bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial human experience with MK‐462 (rizatriptan): a novel 5=HTID agonist
Authors: Sciberras David G. , Polvino William J. , Gertz Barry J. , Cheng Haiyung , Stepanavage Michael , Wittreich Johanna , Olah Timothy , Edwards Mark , Mant Timothy 
Published: August 2010

Aim We evaluated the pharmacokinetics and pharmacodynamics of oral MK‐462 in comparison with oral sumatriptan in healthy male volunteers. Methods Sixteen healthy male volunteers were studied in a rising, single dose, alternating panel design with eight subjects per panel. Matching placebo was administered to two of eight study subjects at each dose level of MK‐462 in a randomized, double‐blind fashion. Results MK‐462 was rapidly absorbed with a median tmax of 1.3 h (range 1–3 h) vs a tmax for sumatriptan of 2.5 h (range 1–4 h, P < 0.001). Administration of either MK‐462 or sumatriptan produced maximal mean elevations of 5–10 mmHg in systolic and diastolic blood pressures without effect on heart rate; the changes occurred sooner following MK‐462, consistent with more rapid absorption. Both MK‐462 and sumatriptan provoked mild increases in serum growth hormone without any effect on serum prolactin concentrations. The most commonly reported symptom following MK‐462 was drowsiness. Conclusions These results indicate that the novel 5‐HT1D agonist, MK‐462, is rapidly absorbed following oral administration and warrants further investigation of its utility in the treatment of acute migraine.
The therapeutic monitoring of antimicrobial agents
Authors: Begg Evan J. , Barclay Murray L. , Kirkpatrick Carl M. J. 
Published: August 2010

Aims  To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents.Methods  Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring are reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualization of therapy, sampling times, methods of analysis, interpretative problems and cost‐effectiveness of monitoring.Results  There is a strong historical case for monitoring aminoglycosides. The recent move to once‐daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances.Conclusions  The approach to monitoring aminoglycosides is being redefined in the light of once daily dosing. It may be that less stringent monitoring is required in some circumstances but toxicity, especially ototoxicity, remains a problem with these drugs. Monitoring to avoid high AUCs (areas under the concentration‐time curve) is recommended. The ideal method for monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is sometimes monitored to ensure efficacy while flucytosine may be monitored to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.
Simultaneous fitting of R‐ and S‐ibuprofen plasma concentrations after oral administration of the racemate
Authors: Lötsch Jörn , Muth‐Selbach Uta , Tegeder Irmgard , Brune Kay , Geisslinger Gerd 
Published: August 2010

Aims To assess the pharmacokinetic equivalence of two different formulations of ibuprofen lysinate with special focus on the expected effects.Methods Sixteen healthy volunteers received cross‐over ibuprofen lysinate as either one tablet of 400 mg (‘test’) or two tablets of 200 mg (‘reference’). Ibuprofen plasma concentrations were followed up for 10 h. Bioequivalence was assessed by standard noncompartmental methods. Ibuprofen plasma concentrations were fitted with a model that took bioinversion of R‐ to S‐ibuprofen into account.Results Peak plasma concentrations of R‐ and S‐ibuprofen were 18.1 and 20 µg ml−1(test), and 18.2 and 20 µg ml−1(reference). Areas under the plasma concentrationvstime curves were 39.7 and 67.5 µg ml−1 h (test), and 41.1 and 68.2 µg ml−1 h (reference). Clearance of R‐ibuprofen was 5.2 (test) and 5 l h−1(reference). A specific plasma concentration was reached with the test formulation about 5 min later than with the reference. Parameters from compartmental modelling were (given for R‐and then for S‐ibuprofen): body clearance: 4.9 and 4.64 l h−1, central volume of distribution: 2.8 and 4.1 l, intercompartment clearance: 5.1 and 5.45 l h−1, peripheral volume of distribution: 4.1 and 5.2 l. The absorption rate constant was 1.52 h−1, and the test but not the reference formulation had a lag time of 0.1 h. Simulations showed similarity between formulations of the expected effects except for a calculated delay of 6 min with the test formulation.Conclusions Ibuprofen formulations were bioequivalent. The pharmacokinetic model may serve as a basis for future pharmacokinetic/pharmacodynamic calculations after administration of racemic ibuprofen.
Polymorphisms in genes encoding acetylsalicylic acid metabolizing enzymes are unrelated to upper gastrointestinal health in cardiovascular patients on acetylsalicylic acid
Authors: Van Oijen Martijn G. H. , Huybers Sylvie , Peters Wilbert H. M. , Drenth Joost P. H. , Laheij Robert J. F. , Verheugt Freek W. A. , Jansen Jan B. M. J. 
Published: August 2010

BackgroundAs acetylsalicylic acid is metabolized by UDP‐glucuronosyltransferase 1A6 (UGT1A6) and cytochrome P450 2C9 (CYP2C9), interindividual differences in activity of these enzymes may modulate the effects and side‐effects of acetylsalicylic acid. The objective of this study was to assess whether polymorphisms in UGT1A6 and CYP2C9 genes are related to the prevalence of upper gastrointestinal symptoms in cardiovascular patients using acetylsalicylic acid for secondary prevention of ischaemic heart disease.MethodsBlood samples were taken from acetylsalicylic acid using patients admitted to the Coronary Care Unit. Dyspepsia‐related health was evaluated at week 2, using a validated upper gastrointestinal complaint questionnaire. A subset of 160 patients responded to a survey and were eligible to participate in this study. DNA was isolated and UGT1A6 and CYP2C9 genotypes were determined using polymerase chain reaction restricted fragment length polymorphism techniques.ResultsSeventy per cent of the patients returned the questionnaire. UGT1A6 and CYP2C9 variant polymorphisms were found in 103 (63%) and 56 (35%) patients, respectively. There was no association between gastrointestinal symptoms and UGT1A6 (OR = 0.80, 95% CI = 0.41–1.56) or CYP2C9 polymorphisms (OR = 0.85, 95% CI = 0.44–1.67).ConclusionsThere was no association between polymorphisms in genes encoding for acetylsalicylic acid metabolizing enzymes on the prevalence of gastric complaints in cardiovascular patients on acetylsalicylic acid.
Obstacles and solutions for spontaneous reporting of adverse drug reactions in the hospital
Authors: Vallano A. , Cereza G. , Pedròs C. , Agustí A. , Danés I. , Aguilera C. , Arnau J. M. 
Published: August 2010

AimTo describe the opinions of hospital physicians concerning problems regarding the spontaneous reporting of adverse drug reactions (ADRs) and ways to solve them.MethodsA qualitative study was carried out. Fifteen focus groups were conducted among physicians working in a tertiary teaching hospital. A total of 208 physicians from different medical specialities participated. The focus group discussions were recorded by three different observers and the transcripts of each session were analysed for issues and themes emerging from the text.ResultsFour types of obstacles to spontaneous reporting were considered particularly important: (i) problems with the ADRS diagnosis; (ii) problems with the usual workload and lack of time; (iii) problems related to the organization and activities of the pharmacovigilance system; (iv) and problems related to potential conflicts. The potential solutions suggested for improving spontaneous reporting were to define the kind of ADRS which should be reported, to facilitate an easy contact and quick access to the hospital pharmacovigilance system, to facilitate information and support for reporting and feedback of pharmacovigilance activities.ConclusionsThe perception of the different obstacles by the hospital physicians is an important factor in determining the causes of the underreporting of ADRs and addressing these obstacles could lead to an improvement in spontaneous reporting. A closer relationship between the doctors and the pharmacovigilance centre is suggested as a means of solving these problems. More information is needed to improve the spontaneous reporting of ADRS in specialized healthcare.
Incorporating family into the formula: family‐directed structural therapy for children with serious emotional disturbance
Authors: Radohl Tamara 
Published: August 2010

ABSTRACTIncreasingly, policy‐makers and consumers alike have been pushing for inclusion of families in the treatment of children with diagnoses of serious and emotionally disturbed (SED). Further, recent trends in service provision highlight the necessity for creation and utilization of evidence‐based practices (EBP), as well as the need for consumer‐ or family‐driven treatment. Although family therapy is a popular intervention for this population, existing evidence‐based family therapy modalities fail to incorporate family direction in the treatment of children with SED. Moreover, the models studied have involved juvenile offenders, and, to date, little research has been conducted to substantiate their use with the SED population. Family‐directed structural therapy (FDST) is an emerging model that unifies evidence‐based practice with family‐directed care. This model actively involves parents and family members in the change process blending consumer‐based principles with a growing empirical base. In FDST, the family is both the fulcrum of power and source of change in the family. A description of this approach and an exemplar are provided to illustrate application of this model with families of children with SED.
Ivermectin-facilitated immunity in onchocerciasis. Reversal of lymphocytopenia, cellular anergy and deficient cytokine production after single treatment
Authors: SOBOSLAY P T , DREWECK C M , HOFFMANN W H , LÜDER C G K , HEUSCHKEL C , GÖRGEN H , BANLA M , SCHULZ-KEY H 
Published: August 2010

SUMMARYA longitudinal investigation has been conducted into the cell-mediated immune responses of onchocerciasis patients after a single-dose treatment with ivermectin. Untreated patients tested for delayed cutaneous hypersensitivity (DCH) to seven recall antigens showed lower responses than infection-free control individuals (P &lt;0·01), but 6 and 14 months after treatment DCH reactions increased to similar levels to those seen in the controls. The in vitro cellular reactivity to Onchocerca volvulus-derived antigen (OvAg) was reduced in untreated patients as compared with controls, and the lymphocyte blastogenic responses to OvAg and streptolysin-O clearly improved up to 14 months after treatment. Peripheral blood mononuclear cells (PBMC) from untreated patients produced IL-Iβ, tumour necrosis factor-alpha (TNF-α) and IL-6 in response to mitogenic stimulation with phytohaemagglutinin (PHA), only low levels of IL-Iβ, IL-2 and TNF-α in response to OvAg, but higher amounts of IL-4 and interferon-gamma (IFN-γ) in response to OvAg than control individuals. After ivermectin treatment, the OvAg-induced production of IL-1β and TNF-α increased significantly I and 14 months after treatment. The PHA-induced production of IL-2 and IL-4 increased 1 month after treatment and remained significantly elevated until 14 months after treatment, whereas the OvAg-specific secretion of IL-2, IL-4 and IFN-γ did not change after ivermectin treatment. Flow cytometric analysis of lymphocyte-subsets in the peripheral blood of untreated patients revealed a relative and absolute (P &lt;0·01) diminution of CD4+ cells and a significantly smaller CD4+/CD8+ cell ratio as compared with controls. By 4 weeks after treatment and thereafter, CD4+ T cells increased relatively and absolutely (P &lt;0·01); likewise there was an absolute increase in T-helper-inducer cells (CD4+CD45RO+) and a temporarily improved CD4+/ CD8+ cell ratio (P=0·001). The expression of the low-affinity receptor for IgE (CD23) on total lymphocytes decreased from 14% to 7% by 14 months after treatment. The CD8+ cells and CD3+TCRγδ+ cells were higher in patients than in controls and both remained elevated until 14 months after treatment. These results suggest a distinctly improved cellular immunity in human onchocerciasis that was facilitated by ivermectin therapy.
Elevated complement activities of sera from patients with high density lipoprotein deficiency (Tangier disease): the presence of normal level of clusterin and the possible implication in the atherosclerosis
Authors: CHOI-MIURA N-H , SAKAMOTO T , OHTAKI S , NAKAMURA H , ISHIZAWA S , TAKAGI Y , GOMI K , TOMITA M 
Published: August 2010

SUMMARYClusterin (apolipoprotein J, SP-40,40), as well as apolipoprotein A-I (apo A-I) and apolipoprotein A-II (apo A-II), are apolipoprotein components of high density lipoprotein (HDL), but not of low density lipoprotein. In spite of the deficiencies of apo A-I, apo A-II and HDL in the sera of patients with Tangier disease, clusterin was found in them at normal level. While clusterin was present as the component of HDL with apo A-I in sera of normal donors, it was present as a protein which did not form a complex in sera of Tangier patients. SC5b-9 made from the sera of Tangier patients contained normal amounts of clusterin and was deficient in apo A-I, indicating that clusterin could be incorporated into the SC5b-9 complex without apo A-I. The complement activities of the sera of the patients were higher than those of normal donors. These results may be explained by the deficiencies of apo A-I, apo A-II and HDL in the patients, because they were suggested to be the inhibitors of the reactive haemolysis of complement. The elevated complement activities of the patients might be related to the severe atherosclerotic lesions in Tangier disease.
Inhibition of histone/anti-histone reactivity by histone-binding serum components; differential effect on anti-Hlversusanti-H2B antibodies
Authors: BUSTOS A , BOIMORTO R , SUBIZA J L , PEREIRA L F , MARCO M , FIGUEREDO M A , DE LA CONCHA E G 
Published: August 2010

SUMMARYIgG fractions were purified on a protein G-agarose column from sera of both systemic lupus erythematosus (SLE) patients and healthy donors. All IgG fractions, after elution with 0·5 M acetic acid, reacted with histones in an anti-histone ELISA assay, and IgG anti-histone activity was in all instances higher in the IgG fraction than in the corresponding whole serum. This was shown to be due to the presence in serum of histone-binding components that inhibited IgG binding to histones. Both normal human and SLE patients' sera had these histone-binding components, and disparity between serum-positive and -negative anti-histone antibody (AHA) tests was not dependent on differences in the blocking capacity but on IgG antibody levels and avidity. Interaction of normal serum IgG fraction with all five histones was of low avidity, whereas interaction of IgG from AHA-positive SLE sera with both H1 and H2B had high avidity. Low-affinity antibodies to every histone fraction, but also high-affinity anti-H1 antibodies, were preferentially inhibited. Our data indicate that several serum protein components are inhibiting histone/anti-histone interaction and may play a protective role against both high-affinity anti-H1 antibodies present in SLE patients, and natural, low-affinity, anti-histone antibodies. As some acute phase proteins, notably C-reactive protein, bind to histones, it is conceivable that they play such a role. High-affinity anti-H2B antibodies, present in some SLE patients, and not inhibited by these serum components, may, on the other hand, participate in the pathogenesis of the disease.
Human serum mannose-binding lectin (MBL)-associated serine protease-1 (MASP-1): determination of levels in body fluids and identification of two forms in serum
Authors: TERAI I , KOBAYASHI K , MATSUSHITA M , FUJITA T 
Published: August 2010

SUMMARYWe developed an ELISA for human serum MASP-1, a Cls-like serine protease which is known to function in C4 and C2 activation. We then determined MASP-1 levels in 1063 sera from normal Japanese subjects ranging in age from 3 to 100 years, as well as in certain body fluids using this assay. Individual serum MASP-1 levels ranged from 1·48 to 121·83 μg/ml, with a normal frequency distribution pattern. The arithmetic mean ± s.d. of MASP-1 levels in serum was 6·27 ± 1·85 μg/ml, whereas levels of MASP-1 in cerebrospinal fluid and in urine were almost undetectable. When the mean ± s.d. of serum MASP-1 was calculated for each age group (10 year range) and values were then compared, the age group consisting of 3–9-year-olds (7·54 ± 1·39; μ/ml) was found to have the highest value. When MASP-1 was measured in cord blood, it was shown that levels were already as high as those of 3–9-year-olds. The serum MASP-1 level was found to be as strongly dependent on age as is the serum MBL level. MASP-1 and MBL are thought to play an active part in immunity in younger people. It was found that the serum level of MASP-1 was much higher than that of MBL, and the major portion of human serum MASP-1 appeared to exist in the circulation as a form unbound to MBL.
Tryptophan metabolism and indoleamine 2,3-dioxygenase expression in coeliac disease
Authors: Torres M I , López-Casado M A , Lorite P , Ríos A 
Published: August 2010

SummaryWe have investigated the possible role of the metabolism of tryptophan and activity of the enzyme indoleamine 2,3-dioxygenase (IDO) in the immune regulation of coeliac disease (CD). Serum concentrations of tryptophan and its metabolites kinurenines were determined by high performance liquid chromatography in 24 patients with CD, seven patients with Crohn's disease and five healthy patients. We detected an increase of kynurenine (4·2 µmol/l ± 0·27 versus 2·6 µmol/l ± 0·54, P &lt; 0002) and of the kynurenine/tryptophan ratio in supernatants of coeliac patients (11·5 µmol/l ± 1·01 versus 6·5 µmol/l ± 1·57, P &lt; 0005) in comparison with healthy patients, respectively, and we found no differences with Crohn's disease patients. Immunohistochemistry analysis of intestinal biopsies from CD patients showed an increased expression of IDO, interferon-γ, interleukin-10 and transforming growth factor-β. Our data suggest that a mechanism(s) dependent on tryptophan catabolism might regulate the immune responses in CD.
Changes in circulating lymphocyte subpopulations following administration of the leucocyte function-associated antigen-3 (LFA-3)/IgG1 fusion protein alefacept
Authors: Larsen R , Ryder L P , Svejgaard A , Gniadecki R 
Published: August 2010

SummaryAlefacept, a recombinant leucocyte function-associated antigen-3 (LFA-3)/IgG1 fusion protein approved for the treatment of psoriasis, is reported to reduce selectively the numbers of circulating CD4+ CD45RO+ and CD8+ CD45RO+ T cells, while sparing the naive cells. The purpose of the present study was to elucidate further the effect of alefacept on various circulating lymphocyte subsets. Sixteen patients, 12 with chronic plaque psoriasis and four with pustular psoriasis, received alefacept 7·5 mg once weekly for 12 weeks. Blood samples collected at study entry and after 12 weeks of treatment were analysed by four-colour flow cytometry. There were statistically significant reductions in the total number of conventional memory (CD45RA– CD27+) and effector (CD45RA– CD27– or CD45RA+ CD27–) T cells, including CD4+ and CD8+ T cells expressing CD161 and CD8+ T cells expressing cutaneous lymphocyte-associated antigen (CLA). Natural killer (NK) T cells were also reduced significantly, while no statistically significant changes were seen in NK cells and CD4+ CD25high cells. The affected subpopulations were all characterized by a high expression of CD2. However, CD4+ CD25low, and CD4+ CLA+ cells, which also expressed relative high levels of CD2, were not reduced significantly. Our results suggest a heterogeneous effect of alefacept on the circulating memory T cell population, indicating that high expression of CD2 may not, by itself, be sufficient to explain the reduction in cell count for a specific subpopulation.
Diffusion of NH+4 and NO−3 mineralized from organic N in soil
Authors: DARRAH P. R. , NYE P. H. , WHITE R. E. 
Published: August 2010

SummaryThe mineralization of native soil organic matter and the simultaneous diffusion of zero NH+4 and NO−3 to a solution sink of zero N concentration was analysed experimentally and theoretically for a fine sandy loam soil. Experimentally, the NH4 and NO3 ions produced in an incubated unsaturated soil column were allowed to diffuse through a sintered glass plate into a stirred solution sink. The distribution of NH+4 and NO−3 in the soil column was measured after various incubation times. The rate of ammonification was measured directly during incubation and the rate of nitrification modelled from nitrifier growth kinetics. A Freundlich equation was used to describe the equilibrium between soluble and exchangeable NH+4 in the soil. Terms for the microbial transformation of N and the adsorption‐desorption of NH+4 were combined with diffusion equations which were solved numerically using finite difference methods. The model constructed was used to predict the NH+4 and NO−3 con‐centration distributions in the soil column, and good agreement was obtained between the experimental and predicted concentration profiles. The use of the model for predicting the diffusive flux of mineral N to the outer surfaces of soil peds, where it is vulnerable to leaching, was demonstrated.
Coupled diffusion and oxidation of ferrous iron in soils. I. Kinetics of oxygenation of ferrous iron in soil suspension
Authors: AHMAD A. R. , NYE P. H. 
Published: August 2010

SUMMARYThe kinetics of oxidation of iron in an aqueous suspension of a thoroughly reduced low‐humus tropical rice paddy soil were followed by measuring the extractable ferrous iron in the whole suspension and in the solution. Three‐quarters of the initial ferrous iron was oxidized rapidly (first‐order rate constant = 9.2 × 10−5 s−1). The subsequent reaction was slow (first‐order rate constant = 9.4 × 10−7 S−1) and was not studied in detail. The pH fell from 6.6 to 4.9 over the course of the fast reaction. In further experiments the rate of oxidation was followed at constant pH values in the range 6.5 to 4.5. It was concluded that the oxidation of adsorbed iron was much faster than solution iron, and that the adsorbed iron was oxidized at a rate that was nearly independent of the pH. During the reaction some ferrous iron is adsorbed on the ferric hydroxide formed. The proportion of the remaining ferrous iron adsorbed on ferric hydroxide rather than the original exchange surfaces was high at pH > 6.0 and low at pH < 5.0. The rate of oxidation of the ferrous iron was similar whether it was adsorbed on exchange sites or on the ferric hydroxide formed. Since the rate of oxidation of the iron adsorbed on ferric hydroxide was very much slower than that on ferric hydroxide formed in the absence of soil, it is suggested that the rate in soil may be controlled by diffusion of oxygen to the adsorption sites.