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Short Half-life (short + half-life)
Selected AbstractsTreatment of erythema multiforme, Stevens,Johnson Syndrome, and toxic epidermal necrolysisDERMATOLOGIC THERAPY, Issue 4 2002Klemens Rappersberger The "erythema multiforme disease spectrum" comprises four distinct, severe, clinical subvariants: (1) bullous erythema multiforme (bullous-EM), (2) Stevens,Johnson syndrome (SJS), (3) SJS,toxic epidermal necrolysis (TEN)-overlap syndrome, and (4) TEN. These diseases are closely related to severe mucocutaneous intolerance reactions that are mostly elicited by drugs/drug metabolites and associated with a high mortality rate. Old age and area of detached skin negatively influence the course of disease, and early withdrawal of causative drugs with short half-life is a positive prognostic factor. Therapeutic management represents a multidisciplinary challenge for colleagues from various specialities including specialized nurses and usually can be performed at a dermatologic ward unless technical equipment of an intensive care unit is needed. Topical therapy with biologic and (semi-)synthetic dressings is aimed at early re-epithelialization and the prevention of scarring, synechia formation, and infection. Systemic treatment includes antibiotics, fluid and electrolyte replacement, protein preparations and blood products, etc. Various anti-inflammatory and immunosuppressive treatment regimens with corticosteroids, cyclosporine A, cyclophosphamide, plasmapheresis have been considered to halt ongoing immunologic pathomechanisms, and some of these have shown significant efficacy. However, because we lack formal clinical trials, none of these regimens can be definitively proposed as a therapy of choice in any of the severe clinical variants of the EM spectrum. [source] Electrochemical Evaluation of Nucleoside Analogue Lamivudine in Pharmaceutical Dosage Forms and Human SerumELECTROANALYSIS, Issue 20 2005Burcu Dogan Abstract Lamivudine (LAM) is a synthetic nucleoside analogue with activity against human immunodeficiency virus-type 1 (HIV-1) and Hepatitis B virus (HBV). The aim of this study was to determine LAM levels in serum and pharmaceutical formulations, by means of electrochemical methods using hanging mercury drop electrode (HMDE). On this electrode, LAM undergoes irreversible reduction at the peak potential near Ep,1.26,V (vs. Ag/AgCl/3,M KCl). Reduction LAM signals were measured by cyclic voltammetry (CV), differential pulse voltammetry (DPV) and square-wave voltammetry (OSW). DPV and OSW techniques for the determination of LAM in acetate buffer at pH,4.5, which allows quantitation over the 4×10,6 to 1×10,4,M range in supporting electrolyte for both methods, were proposed. The linear response was obtained in acetate buffer in the ranges of 2×10,6 to 2×10,4,M for spiked serum samples at pH,4.5 for both techniques. The repeatability and reproducibility of the methods for all media were determined. The standard addition method was used in serum. Precision and accuracy were also checked in all media. No electroactive interferences from the endogenous substances were found in serum. With respect to side effects of high doses and short half-life of LAM, a fast and simple detection method is described in this study. [source] Identification of phospholipids as new components that assist in the in vitro trimerization of a bacterial pore proteinFEBS JOURNAL, Issue 3 2001Hans De Cock The in vitro trimerization of folded monomers of the bacterial pore protein PhoE, into its native-like, heat- and SDS-stable form requires incubations with isolated cell envelopes and Triton X-100. The possibility that membranes could be isolated that are enriched in assembly factors required for assembly of the pore protein was now investigated. Fractionation of total cell envelopes of Escherichia coli via various techniques indeed revealed the existence of membrane fractions with different capacities to support assembly in vitro. Fractions containing mainly inner membrane vesicles supported the formation of trimers that were associated with these membrane vesicles. However, only a proportion of these trimers were heat- and SDS-stable and these were formed with slow kinetics. In contrast, fractions containing mainly outer membrane vesicles supported formation of high amounts of heat-stable trimers with fast kinetics. We identified phospholipids as active assembly components in these membranes that support trimerization of folded monomers in a process with similar characteristics as observed with inner membrane vesicles. Furthermore, phospholipids strongly stimulate the kinetics of trimerization and increase the final yield of heat-stable trimers in the context of outer membranes. We propose that lipopolysaccharides stabilize the assembly competent state of folded monomers as a lipochaperone. Phospholipids are involved in converting the folded monomer into new assembly competent intermediate with a short half-life that will form heat-stable trimers most efficiently in the context of outer membrane vesicles. These results provide biochemical evidence for the involvement of different lipidic components at distinct stages of the porin assembly process. [source] Comparison of single vs. multiple administrations of the AMPA receptors modulator S 18986 in the object recognition task in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2007V. Bertaina-Anglade Abstract The present study aimed at defining the best scheme of administration of the , -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-positive modulator (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986) [once daily (o.d.) administration of 1 mg/kg for 3 days vs. three times daily (t.i.d.) administration of 0.3 mg/kg for 3 days] to get an optimal procognitive activity in the object recognition task in rats. Memory performance [Recognition Index (RI)] of rats was significantly improved 1 h (RI = 41%, P < 0.01) and 3 h (RI = 46%, P < 0.001) following oral administration of S 18986 (1 mg/kg, o.d.) when compared with animals receiving the vehicle (RI = 6%). When the interval between administration and testing was increased to 6 h and 9 h, no statistically significant improvement in memory performance was observed (RI = 42% for 6 h and RI = 18% for 9 h vs. 20% for the vehicle group). When S 18986 was administered at 0.3 mg/kg t.i.d., no statistically significant improvement in memory performance was observed (RI = 36%). These findings show a long-lasting efficacy of the AMPA receptor allosteric modulator in the object recognition task despite a short half-life in plasma and in brain (approximately 1 h). Accordingly, multiple administrations of S 18986 are not required to obtain a maximal efficacy in this paradigm, because a o.d. schedule of administration leads to a powerful procognitive activity. [source] Haemophilia care then, now and in the futureHAEMOPHILIA, Issue 2009J. OLDENBURG Summary., Epidemiological data show the benefits of dramatically improved haemophilia care in all life-stages. There are improved administration techniques and dosing regimens, a shift from on-demand treatment to prophylaxis, successful treatment protocols for immune tolerance induction in patients with inhibitors and enhanced approaches to overall patient management. Improvements also include the introduction of virus inactivation methods for plasma derived clotting factor concentrates and the development of recombinant factor VIII therapy, which practically eliminated the risk of infectious disease transmission. Recombinant factor concentrates are recommended as treatment of choice by several guidelines today. All these developments have resulted in increased health-related quality of life and life expectancy in haemophilia patients, who are transitioning from childhood to adulthood with healthy joints and an overall healthy status today. Because of increased life expectancy, these patients are expected to experience age-related clinical problems that were not previously observed in this population. With respect to this, the spectrum of haemophilia care will be extended to diseases of older ages with the need of including further disciplines in comprehensive haemophilia care programmes. Despite these advances, the short half-life of factor VIII, requiring re-administration every 2 or 3 days and the development of inhibitors remains a challenge. Bayer's research and development currently focuses on the optimization of recombinant coagulation factors to address these challenges. Haemophilia care has experienced significant improvements within the past decades. Novel technologies and continued clinical research have facilitated the development of treatment regimen that resulted in dramatic increases in the life expectancy and quality of life of haemophilia patients. To set the scene for the following papers dealing with haemophilia care from paediatrics to geriatrics, developments behind these improvements and some aspects of future research will be presented in this paper. [source] Management of acquired von Willebrand's sryndrome in a patient requiring major surgeryHAEMOPHILIA, Issue 6 2005J. M. Maddox Summary., We present the case of a patient with acquired von Willebrand's syndrome and a monoclonal gammopathy of undetermined significance who required cystectomy for relapsed transitional cell carcinoma (TCC) of the bladder. We demonstrated that infused von Willebrand factor (VWF) containing factor VIII concentrates had an unacceptably short half-life, but that this was significantly prolonged following combined therapy with plasma exchange and intravenous immunoglobulin (IVIgG). This approach was successfully utilized peri-operatively, with the total surgical blood loss less than would be expected even for a haemostatically normal patient. Trough VWF antigen and Ristocetin co-factor activity levels fell on the second postoperative day and we therefore administered further IVIgG. Levels again fell on the fifth postoperative day with the development of a Staphylococcus aureus septicaemia. At this point bleeding occurred from a surgical drain site requiring ,factor VIII inhibitor bypass activity' to secure haemostasis while further plasma exchange and IVIgG were administered. Now 5 years later, there is no evidence of recurrence of the TCC or progression of the monoclonal gammopathy. [source] Meta-Analysis Examining the Efficacy and Safety of Almotriptan in the Acute Treatment of MigraineHEADACHE, Issue 8 2007Li-Chia Chen PhD Objective.,To evaluate the comparative efficacy and safety of oral almotriptan in treating acute migraine attacks. Background.,Almotriptan is an oral selective sertonin1B/1D receptor agonist (triptan) with a high bioavailability and short half-life, developed for the treatment of migraine. In recent years, a number of randomized controlled trials have been published examining the efficacy and safety of almotriptan in the acute treatment of migraine. Methods.,Systematic review and meta-analysis of randomized controlled trials (RCTs) using a random-effects model to estimate the pooled rate ratios (RRs) and 95% confidence intervals (95%CI) for the proportions of patients achieving headache relief and pain-free responses at 1 or 2 hours post-dose, sustained pain-free response at 2,24 hours post-dose, and safety outcomes (proportions of patients experiencing any adverse events, dizziness, somnolence, asthenia, and chest tightness) comparing almotriptan against placebo, other triptans, and different dosages of almotriptan. Absolute rate differences (ARDs) for 2-hour headache relief, pain free, and sustained pain free responses between almotriptan and placebo were also calculated. Results.,Eight RCTs involving 4995 patients were included in the analysis. Almotriptan 12.5 mg was significantly more effective than placebo for all efficacy outcomes (RRs ranged from 1.47 to 2.15; ARDs ranged from 0.01 to 0.28) and there were no significant differences in any of the safety outcomes. There were also no significant differences in efficacy outcomes comparing almotriptan 12.5 mg against sumatriptan 100 mg and zolmitriptan 2.5 mg, but almotriptan 12.5 mg was associated with significantly fewer adverse events than sumatriptan 100 mg (RR: 0.39, 95%CI: 0.23, 0.67). However, there was no significant difference between almotriptan and sumatriptan in terms of clinically important adverse effects, such as dizziness, somnolence, asthenia, and chest tightness. Almotriptan 12.5 mg was significantly less effective than almotriptan 25 mg for 1-hour pain-free response (RR: 0.45, 95%CI: 0.21, 0.95), but associated with significantly fewer patients experiencing adverse events (RR: 0.61, 95%CI: 0.41, 0.91) than almotriptan 25 mg. Conclusions.,Almotriptan 12.5 mg is an effective treatment for acute attacks of migraine, in particular, it has been found to be as effective as sumatriptan 100 mg and zolmitriptan 2.5 mg. The risk of adverse events associated with almotriptan 12.5 mg was similar to placebo and significantly lower than sumatriptan 100 mg. Further research is required to assess the comparative efficacy of almotriptan against other triptans. [source] Neutrophil mobilization and clearance in the bone marrowIMMUNOLOGY, Issue 3 2008Rebecca C. Furze Summary The bone marrow is the site of neutrophil production, a process that is regulated by the cytokine granulocyte colony-stimulating factor (G-CSF). Mature neutrophils are continually released into the circulation, with an estimated 1011 neutrophils exiting the bone marrow daily under basal conditions. These leucocytes have a short half-life in the blood of ,6·5 hr, and are subsequently destroyed in the spleen, liver and indeed the bone marrow itself. Additionally, mature neutrophils are retained in the bone marrow by the stromal cell-derived factor (SDF-1,)/chemokine (C-X-C motif) receptor 4 (CXCR4) chemokine axis and form the bone marrow reserve. Following infection or inflammatory insult, neutrophil release from the bone marrow reserve is substantially elevated and this process is mediated by the co-ordinated actions of cytokines and chemokines. In this review we discuss the factors and molecular mechanisms regulating the neutrophil mobilization and consider the mechanisms and functional significance of neutrophil clearance via the bone marrow. [source] Infusions of albumin increase free fraction of naproxen in healthy volunteers: a randomized crossover studyACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2010P. A. REINE Background: In vitro and in vivo studies have indicated that stabilizers present in pharmaceutical-grade albumin influence the albumin-binding capacity for highly protein-bound drugs. However, the half-life of the stabilizers and the quantitative effect have been difficult to determine. Method: A randomized crossover study including six healthy volunteers was performed. The study subjects received 750 mg of oral naproxen 2 h before the study. They were randomized to receive either 100 ml of 20% albumin or 100 ml of Ringer's acetate solution intravenously. Frequent blood samples were obtained. The experiment was repeated 4 weeks later with the alternate solution. The serum samples were analysed to determine the concentrations of albumin, N -acetyl- dl -tryptophan, caprylate, and naproxen. Results: The free fraction of naproxen increased significantly after the infusion of albumin (P<0.05). The increase was concurrent with the appearance of N -acetyl- dl -tryptophan and caprylate in serum. The free fraction of naproxen declined rapidly after the albumin infusion was completed. N -acetyl- dl -tryptophan had a half-life of approximately 30 min. The half-life of caprylate was <15 min. Conclusion: A transfusion of albumin results in an increase in the free fraction of naproxen. The transient increase in free-fraction naproxen decreased together with the detectable levels of the stabilizers N -acetyl- dl -tryptophan and caprylate. N -acetyl- dl -tryptophan and caprylate have a short half-life in serum. [source] Evidence that channel catfish, Ictalurus punctatus (Rafinesque), mortality is not linked to ingestion of the hepatotoxin microcystin-LRJOURNAL OF FISH DISEASES, Issue 5 2002G S Snyder Catfish farms located in the south-eastern USA using brackish (3,5 g NaCl L,1) well water experience sporadic fish kills sometimes with high mortality. An investigation of three catastrophic losses occurring in this region identified no involvement of infectious diseases or traditional water quality problems, including oxygen, ammonia or nitrite. The high mortality and time course of the problem was indicative of exposure to a toxin. Attempts by other workers to explain the cause of this unique syndrome (high chloride associated toxicosis of catfish, HCTC), suggested that the losses might be because of microcystin-producing blooms of Microcystis aeruginosa, but our investigations failed to support this conclusion. We found that (1) the liver histology of catfish experimentally exposed to pure microcystin-LR is very different from that of catfish sampled during outbreaks of HCTC; (2) measurements of microcystin-LR concentrations in the three cases were far lower than the concentration required to kill catfish by experimental immersion; (3) the HCTC toxin appears to have a short half-life, whereas microcystin-LR does not; (4) experimental gavage of catfish with massive amounts of microcystin-LR does not cause the acute mortality typical of HCTC; (5) outbreaks of HCTC appear to be associated with heavy blooms of Anacystis marina, a halophytic cyanobacteria, not with blooms of M. aeruginosa. [source] Utility of 1,3,4,6-tetra- O -acetyl-2-deoxy-2-[18F]fluoro-glucopyranoside for no-carrier-added 18F-glycosylation of amino acidsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 10 2005Simone Maschauer Abstract A radiochemical method for the 18F-glycosylation of amino acid side chains was developed starting from peracetylated 2-deoxy-2-[18F]fluoroglucopyranoside (TA-[18F]FDG). O -(2-deoxy-2-[18F]fluoro- D -glucopyranosyl)- L -serine and the corresponding threonyl compound were obtained in a radiochemical yield of 25% and 12% (related to [18F]fluoride), respectively, after Zemplén deprotection within a total reaction time of 90 min. The anomeric configuration of the corresponding 19F-substituted compounds revealed preferential , -stereoselectivity. The 18F-glycosylation method using TA-[18F]FDG is compatible with the short half-life of fluorine-18 and combines glycosylation and 18F-labelling of a target compound within a single reaction step. TA-[18F]FDG is a promising 18F-labelled prosthetic group and could be adapted to 18F-labelling of bioactive peptides to study their pharmacokinetics using positron emission tomography (PET). Copyright © 2005 John Wiley & Sons, Ltd. [source] Targeted delivery of proteins by nanosized carriersJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 1 2008Roberto Solaro Abstract Proteic drug administration poses some additional issues as compared with conventional drugs because of protein high molecular weight and short half-life in plasma. It is well known that protein delivery canbe significantly improved by using targeted nanocarriers. Among the diverse investigated systems, this overview focuses onliposomes and nanoparticles. Indeed, because of their subcellular size, nanocarriers can cross the fenestration of the vascular epithelium and penetrate tissues. Moreover, nanosystems can be confined at the location of choice by conjugation to molecules that strongly bind the target cells. In spite of the significant progress made in the design and engineering of liposomes and nanoparticles tailored to the targeted delivery of proteins, these nanocarriers seldom succeed in delivering proteins directly inside the cell cytosol. Accordingly, some attention is also paid to virosomes and fusion proteins. These systems have a few advantages over conventional nanocarriers, particularly the ability to cross the cell membrane. They also share the main drawback of being highly immunogenic. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1,11, 2008 [source] Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidemJOURNAL OF SLEEP RESEARCH, Issue 4 2009TIM R. M. LEUFKENS Summary Gaboxadol is a selective extrasynaptic GABAA receptor agonist previously in development for the treatment of insomnia. Due to its short half-life (1.5,2 h) it is expected to be free from residual effects the next morning. The present study assessed the residual effects of evening and middle-of-the-night administration of 15 mg of gaboxadol on cognitive, psychomotor and driving performance. Twenty-eight healthy volunteers entered the study with 25 (12 women; mean age 31.4 years) completing a double-blind, placebo-controlled, active-referenced five-way cross-over study. Each treatment night subjects ingested one capsule at 23:00 hours and one at 04:00 hours. Treatments were placebo at both times, 15 mg gaboxadol or 7.5 mg zopiclone followed by placebo, and placebo followed by 15 mg gaboxadol or 10 mg zolpidem. Effects on cognition and psychomotor performance were assessed between 07:30 and 08:30 hours and on driving between 09:00 and 10:00 hours. Driving, as measured by standard deviation of lateral position in an on-the-road driving test, was almost significantly (P < 0.07) impaired after evening administration of gaboxadol for the all-subjects-completed set (n = 25) but significantly (P < 0.05) in the full analysis set (n = 28). Effects of all other active treatments on driving were significant. Evening administration of gaboxadol had minor effects on divided attention only, whereas middle-of-the-night administration impaired performance significantly in all tests except memory. Zolpidem and zopiclone impaired performance significantly in every test except tracking after zopiclone; 15 mg of gaboxadol can produce minor residual effects on driving after evening administration. Administration later at night is associated with moderately impairing residual effects on driving and psychomotor performance but not on memory. [source] Clinical validation of a proANP 31-67 fragment ELISA in the diagnosis of heart failure in the dogJOURNAL OF SMALL ANIMAL PRACTICE, Issue 3 2003A. Boswood Atrial natriuretic peptide (ANP) is a polypeptide hormone found in increased concentrations in the plasma of dogs with heart failure. However, problems arise in using ANP as a diagnostic marker for heart failure because of its short half-life in plasma, proteolysis post-collection and the necessity for a radioimmunoassay. The diagnostic utility of a proANP 31-67 ELISA for the detection of heart failure in dogs was evaluated using plasma collected from 31 dogs with clinical and radiographic signs of heart failure and control samples from 40 dogs considered to be free of cardiac disease. Log proANP 31-67 levels were significantly higher in the heart failure group (P<0·001). In this population of dogs, using a cut-off value of 1750 fmol/ml, the sensitivity and specificity of the assay were 83·9 per cent and 97·5 per cent, respectively. Using a cut-off of 1350 fmol/ml, the sensitivity and specificity were 93·5 per cent and 72·5 per cent, respectively. It is concluded that a proANP 31·67 fragment ELISA should prove to be a useful diagnostic aid in naturally occurring canine heart failure. [source] Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2007E. A. SILVA Summary. Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) delivery may provide a new approach for the treatment of ischemic diseases, but current strategies to deliver VEGF rely on either bolus delivery or systemic administration, resulting in limited clinical utility, because of the short half-life of VEGF in vivo and its resultant low and transient levels at sites of ischemia. We hypothesize that an injectable hydrogel system can be utilized to provide temporal control and appropriate spatial biodistribution of VEGF in ischemic hindlimbs. A sustained local delivery of relatively low amounts of bioactive VEGF (3 ,g) with this system led to physiologic levels of bioactive VEGF in ischemic murine (ApoE,/,) hindlimbs for 15 days after injection of the gel, as contrasted with complete VEGF deprivation after 72 h with bolus injection. The gel delivery system resulted in significantly greater angiogenesis in these limbs as compared to bolus (266 vs. 161 blood vessels mm,2). Laser Doppler perfusion imaging showed return of tissue perfusion to normal levels by day 28 with the gel system, whereas normal levels of perfusion were never achieved with saline delivery of VEGF or in control mice. The system described in this article could represent an attractive new generation of therapeutic delivery vehicle for treatment of cardiovascular diseases, as it combines long-term in vivo therapeutic benefit (localized bioactive VEGF for 1,2 weeks) with minimally invasive delivery. [source] Pharmacokinetics and pharmacodynamics of clemastine in healthy horsesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2003K. Törneke Clemastine is an H1 antagonist used in certain allergic disorders in humans and tentatively also in horses, although the pharmacology of the drug in this species has not yet been investigated. In the present study we determined basic pharmacokinetic parameters and compared the effect of the drug measured as inhibition of histamine-induced cutaneous wheal formation in six horses. The most prominent feature of drug disposition after intravenous dose of 50 ,g/kg bw was a very rapid initial decline in plasma concentration, followed by a terminal phase with a half-life of 5.4 h. The volume of distribution was large, Vss = 3.8 L/kg, and the total body clearance 0.79 L/h kg. Notably, oral bioavailability was only 3.4%. There was a strong relationship between plasma concentrations and effect. The effect maximum (measured as reduction in histamine-induced cutaneous wheal formation) was 65% (compared with controls where saline was injected) and the effect duration after i.v. dose was approximately 5 h. The effect after oral dose of 200 ,g/kg was minor. The results indicate that clemastine is not appropriate for oral administration to horses because of low bioavailability. When using repeated i.v. administration, the drug has to be administered at least three to four times daily to maintain therapeutic plasma concentrations because of the short half-life. However, if sufficient plasma concentrations are maintained the drug is efficacious in reducing histamine-induced wheal formations. [source] A method of measuring oil consumption by labelling with radioactive bromineLUBRICATION SCIENCE, Issue 3 2000H. Zellbeck Abstract A method of determining the oil consumption rate of combustion engines is presented. It is based on labelling the individual oil fractions of engine oil with radioactive bromine isotope82 Br and on the quantitative absorption of radioactive bromine compounds in the exhaust gas in an aqueous solution of nitric acid and silver nitrate. The advantages of this method are that the oil that is consumed in the exhaust gas can be directly measured, without the fluctuating amounts of oil in the sump influencing the result, and the behaviour of the individual components of the oil in the consumption process can be determined. The test is quick, only twenty minutes being required to detect oil consumption at one operating point; and with a single labelling, the oil consumption at a great number of working engine points can be measured 82 Br has a short half-life of only 36 h, so that compliance with radiation protection measures is inexpensive and investigations can be carried out using a conventional testing device. As part of the research project, a study was made of the influence of different base oil types, with and without polymer additives, on consumption. Results showed that Noack evaporation loss correlated with oil consumption only with boiling fractions of exactly the same base oil, and not with different, in particular synthetic, base oils; that polymer additives (VI improvers) significantly reduced the rate of oil consumption; and that the polymer additive and the type of base oil both had more influence on oil consumption than viscosity. [source] Microarray expression profiling: capturing a genome-wide portrait of the transcriptomeMOLECULAR MICROBIOLOGY, Issue 4 2003Tyrrell Conway Summary The bacterial transcriptome is a dynamic entity that reflects the organism's immediate, ongoing and genome-wide response to its environment. Microarray expression profiling provides a comprehensive portrait of the transcriptional world enabling us to view the organism as a ,system' that is more than the sum of its parts. The vigilance of microorganisms to environmental change, the alacrity of the transcriptional response, the short half-life of bacterial mRNA and the genome-scale nature of the investigation collectively explain the power of this method. These same features pose the most significant experimental design and execution issues which, unless surmounted, predictably generate a distorted image of the transcriptome. Conversely, the expression profile of a properly conceived and conducted microarray experiment can be used for hypothesis testing: disclosure of the metabolic and biosynthetic pathways that underlie adaptation of the organism to chang-ing conditions of growth; the identification of co-ordinately regulated genes; the regulatory circuits and signal transduction systems that mediate the adaptive response; and temporal features of developmental programmes. The study of bacterial pathogenesis by microarray expression profiling poses special challenges and opportunities. Although the technical hurdles are many, obtaining expression profiles of an organism growing in tissue will probably reveal strategies for growth and survival in the host's microenvironment. Identifying these colonization strategies and their cognate expression patterns involves a ,deconstruction' process that combines bioinformatics analysis and in vitro DNA array experimentation. [source] Medicine-taking behavior: Implications of suboptimal compliance in Parkinson's diseaseMOVEMENT DISORDERS, Issue 11 2005Katherine A. Grosset MBChB Abstract Management of Parkinson's disease (PD) depends primarily on oral medication. There are several drug classes and multiple doses and formulations, which make optimizing therapy complex. Variable drug absorption and the short half-life of most antiparkinson treatments, especially levodopa, are a main focus in understanding complications and have encouraged alternative delivery systems to limit fluctuation and dyskinesia at later stages. Comparatively little attention is paid to the way patients take their oral medication. Variable medicine-taking behavior can affect the clinician's understanding of the diagnosis and rate of progression, and further prescription of PD medication. Medicine overuse in later stage PD is well documented and causes psychiatric disturbance and increases motor complications, but evidence of undertreatment and erratic intake is emerging, which is likely to affect motor control and quality of life adversely. Methods of quantifying compliance are compared for accuracy and limitations. Understanding medicine-taking behavior is a first step in optimizing therapy and requires consideration of a patient's personal beliefs about their medicines. Although the benefits of regularizing oral medicine-taking in a practical, achievable way in PD remain untested, such an approach might prolong and smooth the benefits of oral medication and is worthy of further research. © 2005 Movement Disorder Society [source] Levodopa in the treatment of Parkinson's disease: Current controversiesMOVEMENT DISORDERS, Issue 9 2004C. Warren Olanow Abstract Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy. © 2004 Movement Disorder Society [source] Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleedingARTHRITIS & RHEUMATISM, Issue 6 2010Elvira L. Massó González Objective Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX-1) and COX-2 in vitro. Methods We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation. Results The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82,5.31) for traditional NSAIDs and 1.88 (95% CI 0.96,3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17,3.33]), rofecoxib (2.12 [95% CI 1.59,2.84]), aceclofenac (1.44 [95% CI 0.65,3.2]), and celecoxib (1.42 [95% CI 0.85,2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87,36.04]) and piroxicam (9.94 [95% CI 5.99,16.50). Estimated RRs were 5.63 (95% CI 3.83,8.28) for naproxen, 5.57 (95% CI 3.94,7.87) for ketoprofen, 5.40 (95% CI 4.16,7.00) for indomethacin, 4.15 (95% CI 2.59,6.64) for meloxicam, and 3.98 (95% CI 3.36,4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r2 = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life. Conclusion The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation. [source] Development and characterization of a fusion protein between thermally responsive elastin-like polypeptide and interleukin-1 receptor antagonist: Sustained release of a local antiinflammatory therapeuticARTHRITIS & RHEUMATISM, Issue 11 2007Mohammed F. Shamji Objective Interleukin-1 receptor antagonist (IL-1Ra) has been evaluated for the intraarticular treatment of osteoarthritis. Such administration of proteins may have limited utility because of their rapid clearance and short half-life in the joint. The fusion of a drug to elastin-like polypeptides (ELPs) promotes the formation of aggregating particles that form a "drug depot" at physiologic temperatures, a phenomenon intended to prolong the presence of the drug. The purpose of this study was to develop an injectable drug depot composed of IL-1Ra and ELP domains and to evaluate the properties and bioactivity of the recombinant ELP-IL-1Ra fusion protein. Methods Fusion proteins between IL-1Ra and 2 distinct sequences and molecular weights of ELP were overexpressed in Escherichia coli. Environmental sensitivity was demonstrated by turbidity and dynamic light scattering as a function of temperature. IL-1Ra domain activity was evaluated by surface plasmon resonance, and in vitro antagonism of IL-1,mediated lymphocyte and thymocyte proliferation, as well as IL-1,induced tumor necrosis factor , (TNF,) expression and matrix metalloproteinase 3 (MMP-3) and ADAMTS-4 messenger RNA expression in human intervertebral disc fibrochondrocytes. IL-1Ra immunoreactivity was assessed before and after proteolytic degradation of the ELP partner. Results Both fusion proteins underwent supramolecular aggregation at subphysiologic temperatures and slowly resolubilized at 37°C. Interaction with IL-1 receptor was slower in association but equivalent in dissociation as compared with the commercial antagonist. Anti,IL-1 activity was demonstrated by inhibition of lymphocyte and thymocyte proliferation and by decreased TNF, expression and ADAMTS-4 and MMP-3 transcription by fibrochondrocytes. ELP domain proteolysis liberated a peptide of comparable size and immunoreactivity as the commercial IL-1Ra. This peptide was more bioactive against lymphocyte proliferation, nearly equivalent to the commercial antagonist. Conclusion The ELP-IL-1Ra fusion protein proved to retain the characteristic ELP inverse phase-transitioning behavior as well as the bioactivity of the IL-1Ra domain. This technology represents a novel drug carrier designed to prolong the presence of bioactive peptides following intraarticular delivery. [source] The Use of Bivalirudin for Cardiopulmonary Bypass Anticoagulation in Pediatric Heparin-Induced Thrombocytopenia PatientsARTIFICIAL ORGANS, Issue 8 2010Richard Gates Abstract Infants with heparin-induced thrombocytopenia (HIT) represent a challenging and high-risk group of patients when they require cardiopulmonary bypass (CPB). Bivalirudin offers many potential pharmacologic advantages over other nonheparin anticoagulants for such patients. We describe our protocol for the use of bivalirudin in a 5-month-old infant undergoing stage 2 Norwood for hypoplastic left heart syndrome. The patient was a 5- month-old, 6-kg infant who developed HIT after a bowel resection complicating initial Norwood stage 1. After sternotomy and dissection had been redone, the child received an initial dose of bivalirudin of 1.0 mg/kg and 0.5 mg/kg 5 min later. The CPB circuit was primed with 50 mg/kg bivalirudn/400 cc volume. With the initiation of CPB, a continuous infusion of 2.5 mg/kg bivalirudin was begun. Activated clotting time (ACT) was targeted for over 400 s, with an examination prior to bypass and each 15 min thereafter. Bivalirudin was discontinued with separation from bypass and during modified ultrafiltration (MUF). The ACT was 286 s after the initial 1 mg/kg bolus and 597 s after the second 0.5 mg/kg bolus and initiation of CPB. At a rate of 2.5 mg/kg/min, ACT ranged between 461 and 597 s. At the completion of MUF, the ACT was 316 s. The ACT was 214 s 20 min after MUF. No clots were noted in the CPB circuit, and good hemostasis was achieved within 10 min after MUF was completed. Incision to closure time was 160 min; time from completion of MUF to sternal closure was 30 min. Post-MUF, 60 cc of processed cell saver blood was reinfused, and no clotting factors were required. Chest tube output was 10, 10, 3, and 4 ccs, respectively, at hours 1,4 post operation. Bivalirudin provides effective anticoagulation in infants requiring CPB in the presence of HIT. Bivalirudin's efficacy is effectively monitored by ACT, and, after CPB, its short half-life and ability to be ultrafiltered facilitate the ability to achieve hemostasis in a timely fashion. [source] Determination of carboplatin in canine plasma by high-performance liquid chromatographyBIOMEDICAL CHROMATOGRAPHY, Issue 8 2010Nicolas Villarino Abstract Carboplatin is an antineoplastic drug administered to treat different tumoral conditions in canine oncology. The objective of this study was to validate a high-performance chromatographic (HPLC) method which could be applied in canine pharmacokinetic studies. Following ultrafiltration using a Centrifree device, standards, quality controls and plasma samples were separated by isocratic reversed-phase HPLC on an Inertsil ODS-2 (250 × 4.6,mm i.d.) analytical column and quantified using UV detection at 220,nm. The mobile phase was potassium phosphate (pH 4.5), with a flow-rate of 1.0,mL/min. The procedure produced a linear curve (r2 > 0.999) over the concentration range 1,200,,g/mL. The lower limit of quantification was 1,,g/mL. The intra-assay and inter-assay precision was ,90%. The overall recovery was ,90%. The method was illustrated with a preliminary pharmacokinetic analysis on nine dogs treated with carboplatin at our hospital. Carboplatin disposition followed a monocompartmental structure in dogs and was characterized by a short half-life (50,min). Copyright © 2009 John Wiley & Sons, Ltd. [source] The treatment of uveal melanoma with iodine plaque brachytherapyACTA OPHTHALMOLOGICA, Issue 2009T KIVELÄ Purpose To provide an overview of managing uveal melanoma (UM) with iodine brachytherapy (IBT). Methods Personal experience of the author in using IBT since 1990. Results IBT is an effective option for managing a UM of any size, although it is mostly used for medium-sized tumours, preference being given to ruthenium brachytherapy (RBT) when the tumour is <5-6 mm thick and to transscleral local resection when thickness is >6 mm, especially when vision is good. IBT is also a safe alternative to enucleation of large UM >10 mm in thickness if the patient is keen to preserve the eye and motivated to accept eventual complications. The plaque is positioned over the UM with a 1-2 mm safety margin when using a collimated/rimmed plaque. Because of stray radiation, a safety margin is not mandatory when the plaque is non-collimated/non-rimmed. Otherwise, surgical technique does not differ from RBT. An advantage of IBT is that the radioactive seeds are separate from the plaque, allowing economical use of plaques of many different sizes and shapes and individual positioning of the seeds in a conformal way. A disadvantage is a short half-life; the seeds need to be changed every 6 months. The dose the author uses is 80 Gy to tumour apex, which is reduced on an individual basis to 60-70 Gy when the UM is very thick. Local tumour control rate is 90% and, paradoxically, not worse for large UM as compared to smaller ones. There are no unequivocal safety distances for avoiding radiation cataract, maculopathy and optic neuropathy, which are more or less frequent depending on the size and location of the UM. Conclusion IBT achieves good local tumour control of UM of all sizes, but preservation of vision is decidedly less frequent than after RBT, which is always given preference. [source] Disposition of isosteviol in the rat isolated perfused liverCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2010Hongping Jin Summary 1. The aim of the present study was to investigate the mechanisms involved in the clearance of isosteviol using the rat isolated perfused liver. 2. Six livers from male Sprague-Dawley rats were perfused with 15.7 ,mol isosteviol in a recirculating system. Perfusate and bile samples were collected for 60 min and the liver was collected at the end of the perfusion. All samples collected were incubated with ,-glucuronidase. Isosteviol,glucuronide was determined as equivalent isosteviol. Isosteviol concentrations were determined using a previously developed liquid chromatography,tandem mass spectrometry method. The final isosteviol liver/perfusate (L/P), bile/liver (B/L) and isosteviol-glucuronide in bile/liver (BG/LG) ratios were determined. 3. Isosteviol has a high clearance (21.4 ± 4.8 mL/min) from the perfusate, with a short half-life (13 ± 4 min). ,-Glucuronidase incubation revealed that isosteviol is conjugated in the liver and excreted into the bile. There was no isosteviol-glucuronide detected in perfusate samples. The total recovery of the rat isolated perfused liver system is 74 ± 14% and glucuronidated isosteviol accounted for 23 ± 4% of the administered dose. 4. In conclusion, we are the first to characterize the metabolism of isosteviol using rat isolated liver perfusion. Our results strongly suggest that the liver is the main organ of isosteviol elimination and that isosteviol is glucuronidated in the liver before it is excreted into the bile. [source] | ||||||||||||||||||||||||||||