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Doses Used (dose + used)
Selected AbstractsLack of teratogenicity of microcystin-LR in the mouse and toadJOURNAL OF APPLIED TOXICOLOGY, Issue 1 2002N. Chernoff Abstract Microcystin-LR (MC-LR) is a cyanobacterial toxin generated by the organism Microcystis aeruginosa. Although the hepatotoxicity of this chemical has been characterized, the potential developmental toxicity in vertebrates has not been well studied. The purpose of this study was to elucidate the effects of this toxin on the in vivo and in vitro development of mammals and the development of an Anuran (toad). Initial acute toxicity experiments with female CD-1 mice were accomplished with MC-LR administered i.p. in saline. Lethality occurred at 128 and 160 µg kg ,1 and histopathology revealed massive hepatic necrosis with diffuse hemorrhage. Developmental toxicity studies were done with MC-LR administered i.p. for 2-day periods: gestation days 7,8, 9,10 or 11,12. Doses used ranged from 2 to 128 µg kg,1. On gestation day 17, fetuses were weighed and analyzed for gross morphological and skeletal defects. No treatment-related differences were seen in litter size, viability, weight or the incidence of anomalies. Groups of dams dosed with 32,128 µg kg,1 on gestation days 7,8, 9,10 or 11,12 were allowed to give birth and the growth and development of their pups were followed postnatally. There were no significant effects noted in the offspring of the treated dams. Neurulation-staged CD-1 mouse conceptuses were exposed to 50,1000 nM MC-LR in whole embryo culture for 24 h. No significant increase in abnormalities or developmental delays was observed. Finally, exposure of the developing toad. Bufo arenarum was done from stage 17 (tail bud) for 10 days at concentrations of 1,20 mg l,1. No effect on morphological development or survival was noted in any exposed groups. These data indicate that microcystin does not appear to affect development adversely in the mouse (in vivo or in vitro) or the toad at the doses and exposure parameters used. Copyright © 2002 John Wiley & Sons, Ltd. [source] Effect of Flavonoids on Daunorubicin-induced Toxicity in H9c2 CardiomyoblastsPHYTOTHERAPY RESEARCH, Issue 1 2009Gabriela Moj Abstract Daunorubicin (DNR) is one of the most important antitumor agents belonging to the anthracycline group. However, its use is seriously limited by the development of cardiac toxicity. The present study was designed to investigate the effects of quercetin, pycnogenol and naringenin on daunorubicin-induced cytoxicity in H9c2 cells. Protection of H9c2 cardiomyocyte cells was concentration/dose dependent for quercetin > naringenin > pycnogenol = trolox. Quercetin (10,4,10,5 mol/L) after 24 h of co-incubation with DNR significantly increased the cardiomyocyte survival (p < 0.001 and p < 0.05, respectively). A protective effect of other compounds was observed only in the highest concentration/dose used (p < 0.01). After 48 h of incubation quercetin and naringenin significantly decreased daunorubicin-induced cell death at concentrations of 10,4,10,5 mol/L (p < 0.001 and p < 0.01, respectively). The protective effect of pycnogenol and trolox was weaker but significant in the two highest concentrations/doses (p < 0.001 and p < 0.05, respectively). This study also investigated DNR-induced apoptosis and it was shown that both quercetin and naringenin inhibit apoptosis of H9c2 cardiomyocytes cells in vitro. The findings provide evidence that quercetin and naringenin may act as survival factors. The protective effect of flavonoids was compared with that of trolox, a known cardioprotective antioxidant. These results are consistent with the notion that the use of flavonoids may be beneficial in modulating or preventing the cardiotoxicity associated with DNR therapy. Copyright © 2008 John Wiley & Sons, Ltd. [source] Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital settingEMERGENCY MEDICINE AUSTRALASIA, Issue 1 2009Joanne Grindlay Abstract This article reviews the evidence for the analgesic efficacy of methoxyflurane in both prehospital and ED settings, as well as the adverse event profile associated with methoxyflurane use. Although there are no published controlled trials of methoxyflurane in sub-anaesthetic doses, available data indicate that it is an efficacious analgesic. There is inadequate evidence regarding its use as an agent for procedural pain. Despite the potential for renal impairment evident when it was used in anaesthetic doses, no significant adverse effects have been reported in the literature, neither in patients nor occupationally, when the dose used is limited to that currently recommended. [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 2004Akinori 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 ethinylestradiolENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2002Sandra 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] Underdosing of Midazolam in Emergency Endotracheal IntubationACADEMIC EMERGENCY MEDICINE, Issue 4 2003Mark J. Sagarin MD Objectives: To determine whether midazolam, when used as an induction agent for emergency department (ED) rapid-sequence intubation (RSI), is used in adequate and recommended induction doses (0.1 to 0.3 mg/kg), and to compare the accuracy of the dosing of midazolam for ED RSI with the accuracy of dosing of other agents. Methods: The authors conducted a systematic query of a prospectively collected database of ED intubations using the National Emergency Airway Registry data, gathered in 11 participating EDs over a 16-month period. A data form completed at the time of emergency department intubation (EDI) enabled analysis of patients' ages, weights, and indications for EDI, as well as the techniques and drugs used to facilitate EDI. Data were analyzed to determine whether midazolam is used in recommended doses during RSI. Patients intubated with midazolam alone were compared with patients who received other induction agents for RSI. Results: Of 1,288 patients entered in the study, 1,023 (79%) underwent RSI. Of the 888 RSI patients with an age recorded, midazolam was used as the sole induction agent in 140 (16%). The mean (±SD) dosages of midazolam used in RSI were 2.6 (±1.7) mg in children (age , 18) and 3.7 (±2.5) mg in adults (age ,19); the mean (±SD) dosages by weight were 0.08 (±0.04) mg/kg in children and 0.05 (±0.03) mg/kg in adults. More than half (56%) of the children, and nearly all (92%) of the adults, received dosages lower than the minimum recommended dosage (0.1 mg/kg). Of patients who received barbiturates, only 21% of children and 21% of adults received a dose lower than the minimum recommended. When combined with another induction agent, midazolam was dosed similarly to when it was used alone: mean adult doses were 3.1 (±1.2) mg and 0.04 (±0.02) mg/kg. Conclusions: Underdosing of midazolam during ED RSI is frequent, and appears to be related to incorrect dosage selection, rather than to a deliberate intention to reduce the dose used. [source] Effects of Low-Dose Prednisone on Bone Metabolism,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2005Francine N Ton MD Abstract Prednisone 5 mg/day suppresses multiple indices of bone formation in a randomized placebo-controlled trial in healthy postmenopausal females. This suggests that even low doses of prednisone may reduce bone repair or renewal and may have adverse effects on bone mass and/or bone strength. Introduction: High doses of chronic glucocorticoids are known to have adverse effects on bone, and measures to prevent bone loss are well established for doses >7.5 mg daily, because these doses can cause premature or exaggerated osteoporosis. However, it is unclear if chronic prednisone doses of 5 mg daily have the same effects on bone. There are no established recommendations for preventing glucocorticoid-induced osteoporosis in people taking prednisone 5 mg daily, a dose used frequently in medical practice to treat diseases of the lungs, joints, skin, muscles, eyes, nerves, etc. Our primary objective was to test whether prednisone 5 mg daily affects serum and urine indices of bone metabolism in healthy postmenopausal women. Our secondary objectives were to determine if prednisone 5 mg affected systolic or diastolic blood pressure or causes side effects. Materials and Methods: A double-blinded randomized placebo-controlled 8-week trial in 50 healthy postmenopausal women was conducted at the Massachusetts General Hospital Outpatient General Clinical Research Center. Patients were randomly assigned to prednisone 5 mg daily or matching placebo for 6 weeks, followed by a 2-week recovery phase. Markers of bone formation and resorption were determined at weeks 0, 2, 4, 6, and 8. Indices of osteoblast activity included serum propeptide of type I N-terminal procollagen (PINP), propeptide of type I C-terminal procollagen (PICP), osteocalcin, and bone-specific alkaline phosphatase (BSALP). Indices of osteoclast activity included urine and serum type I collagen N-telopeptide (NTX) and free urinary deoxypyridinoline (DPD). Results and Conclusions: Prednisone rapidly and significantly decreased serum PINP (p < 0.01), PICP (p < 0.01), and osteocalcin (p < 0.01) and free urinary deoxypyridinoline (p = 0.017). These changes were largely reversed during the recovery period. Side effects were indistinguishable in the two groups. Neither systolic nor diastolic blood pressure changed significantly throughout the study between the two groups. In conclusion, low-dose prednisone significantly decreases indices of bone formation and may decrease indices of bone resorption in postmenopausal women. Further studies are needed to assess the effects of low-dose prednisone on BMD and fracture risk. [source] In-vitro anti-inflammatory effect of Eucalyptus globulus and Thymus vulgaris: nitric oxide inhibition in J774A.1 murine macrophagesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2004E. Vigo ABSTRACT It is well known that nitric oxide (NO) plays an important role in the pathogenesis of inflammatory diseases. Eucalyptus globulus Labill. and Thymus vulgaris L. have been used in traditional medicine in the treatment of bronchitis, asthma and other respiratory diseases. The present study focuses on the effects of these two extracts on NO production induced by lipopolysaccharide (LPS) and interferon-, (IFN-,) in the murine macrophage cell line J774A.1. In addition, cell viability, scavenging activity and inducible nitric oxide synthase (iNOS) mRNA expression were evaluated. E. globulus and T. vulgaris extracts significantly inhibited the enhanced production of NO induced by LPS and IFN-, in a dose-dependent manner. Treatment with these two extracts did not reduce cell viability at any dose used. Both plant extracts showed significant scavenging of NO radicals released by an NO donor, PAPANONOate. Results also show that pre-treatment with E. globulus and T. vulgaris extracts significantly inhibits iNOS mRNA expression. This study thus suggests that the inhibition of net NO production by these two extracts may be due to their NO scavenging activity and/or their inhibitory effects on iNOS gene expression. [source] Analysis of pesticide residues by online reversed-phase liquid chromatography,gas chromatography in the oil from olives grown in an experimental plot.JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 12 2006Part II Abstract The effect of the pesticide dose used to control pests in olive trees and the date of treatment on the residues present in the oil were studied for four organophosphorus pesticides (diazinon, malathion, trichlorphon and chlorfenvinphos) and one organochlorine (endosulfan). Pesticide residue analysis was performed using online reversed-phase liquid chromatography,gas chromatography, using an automated through oven transfer adsorption desorption interface and selective detectors, such as nitrogen,phosphorus detector and electronic capture detector. A simple filtration step was necessary before the chromatographic analysis of samples. The obtained data were statistically analyzed and conclusions about olive pesticide treatments are presented. Copyright © 2006 Society of Chemical Industry [source] Iron and inflammatory bowel diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2001B. Oldenburg Both anaemia of iron deficiency and anaemia of chronic disease are frequently encountered in inflammatory bowel disease. Anaemia of iron deficiency is mostly due to inadequate intake or loss of iron. Anaemia of chronic disease probably results from decreased erythropoiesis, secondary to increased levels of proinflammatory cytokines, reactive oxygen metabolites and nitric oxide. Assessment of the iron status in a condition associated with inflammation, such as inflammatory bowel disease, is difficult. The combination of serum transferrin receptor with ferritin concentrations, however, allows a reliable assessment of the iron deficit. The best treatment for anaemia of chronic disease is the cure of the underlying disease. Erythropoietin reportedly may increase haemoglobin levels in some of these patients. The anaemia of iron deficiency is usually treated with oral iron supplements. Iron supplementation may lead to an increased inflammatory activity through the generation of reactive oxygen species. To date, data from studies in animal models of inflammatory bowel disease support the theoretical disadvantage of iron supplementation in this respect. The results, however, cannot easily be extrapolated to the human situation, because the amount of supplemented iron in these experiments was much higher than the dose used in patients with iron deficiency. [source] Intraoperative loading attenuates nausea and vomiting of tramadol patient-controlled analgesia. (Show-Chwan Memorial Hospital, Changhua, Taiwan) Can J Anaesth 2000;47:968,973.PAIN PRACTICE, Issue 2 2001Wei-Wu Pang Sixty adult patients scheduled for elective abdominal surgery were enrolled into this prospective, randomized, double-blinded study. The patients were anesthetized in a similar manner. At the beginning of wound closure, the patients were randomly allocated to receive tramadol (Group 1) or normal saline (Group 2). Pain control and adverse effect assessments were done in the PACU and every 6 h for 48 h post drug by an independent observer. The loading dose was 290 ± 45 mg in Group 1 and 315 ± 148 mg in Group 2. In PACU, more nausea and vomiting both in terms of incidence and severity were observed in patients with postoperative loading than in those with intraoperative loading of tramadol. Conclude that administering the loading dose of tramadol during surgery decreases the nausea and vomiting associated with a high dose of tramadol and improves the quality of tramadol PCA in the relief of postoperative pain. Comment by Lian-Kah Ti, M.D. The clinical application and conclusions of this study have to be questioned. It was not surprising that a loading dose of tramadol could effectively be given intraoperatively. What was surprising was that the authors chose not to give any analgesics either preoperatively or intraoperatively for relatively major surgery in an older population, potentially risking morbidity. Indeed, analgesics were withheld in the control group until the patients were extubated, awake, responsive, and complained of pain. Another source of concern was the large loading dose used. Based on their own experience, the authors gave doses of 300 mg of tramadol, which far exceeded the maximum recommended single dose of 100 mg as stated in the manufacturer's instruction for use. The authors did not report any intraoperative hemodynamic consequences from the loading dose, although they noted that the amount of isoflurane required was decreased. The authors concluded that the decreased nausea and vomiting seen in the patients receiving tramadol intraoperatively resulted from the patients being anesthetized at the point when peak plasma levels were achieved. An alternative explanation could be that the patients in the control group had greater postoperative pain (initial VAS of 5.9), and that pain itself resulted in the increased nausea and vomiting. Therefore, the value of this study is doubtful. [source] Profound changes in the GH,IGF-I system in adolescent girls with IDDM: can IGFBP1 be used to reflect overall glucose regulation?PEDIATRIC DIABETES, Issue 3 2000MU Halldin Disturbances in the relations between insulin, growth hormone (GH) and insulin-like growth factor I (IGF-I) may be a major cause behind deteriorated metabolic control in adolescent girls with type I diabetes. These patients have increased GH secretion and low IGF-I concentrations. The aim of this study was to identify possible endocrine mechanisms behind good and poor glycaemic control in such girls, focusing on the insulin,GH,IGF-I axis. Ten girls with well-controlled insulin-dependent diabetes mellitus (IDDM), hemoglobin A1c (HbA1c) 6.5±0.4% (normal range 3.9,5.2%) and nine healthy controls were investigated and compared with 11 girls with poor glucose regulation, HbA1c 10.9±0.4%, and their corresponding controls. Serum profiles of glucose, insulin, GH and IGF-binding protein 1 (IGFBP1) were analysed in addition to IGF-I and HbA1c. Two interesting observations were made. GH concentrations were equally elevated in the two diabetic groups regardless of metabolic control (mean 24 h GH , girls with poorly controlled diabetes 10.0±1.0 mU/L vs 9.8±1.7 , girls with well-controlled diabetes; p=ns). Likewise, the IGF-I concentrations were reduced to the same extent (233±19 vs 242±23 ,g/L; p=0.75). Secondly, despite similar insulin concentrations (mean 24 h insulin , girls with poorly controlled diabetes 22.9±2.6 and girls with well-controlled diabetes 27.3±2.9 mU/L, respectively; p=0.26), there was a marked difference in IGFBP1 concentrations between the two groups with IDDM (mean IGFBP1 , girls with poorly controlled diabetes 70.5±9.1 ,g/L vs girls with well-controlled diabetes 28.6±3.3; p<0.001). Despite equally elevated GH concentrations that may induce insulin resistance, the markedly lower concentrations of IGFBP1 in the well-controlled group indicate a higher hepatic insulin sensitivity in these girls compared with those with a poor control. Furthermore, in spite of similar total IGF-I concentrations, the lower IGFBP1 concentrations may result in higher IGF-I bioactivity in the well-controlled group. This may be reflected in better growth of the well-controlled group whose height of 168.7±0.9 vs 163.6±1.2 cm was significantly different (p<0.004). IGFBP1 may be a marker of overall insulinization in adolescents with type 1 diabetes, independent of the absolute insulin dose used for therapy. [source] Betaine and homocysteine concentrations in foodsPEDIATRICS INTERNATIONAL, Issue 4 2002Akiko Sakamoto Abstract Background: Betaine (Bet) supplementation is an effective strategy for dietary treatment of homocystinuria. However,previous reports on diet therapy have only examined methionine (Met) and cystine concentrations, but not those of Bet and homocysteine(Hcy) in food items. We set up a hypothesis that there are some food items, which contain a small amount of Met, but a great amountof Hcy and Bet. Methods: We measured Bet and Hcy concentrations in 58 food items, which were regarded as containing low Met. Results: Products of wheat flour are rich in Bet. The amount of Bet in food items investigated in this study is muchsmaller than the dose used to treat homocystinuria patients. Vegetables contained little Hcy, however sprouted beans and sprouted alfalfaseeds contained ample Hcy. Conclusion: Patients with homocystinuria do not have to be too concerned about Hcy in food items because the amountis small. Therefore, we encourage homocystinuria patients to continue a low Met diet therapy without anxiety of Hcy and Bet, and if necessary,Bet will be supplemented. [source] Nurse dose: What's in a concept?,RESEARCH IN NURSING & HEALTH, Issue 4 2008Milisa Manojlovich Abstract Many researchers have sought to address the relationship between nursing care and patient outcomes, with inconsistent and contradictory findings. We conducted a concept analysis and concept derivation, basing our work on theoretical and empirical literature, to derive nurse dose as a concept that pulls into a coherent whole disparate variables used in staffing studies. We defined nurse dose as the level of nursing reflected in the purity, amount, frequency, and duration of nursing care needed to produce favorable outcomes. All four parameters of nurse dose used together can facilitate our understanding of how nursing contributes to patient outcomes. Ongoing investigation will help to identify the parameters of nurse dose that have the greatest effect on outcomes. © 2008 Wiley Periodicals, Inc. Res Nurs Health 31:310,319, 2008 [source] Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis,ANNALS OF NEUROLOGY, Issue 2 2009Sanne Piepers MD Objective To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design. Methods Between April 2005 and January 2007, 163 ALS patients received VPA 1,500mg or placebo daily. Primary end point was survival. Secondary outcome measure was decline of functional status measured by the revised ALS Functional Rating Scale. Analysis was by intention to treat and according to a sequential trial design. This trial was registered with ClinicalTrials.gov (number NCT00136110). Results VPA did not affect survival (cumulative survival probability of 0.72 in the VPA group [standard error (SE), 0.06] vs 0.88 in the placebo group [SE, 0.04] at 12 months, and 0.59 in the VPA group [SE, 0.07] vs 0.68 in the placebo group [SE, 0.08] at 16 months) or the rate of decline of functional status. VPA intake did not cause serious adverse reactions. Interpretation Our finding that VPA, at a dose used in epilepsy, does not show a beneficial effect on survival or disease progression in patients with ALS has implications for future trials with histone deacetylase inhibitors in ALS and other neurodegenerative diseases. The use of a sequential trial design allowed inclusion of only half the number of patients required for a classic trial design and prevented patients from unnecessarily continuing potentially harmful study medication. Ann Neurol 2009;66:227,234 [source] A Statistical Framework for Quantile Equivalence Clinical Trials with Application to Pharmacokinetic Studies that Bridge from HIV-Infected Adults to ChildrenBIOMETRICS, Issue 4 2008Lixia Pei Summary Bridging clinical trials are sometimes designed to evaluate whether a proposed dose for use in one population, for example, children, gives similar pharmacokinetic (PK) levels, or has similar effects on a surrogate marker as an established effective dose used in another population, for example, adults. For HIV bridging trials, because of the increased risk of viral resistance to drugs at low PK levels, the goal is often to determine whether the doses used in different populations result in similar percentages of patients with low PK levels. For example, it may be desired to evaluate that a proposed pediatric dose gives approximately 10% of children with PK levels below the 10th percentile of PK levels for the established adult dose. However, the 10th percentile for the adult dose is often imprecisely estimated in studies of relatively small size. Little attention has been given to the statistical framework for such bridging studies. In this article, a formal framework for the design and analysis of quantile-based bridging studies is proposed. The methodology is then developed for normally distributed outcome measures from both frequentist and Bayesian directions. Sample size and other design considerations are discussed. [source] Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and convulsionsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2008Simon N. Muchohi WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Midazolam (MDZ), a water-soluble benzodiazepine, can be administered via several routes, including intravenously (IV), intramuscularly (IM) and buccal routes to terminate convulsions. It may be a suitable alternative to diazepam to stop convulsions in children with severe malaria, especially at peripheral healthcare facilities. The pharmacokinetics of MDZ have not been described in African children, in whom factors such as the aetiology and nutritional status may influence the pharmacokinetics. WHAT THIS STUDY ADDS , Administration of MDZ (IV, IM, or buccal) at the currently recommended dose (0.3 mg kg,1) resulted in rapid achievement of median maximum plasma concentrations of MDZ within the range 64,616 ng ml,1, with few clinically significant cardio-respiratory effects. A single dose of MDZ rapidly terminated (within 10 min) seizures in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration, respectively. Although IM and buccal MDZ may be the preferred treatment for children in the pre-hospital settings the efficacy appears to be poorer. AIM To investigate the pharmacokinetics and clinical efficacy of intravenous (IV), intramuscular (IM) and buccal midazolam (MDZ) in children with severe falciparum malaria and convulsions. METHODS Thirty-three children with severe malaria and convulsions lasting ,5 min were given a single dose of MDZ (0.3 mg kg,1) IV (n = 13), IM (n = 12) or via the buccal route (n = 8). Blood samples were collected over 6 h post-dose for determination of plasma MDZ and 1,-hydroxymidazolam concentrations. Plasma concentration,time data were fitted using pharmacokinetic models. RESULTS Median (range) MDZ Cmax of 481 (258,616), 253 (96,696) and 186 (64,394) ng ml,1 were attained within a median (range) tmax of 10 (5,15), 15 (5,60) and 10 (5,40) min, following IV, IM and buccal administration, respectively. Mean (95% confidence interval) of the pharmacokinetic parameters were: AUC(0,,) 596 (327, 865), 608 (353, 864) and 518 (294, 741) ng ml,1 h; Vd 0.85 l kg,1; clearance 14.4 ml min,1 kg,1, elimination half-life 1.22 (0.65, 1.8) h, respectively. A single dose of MDZ terminated convulsions in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration. Four children (one in the IV, one in the IM and two in the buccal groups) had respiratory depression. CONCLUSIONS Administration of MDZ at the currently recommended dose resulted in rapid achievement of therapeutic MDZ concentrations. Although IM and buccal administration of MDZ may be more practical in peripheral healthcare facilities, the efficacy appears to be poorer at the dose used, and a different dosage regimen might improve the efficacy. [source] Quantification of heparin-induced TFPI release: a maximum release at low heparin doseBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2002Michiel J. B. Kemme Aims Heparin releases tissue factor pathway inhibitor (TFPI) from the endothelium and this release may decrease after repeated high dose heparin administration. The primary aim was to investigate and quantify this phenomenon during a short low dose heparin infusion. Also, the effects of heparin on tissue plasminogen activator (t-PA) were studied. Methods Nine healthy, nonsmoking, male volunteers (range 19,23 years) received a continuous heparin infusion (2000 IU) over 40 min. The endothelial TFPI release rate was estimated from the total TFPI concentration profile using a pharmacokinetic model. Results , Mean ,±,s.d. ,total ,and ,free ,TFPI ,increased ,from ,62.9 ± 9.4/8.3 ± 2.1 ng ml,1 at baseline to 237.2 ± 40.9/111.0 ± 19.9 ng ml,1 after 40 min infusion. The relationship between heparin concentration (anti-IIa activity) and TFPI concentration followed a maximum effect model and a clockwise loop (proteresis) was observed. The TFPI release rate rapidly increased to maximum of 200 ± 45 µg min,1 after 17.5 min heparin infusion but did not increase further although heparin concentrations further doubled. In contrast to TFPI, t-PA antigen decreased from 5.6 ± 1.0 at baseline to 4.5 ± 1.0 ng ml,1 at the end of infusion (t = 40 min) (difference of 1.1 ng ml,1 (95% confidence interval; 0.9, 1.3). Conclusions Our application of concentration-effect models and pharmacokinetic principles to these haemostatic variables showed that endothelial TFPI release has a maximum that is already reached at low heparin dose, corresponding with an anti-IIa activity of 0.08 IU ml,1. The relationship between anti-IIa activity and TFPI release rate showed signs of acute tolerance (clockwise loop) indicating exhaustion of endothelial TFPI pools. These findings may be of importance for the heparin dose used in conditions such as unstable angina, in which the favourable effects of heparin have been ascribed to its ability to release TFPI. [source] Antigen dose-dependent suppression of murine IgE responses is mediated by CD4,CD8, double-negative T cellsCLINICAL & EXPERIMENTAL ALLERGY, Issue 6 2010C. Barwig Summary Background The IgE response against protein antigens is profoundly influenced by the dose used for sensitization. Objective The aim of the study was to identify immune cells that are involved in antigen dose-dependent regulation of IgE formation. Methods Wild-type mice as well as T helper (Th)1-deficient IL-12p40,/, and IFN-,,/, mice were immunized by repeated intraperitoneal injection of either low doses (K01 mice) or high doses (K100 mice) of keyhole limpet haemocyanin adsorbed to aluminium hydroxide. Splenocytes of immunized mice were restimulated in vitro and antigen-dependent T cell proliferation and cytokine production were measured. The frequency of regulatory T cell subsets among splenocytes from K01 and K100 mice was compared using fluorocytometry and RT-PCR analysis. Splenocytes or T cell subpopulations were transferred into naďve mice and the effect of lymphocyte transfer on IgE production after priming of recipients with low antigen doses was determined. Results Specific IgE production was considerably impaired in K100 mice. Antigenic restimulation revealed hypoproliferation of K100 splenocytes and reduced production of Th2 cytokines IL-4, IL-5 and IL-13, but no induction of IFN-, production. Moreover, lymphocytes from K01 and K100 mice did not show significant differences in the expression of molecules associated with the phenotype or activity of conventional regulatory T cells. Transfer of splenocytes or purified T cells from K100 mice substantially suppressed the induction of IgE production in the recipients in an antigen- and isotype-specific manner. Neither CD4+ nor CD8+ T cells from K100 mice were able to inhibit IgE formation; instead, we identified CD4,CD8, double-negative T cells (dnT cells) as the principal T cell population, which potently suppressed IgE production. Conclusion Our data demonstrate that CD4,CD8, dnT cells play a major role in the regulation of IgE responses induced by high antigen doses. [source] Botulinum Toxin Type B (MYOBLOC) Versus Botulinum Toxin Type A (BOTOX) Frontalis Study: Rate of Onset and Radius of DiffusionDERMATOLOGIC SURGERY, Issue 5 2003Timothy Corcoran Flynn MD Background. Botulinum toxin types A and B can improve the appearance of facial wrinkles. Differences in the time until onset and the degree of diffusion have been observed anecdotally, but no direct comparative studies have been done. Objective. To compare the rate of onset and the radius of diffusion of botulinum toxin types A and B in the rhytides of the forehead. Methods. Adults with symmetrical moderate to severe forehead wrinkles at full contracture received botulinum toxin type A (BOTOX; 5 U) on one side of the forehead and type B (MYOBLOC; 500 U) on the other side. Photographs taken at rest and full frontalis contracture were analyzed by computer, and a time-lapse motion picture was created. Radius of diffusion and time until full effect were measured. Results. Botulinum toxin type B had a slightly faster onset of action than type A. All patients responded to type B quickly, whereas some had a delayed response to type A. A greater radius of diffusion was consistently observed with botulinum toxin type B, as measured by the greater area of wrinkle reduction at the doses used. Conclusions. In this comparative study of patients with symmetrical forehead wrinkles, botulinum toxin type B produced a greater area of diffusion and a more rapid onset of action than type A. [source] What is the nature of the emergence phenomenon when using intravenous or intramuscular ketamine for paediatric procedural sedation?EMERGENCY MEDICINE AUSTRALASIA, Issue 4 2009Greg Treston Abstract Objective: Ketamine has become the drug most favoured by emergency physicians for sedation of children in the ED. Some emergency physicians do not use ketamine for paediatric procedural sedation (PPS) because of concern about emergence delirium on recovery. The present study set out to determine the true incidence and nature of this phenomenon. Methods: Prospective data relating to any emergence agitation, crying, hallucinations, dreams, altered perceptions, delirium and necessary interventions were recorded in consecutive cases of ketamine PPS from March 2002 to June 2007, and analysed. Standard inclusion and exclusion criteria for the use of ketamine were followed. Results: A total of 745 prospective data collection records were available for analysis over the 5 year period. Of all, 93 (12.5%) children cried on awakening when recovering from PPS, 291 (39%) experienced pleasant altered perceptions and 16 (2.1%) experienced what was called ,emergence delirium'. None required any active treatment and all except one settled within 20 min. There was no evidence of an increased rate of nightmares on telephone follow up in the weeks post procedure. Conclusion: The belief that ketamine, in the doses used for ED PPS, causes frequent emergence delirium is flawed. A pleasant emergence phenomenon is common, but is not distressing for the child, and has no long-term (up to 30 days) negative sequelae. Rarely, there is anxiety or distress on awakening from ketamine sedation, which settles spontaneously. This should not deter emergency physicians from using ketamine for PPS. [source] BRIEF REPORT: Single exposure to cocaine or ecstasy induces DNA damage in brain and other organs of miceADDICTION BIOLOGY, Issue 1 2010Tathiana A. Alvarenga ABSTRACT We evaluated the overall genetic damage induced by different doses of cocaine and MDMA (3,4-Methylenedioxymethamphetamine) in several organs. One hour after intraperitoneal drug administration, mice were euthanized; peripheral blood, liver and brain were collected, and the cellular suspensions were used for the single cell gel (comet) assay. We determined that all doses of cocaine and MDMA tested were able to induce DNA damage in blood cells. Extensive genotoxic damage was induced by cocaine or MDMA at the highest doses used in liver cells. Brain cells were affected by all doses administrated. These findings demonstrate that cocaine and MDMA are potent genotoxins. [source] Combined therapy in the treatment of hypertensionFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2010Carlos Escobar Abstract The majority of patients with hypertension need at least two antihypertensive agents to achieve blood pressure (BP) objectives. As current European guidelines for the treatment of arterial hypertension recommend, combined therapy is required when monotherapy fails and as a first-line treatment in certain situations, such as subjects at high or very high cardiovascular risk, markedly elevated BP values, or when lower targets are required (<130/80 mmHg). The advantages of combined therapy are well known and include an earlier and higher antihypertensive efficacy because of complementary mechanisms of action, and a lower incidence of side effects due to the possible compensatory responses and, in many cases, the lower doses used. In the present study, available evidence about the efficacy and tolerability of combined therapy for the treatment of hypertension is updated. [source] Efficiency of combined methotrexate/chloroquine therapy in adjuvant-induced arthritisFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2005M.A.R.C.P. Silva Abstract The present study evaluates the effects of methotrexate (MTX) and chloroquine (CQ), and of combined MTX + CQ treatment, on the inflammatory response and on plasma and liver phosphatase and transaminase activities, employing an adjuvant-induced arthritis model in rats. Arthritis was induced by the intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil into the plantar surface of the hind paws. Development of the inflammatory response was assessed over a 21-day period. Animal groups received either: (i) MTX, administered i.p., weekly, in 0.15, 1.5, 3, 6 or 12 mg/kg doses; (ii) CQ, given intragastrically, in daily 25 or 50 mg/kg doses; or (iii) MTX + CQ, administered in two combinations (MTX1.5 mg/kg + CQ50 mg/kg, or MTX6 mg/kg + CQ50 mg/kg). At the end of the experimental period, the animals were anesthetized and killed, blood and liver samples were collected and prepared for measurement of acid and alkaline phosphatase (AP, ALP), and aspartate (AST) and alanine aminotransferase (ALT) activities. MTX at 6 and 12 mg/kg reduced the inflammatory response while CQ had no effect. MTX6 mg/kg + CQ50 mg/kg reduced the inflammatory response similar to MTX12 mg/kg, without affecting the bone marrow. Plasma AP and liver ALP activities were very elevated in the arthritic rats. While MTX treatment partially reduced both plasma AP and liver ALP activities at all doses used in the arthritic rats, CQ treatment reduced plasma AP, but increased liver AP activity. MTX + CQ treatment decreased plasma AP and liver ALP activities in the arthritic rats to control values. Plasma and liver AST activities were unaltered in the arthritic rats, and were unaffected by treatment. However, plasma and liver ALT activities were significantly reduced in the arthritic rats. While MTX or CQ treatment did not alter plasma transaminase activity in the arthritic rats, after MTX + CQ treatment, plasma ALT activity returned to normal values. In conclusion, the present data suggest that MTX + CQ treatment provides more effective anti-inflammatory protection against adjuvant-induced arthritis than does MTX alone, reverting the alterations in enzyme activities induced by this inflammatory disease in rats. [source] Metal Ion Implantation for the Fabrication of Stretchable Electrodes on ElastomersADVANCED FUNCTIONAL MATERIALS, Issue 3 2009Samuel Rosset Abstract Here, the use of low-energy metal ion implantation by filtered cathodic vacuum arc to create highly deformable electrodes on polydimethylsiloxane (PDMS) membranes is reported. Implantation leads to the creation of nanometer-size clusters in the first 50,nm below the surface. When the elastomer is stretched, these small clusters can move relative to one another, maintaining electrical conduction at strains of up to 175%. Sheet resistance versus ion dose, resistance versus strain, time stability of the resistance, and the impact of implantation on the elastomer's Young's modulus are investigated for gold, palladium, and titanium implantations. Of the three tested metals, gold has the best performance, combining low and stable surface resistance, very high strain capabilities before loss of electrical conduction, and low impact on the Young's modulus of the PDMS membrane. These electrodes are cyclically strained to 30% for more than 105 cycles and remain conductive. In contrast, sputtered or evaporate metals films cease to conduct at strains of order 3%. Additionally, metal ion implantation allows for creating semi-transparent electrodes. The optical transmission through 25-µm-thick PDMS membranes decreases from 90% to 60% for Pd implantations at doses used to make stretchable electrodes. The implantation technique presented here allows the rapid production of reliable stretchable electrodes for a number of applications, including dielectric elastomer actuators and foldable or rollable electronics. [source] Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: Long-term follow-up of a Brown University Oncology Group Phase II Study (HN-53)HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 3 2008Prakash B. Chougule MD Abstract Background. A phase II study was conducted using concurrent paclitaxel, carboplatin, and external beam radiotherapy (RT) in patients with advanced head and neck cancer. Methods. Forty-three patients (stage III, n = 12; stage IV, n = 31) were treated with 8 cycles of weekly paclitaxel (60 mg/m2), carboplatin (area under the curve [AUC] = 1), and RT (1.8 Gy daily; total dose, 66,72 Gy). Patients with initially palpable lymph nodes underwent neck dissection. Results. The overall clinical response rate was 91% (65% complete, 26% partial). Severe mucositis occurred in 37 (90%) patients, necessitating hospitalization in 13 (31%) patients. With a median follow-up of 49 months, the locoregional and distant failure rates were 26% and 21%, respectively. Conclusions. Concurrent paclitaxel, carboplatin, and RT for advanced head and neck cancer results in high complete response rates. Long-term follow-up has revealed the curative potential of this regimen, though the doses used resulted in unacceptable toxicity. © 2007 Wiley Periodicals, Inc. Head Neck 2008 [source] No significant effect of uridine or pravastatin treatment for HIV lipoatrophy in men who have ceased thymidine analogue nucleoside reverse transcriptase inhibitor therapy: a randomized trial,HIV MEDICINE, Issue 8 2010A Calmy Background Lipoatrophy can complicate thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI)-based antiretroviral therapy (ART). Lipoatrophy may be less likely with ART including ritonavir-boosted lopinavir (LPV/r). Small, placebo-controlled studies found that uridine (in tNRTI recipients) and pravastatin improved HIV lipoatrophy over 12 weeks. Today, most patients with lipoatrophy receive non-tNRTI-based ART; the effect of uridine in such patients is unknown. Methods We performed a prospective, randomized trial in lipoatrophic adults with plasma HIV RNA<50 HIV-1 RNA copies/mL on tNRTI-sparing ART including LPV/r. Patients received uridine [36 g three times a day (tid) on 10 consecutive days per month; n=10], pravastatin [40 mg every night (nocte); n=12], uridine plus pravastatin (n=11) or neither (n=12) for 24 weeks. The primary endpoint was mean change in limb fat mass as assessed by dual-energy X-ray absorptiometry (DEXA). With 20 patients per intervention, the study had 80% power to detect a mean difference between a treatment and the control of 0.5 kg, assuming a standard deviation of 0.9 and an alpha threshold equal to 5% (two-sided). Results Of 45 participants (all men, with median age 49.5 years and median limb fat 2.6 kg), two discontinued pravastatin and one participant stopped both pravastatin and uridine. The difference between the mean changes in limb fat mass for uridine vs. no uridine was 0.03 kg [95% confidence interval (CI) ,0.35, +0.28; P=0.79]. The respective difference for pravastatin was ,0.03 kg (95% CI ,0.29, +0.34; P=0.84). Pravastatin slightly decreased total cholesterol (0.44 mmol/L; P=0.099). Visceral adipose tissue measured by computed tomography did not change significantly. Conclusion In this population and at the doses used, neither uridine nor pravastatin for 24 weeks significantly increased limb fat mass. [source] Hepatotoxic effect of cyclosporin A in the mitochondrial respiratory chainJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2007Lilia Cristina De la Cruz Rodríguez Abstract Cyclosporin A (CyA), a potent immunosuppressant, was used to determine the hepatotoxic effect in long-term treatments. Male Wistar rats were used in these experiments. They were given CyA chronically at doses used in patients for 120 days, and at doses of 5, 10, 15 and 20 mg kg,1 day,1. These doses amount to CyA values in blood of 200 ± 24, 314 ± 40, 445 ± 33 and 598 ± 53 ng ml,1, respectively. A significant increase in glutamate dehydrogenase (GLDH) was found in the groups treated with 15 and 20 mg kg,1 day,1, which would point to mitochondria as the potential target of the toxic action of CyA. The mitochondrial respiratory chain of rat livers was studied in enzyme complexes I and II. Enzyme complex I was determined by spectrophotometry at 340 nm using NADH oxidase with the respirable substrate 10 mm NADH; enzyme complex II was determined by monitoring succinate dehydrogenase by oxymetry using the respirable substrate 10 mm succinate. The results show the inhibition of NADH oxidase in the groups treated with 10, 15 and 20 mg kg,1 day,1, an effect dependent both on time and on CyA concentration. Enzyme complex II showed a decrease in oxygen consumption. These findings were confirmed by histological studies (hematoxylin-eosin technique). Conclusions: Long-term treatment with CyA at doses of 15 and 20 mg kg,1 day,1, amounting to concentrations in blood of 445 ± 33 and 598 ± 53 ng ml,1, causes alterations in the mitochondria, revealed by the increase in serum GLDH and by the functional alteration of enzyme complexes I and II of the mitochondrial respiratory chain. Copyright © 2007 John Wiley & Sons, Ltd. [source] Pollinex® Quattro Ragweed: safety evaluation of a new allergy vaccine adjuvanted with monophosphoryl lipid A (MPL®) for the treatment of ragweed pollen allergyJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2007Paul Baldrick Abstract A novel allergy vaccine (Pollinex® Quattro Ragweed) has been developed for the prevention or relief of allergic symptoms caused by pollen from Ambrosia spp. (ragweed). An extract from the pollen (chemically modified by glutaraldehyde) is adsorbed onto l -tyrosine with addition of the immunostimulatory adjuvant, monophosphoryl lipid A (MPL®). A specific preclinical safety testing strategy was developed to support clinical use and comprised reference to preclinical data available for the marketed non-MPL® adjuvanted form of the ragweed vaccine (Pollinex® R) and a new repeat dose toxicity study in the rat. Studies with Pollinex® R comprised single dose subcutaneous toxicity studies in mice and rats, repeat dose (10 injections over 20 days) parenteral toxicity studies in rats and dogs, an in vitro gene mutation assay along with single and multiple injection local tolerance studies in rats and dogs. The repeat dose subcutaneous toxicity study with Pollinex® Quattro Ragweed involved seven injections over 3 weeks (which was more aggressive than the four weekly doses used in the clinic) with dose levels of up to 0.5 ml per animal used. Overall, the product showed no toxicological findings of significance at levels greatly in excess of those proposed for clinical use. As is a feature with vaccination, some dose site irritation was seen. Copyright © 2007 John Wiley & Sons, Ltd. [source] Selection of glycoprotein IIb/IIIa inhibitors for upstream use in patients with diabetes experiencing unstable angina or non-ST segment elevation myocardial infarction.JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2004What have we learned in the last 10 years? Summary Coronary disease accounts for the majority of deaths among patients with diabetes and the thrombotic milieu accelerated by diabetes results in unstable angina (UA), non-ST segment elevation myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI) or death. Upstream use of a glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor with percutaneous coronary intervention (PCI) as part of an early invasive approach is preferred. However substantial numbers of patients present to rural or non-teaching hospitals without immediate access to a catheterization laboratory. Enhanced GP IIb/IIIa receptor mobilization, TXA2 production and platelet activation together present an extensive thrombotic challenge that may not be overcome with current doses of GP IIb/IIIa inhibitors when used without PCI. Heterogeneity of platelet aggregometric analysis may have identified GP IIb/IIIa doses used in clinical trials that may not fully overcome the thrombotic challenge in patients with diabetes. GUSTO-IV ACS failed to demonstrate a difference in mortality when used without PCI. The PURSUIT trial provided evidence that eptifibatide decreases death or non-fatal myocardial infarction (MI) in the main group and in the diabetic subgroup. Reductions in this primary endpoint were driven by the reduction in non-fatal MI. The PRISM and PRISM-PLUS trials demonstrated a reduction in death, MI or refractory ischaemia at 48 h or 7 days in the main cohort but not specifically in patients with diabetes. Data supporting use of GP IIb/IIIa inhibitors are inconsistent, raising the question of whether these agents should be used at all without PCI. Variability in experimental methodology of platelet aggregometry and selection of anticoagulant used during dose finding studies may have generated doses that are insufficient to overcome the thrombotic burden. A new marker of active inflammation, sCD40L is found to be upregulated at subtherapeutic doses of GP IIb/IIIa inhibitors, suggesting that rebound inflammatory processes may partially account for absence of clear evidence of benefit with some GP IIb/IIIa inhibitors in patients with diabetes experiencing UA/NSTEMI. [source] | |||||||||||||||||||