ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2003
Nancy H. Golden
Abstract Although lead can attain high concentrations in feathers, interpretation of the biological significance of this phenomenon is difficult. As part of an effort to develop and validate noninvasive methods to monitor contaminant exposure in free-ranging birds, lead uptake by feathers of nestling black-crowned night herons (Nycticorax nycticorax) was evaluated in a controlled exposure study. Four- to 6-d-old heron nestlings (one/nest) at Chincoteague Bay, Virginia (USA), received a single intraperitoneal injection of dosing vehicle (control, n = 7) or a dose of lead nitrate in water (0.01, 0.05, or 0.25 mg Pb/g body wt of nestling; n = 6 or 7/dose) chosen to yield feather lead concentrations found at low- to moderately polluted sites. Nestlings were euthanized at 15 d of age. Lead accumulation in feathers was associated with concentrations in bone, kidney, and liver (r = 0.32,0.74, p < 0.02) but exhibited only modest dose dependence. Blood delta-aminolevulinic acid dehydratase activity was inhibited by lead, although effects on other biochemical endpoints were marginal. Tarsus growth rate was inversely related to feather lead concentration. Culmen growth rate was depressed in nestlings treated with the highest dose of lead but not correlated with feather lead concentration. These findings provide evidence that feathers of nestling herons are a sensitive indicator of lead exposure and have potential application for the extrapolation of lead concentrations in other tissues and the estimation of environmental lead exposure in birds. [source]

Population pharmacokinetic investigation of disopyramide by mixed effect modelling using routine clinical pharmacokinetic data in Japanese patients

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2005
E. Yukawa PhD
Summary Objective:, To estimate the population pharmacokinetic parameters of disopyramide using non-linear mixed effects modelling. Method:, A total of 148 serum levels from 109 patients (61 males and 48 females) receiving disopyramide were collected. Results:, The final pharmacokinetic model was Cl (L/h) = 3·75·TBW0·567·AGE,0·374·Conc,0·719·1·48DOSE , 5, Vd (L/kg) = 4·13 and ka (h,1) = 0·363, where Cl is total body clearance, Vd is apparent volume of distribution, ka is absorption rate constant, TBW is total bodyweight (kg), AGE is age (years), Conc is the concentration of disopyramide (,g/mL), and DOSE , 5 = 1 for patient received 5 mg/kg/day of disopyramide dosage or over and 0 otherwise. Conclusion:, Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target disopyramide concentrations and the desired therapeutic effect. [source]

Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in Japanese patients

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2003
E. Yukawa
Summary Non-linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam,valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 0·3,32·6 years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CL = 144·0 TBW,0·172 1·14VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPA = 1 for concomitant administration of valproic acid and VPA = zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h) = 17·2 TBW,0·264 DOSE0·159 0·821CZP 0·896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZP = 1 for concomitant administration of clonazepam and CZP = zero otherwise; GEN = 1 for female and GEN = zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 17·9% decrease in valproic acid clearance. [source]

INFECTIVE DOSE OF FOODBORNE PATHOGENS IN VOLUNTEERS: A REVIEW

JOURNAL OF FOOD SAFETY, Issue 1 2001
MAHENDRA H. KOTHARY
ABSTRACT Risk assessment and impact of foodborne pathogens on the health of different populations was one of the goals identified in the Presidential Food Safety Initiative three-year plan. This entailed estimation of dose-response relationship for foodborne pathogens to humans, either by feeding studies or from outbreaks. For certain pathogens, such as Listeria monocytogenes and Escherichia coli O157:H7, there are no feeding studies due to ethical reasons, and the results from outbreaks are normally used to estimate the infectious dose. The focus of this review is to compile dose-response information in volunteers for several foodborne pathogens including Salmonella, Shigella spp., Campylobacter jejuni, Vibrio spp., Escherichia coli, Cryptosporidium parvum and Entamoeba coli. The infectious dose for different serovars of Salmonella and strains of E. coli was quite large (> 105 organisms), while the infectious dose for some Shigella spp. seemed to be as low as less than 10 organisms. Toxigenic V. cholerae (O1 and O139 serotypes) were infective at a dose of 104 organisms; a non-O1 strain was infective at a much higher dose (106 organisms). C. jejuni, C. parvum and Entamoeba coli appeared to have infectious doses as low as 500 organisms, 10 oocysts, and 1 cyst, respectively. The infectious dose and the dose response are dependent upon the strains used, and the age and physical condition of the individuals, and can therefore show wide variations. In addition, since many of the volunteer studies are carried out by feeding the organisms in a nonfood matrix after neutralizing the stomach acidity, results obtained may not reflect the true dose response. [source]

DOSE,RESPONSE OF ROPIVACAINE ADMINISTERED CAUDALLY TO CHILDREN UNDERGOING SURGICAL PROCEDURES UNDER SEDATION WITH MIDAZOLAM

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2004
F Tonatiu Aguirre-Garay
SUMMARY 1.,In a double-blind randomized controlled design, 50 children were allocated to receive bupivacaine 0.25% or ropivacaine 0.25%, 0.32%, 0.40% or 0.50% by caudal block. 2.,Caudal block was performed after induction of anaesthesia with 2,5% sevoflurane, atropine 10 µg/kg and midazolam 100,300 µg/kg. During the surgical procedure, patients were maintained under spontaneous ventilation and no intravenous or inhalatory anaesthetic agent was administered. For transoperative sedation, midazolam 100,300 µg/kg was administered every 0.5,1.0 h. Transoperative cardiovascular response, postoperative analgesia and local and systemic complications were evaluated. 3.,Groups were similar (P > 0.05) in sex, age, weight and in the time elapsed from caudal block to the beginning of the surgical procedure. The surgical time was significantly lower in the ropivacaine 0.25% group. The duration of analgesia was 24 h with ropivacaine 0.25% and approximately 10 h in the other four groups (P < 0.001). Linear regression analysis revealed a significant relationship between the postoperative analgesic period produced by ropivacaine and the surgical time (r = , 0.48, two-sided P = 0.002). Systolic and diastolic blood pressures remained in the physiologically normal range for the duration of the transoperative period. Vomiting was present in only one patient receiving ropivacaine 0.50%. 4.,In children, the duration of analgesia produced by caudal block with ropivacaine may be affected by surgical time. At surgical times of 0.5,1 h, ropivacaine 0.25% produced at least 24 h postoperative analgesia. At similar surgical times, ropivacaine 0.32%, 0.40% and 0.50% produced similar analgesic times to bupivacaine 0.25%. [source]

MEDICINE IN SMALL DOSES

ANZ JOURNAL OF SURGERY, Issue 11 2008
Bruce P. Waxman
No abstract is available for this article. [source]

Dose per unit area , a study of elicitation of nickel allergy

CONTACT DERMATITIS, Issue 5 2007
Louise Arup Fischer
Background:, Experimental sensitization depends upon the amount of allergen per unit skin area and is largely independent of the area size. Objectives:, This study aimed at testing if this also applies for elicitation of nickel allergy. Patients/methods:, 20 nickel allergic individuals were tested with a patch test and a repeated open application test (ROAT). Nickel was applied on small and large areas. The varying parameters were area, total dose and dose per unit area. Results:, In the patch test, at a low concentration [15 ,g nickel (,gNi)/cm2], there were significantly higher scores on the large area with the same dose per area as the small area. At higher concentrations of nickel, no significant differences were found. In the ROAT at low concentration (6.64 ,gNi/cm2), it was found that the latency period until a reaction appeared was significantly shorter on the large area compared to the small area. It was also found that the ROAT threshold (per application) was lower than the patch test threshold. Conclusion:, For elicitation of nickel allergy, the size of the exposed area and therefore the total amount of applied nickel, influence the elicitation reaction at some concentrations, even though the same dose per unit area is applied. [source]

Effect of dark test-substance pigmentation on skin perfusion assessments and effect of test technique on balsam of Peru patch-test results

CONTACT DERMATITIS, Issue 6 2000
Bolli Bjarnason
13 balsam of Peru (Myroxylon Pereirae) patch-test-positive subjects are re-tested with 25% balsam of Peru in petrolatum and with serial doses printed on polyester squares. All substances are applied with tape strips for 3, 6, 24 (1 day [D]), 48 (2D), 72 (3D) and 96 h (4D) on each subject and for 96 h (4D) with plastic foils. Tests are followed visually and with perfusion assessments from 3 h to 9 days. Results show that pigment remnants following detachment of patches affect perfusion assessments. Such effect due to pigment is supported by readings of patch tests through the petrolatum test substance while applied with transparent foils. For most reactions, good agreement is observed between the assessment techniques when peak assessment values of reactions are compared. There is inter-individual variation in perfusion with identical tests. With the petrolatum test substance, increased visible reactivity was observed when the application time was extended up to 24 h (1D), while extension of application time increased perfusion in most cases except for an extension from 24 (2D) to 48 h (4D) where decreased perfusion resulted in most cases. Dose and application time did not affect the timing of highest reactivity of reactions in most cases. [source]

Amisulpride , dose, plasma concentration, occupancy and response: implications for therapeutic drug monitoring

ACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2009
A. Sparshatt
Objective:, To evaluate the relationships between dose, plasma concentration, pharmacological activity and clinical outcome to evaluate the appropriateness of therapeutic drug monitoring (TDM) in patients receiving amisulpride. Method:, Literature search of Embase, Medline and PubMed databases. Results:, Amisulpride plasma concentration is closely correlated with dose (r2 = 0.96, P < 0.0001), dopamine occupancy, response and with extra-pyramidal symptoms (EPS). Dose is correlated with response, dopamine occupancy and EPS. Optimal clinical response was found at doses of 400,800 mg/day, corresponding to plasma levels of approximately 200,500 ng/ml. EPS appears to be more reliably predicted by a plasma level above 320 ng/ml than by a particular dose. Conclusion:, The effects and safety of amisulpride in the treatment of schizophrenia and schizoaffective disorder are predicted by daily dose. The plasma concentration threshold for response appears to be approximately 200 ng/ml. EPS are more reliably predicted by plasma level than by dose. TDM for patients prescribed amisulpride is thus of some clinical value. [source]

Dose and age-dependent axonal responses of embryonic trigeminal neurons to localized NGF via p75NTR receptor

DEVELOPMENTAL NEUROBIOLOGY, Issue 2 2005
P. Hande Özdinler
Abstract Nerve growth factor (NGF) and related neurotrophins are target-derived survival factors for sensory neurons. In addition, these peptides modulate neuronal differentiation, axon guidance, and synaptic plasticity. We tested axonal behavior of embryonic trigeminal neurons towards localized sources of NGF in collagen gel assays. Trigeminal axons preferentially grow towards lower doses of localized NGF and grow away from higher concentrations at earlier stages of development, but do not show this response later. Dorsal root ganglion axons also show similar responses to NGF, but NGF-dependent superior cervical ganglion axons do not. Such axonal responses to localized NGF sources were also observed in Bax,/, mice, suggesting that the axonal effects are largely independent of cell survival. Immunocytochemical studies indicated that axons, which grow towards or away from localized NGF are TrkA-positive, and TrkA,/, TG axons do not respond to any dose of NGF. We further show that axonal responses to NGF are absent in TG derived from mice that lack the p75 neurotrophin receptor (p75NTR). Collectively, our results suggest that localized sources of NGF can direct axon outgrowth from trigeminal ganglion in a dose- and age-dependent fashion, mediated by p75NTR signaling through TrkA expressing axons. © 2004 Wiley Periodicals, Inc. J Neurobiol, 2005 [source]

Original Article: Treatment: Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial

DIABETIC MEDICINE, Issue 9 2010
R. E. Ratner
Diabet. Med. 27, 1024,1032 (2010) Abstract Aims, To evaluate the dose,response relationship of lixisenatide (AVE0010), a glucagon-like peptide-1 (GLP-1) receptor agonist, in metformin-treated patients with Type 2 diabetes. Methods, Randomized, double-blind, placebo-controlled, parallel-group, 13 week study of 542 patients with Type 2 diabetes inadequately controlled [glycated haemoglobin (HbA1c) , 7.0 and < 9.0% (, 53 and < 75 mmol/mol)] on metformin (, 1000 mg/day) treated with subcutaneous lixisenatide doses of 5, 10, 20 or 30 ,g once daily or twice daily or placebo. The primary end-point was change in HbA1c from baseline to 13 weeks in the intent-to-treat population. Results, Lixisenatide significantly improved mean HbA1c from a baseline of 7.55% (59.0 mmol/mol); respective mean reductions for 5, 10, 20 and 30 ,g doses were 0.47, 0.50, 0.69 and 0.76% (5.1, 5.5, 7.5 and 8.3 mmol/mol), on once-daily and 0.65, 0.78, 0.75 and 0.87% (7.1, 8.5, 8.2 and 9.5 mmol/mol) on twice-daily administrations vs. 0.18% (2.0 mmol/mol) with placebo (all P < 0.01 vs. placebo). Target HbA1c < 7.0% (53 mmol/mol) at study end was achieved in 68% of patients receiving 20 and 30 ,g once-daily lixisenatide vs. 32% receiving placebo (P < 0.0001). Dose-dependent improvements were observed for fasting, postprandial and average self-monitored seven-point blood glucose levels. Weight changes ranged from ,2.0 to ,3.9 kg with lixisenatide vs. ,1.9 kg with placebo. The most frequent adverse event was mild-to-moderate nausea. Conclusions, Lixisenatide significantly improved glycaemic control in mildly hyperglycaemic patients with Type 2 diabetes on metformin. Dose,response relationships were seen for once- and twice-daily regimens, with similar efficacy levels, with a 20 ,g once-daily dose of lixisenatide demonstrating the best efficacy-to-tolerability ratio. This new, once-daily GLP-1 receptor agonist shows promise in the management of Type 2 diabetes to be defined further by ongoing long-term studies. [source]

Dose,response relationship of selective serotonin reuptake inhibitors treatment-emergent hypomania in depressive disorders

ACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2001
R. Ramasubbu
Objective:,The notion that antidepressant treatment-associated hypomania or mania being pharmacologically induced has been challenged. To determine whether selective serotonin reuptake inhibitors (SSRI) induced hypomania is secondary to medication effects, we examined the dose,response relationship of SSRI-induced hypomania in two patients with depressive disorder. Method:,Case study. Result:,Hypomanic symptoms emerged during treatment with sertraline at the dose of 300 mg per day in a 45-year-old male with major depression. Paroxetine treatment at the dose of 80 mg per day induced hypomania in a 37-year-old female with dysthymia and trichitillomania. These patients have no family or personal history of bipolar disorder. Hypomania resolved when sertraline was decreased to 200 mg per day and paroxetine to 40 mg per day. No hypomanic switch was observed during 18,24 months follow-up. Conclusion:,In the absence of risk factors for manic switch, SSRI-induced hypomania may be dose-dependent medication effects. [source]

The relation between different dimensions of alcohol consumption and burden of disease: an overview

ADDICTION, Issue 5 2010
Jürgen Rehm
ABSTRACT Aims As part of a larger study to estimate the global burden of disease and injury attributable to alcohol: to evaluate the evidence for a causal impact of average volume of alcohol consumption and pattern of drinking on diseases and injuries; to quantify relationships identified as causal based on published meta-analyses; to separate the impact on mortality versus morbidity where possible; and to assess the impact of the quality of alcohol on burden of disease. Methods Systematic literature reviews were used to identify alcohol-related diseases, birth complications and injuries using standard epidemiological criteria to determine causality. The extent of the risk relations was taken from meta-analyses. Results Evidence of a causal impact of average volume of alcohol consumption was found for the following major diseases: tuberculosis, mouth, nasopharynx, other pharynx and oropharynx cancer, oesophageal cancer, colon and rectum cancer, liver cancer, female breast cancer, diabetes mellitus, alcohol use disorders, unipolar depressive disorders, epilepsy, hypertensive heart disease, ischaemic heart disease (IHD), ischaemic and haemorrhagic stroke, conduction disorders and other dysrhythmias, lower respiratory infections (pneumonia), cirrhosis of the liver, preterm birth complications and fetal alcohol syndrome. Dose,response relationships could be quantified for all disease categories except for depressive disorders, with the relative risk increasing with increased level of alcohol consumption for most diseases. Both average volume and drinking pattern were linked causally to IHD, fetal alcohol syndrome and unintentional and intentional injuries. For IHD, ischaemic stroke and diabetes mellitus beneficial effects were observed for patterns of light to moderate drinking without heavy drinking occasions (as defined by 60+ g pure alcohol per day). For several disease and injury categories, the effects were stronger on mortality compared to morbidity. There was insufficient evidence to establish whether quality of alcohol had a major impact on disease burden. Conclusions Overall, these findings indicate that alcohol impacts many disease outcomes causally, both chronic and acute, and injuries. In addition, a pattern of heavy episodic drinking increases risk for some disease and all injury outcomes. Future studies need to address a number of methodological issues, especially the differential role of average volume versus drinking pattern, in order to obtain more accurate risk estimates and to understand more clearly the nature of alcohol,disease relationships. [source]

Alcohol and hypertension: gender differences in dose,response relationships determined through systematic review and meta-analysis

ADDICTION, Issue 12 2009
Benjamin Taylor
ABSTRACT Aims To analyze the dose,response relationship between average daily alcohol consumption and the risk of hypertension via systematic review and meta-analysis. Design A computer-assisted search was completed for 10 databases, followed by hand searches of relevant articles. Only studies with longitudinal design, quantitative measurement of alcohol consumption and biological measurement of outcome were included. Dose,response relationships were assessed by determining the best-fitting model via first- and second-degree fractional polynomials. Various tests for heterogeneity and publication bias were conducted. Findings A total of 12 cohort studies were identified from the literature from the United States, Japan and Korea. A linear dose,response relationship with a relative risk of 1.57 at 50 g pure alcohol per day and 2.47 at 100 g per day was seen for men. Among women, the meta-analysis indicated a more modest protective effect than reported previously: a significant protective effect was reported for consumption at or below about 5 g per day, after which a linear dose,response relationship was found with a relative risk of 1.81 at 50 g per day and of 2.81 at an average daily consumption of 100 g pure alcohol per day. Among men, Asian populations had higher risks than non-Asian populations. Conclusions The risk for hypertension increases linearly with alcohol consumption, so limiting alcohol intake should be advised for both men and women. [source]

Development of off-line and on-line capillary electrophoresis methods for the screening and characterization of adenosine kinase inhibitors and substrates

ELECTROPHORESIS, Issue 12 2006
Jamshed Iqbal
Abstract Fast and convenient CE assays were developed for the screening of adenosine kinase,(AK) inhibitors and substrates. In the first method, the enzymatic reaction was performed in a test tube and the samples were subsequently injected into the capillary by pressure and detected by their UV absorbance at 260,nm. An MEKC method using borate buffer (pH,9.5) containing 100,mM SDS (method,A) was suitable for separating alternative substrates (nucleosides). For the CE determination of AMP formed as a product of the AK reaction, a phosphate buffer (pH,7.5 or 8.5) was used and a constant current (95,,A) was applied (method,B). The methods employing a fused-silica capillary and normal polarity mode provided good resolution of substrates and products of the enzymatic reaction and a short analysis time of less than 10,min. To further optimize and miniaturize the AK assays, the enzymatic reaction was performed directly in the capillary, prior to separation and quantitation of the product employing electrophoretically mediated microanalysis (EMMA, method,C). After hydrodynamic injection of a plug of reaction buffer (20,mM Tris-HCl, 0.2,mM MgCl2, pH,7.4), followed by a plug containing the enzyme, and subsequent injection of a plug of reaction buffer containing 1,mM,ATP, 100,,M adenosine, and 20,,M,UMP as an internal standard,(I.S.), as well as various concentrations of an inhibitor, the reaction was initiated by the application of 5,kV separation voltage (negative polarity) for 0.20,min to let the plugs interpenetrate. The voltage was turned off for 5,min (zero-potential amplification) and again turned on at a constant current of ,60,,A to elute the products within 7,min. The method employing a polyacrylamide-coated capillary of 20,cm effective length and reverse polarity mode provided good resolution of substrates and products. Dose,response curves and calculated Ki values for standard antagonists obtained by CE were in excellent agreement with data obtained by the standard radioactive assay. [source]

Resistance of apple trees to Cydia pomonella egg-laying due to leaf surface metabolites

ENTOMOLOGIA EXPERIMENTALIS ET APPLICATA, Issue 1 2008
Nadia Lombarkia
Abstract During host plant selection and particularly after alighting on a plant, chemical cues from the plant surface influence an insect's acceptance of the plant and, subsequently, its egg-laying behaviour. Primary metabolites in the phylloplane may be more important than hitherto known. We have shown that soluble carbohydrates, such as glucose, fructose, and sucrose, and sugar alcohols, such as sorbitol, quebrachitol, and myo -inositol, can be detected by insects after contacting the plant and that they positively influence egg-laying of the codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae), on apple trees. We addressed the question whether a lack of these substances could also explain apple tree resistance to C. pomonella in terms of reduced egg-laying. Leaf surface washings were collected in an apple orchard by spraying water on the resistant cultivar X65-11 and on the susceptible cultivar P5R50A4. The washings were tested on a nylon cloth on isolated females under no-choice conditions. The washings were analysed and synthetic blends, each consisting of the six metabolites in the proportions established in the leaf surface washings of both cultivars, were then tested for their effect on egg-laying of C. pomonella. Dose,response egg-laying tests were carried out on substrates impregnated with the X65-11 leaf surface blend at 1, 100, 1 000, and 10 000 times the natural dose. Egg-laying behaviour in the bioassays with leaf surface washings of both cultivars closely resembled egg-laying in the orchard. Washings of P5R50A4 stimulated egg-laying to a greater extent than those of X65-11 and the water control. Synthetic blends reduced substrate acceptance and egg-laying, compared to the washings of X65-11. Ratios between components within the blend are responsible for this resistance. In conclusion, quantities and ratios of the six primary metabolites found on the leaf surface may influence host preference of C. pomonella as well as their egg-laying behaviour, thus they may play a role in the trees' resistance to the codling moth. [source]

Dose- and time-dependent responses for micronucleus induction by X-rays and fast neutrons in gill cells of medaka (Oryzias latipes)

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2004
Akinori Takai
Abstract Medaka fish (Oryzias latipes) were exposed to various doses of X-rays or fast neutrons, and the frequency of micronucleated cells (MNCs) was measured in gills sampled at 12- or 24-hr intervals from 12 to 96 hr after exposure. The resulting time course of MNC frequency was biphasic, with a clear peak 24 hr after exposure, irrespective of the kind of radiation applied and the dose used. The half-life of MNCs induced in the gill tissues by the two exposures fluctuated around 28 hr, with no significant dose-dependent trend for either X-ray- or neutron-exposed fish. As assayed 24 hr after exposure, the MNC frequency increased linearly over the control level with increasing doses of both X-rays and fast neutrons. The relative biological effectiveness (RBE) of fast neutrons to X-rays for MNC induction was estimated to be 4.3 ± 0.6. This value is close to the RBE value of 5.1 ± 0.3 reported for fast neutron induction of somatic crossing-over mutations in Drosophila melanogaster that arise from recombination repair of DNA double-strand breaks. These results and other data support our conclusion that the medaka gill cell micronucleus assay is a reliable short-term test for detecting potential inducers of DNA double-strand breaks. Environ. Mol. Mutagen. 44:108,112, 2004. © 2004 Wiley-Liss, Inc. [source]

Dose,response and time course relationships for vitellogenin induction in male western fence lizards (Sceloporus occidentalis) exposed to ethinylestradiol

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2002
Sandra M. Brasfield
Abstract The long-term goal of this research is to develop and validate an in vivo reptile model for endocrine-mediated toxicity using fence lizards (Sceloporus spp.). One of the best defined estrogenic responses in oviparous vertebrates is induction of the yolk precursor protein, vitellogenin (Vtg). In this study, dose,response and time course relationships for Vtg induction were determined in male western fence lizards (Sceloporus occidentalis) given intraperitoneal injections of 17,-ethinylestradiol (EE2). Plasma Vtg was quantified directly with an antibody-capture enzyme-linked immunosorbent assay (ELISA) and indirectly using plasma alkalinelabile phosphate (ALP) in order to compare these two methods. Both ELISA and ALP predicted similar median effective dose (ED50 [dose causing a 50% maximal response]) values for plasma Vtg induction (0.167 mg/kg for ELISA and 0.095 mg/kg for ALP). In addition, both ELISA and ALP detected significant Vtg induction at a dose of 0.0003 mg/kg of EE2, which was the lowest dose used in our study. A decrease in body weight at the highest dose (10 mg/kg) and an increase in hepatosomatic index at the four highest doses were observed. Serial dilutions of plasma from an EE2 -exposed male revealed a high correlation between plasma Vtg and ALP determinations in this species. In conclusion, our data show that plasma ALP may be a suitable alternative for measuring plasma Vtg compared with developing a Vtg ELISA in fence lizards exposed to estrogenic compounds. [source]

Dose,time,response modeling of longitudinal measurements for neurotoxicity risk assessment

ENVIRONMETRICS, Issue 6 2005
Yiliang Zhu
Abstract Neurotoxic effects are an important non-cancer endpoint in health risk assessment and environmental regulation. Neurotoxicity tests such as neurobehavioral screenings using a functional observational battery generate longitudinal dose,response data to profile neurological effects over time. Analyses of longitudinal neurotoxicological data have mostly relied on analysis of variance; explicit dose,time,response modeling has not been reported in the literature. As dose,response modeling has become an increasingly indispensible component in risk assessment as required by the use of benchmark doses, there are strong interests in and needs for appropriate dose,response models, effective model-fitting techniques, and computation methods for benchmark dose estimation. In this article we propose a family of dose,time,response models, illustrate statistical inference of these models in conjunction with random-effects to quantify inter-subject variation, and describe a procedure to profile benchmark dose across time. We illustrate the methods through a dataset from a US/EPA experiment involving the FOB tests on rats administered to a single dose of triethyl tin (TET). The results indicate that the existing functional observational battery data can be utilized for dose,response and benchmark dose analyses and the methods can be applied in general settings of neurotoxicity risk assessment. Copyright © 2005 John Wiley & Sons, Ltd. [source]

Comparison of in vivo effects of nitroglycerin and insulin on the aortic pressure waveform

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2004
J. Westerbacka
Abstract Background, Individuals whose platelets are resistant to the antiaggregatory effects of insulin in vitro are also resistant to the antiaggregatory effects of nitroglycerin (GTN). We have previously shown that insulin acutely diminishes central wave reflection in large arteries and that this action of insulin is blunted in insulin-resistant subjects. However, as yet, no studies have compared the haemodynamic effects of insulin and GTN on large arterial function in the same group of subjects. The aim of this study was to determine whether resistance to the haemodynamic effects of insulin is a defect specific to insulin or whether individuals resistant to the vascular actions of insulin are also resistant to GTN. Design and results, Dose,response characteristics of insulin and GTN on the aortic waveform were determined using applanation tonometry and pulse wave analysis (PWA) in seven healthy men (age 26 ± 1 year, BMI 25 ± 2 kg m,2). Three doses of sublingual GTN (500 µg for 1, 3 or 5 min) and insulin (0·5, 1 or 2 mU kg,1 min,1 for 120 min) were administered on three separate occasions. Both agents dose-dependently decreased central pulse pressure and the augmentation index (AIx) without changing brachial artery blood pressure. We next compared responses to insulin (2 mU kg,1 min,1 for 120 min) and sublingual GTN (500 µg for 5 min) in 20 nondiabetic subjects (age 50 ± 2 year, BMI 21·0,36·3 kg m,2). Again, both agents significantly decreased AIx. Although the vascular effects of insulin and GTN vascular were positively correlated [Spearman's r = 0·92 (95% confidence interval 0·81,0·97), P < 0·0001], the time-course for the action GTN was faster than that of insulin. Brachial systolic blood pressure remained unchanged during the insulin infusion (122 ± 3 vs. 121 ± 3 mmHg, 0 vs. 120 min) but aortic systolic blood pressure decreased significantly by 30 min (111 ± 3 vs. 107 ± 3 mmHg, 0 vs. 30 min, P < 0·01). Similarly, GTN decreased aortic systolic blood pressure from 119 ± 4 to maximally 112 ± 3 mmHg (P < 0·001) without significantly decreasing systolic blood pressure in the brachial artery. Conclusions, The effects of insulin and GTN on large arterial haemodynamics are dose-dependent and significantly correlated. The exact mechanisms and sites of action of insulin and GTN in subjects with insulin resistance remain to be established. [source]

MDMA self-administration in rats: acquisition, progressive ratio responding and serotonin transporter binding

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2007
Susan Schenk
Abstract 3,4-Methylenedioxymethamphetamine (MDMA) self-administration has been shown in animals with extensive drug histories, but only a small number of studies have examined high rates of responding maintained by MDMA in previously drug-naïve animals. In the present study, influence of dose (0.25 or 1.0 mg/kg/infusion) on the acquisition of MDMA self-administration was measured during daily 6-h sessions. Dose,effect data were obtained for MDMA (0.25,1.0 mg/kg/infusion) self-administration under a progressive ratio (PR) schedule of reinforcement. The effect of experimenter- or self-administered MDMA on [3H] paroxetine binding in several brain regions was measured. Acquisition of MDMA self-administration was highly variable and not different for 0.25 or 1.0 mg/kg/infusion progressed with approximately 60% of the rats acquiring reliable self-administration during the 15-day test period. The percentage of rats that acquired MDMA self-administration was lower than the percentage of rats that acquired cocaine (0.5 mg/kg/infusion) self-administration, and cocaine self-administration was acquired with a shorter latency. Responding maintained by MDMA was dose dependent, and breakpoints under a PR schedule increased with dose. Radioligand binding and autoradiography demonstrated lower densities of serotonin transporter sites (SERT) in MDMA self-administering rats as compared with controls across brain regions. The reduction in SERT densities was comparable in magnitude to rats treated with experimenter-administered doses of MDMA. These data support the idea that MDMA is a drug with high abuse liability, and long-term self-administration may lead to long-lasting deficits in serotonin neurotransmission. [source]

Molecular analysis of the A322D mutation in the GABAA receptor ,1 -subunit causing juvenile myoclonic epilepsy

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2005
Klaus Krampfl
Abstract Juvenile myoclonic epilepsy (JME) belongs to the most common forms of hereditary epilepsy, the idiopathic generalized epilepsies. Although the mode of inheritance is usually complex, mutations in single genes have been shown to cause the disease in some families with autosomal dominant inheritance. The first mutation in a multigeneration JME family has been recently found in the ,1 -subunit of the GABAA receptor (GABRA1), predicting the single amino acid substitution A322D. We further characterized the functional consequences of this mutation by coexpressing ,1 -, ,2 - and ,2 -subunits in human embryonic kidney (HEK293) cells. By using an ultrafast application system, mutant receptors have shown reduced macroscopic current amplitudes at saturating GABA concentrations and a highly reduced affinity to GABA compared to the wild-type (WT). Dose,response curves for current amplitudes, activation kinetics, and GABA-dependent desensitization parameters showed a parallel shift towards 30- to 40-fold higher GABA concentrations. Both deactivation and resensitization kinetics were considerably accelerated in mutant channels. In addition, mutant receptors labelled with enhanced green fluorescent protein (EGFP) were not integrated in the cell membrane, in contrast to WT receptors. Therefore, the A322D mutation leads to a severe loss-of-function of the human GABAA receptor by several mechanisms, including reduced surface expression, reduced GABA-sensitivity, and accelerated deactivation. These molecular defects could decrease and shorten the resulting inhibitory postsynaptic currents (IPSCs) in vivo, which can induce a hyperexcitability of the postsynaptic membrane and explain the occurrence of epileptic seizures. [source]

Intratumoral cisplatin/epinephrine gel in advanced head and neck cancer: A multicenter, randomized, double-blind, phase III study in North America,

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 9 2003
Dan J. Castro MD
Abstract Background. The objective was to evaluate the efficacy and safety of a novel intratumoral cisplatin/epinephrine injectable gel (CDDP/epi gel) for local control and palliation of tumor-related symptoms in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Patients and Methods. Eighty-seven patients were randomly assigned to either CDDP/epi or placebo gel in this phase III, double-blind study. Tumors were ,20 cm3; most recurrences (88%) were in a previously irradiated field. The most symptomatic or threatening tumor was designated as the target tumor. Dose: 0.25 mL CDDP/epi gel/cm3 tumor volume. Treatments: ,6 weekly intratumoral injections in an 8-week period. Primary outcomes: target tumor response and symptom relief. Results. During the blinded phase, 34% (21 of 62) of patients achieved an objective response (CR or PR) in the target tumor treated with CDDP/epi gel vs 0% (0 of 24) treated with placebo gel (p < .001). Responses occurred within a median of four treatments (range, 2,6) and were durable (median, 95 days; range, 34,168+ days). More patients treated with CDDP/epi gel achieved palliative benefit than did those treated with placebo gel (37% vs 12%, p = .036). Most frequent side effects were local pain and local cutaneous reactions, which resolved over 3,12 weeks. Renal and hematologic toxicities were rare. Conclusions. This phase III trial showed that CDDP/epi gel significantly reduces tumor burden, palliates tumor-related symptoms, and is an effective local treatment for recurrent tumors. © 2003 Wiley Periodicals, Inc. Head Neck 25: 717,731, 2003 [source]

Long-Term Tolerability of Sumatriptan Nasal Spray in Adolescent Patients With Migraine

HEADACHE, Issue 10 2004
Shankar Natarajan MD
Objective.,This 1-year, open-label, multicenter study was designed to assess the long-term tolerability and efficacy of sumatriptan nasal spray 20 mg in adolescent patients with migraine. Methods.,A prospective, multicenter, open-label study was conducted in patients aged 12 to 17 years who were allowed to treat an unlimited number of migraines at severe, moderate, or mild pain intensity with sumatriptan nasal spray for up to 1 year. All patients started the study at the 20-mg dose of sumatriptan nasal spray. Dose could be adjusted downward to 5 mg at the discretion of the investigator to optimize therapy. Results.,A total of 484 adolescent migraineurs treated 4676 migraines with sumatriptan nasal spray 20 mg (3593 during the first 6 months and 1083 during the second 6 months). A total of 3940 migraines and 699 migraines were treated with one and two 20-mg doses of sumatriptan nasal spray, respectively. Only 10 patients (treating 42 migraines) took the 5-mg dose of sumatriptan nasal spray. The overall percentage of migraines treated with either one 20-mg dose or one, two, or three 20-mg doses with at least 1 drug-related adverse event was 19%. The most common specific drug-related adverse event was unpleasant taste, reported in 17% of migraines. No other single drug-related adverse event was reported in more than 1% of migraines over the 1-year treatment period. When unpleasant taste was excluded from the adverse-event tabulations, the percentages of migraines with at least 1 drug-related adverse event after one or one, two, or three 20-mg doses declined to 4% and 3%, respectively. No patient experienced any drug-related changes in 12-lead ECGs, vital signs, or nasal assessments; and no clinically meaningful changes in clinical laboratory values were observed. Across all migraines with evaluable efficacy data (n = 4334), headache relief was reported in 43% of migraines at 1 hour and in 59% at 2 hours after dosing with sumatriptan nasal spray 20 mg. Of the 2561 migraines with headache relief 2 hours postdose, headache recurrence was reported within 24 hours of initial dosing in 7% of migraines. None of the efficacy or tolerability results varied as a function of time in the study (ie, first 6 months vs. second 6 months). Conclusion.,Sumatriptan nasal spray 20 mg is generally well tolerated and may be beneficial during long-term use by adolescent migraineurs ages 12 to 17 years. [source]

The HOMER Study: The Effect of Increasing the Dose of Metronidazole When Given with Omeprazole and Amoxicillin to Cure Helicobacter pylori Infection

HELICOBACTER, Issue 4 2000
Karna Dev Bardhan
Background.Helicobacter pylori eradication with omeprazole, amoxycillin, and metronidazole is both effective and inexpensive. However, eradication rates with different dosages and dosing vary, and data on the impact of resistance are sparse. In this study, three different dosages of omeprazole, amoxycillin, and metronidazole were compared, and the influence of metronidazole resistance on eradication was assessed. Methods. Patients (n = 394) with a positive H. pylori screening test result and endoscopy-proven duodenal ulcer in the past were enrolled into a multicenter study performed in four European countries and Canada. After baseline endoscopy, patients were randomly assigned to treatment for 1 week with either omeprazole, 20 mg twice daily, plus amoxycillin, 1,000 mg twice daily, plus metronidazole, 400 mg twice daily (low M); or omeprazole, 40 mg once daily, plus amoxycillin, 500 mg three times daily, plus metronidazole, 400 mg three times daily (medium M); or omeprazole, 20 mg twice daily, plus amoxycillin, 1,000 mg twice daily, plus metronidazole, 800 mg twice daily (high M). H. pylori status at entry was assessed by a 13C urea breath test and a culture. Eradication was defined as two negative 13C-urea breath test results 4 and 8 weeks after therapy. Susceptibility testing using the agar dilution method was performed at entry and in patients with persistent infection after therapy. Results. The eradication rates, in terms of intention to treat (ITT) (population n = 379) (and 95% confidence interval [CI]) were as follows: low M 76% (68%, 84%), medium M 76% (68%, 84%), and high M 83% (75%, 89%). By per-protocol analysis (population n = 348), the corresponding eradication rates were: low M 81%, medium M 80%, and high M 85%. No H. pylori strains were found to be resistant to amoxycillin. Prestudy resistance of H. pylori strains to metronidazole was found in 72 of 348 (21%) of the cultures at entry (range, 10%,39% in the five countries). The overall eradication rate in prestudy metronidazole-susceptible strains was 232 of 266 (87%) and, for resistant strains, it was 41 of 70 (57%; p < .001). Within each group, the results were as follows (susceptible/resistant): low M, 85%/54%; medium M, 86%/50%; and high M, 90%/75%. There were no statistically significant differences among the treatment groups. 23 strains susceptible to metronidazole before treatment were recultured after therapy failed; 20 of these had now developed resistance. Conclusions.H. pylori eradication rates were similar (approximately 80%) with all three regimens. Metronidazole resistance reduced efficacy; increasing the dose of metronidazole appeared not to overcome the problem or significantly improve the outcome. Treatment failure was generally associated with either prestudy or acquired metronidazole resistance. These findings are of importance when attempting H. pylori eradication in communities with high levels of metronidazole resistance. [source]

Dose- and time-dependent oval cell reaction in acetaminophen-induced murine liver injury,

HEPATOLOGY, Issue 6 2005
Alexander V. Kofman
We examined the response of murine oval cells, that is, the putative liver progenitor cells, to acetaminophen. Female C57BL/6J mice were injected intraperitoneally with varying doses of N -acetyl-paraaminophen (APAP) (250, 500, 750, and 1,000 mg/kg of weight) and sacrificed at 3, 6, 9, 24, and 48 hours. In preliminary studies, we showed that anticytokeratin antibodies detected A6-positive cells with a sensitivity and specificity of greater than 99%. The oval cell reaction was quantified, on immunostaining for biliary-type cytokeratins, as both number and density of oval cells per portal tract, analyzed by size of portal tract. Acetaminophen injury was followed by periportal oval cell accumulation displaying a moderate degree of morphological homogeneity. Oval cell response was biphasic, not temporally correlating with the single wave of injury seen histologically. Increases in oval cells were largely confined to the smallest portal tracts, in keeping with their primary derivation from the canals of Hering, and increased in a dose-dependent fashion. The timing of the two peaks of the oval cell reaction also changed with increasing dose, the first becoming earlier and the second later. In conclusion, our studies indicate a marked oval cell activation during the height of hepatic injury. Oval cells appear to be resistant to acetaminophen injury. The close fidelity of mechanism and histology of acetaminophen injury between mouse and human livers makes it a useful model for investigating liver regeneration and the participation of stem/progenitor cells in that process. (HEPATOLOGY 2005.) [source]

Examination of cytotoxicity and mutagenicity of AH26 and AH Plus sealers

INTERNATIONAL ENDODONTIC JOURNAL, Issue 5 2003
I. Mileti
Abstract Aim ,To study in vitro the cytotoxic and mutagenic effects of AH26 and AH Plus. Methodology ,Cytotoxic effects on Chinese hamster V79 cells were determined by counting viable cells following incubation with eluations of AH26 and AH Plus. In one set of experiments, the materials were mixed, set for 1 h and then eluted with dimethyl sulphoxide (DMSO) for 1 h, 24 h and 7 days. In the other set, AH26 and AH Plus were mixed and set for 1 h, 24 h and 7 days in physiological saline then crushed and eluted in DMSO for 24 h. The cytotoxic effects of these eluates were evaluated. Three concentrations were chosen to examine the mutagenic effects of AH26 and AH Plus: 5.57, 16.7 and 55.7 ,g mL,1. The structural chromosomal aberration analysis and micronucleus test were performed on human lymphocytes according to standard procedures. Results ,Dose,response curves of cell survival were obtained. Both materials were shown to be cytotoxic in doses larger than 55.7 ,g mL,1, except for AH26, after 7 days setting time. AH Plus was also shown to be toxic in concentrations of 16.7 ,g mL,1, except after 7 days setting time. Neither AH26 nor AH Plus induced a significant increase of chromosomal aberrations or micronuclei induction at any setting time or concentration. Conclusion ,There was no mutagenicity found for AH26 and AH Plus on human lymphocytes in highly controlled conditions in vitro. [source]

Measuring the Dose of Nursing Intervention

INTERNATIONAL JOURNAL OF NURSING TERMINOLOGIES AND CLASSIFICATION, Issue 4 2007
David Reed PhD
PURPOSE.,To increase awareness of the many issues involved in measuring the dose of nursing intervention in nursing interventions effectiveness research. METHODS.,Identify critical issues in measurement of the dose of nursing intervention and discuss decisions regarding dosage measurement made in a study of the effectiveness of nursing interventions. FINDINGS.,A single method can be applied to resolve two critical issues in intervention dosage measurement. CONCLUSIONS.,Those conducting nursing interventions effectiveness research must think explicitly about how intervention dosage will be measured and reported so that dosage can be replicated in research and practice. PRACTICE IMPLICATIONS.,,Measuring and reporting the dose of nursing intervention in research is essential to the development of an evidence base adequate to support practice. [source]

Changes in Muscle Mass, Muscle Strength, and Power but Not Physical Function Are Related to Testosterone Dose in Healthy Older Men

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 11 2008
Thomas W. Storer PhD
OBJECTIVES: To examine the effect of graded doses of testosterone on physical function and muscle performance in healthy, older men. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: General clinical research center. PARTICIPANTS: Community-dwelling healthy men aged 60 to 75 (N=44). INTERVENTION: Monthly treatment with a gonadotropin-releasing hormone agonist plus 25, 50, 125, or 300 mg/wk of intramuscular injections of testosterone enanthate for 20 weeks. MEASUREMENTS: Skeletal muscle mass (SMM) was estimated using dual-energy X-ray absorptiometry. Leg press strength was measured by one repetition maximum, leg power by Nottingham Leg Rig, and muscle fatigability by repetitions to failure in the leg press exercise. Stair climbing, 6-meter and 400-meter walking speed, and a timed-up-and-go (TUG) test were used to assess physical function. RESULTS: Significant testosterone dose- and concentration-dependent increases were observed in SMM (P<.001) and maximal strength (P=.001) but not muscle fatigability. Leg power also increased dose-dependently (P=.048). In contrast, changes in self-selected normal and fast walking speed over 6 or 400 meters, stair climbing power, and time for the TUG were not significantly related to testosterone dose, testosterone concentrations, or changes in muscle strength or power, or SMM. CONCLUSION: Testosterone administration was associated with dose-dependent increases in SMM, leg strength, and power but did not improve muscle fatigability or physical function. The observation that physical function scores did not improve linearly with strength suggests that these high-functioning older men were already in the asymptotic region of the curve describing the relationship between physical function and strength. [source]

Potentially Inappropriate Prescribing in Elderly Veterans: Are We Using the Wrong Drug, Wrong Dose, or Wrong Duration?

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 8 2005
Mary Jo V. Pugh PhD
Objectives: To identify the extent of inappropriate prescribing using criteria for proper use developed by the Agency for Healthcare Research and Quality (AHRQ) and dose-limitation criteria defined by Beers, as well as to describe duration of use and patient characteristics associated with inappropriate prescribing for older people. Design: Retrospective national Veterans Health Administration (VA) administrative database analysis. Setting: VA outpatient facilities during fiscal year 2000 (FY00). Participants: Veterans aged 65 and older having at least one VA outpatient visit in FY00 (N=1,265,434). Measurements: Operational definitions of appropriate use were developed based on recommendations of an expert panel convened by the AHRQ (Zhan criteria). Inappropriate use was identified based on these criteria and inappropriate use of drugs per Beers criteria for dose-limitations in older people. Furthermore, duration of use and patient characteristics associated with inappropriate use were described. Results: After adjusting for diagnoses, dose, and duration, inappropriate prescribing decreased from 33% to 23%. Exposure to inappropriate drugs was prolonged. Pain relievers, benzodiazepines, antidepressants, and musculoskeletal agents constituted 61% of inappropriate prescribing. Whites, patients with psychiatric comorbidities, and patients receiving more medications were most likely to receive inappropriate drugs. Women were more likely to receive Zhan criteria drugs; men were more likely to receive dose-limited drugs Conclusion: For the most part, the Zhan criteria did not explain inappropriate prescribing, which includes problems related to dose and duration of prescriptions. Interventions targeted at prescriptions for pain relievers, benzodiazepines, antidepressants, and musculoskeletal agents may dramatically decrease inappropriate prescribing and improve patient outcomes. [source]