively valenced and/or positively valenced responses to alcohol as usually assessed, it is unclear which rodent responses are analogous. Stimulated heart rate appears to be consistent in animal and human studies, although at-risk subjects appear to be more rather than less sensitive to alcohol using this measure. The hormone and electrophysiological data offer strong possibilities of understanding the neurobiological mechanisms, but the rodent data in particular are rather sparse and unsystematic. Therefore, we suggest that more effort is still needed to collect data using refined measures designed to be more directly comparable in humans and animals. Additionally, the genetically mediated mechanisms underlying this endophenotype need to be characterized further across species. [source] A specific inducible nitric oxide inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male ApcMin/+ miceINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Hiroyuki Kohno Abstract It is generally assumed that inflammation influences carcinogenesis. We previously reported that dextran sodium sulfate (DSS) strongly enhances colon carcinogenesis in the ApcMin/+ mice and the over-expression of inducible nitric oxide synthase (iNOS) contributes to this enhancement. In the current study, we investigated the effect of a selective iNOS inhibitor, ONO-1714 on colitis-related colon carcinogenesis in the ApcMin/+ mouse treated with DSS. Male C57BL/6J ApcMin/+ and Apc+/+ mice were exposed to 1% DSS in their drinking water for 7 days. ONO-1714 was given to the mice at a dose level of 50 or 100 ppm in diet for 5 weeks (during the administration of DSS). The tumor inhibitory effects by ONO-1714 were assessed at week 5 by counting the incidence and multiplicity of colonic neoplasms. Additionally, we assessed serum lipid levels and colonic mRNA expression for cyclooxygenase (COX)-2, iNOS, tumor necrosis factor (TNF)-, and interleukin (IL)-1,. Feeding with ONO-1714 significantly inhibited the occurrence of colonic adenocarcinoma in a dose-dependent manner in the ApcMin/+ mice. In addition, the treatment with ONO-1714 significantly lowered the serum triglyceride levels and mRNA expression levels of COX-2, TNF, and IL-1, of colonic mucosa in the DSS-treated ApcMin/+ mice. Neither ONO-1714 nor DSS affected the colonic pathology in the Apc+/+ mice. Our findings may suggest that ONO-1714 could therefore serve as an effective agent for suppression of colitis-related colon cancer development in the ApcMin/+ mice. © 2007 Wiley-Liss, Inc. [source] Iloperidone for schizophrenia: a review of the efficacy and safety profile for this newly commercialised second-generation antipsychoticINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 8 2009L. Citrome Summary Objective:, The aim of the study was to describe the efficacy and safety of iloperidone for the treatment of schizophrenia. Data sources:, The pivotal registration trials were accessed by querying http://www.pubmed.gov, http://www.fda.gov and http://www.clinicaltrials.gov for the search term ,iloperidone'. Study selection:, Four published primary reports of phase III studies were identified as well as preclinical animal and receptor affinity studies that describe potential mechanisms of action and pharmacogenomic studies that identify potential genetic biomarkers for efficacy and tolerability. Product labelling provided additional data. Data extraction:, Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports. Additional safety outcomes subject to NNH analysis were obtained from product labelling. Data synthesis:, Iloperidone is a second-generation antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone has been evaluated in several double-blind placebo-controlled clinical trials. The oral formulation has demonstrated efficacy in reducing the symptoms of acute schizophrenia at fixed daily doses ranging from 12 to 24 mg. Data reported for categorical definitions of response using the Positive and Negative Syndrome Scale were limited to one study and specifically to rates of achieving a , 20% decrease in the positive subscale from baseline; significantly more patients receiving iloperidone 24 mg/day (72%) than placebo (52%) met this criterion, yielding a NNT of five. Iloperidone should be titrated slowly to avoid orthostatic hypotension, potentially delaying the achievement of a therapeutic dose level. There appears to be a dose relationship for adverse events such as dizziness, somnolence and dry mouth; for example NNH vs. placebo for somnolence was 25 for iloperidone 10,16 mg/day and 10 for 20,24 mg/day. There is a possibility of a therapeutic dose response as well. Iloperidone is essentially free of extra-pyramidal side effects. Iloperidone is associated with weight gain comparable with risperidone. Long-term double-blind maintenance studies have demonstrated iloperidone's non-inferiority to haloperidol for relapse prevention. Product labelling includes a warning about the potential for QT interval prolongation. At present there are no efficacy studies available that are powered to directly compare iloperidone with other second-generation antipsychotics. The development of a depot formulation of iloperidone as well as efforts to identify genetic biomarkers for prediction of both efficacy and tolerability are in progress. Conclusions:, Aside from paliperidone, iloperidone is the first new second-generation antipsychotic to be commercialised in the USA since 2002. From the limited registration data, iloperidone appears to be relatively well tolerated once titrated to a therapeutic level and can be a useful option to consider. The development of a depot formulation and potential for genetic biomarkers may make this agent compelling. Further comparisons with other available agents among patients with schizophrenia in the ,real world' are needed. [source] Effect of gamma irradiation and sulphitation treatments on keeping quality of white button mushroom Agaricus bisporus (J. Lge)INTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 5 2009Ali M. Wani Summary Gamma irradiation, alone and in combination with sulphitation, was tested for preventing the browning and maintaining the quality attributes of the white button mushrooms. Mushrooms were subjected to treatment of gamma irradiation in the dose range of 0.5,2.0 kGy and to combination treatments of sulphitation at a concentration of 0.1% potassium metabisulphite (KMS) and gamma irradiation (dose range 0.5,2.0 kGy) followed by storage at 10 ± 2 °C (RH 85%). A dose of 2.0 kGy significantly reduced the weight loss, prevented browning and mould growth. Cap and veil opening of mushrooms was delayed by 9 days and shelf life was extended by 12 days at a dose level of 2.0 kGy. Sulphitation alone at a concentration of 0.1% KMS was effective in controlling browning only upto 3 days, beyond which both browning and cap opening increased significantly (P , 0.05) and the samples were unacceptable after 6 days of storage. No synergistic effect of sulphitation and irradiation was observed with respect to the shelf-life extension of mushroom. [source] Blends of triazine-based hyperbranched polyether with LDPE and plasticized PVCJOURNAL OF APPLIED POLYMER SCIENCE, Issue 1 2007Jyotishmoy Borah Abstract Triazine-based hyperbranched polyether was obtained by earlier reported method and blended with low density polyethylene (LDPE) and plasticized poly(vinyl chloride) (PVC) separately to improve some desirable properties of those linear polymers. The properties like processability, mechanical properties, flammability, etc. of those linear polymers were studied by blending with 1,7.5 phr of hyperbranched polyether. The mechanical properties were also measured after thermal aging and leaching in different chemical media. SEM study indicates that both polymers exhibit homogenous morphology at all dose levels. The mechanical properties like tensile strength, elongation at break, hardness, etc. of LDPE and PVC increase with the increase of dose level of hyperbranched polyether. The flame retardant behavior as measured by limiting oxygen index (LOI) for all blends indicates an enhanced LOI value compared to the polymer without hyperbranched polyether. The processing behavior of both types of blends as measured by solution viscosity and melt flow rate value indicates that hyperbranched polyether acts as a process aid for those base polymers. The effect of leaching and heat aging of these linear polymers on the mechanical properties showed that hyperbranched polyether is a superior antidegradant compared to the commercially used N -isopropyl- N -phenyl p -phenylene diamine. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 104: 648,654, 2007 [source] Neurobehavioral toxicity study of dibutyl phthalate on rats following in utero and lactational exposureJOURNAL OF APPLIED TOXICOLOGY, Issue 7 2009Yuanfeng Li Abstract To investigate the neurobehavioral effects of dibutyl phthalate (DBP), an important endocrine disruptor known for reproductive toxicity, on rodent offspring following in utero and lactational exposure, pregnant Wistar rats were treated with DBP (0, 0.037, 0.111, 0.333 and 1% in the diet) from gestation day (GD) 6 to postnatal day (PND) 28, and selected developmental and neurobehavioral parameters of the offspring were measured. There were no significant effects of DBP on body weight gain of the dams during GD 6,20 or on the pups' ages of pinna detachment, incisor eruption or eye opening. Exposure to 1% DBP prolonged gestation period, decreased body weight in both male and female pups, depressed surface righting (PND 7) in male pups, shortened forepaw grip time (PND 10), enhanced spatial learning and reference memory (PND 35) in male pups. Exposure to 0.037% DBP also shortened forepaw grip time (PND 10), but inhibited spatial learning and reference memory in male pups. Sex × treatment effects were found in forepaw grip time (PND 10), spatial learning and reference memory, and the male pups appeared to be more susceptible than the females. However, all levels of DBP exposure did not significantly alter surface righting (PND 4), air righting (PND 16), negative geotaxis (PND 4 or 7), cliff avoidance (PND 7) or open field behavior (PND 28) in either sex. Overall, the dose level of DBP in the present study produced a few adverse effects on the neurobehavioral parameters, and it may alter cognitive abilities of the male rodent. Copyright © 2009 John Wiley & Sons, Ltd. [source] Methyl tert -butyl ether (MTBE)-induced cytotoxicity and oxidative stress in isolated rat spermatogenic cellsJOURNAL OF APPLIED TOXICOLOGY, Issue 1 2007Dongmei Li Abstract Methyl tert -butyl ether (MTBE) is a class of synthetic organic chemical. In the USA, MTBE pollution is regarded as a serious environmental problem. The objective of the present study was to investigate the cytotoxic effects and oxidative stress induced by MTBE in isolated rat spermatogenic cells. In cytotoxic experiments, spermatogenic cells isolated from the testes of adult Sprague-Dawley rats by a mechanical procedure without the use of trypsin were incubated with medium alone (control), 0.5, 5, 50 mm MTBE, respectively, for 6, 12 and 18 h. MTT assay, staining with fluorescein diacetate (FDA) and propidium iodide (PI) and flow cytometric analyses were used. In oxidative stress experiments, the spermatogenic cells were incubated with medium alone (control) and with 0.5, 50 ,m, 5 mm MTBE. For 1, 2, 6, 12, 18 h incubation, ROS production was tested using a 2,,7,-dichlorofluorescein diacetate (DCHF-DA) probe; for 1, 3, 6, 12, 18 h incubation, cytosolic superoxide dismutase (SOD) and extracellular SOD (SODEX) activity was assessed; and for 18 h incubation, lipid peroxidation was assessed. The results showed that MTBE at high doses significantly decreased the spermatogenic cell viability and increased plasma membrane damage and the ratio of necrotic cells compared with the control. Assessment of the MTBE-induced oxidative stress revealed that MTBE increased the production of reactive oxygen species (ROS) and enhanced lipid peroxidation. In addition, although SODEX activity increased at a high dose level, cytosolic SOD activity decreased. These results suggest that an increase of MTBE-induced ROS production and an enhancement of membrane lipid peroxidation may play an important role in its cytotoxicity in isolated rat spermatogenic cells. Copyright © 2006 John Wiley & Sons, Ltd. [source] Effect of textile waste water on the spermatogenesis of male albino ratsJOURNAL OF APPLIED TOXICOLOGY, Issue 3 2003R. S. Gupta Abstract Textile waste water released from dyeing and printing industries situated in Sanganer, Jaipur (India), brought about inhibition of spermatogenesis in male rats. Water analysis showed the presence of heavy metals at more than permissible limits. Oral administration of waste water to the rats at the dose level of 26.6 ml kg,1 body wt. significantly reduced the weights of testes, epididymides and seminal vesicle. Treated animals showed a notable depression of various stages of spermatogenesis. The production of spermatids was inhibited by 70.8% in waste-water-treated rats. The populations of spermatogonia, preleptotene spermatocytes and secondary spermatocytes were decreased by 67.2, 71.1 and 73.2%, respectively. The total number of Sertoli cells was affected after waste water treatment. Reduced sperm count and motility resulted in treated groups. A significant fall in the content of various biochemical parameters of reproductive tissues was observed after water treatment. Copyright © 2003 John Wiley & Sons, Ltd. [source] Subchronic toxicity of chloral hydrate on rats: a drinking water studyJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2002R. Poon Abstract The subchronic toxicity of chloral hydrate, a disinfection byproduct, was studied in rats following 13 weeks of drinking water exposure. Male (262 ± 10 g) and female (190 ± 8 g) Sprague-Dawley rats, ten animals per group, were administered chloral hydrate via drinking water at 0.2, 2, 20 and 200 ppm. Control animals received distilled water only. Gross and microscopic examinations, serum chemistry, hematology, biochemical analysis, neurogenic amine analysis and serum trichloroacetic acid (TCA) analysis were performed at the end of the treatment period. Bronchoalveolar fluids were collected at necropsy and urine specimens were collected at weeks 2, 6 and 12 for biochemical analysis. No treatment-related changes in food and water intakes or body weight gains were observed. There were no significant changes in the weights of major organs. Except for a mild degree of vacuolation within the myelin sheath of the optic nerves in the highest dose males, there were no notable histological changes in the tissues examined. Statistically significant treatment-related effects were biochemical in nature, with the most pronounced being increased liver catalase activity in male rats starting at 2 ppm. Liver aldehyde dehydrogenase (ALDH) was significantly depressed, whereas liver aniline hydroxylase activity was significantly elevated in both males and females receiving the highest dose. A dose-related increase in serum TCA was detected in both males and females starting at 2 ppm. An in vitro study of liver ALDH confirmed that chloral hydrate was a potent inhibitor, with an IC50 of 8 µM, whereas TCA was weakly inhibitory and trichloroethanol was without effect. Analysis of brain biogenic amines was conducted on a limited number (n = 5) of male rats in the control and high dose groups, and no significant treatment-related changes were detected. Taking into account the effect on the myelin sheath of male rats and the effects on liver ALDH and aniline hydroxylase of both males and females at the highest dose level, the no-observed-effect level (NOEL) was determined to be 20 ppm or 1.89 mg kg,1 day,1 in males and 2.53 mg kg,1 day,1 in females. This NOEL is ca. 1000-fold higher than the highest concentration of chloral hydrate reported in the municipal water supply. Copyright © 2002 Crown in the right of Canada. Published by John Wiley & Sons, Ltd. [source] Goitrogenic activity of p -coumaric acid in ratsJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2003Fatima Khelifi-Touhami Abstract The effects of three natural phenolic acids (caffeic, ferulic, and p -coumaric) on the rat thyroid gland were examined in a 3-week oral-treatment study. Forty male Wistar albino rats, divided into groups of 10 rats each and fed iodine-rich diet, were administered by gastrointestinal tube saline (control), caffeic acid, ferulic acid, or p -coumaric acid at a dose level of 0.25 ,mol/kg/day for 3 weeks. The mean absolute and relative thyroid weights in caffeic, ferulic, or p -coumaric acid groups were significantly increased to 127 and 132%, 146 and 153%, or 189 and 201% compared to control value, respectively. Histological examination of the thyroids of p -coumaric acid group revealed marked hypertrophy and/or hyperplasia of the follicles. Caffeic or ferulic groups showed slight to moderate thyroid gland enlargement. Thyroid lesions in p -coumaric acid group were associated with significant increases in cellular proliferation as indicated by [3H]thymidine incorporation. In addition, the goitrogenic effect of p -coumaric acid was further confirmed by significant decreases (50%) in serum tri-iodothyronine (T3) and thyroxine (T4), and a parallel increase (90%) in serum thyroid stimulating hormone (TSH) compared to control group. These results indicate that administration of p -coumaric acid at relatively high doses induces goiter in rats. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:324,328, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10094 [source] Pharmacokinetics of Dietary 13C-Labeled Docosahexaenoic Acid and Docosapentaenoic Acid in Red Sea Bream Chrysophrys majorJOURNAL OF THE WORLD AQUACULTURE SOCIETY, Issue 2 2002Akio Tago The objectives of this study were to investigate: 1) the pharmacokinetics of dietary docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) using 13C-labeled fatty acids; 2) the interorgan transport of DHA in the red sea bream by monitoring the DHA level of several organs; and 3) the relationship between the plasma DHA level and optimum dietary DHA level in the plasma of the red sea bream Chrysophrys major. For this purpose, a mixture of 38.5% of [13C]DHA, 8.5% of [13C]DPA, and 4.2% of [13C]palmitic acid were given to the red sea bream at dose level of 8.0, 16.0, and 47.9 mg/kg by a single oral administration. For [13C]DHA, the maximum plasma concentration (tmax) occurred at 2.00,3.00 h after the oral administration. The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve to 24 h (AUC0-24 for [13C]DHA level linearly increased with respect to dosage. [13C]DHA appeared in each organ (plasma, erythrocyte and the fat body of the orbit, liver, intestine, skin, brain, heart and muscle) at 0.5 h and was observed until 24 h. From the values determined for the pharmacokinetic parameters, the range of the effective plasma DHA level for normal growth of the red sea bream was suggested to be between 21.0 and 40.3 ,g/mL. For [13C]DPA, the AUC0-24 and Cmax values also linearly increased with the dosage, but tmax did not depend on it. [source] Pharmacokinetics and bioavailability of imidocarb dipropionate in swineJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2007D. SU A two-way crossover study was performed in eight healthy young pigs to determine the pharmacokinetics of imidocarb dipropionate (IMDP) following intravenous (2 mg/kg b.w.) and intramuscular (2 mg/kg b.w.) administrations. Each animal received one intravenous and one intramuscular injection with a 30-day washout period between the two-treatments. Plasma concentrations were measured by high-performance liquid chromatography (HPLC) assay with UV detector at regular intervals for up to 24 h post-injection. Intravenous plasma concentration profiles best fit a three-compartmental model yielding a mean system clearance (Cl(s)) of 558 mL/kg·h and a mean half-life of 13.91 h. Mean imidocarb AUC(0,,) (,g·h/mL), Vc (L/kg), Vd(area)(L/kg) and MRT(0-t) (h) values were 3.58, 0.11, 14.36 and 1.46, respectively. Compartmental modeling of imidocarb, after intramuscular administration produced best fit for two-compartmental model yielding mean K, (h,1), Cmax (,g/mL), tmax (h), and bioavailability (%) of 3.89, 2.02, 0.54, and 86.57 for the 2 mg/kg dose level. The present studies showed that IMDP was rapidly absorbed, widely distributed, and slowly eliminated. No adverse effects were observed in any of the pigs after i.v. and i.m. administrations of IMDP. The favorable PK behavior, such as the long half-life, acceptable bioavailability indicated that it is likely to be effective in pigs. [source] Correlation between serum concentrations following continuous intravenous infusion of dexmedetomidine or medetomidine in cats and their sedative and analgesic effectsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2000Ansah Dexmedetomidine (DEX) may have some therapeutic advantages over the racemate medetomidine (MED). Here we have examined how serum concentrations of DEX correlate with some of its anaesthetic effects. Cats (n = 6) were administered with a continuous stepwise intravenous (i.v.) infusion of DEX or MED on different occasions in a cross-over design. Maintenance infusion rates (mg/kg/min) used were: DEX = 0.25 (MED = 0.50); DEX = 1 (MED = 2) and DEX = 4 (MED = 8) for infusion steps 1, 2 and 3, respectively. Each maintenance infusion lasted at least 50 min and was preceded with a loading dose. There was no significant difference between serum DEX and 0.5 serum MED concentrations at any dose level nor was there a significant difference between serum DEX and the (entire) serum MED concentrations. There was no significant difference between DEX and MED for sedation, analgesia, muscular relaxation and heart and respiratory rates. For both DEX and MED, serum drug concentration and analgesia were dose-dependent and sedation increased until the end of infusion step 2 (dose level 2) and decreased at the end of step 3 (dose level 3). Muscular relaxation was not dose-dependent. We conclude that increasing the blood concentration of DEX or MED beyond a certain level decreases the level of sedation instead of increasing it even though analgesia increases. The rate at which DEX and MED are metabolized in cats may not be the same. [source] Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): A report from the therapeutic advances in childhood leukemia (TACL) consortium,PEDIATRIC BLOOD & CANCER, Issue 2 2010Yoav Messinger MD Abstract Background Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies. Procedure This is a Phase I study of escalating doses bortezomib administered days 1, 4, 8, and 11, added to 4-drug induction chemotherapy with vincristine, dexamethasone, pegylated L -asparaginase, and doxorubicin (VXLD) in children with relapsed ALL. Results Ten patients were enrolled, five in first marrow relapse, and five in second relapse. Four patients were enrolled at dose level 1 (bortezomib 1,mg/m2). One patient was not evaluable for toxicity because of omitted dexamethasone doses. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (bortezomib 1.3,mg/m2). One patient had dose-limiting hypophosphatemia and rhabdomyolysis after 1 dose of bortezomib, and died from a diffuse zygomyces infection on day 17. Five additional patients were enrolled with no subsequent DLTs. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Two patients had mild peripheral neuropathy (grades 1 and 2). Six of nine evaluable patients (67%) achieved a complete response (CR), and one had a bone marrow CR with persistent central nervous system leukemia. Conclusions The combination of bortezomib (1.3,mg/m2) with VXLD is active with acceptable toxicity in pretreated pediatric patients with relapsed ALL. We are expanding the 1.3,mg/m2 cohort for a phase II estimate of response. Study registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00440726). Pediatr Blood Cancer 2010;55:254,259. © 2010 Wiley-Liss, Inc. [source] Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors,PEDIATRIC BLOOD & CANCER, Issue 7 2010René Y. McNall-Knapp MD Abstract Background The combination of irinotecan, temozolomide, and vincristine is appealing because of potentially synergistic mechanisms of action and non-overlapping toxicities. This phase I study was designed to determine the toxicity and maximum tolerated dose (MTD) of escalating daily protracted doses of irinotecan given in this combination. With extended accrual, we more fully explored the toxicity of multiple courses at the MTD. Procedure Patients under 22 years with recurrent or refractory solid tumors were eligible. A course of chemotherapy was given every 28 days. Cefpodoxime was given for diarrhea prophylaxis. Vincristine (1.5,mg/m2, max 2,mg) was given intravenously (IV) on days 1 and 8. Temozolomide (100,mg/m2/day) was given orally on days 1,5. Irinotecan was given IV over 1,hr on days 1,5 and 8,12. Dose escalation was done in the standard 3,+,3 cohort design, starting at 15,mg/m2/day. Results Twenty-five of 26 eligible patients were evaluable for toxicity and response. They received 111 courses (1,13, median 4). Dose limiting toxicity (DLT,pancreatitis, transaminitis) was seen in two of three patients at dose level 2 (20,mg/m2). No patients at level 1 had DLT during the first two cycles. Thus, the MTD of irinotecan in this combination is 15,mg/m2/day,×,10 doses. Hematologic toxicity was mild and not prolonged. Grade 3 diarrhea was seen in five courses. Responses included two complete and two partial with 12 stable disease (SD) (median 6 months). Conclusions This combination is safe and shows activity in pediatric patients with recurrent malignancy. Pediatr Blood Cancer 2010;54:909,915 © 2010 Wiley-Liss, Inc. [source] Phase I study of paclitaxel with standard dose ifosfamide in children with refractory solid tumors: A Pediatric Oncology Group study (POG 9376)PEDIATRIC BLOOD & CANCER, Issue 3 2009James I. Geller MD Abstract Purpose A dose-escalation Phase I study of taxol (paclitaxel) administered in combination with standard dose ifosfamide was conducted in children with relapsed or refractory solid tumors. Primary objectives were to estimate the maximum tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs). Patients and Methods Paclitaxel was administered as a 6-hr continuous infusion (hr 0,6), followed by intravenous ifosfamide (2 g/m2/day,×,3 days) over 1 hr at hours 6,7, 24,25, and 48,49. Patients at dose level 1 received 250 mg/m2 paclitaxel. Subsequent dose escalation proceeded using a standard 3,×,3 Phase I design. Results Fifteen patients received a combined 46 courses of therapy. The median age was 14.5 years (range, 2,19 years), and diagnoses included sarcoma (7), neuroblastoma (3), and other (5). Three patients received paclitaxel at 250 mg/m2 (10 courses), six at 325 mg/m2 (19 courses), three at 425 mg/m2 (8 courses), and three at 550 mg/m2 (9 courses). DLTs occurred in 2/3 patients at 550 mg/m2 paclitaxel during cycle 1, including grade 3 hypotension and grade 4 anaphylaxis in 1 patient each. Common non-dose-limiting toxicities included bone marrow suppression and peripheral neuropathy. Response was evaluable in 14 patients and included mixed response (3), stable disease (5), and progressive disease (6). Conclusion Paclitaxel hypersensitivity reactions were dose limiting when the drug was administered as a 6-hr infusion. The MTD and recommended Phase II dose of paclitaxel administered as a 6-hr continuous intravenous infusion followed by standard dose intravenous ifosfamide is 425 mg/m2 paclitaxel. Pediatr Blood Cancer 2009;52:346,350. © 2008 Wiley-Liss, Inc. [source] Anti-tumour and immuno-stimulating activities of the fruiting bodies of Paecilomyces japonica, a new type of Cordyceps spp.PHYTOTHERAPY RESEARCH, Issue 7 2003Kuk Hyun Shin Abstract The anti-tumor and immuno-stimulating activities of the fruiting bodies of Paecilomyces japonica (PJ), grown on silk-worm larvae and of Cordyceps sinensis (CS), a wild form of Cordyceps Fungi, were investigated. Ethanol extracts of both fungi, when administered for 9 consecutive days, at 50 and 100 mg/kg i.p., caused a signi,cant increase in life span and a signi,cant decrease in tumor weights and volumes, in mice inoculated with Sarcoma-180 tumor cells. Both fungal extracts were demonstrated to exhibit phagocytosis enhancing activity as measured by carbon clearance in mice. PJ extracts, when administered i.p. at 50 mg/kg/day for 3 consecutive days, exhibited a signi,cant enhancement of phagocytosis, its potency as expressed by the regression coef,cient ratio, RCtr/RCc, being 1.64 (the phagocytosis index = 2). This was approximately the same for that of zymosan (RCtr/RCc = 1.55, PI = 2), a typical phagocytosis enhancer, whereas CS extracts exhibited a moderate phagocytosis enhancing activity at the same dose level (RCtr/RCc = 1.30, PI = 1). Both fungal extracts caused a signi,cant increase in an acid phosphatase activity, representing lysosomal enzymes, in macrophages at 20 and 100 µg/ml in vitro, in compliance with in vivo results. These results suggest that the anti-tumor activity of both fungi might be related to an immuno-stimulating function. Copyright © 2003 John Wiley & Sons, Ltd. [source] Allogeneic retrovirally transduced, IL-2- and IFN-,-secreting cancer cell vaccine in patients with hormone refractory prostate cancer,a phase I clinical trialTHE JOURNAL OF GENE MEDICINE, Issue 7 2007T. H. Brill Background The purpose of this vaccine study was to determine the safety and feasibility of vaccination with an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant interleukin-2 (IL-2) and interferon-, (IFN-,) and to evaluate the efficacy of inducing tumor-specific immune responses in HLA-A2-matched patients with hormone refractory prostate cancer (HRPC). Methods In a dose-escalating phase I study, HLA-A2-matched HRPC patients received four vaccinations of irradiated allogeneic LNCaP cells retrovirally transduced to secrete IL-2 and IFN-, at study day 1, 15, 29 and 92 and subsequently every 91 days unless tumor progression was evident. Results Three patients receiving the first dose level (7.5 million cells) showed no evidence of dose-limiting toxicity or vaccine-related adverse events including autoimmunity. One of three patients receiving the second dose level (15 million cells) developed a transient self-limiting grade 3 local injection site reaction (ulceration) after the eighth vaccination. Vaccine-induced immune responses against a broad array of prostate tumor associated antigens were detected in all six patients. Two of the three patients receiving the higher dose showed a decline in serum prostate-specific antigen (PSA) values of more than 50%, with one patient remaining on protocol for 3 years. Conclusions Immunisation with the allogeneic LNCaP/IL-2/IFN-, vaccine is safe and feasible without any dose-limiting toxicity or autoimmunity. A 50% PSA decline was achieved in two of the six patients. This encouraging data provides the scientific rationale for further investigation of the vaccine in a phase II trial. Copyright © 2007 John Wiley & Sons, Ltd. [source] Hepatopancreatic and muscular distribution of oxytetracycline antibiotics in farmed pacific white shrimp (Penaeus vannamei): a physiological-based pharmacokinetic model approachAQUACULTURE RESEARCH, Issue 1 2009Damrongsak Faroongsarng Abstract Oxytetracycline (OTC) pharmacokinetic models previously used to investigate Penaeus vannamei have not addressed the specific problems related to drug distribution/disposition in particular tissues. This study aimed to provide an insight into OTC kinetics in the hepatopancreas and muscle based on a physiological model approach. Adult male P. vannamei at the C-D0 inter-moulting stage were randomly assigned to intra-sinus and oral administrations. In the intra-sinus group, shrimps were dosed via the ventral sinus at an OTC level of 10.0 ,g g,1 body weight, while in the oral one, they were force fed at a dose level of 50.2 ,g g,1. The medicated animals were sampled at various time intervals until 170 h after dosing. Haemolymph, muscle and hepatopancreas samples were taken and OTC levels were determined using the validated HPLC method. A model focused on the hepatopancreas and muscle was developed. Oxytetracycline pharmacokinetic profiles in particular tissues were fitted into the model with an R2 of between 0.6568 and 0.9904. Oxytetracycline muscular distributions were essentially identical for both groups and the drug did not accumulate in muscle. The distributions in the hepatopancreas for both groups were extensive, whereas that for oral administration was approximately 2.3 times greater than that for the intra-sinus one. It was demonstrated that hepatopancreatic OTC may undergo significant first-pass elimination with non-linear kinetics. [source] Synthesis of New 2,3-Dihydroquinazolin-4(1H)-one Derivatives for Analgesic and Anti-inflammatory EvaluationARCHIV DER PHARMAZIE, Issue 5 2010Osama I. El-Sabbagh Abstract Starting from isatoic anhydrides, several new 2,3-dihydroquinazolin-4(1H)-one derivatives bearing chalcone or pyrazole or thiazole moieties at the third position were synthesized. The analgesic and anti-inflammatory activities for most compounds were studied at a dose level of 50 mg/kg via the acetic-acid-induced writhing-response method and carrageenan-induced edema method, respectively. The study showed that the chalcones bearing a 4-chlorophenyl group 4c or 4-nitrophenyl group 4b were the most active ones as analgesics. Both chalcone 4c and N -phenyl pyrazole bearing 4-methoxy phenyl group 5b showed a higher anti-inflammatory activity than celecoxib but still lower than that of diclofenac sodium. Moreover, the chalcone 4c has nearly the same ulcerogenic index as the selective cyclooxygenase-2 inhibitor celecoxib. [source] Synthesis and Evaluation on Anticonvulsant and Antidepressant Activities of 5-Alkoxy-tetrazolo[1,5- a]quinazolinesARCHIV DER PHARMAZIE, Issue 11 2009Huo-Jian Wang Abstract Several 5-alkoxy-tetrazolo[1,5- a]quinazoline derivatives have been synthesized by reacting 2,4-dichloroquinazoline with various phenols or aliphatic alcohol and then with sodium azide. The structures of these compounds have been confirmed by IR, MS, 1H-NMR, and elementary analysis. Anticonvulsant activities were evaluated using the maximal electroshock (MES) test. Most of the synthesized compounds displayed weak anticonvulsant activity at a dose of 300 mg/kg. Antidepressant activities were investigated by forced swimming test. Two compounds, namely 5-(hexyloxy)tetrazolo[1,5- a]quinazoline and 5-(4-methoxyphenoxy)tetrazolo[1,5- a]quinazoline, showed significant antidepressant activity, which decreased the immobility time by 62.2 and 51.7% at 100 mg/kg dose level. [source] Myrica nagi Attenuates Cumene Hydroperoxide-Induced Cutaneous Oxidative Stress and Toxicity in Swiss Albino MiceBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2000Aftab Alam In recent years, considerable efforts have been made to identify new chemopreventive agents which could be useful for man. Myrica nagi, a subtropical shrub, has been shown to possess significant activity against hepatotoxicity and other pharmacological and physiological disorders. We have shown a chemopreventive effect of Myrica nagi on cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in mice. Cumene hydroperoxide treatment at a dose level of 30 mg/animal/0.2 ml acetone enhances susceptibility of cutaneous microsomal membrane for iron-ascorbate-induced lipid peroxidation and induction of xanthine oxidase activity which are accompanied by decrease in the activities of cutaneous antioxidant enzymes such as catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and depletion in the level of cutaneous glutathione. Parallel to these changes a sharp decrease in the activities of phase II metabolizing enzymes such as glutathione S-transferase and quinone reductase has been observed. Application of Myrica nagi at doses of 2.0 mg and 4.0 mg/kg body weight in acetone prior to that of cumene hydroperoxide (30 mg/animal/0.2 ml acetone) treatment resulted in significant inhibition of cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in a dose-dependent manner. Enhanced susceptibility of cutaneous microsomal membrane for lipid peroxidation induced by iron ascorbate and xanthine oxidase activities were significantly reduced (P<0.05). In addition the depleted level of glutathione, the inhibited activities of antioxidants, and phase II metabolizing enzymes were recovered to a significant level (P<0.05). The protective effect of Myrica nagi was dose-dependent. In summary our data suggest that Myrica nagi is an effective chemopreventive agent in skin and capable of ameliorating cumene hydroperoxide-induced cutaneous oxidative stress and toxicity. [source] | |||||||||||||||||||||||||||||||||||||||||||