bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of captopril, enalaprilat and mercaptopropionyl glycine (MPG) on the oxidative activity of human isolated neutrophils.
Authors: Clapperton M , Beswick PH , Abdullah I , Dargie HJ , Fisher AC , McMurray J
Published: July 2012

1. Neutrophil NADPH oxidase produces the superoxide anion (O2‐) anion radical from oxygen. The thiol containing ACE inhibitor, captopril has been reported to inhibit isolated NADPH oxidase. The above effect of captopril, if present in intact cells, could contribute to the ability of this drug to alleviate neutrophil‐mediated tissue damage. We have, therefore, investigated the effect of captopril on the oxidative activity of intact human isolated neutrophils. 2. The effects of captopril on neutrophil oxidative activity were compared with those of enalaprilat (a non‐thiol ACE inhibitor) and N‐mercaptopropionyl glycine (MPG) (a simple thiol). 3. The oxidative response of PMA‐stimulated neutrophils measured by lucigenin chemiluminescence was not affected by any of these test agents. The thiol captopril and MPG (but not enalaprilat) caused an initial delay in luminol chemiluminescence production by PMA‐stimulated neutrophils. 4. Captopril and MPG (but not enalaprilat) increased, rather than decreased oxygen uptake, when added to PMA‐stimulated neutrophils. Thiol oxidation was determined to be, at least partly, responsible for the excess oxygen uptake observed. 5. NADPH oxidase activity in intact neutrophils was not affected by captopril, MPG or enalaprilat. The inhibition of NADPH oxidase activity is unlikely to contribute to the therapeutic effects of captopril and other thiols.
Stereoselective disposition of ibuprofen in patients with compromised renal haemodynamics.
Authors: Chen CY , Chen CS
Published: July 2012

1. The primary aim of this study was to assess the impact of renal haemodynamics on the pharmacokinetic behaviour of ibuprofen enantiomers. Thirty‐two patients and ten age‐matched healthy volunteers participated in this study. These patients had at least one of the following risk factors for cardiovascular disorders: hypertension, diabetes mellitus, hyperlipidaemia and hyperuricaemia with or without consequent complications such as coronary artery disease, congestive heart failure, cerebral vascular disease, and chronic renal failure. Renal function in these patients was thus characterized by unstable renal haemodynamics that might render them susceptible to ibuprofen‐ incurred renal damage. 2. Each subject received a single oral dose of 800 mg of racemic ibuprofen. The pharmacokinetic parameters of (S)‐ and (R)‐ibuprofen, t 1/2(S), t 1/2(R), AUC(S), AUC(R), V/F(R), and CL/F(R), for each individual were determined from respective plasma concentration‐time curves. To assess the effect of individual clinical conditions on the disposition of ibuprofen enantiomers, the arithmetic means of these pharmacokinetic parameters for each disease group were compared with those of the healthy volunteers by a t‐test. 3. All of these disease groups showed elevated AUC(S) and higher (S)/(R) AUC ratios. These disease states along with gender and age were analyzed by multiple linear regression to discern significant factors for elevating AUC(S). Of these, advanced age (P = 0.02) and hypertension (P = 0.03) were identified as independent factors contributing to AUC(S) increase in this population. Thus, patients with these two clinical conditions are at particular risk from the adverse renal effect of ibuprofen.
The effect of delay, multiple actuations and spacer static charge on the in vitro delivery of budesonide from the Nebuhaler.
Authors: Barry PW , O'Callaghan C
Published: July 2012

A multistage liquid impinger was used to determine the amount of budesonide available from the Nebuhaler spacer device following alteration of spacer static charge, delay in sampling from the spacer, and multiple actuations of the metered dose inhaler into the spacer prior to sampling. The mean amount of budesonide (s.d.) recovered per 200 micrograms actuation in particles smaller than 5 microns increased from 30.5 micrograms (8.8) to 69.3 micrograms (17.9) with a low static spacer. A 20 s delay between actuation and inhalation reduced the amount recovered to 10.9 micrograms (3.2), but no reduction was seen when using a low static spacer after the same delay. Multiple actuations into the spacer before sampling also reduced the recovery to 24.8 micrograms (3.4) after two actuations, and 13.5 micrograms (7.6) after five actuations. When using a Nebuhaler with budesonide metered dose inhalers, more respirable drug will be obtained if the aerosol is inhaled immediately after actuation, and multiple actuations into the spacer device are avoided. Low static spacers may also improve drug delivery. Attention to the details of spacer use may reduce the incidence of therapeutic failure and the cost of inhaled medications.
Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.
Authors: Sampol E , Lacarelle B , Rajaonarison JF , Catalin J , Durand A
Published: July 2012

Zidovudine (ZDV) is extensively metabolised by the liver to an inactive glucuronide (GZDV). Since ZDV is often administered with antimycotic drugs, we studied the effect of six systemic antifungal agents on the in vitro glucuronidation of ZDV by human liver microsomes. 5‐ fluorocytosine and itraconazole had no inhibitory effect whereas amphotericine B, ketoconazole, miconazole and fluconazole inhibited in vitro GZDV formation (Ki values were 0.13, 0.08, 0.18 and 1.4 mM respectively).
An in vitro technique for the rapid determination of drug entry into breast milk.
Authors: Notarianni LJ , Belk D , Aird SA , Bennett PN
Published: July 2012

1. A simple in vitro technique that predicts drug transfer into breast milk is described. 2. Drugs of differing physical and chemical characteristics were tested. 3. The technique provides an experimental system for studying plasma to milk transfer with changing milk composition. 4. A mechanism proposing a role of milk proteins in controlling drug entry into milk is discussed.
The pharmacokinetics of 8‐methoxypsoralen following i.v. administration in humans [see comments]
Authors: Billard V , Gambus PL , Barr J , Minto CF , Corash L , Tessman JW , Stickney JL , Shafer SL
Published: July 2012

1. 8‐methoxypsoralen (8‐MOP) is a naturally occurring photoreactive substance which, in the presence of u.v. light, forms covalent adducts with pyrimidine bases in nucleic acids. For many years, 8‐MOP has been used in PUVA therapy for treatment of psoriasis. Recently, the drug has been found to inactivate effectively bacteria spiked into platelet concentrates. The purpose of this study was to determine the pharmacokinetics and safety of 8‐MOP administered intravenously in the bactericidal dosage range. 2. Eighteen volunteers were divided into three treatment groups to receive, respectively, 5, 10, and 15 mg 8‐MOP infused over 60 min. Frequent arterial samples were gathered, and the blood and plasma were assayed for 8‐MOP concentration. The pharmacokinetic parameters were determined by moment and compartmental population analysis, the latter performed with the program NONMEM. Haemodynamics, ventilatory pattern, and subjective effects were recorded throughout the study. 3. The intravenously administered 8‐MOP was well tolerated in all individuals, and no acute toxicity was observed. 4. The pharmacokinetics of 8‐MOP were best described by a three‐compartment mammillary model in which the volumes and clearances were proportional to weight. The mean pharmacokinetic parameters for the plasma concentrations were: V1 = 0.045 1 kg‐1, V2 = 0.57 1 kg‐1, V3 = 0.15 1 kg‐1, CL1 (systemic) = 0.010 1 kg‐1 min‐1, CL2 = 0.0067 1 kg‐1 min‐1, CL3 = 0.012 1 kg‐1 min‐1. The mean pharmacokinetic parameters for the blood concentrations were: V1 = 0.061 1 kg‐1, V2 = 1.15 1 kg‐1, V3 = 0.21 1 kg‐1, CL1 (systemic) = 0.015 1 kg‐1 min‐1, CL2 = 0.011 1 kg‐ 1 min‐1 and CL3 = 0.015 1 kg‐1 min‐1. 5. The plasma pharmacokinetic model described the observations with a median absolute error of 17%, and the blood pharmacokinetic model described the observations with a median absolute error of 18%. Analysis of the relative concentration of 8‐MOP between plasma and red blood cells suggested concentration‐ dependent partitioning. 6. The addition of 7.5 mg 8‐MOP to 300 ml platelet concentrate would produce bactericidal concentrations of 25 micrograms ml‐1. Simulations based upon our data show that intravenous administration of 7.5 mg over 60 min would result in systemic concentrations of 8‐MOP similar to those observed with conventional PUVA therapy. We conclude that the extensive safety history established in PUVA therapy will be applicable to this new application of 8‐MOP.
An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems.
Authors: Halliday RC , Jones BC , Smith DA , Kitteringham NR , Park BK
Published: July 2012

1. We have assessed the interaction of the antimalarial halofantrine with cytochrome P450 (CYP) enzymes in vitro, with the use of microsomes from human liver and recombinant cell lines. 2. Rac‐halofantrine was a potent inhibitor (IC50 = 1.06 microM, Ki = 4.3 microM) of the 1‐ hydroxylation of bufuralol, a marker for CYP2D6 activity. Of a group of structurally related antimalarials tested, only quinidine (IC50 = 0.04 microM) was more potent. 3. Microsomes prepared from recombinant CYP2D6 and CYP3A4 cell lines were shown to catalyse halofantrine N‐ debutylation. 4. The metabolism of halofantrine to its N‐desbutyl metabolite by human liver microsomes showed no correlation with CYP2D6 genotypic or phenotypic status and there was no consistent inhibition by quinidine. 5. The rate of halofantrine metabolism showed a significant correlation with both CYP3A4 protein levels (r = 0.88, P = 0.01) and the rate of felodipine metabolism (r = 0.86, P = 0.013), a marker substrate for CYP3A4 activity. Inhibition studies showed that ketoconazole is a potent inhibitor of halofantrine metabolism (IC50 = 1.57 microM). 6. In conclusion, we have demonstrated that halofantrine is a potent inhibitor of CYP2D6 in vitro and can also be metabolised by the enzyme. However, in human liver microsomes it appears to be metabolised largely by CYP3A4.
Lack of effect of a 5‐HT3 antagonist, pancopride, on lower oesophageal sphincter pressure in volunteers.
Authors: Grande L , Lacima G , Perez A , Zayas JM
Published: July 2012

Effects of pancopride (5 and 10 mg, intravenously), on lower oesophageal sphincter pressure (LOESP), were assessed in healthy volunteers by means of oesophageal manometry. After pancopride 10 mg, the LOESP was higher than placebo and 5 mg pancopride but there were no differences among the three treatments (P = 0.42). The areas under the curve were similar without differences, neither with absolute measurements (P = 0.53) nor after a baseline correction (P = 0.16). In conclusion, pancopride has no clinically relevant effect on lower oesophageal sphincter pressure.
The effect of selegiline on the peripheral pharmacokinetics of levodopa in young volunteers.
Authors: Roberts J , Waller DG , O'Shea N , Macklin BS , Renwick AG
Published: July 2012

The plasma pharmacokinetics of levodopa were studied in eight healthy young subjects following an i.v. infusion of 50 mg over 5 min. Subjects were studied on two occasions in random order following treatment with carbidopa; on one occasion they were pretreated with selegiline (four doses of 10 mg over the preceding 3 days) and on the other with a placebo. The mean plasma concentration‐time curves on each occasion were essentially superimposable and there were no significant differences in any calculated pharmacokinetic parameter. Selegiline does not significantly alter the distribution or elimination of levodopa from plasma.
A suggested approach to once‐daily aminoglycoside dosing.
Authors: Begg EJ , Barclay ML , Duffull SB
Published: July 2012

1. Once‐daily aminoglycoside dosing has many advantages and has been widely advocated. However, existing guidelines for methods of administration and monitoring are non‐specific and may lead to excessive dosing. 2. The traditional approach of aiming for target peak and trough concentrations is not appropriate for once‐daily dosing. 3. A method is proposed which uses a target area under the concentration‐ time curve (AUC) for the aminoglycoside based on the 24 h AUC that would result with conventional dosing. This method requires measurement of two drug concentrations, one approximately 0.5 h after the end of the infusion and another at a later time (6‐22 h) depending on renal function. 4. A simpler, graphical method is also proposed for patients with normal renal function, which requires the measurement of a single concentration at a time between 6 and 14 h. 5. Both methods are likely to be safer than existing guidelines.
Absorption of cyclosporin from conventional and new microemulsion oral formulations in liver transplant recipients with external biliary diversion.
Authors: Trull AK , Tan KK , Tan L. , Alexander GJ , Jamieson NV
Published: July 2012

1. Less than 5% of a dose of the conventional oral formulation of cyclosporin, Sandimmun, is absorbed in liver transplant recipients with external biliary drainage, necessitating intravenous administration of the drug and exposing the patient to increased risk of severe side‐ effects. 2. We compared the pharmacokinetics of the conventional oral formulation of cyclosporin with that of the new microemulsion formulation, Neoral, in eight liver transplant recipients with external biliary diversion. Patients were maintained on a continuous infusion of cyclosporin until steady‐state conditions had been achieved. They were then given a test dose (10 mg kg‐1) of either the conventional or microemulsion formulation (randomised order) followed by the same dose of the other formulation. Parent cyclosporin concentrations were measured in whole blood samples collected at timed intervals over the 24 h after the oral doses and pharmacokinetic parameters calculated. 3. The bioavailability of cyclosporin from the microemulsion formulation was, on average, 6.5‐fold (95% C.I. 1.9 to 11.1‐fold) greater than that of the conventional formulation, indicating the improved absorption characteristics of the new oral microemulsion formulation during external bile drainage. 4. A significant negative correlation was found between the external bile drainage volume and bioavailability of cyclosporin from the microemulsion formulation (r = ‐0.8; P = 0.016), suggesting that variability in cyclosporin absorption from the microemulsion formulation may still be at least partly attributable to bile‐ dependence.(ABSTRACT TRUNCATED AT 250 WORDS)
The placebo effect in healthy volunteers: influence of experimental conditions on physiological parameters during phase I studies.
Authors: Rosenzweig P. , Brohier S. , Zipfel A.
Published: July 2012

1. Although placebo administration is now commonly used as a control condition during clinical pharmacology studies conducted in healthy volunteers, data in placebo‐treated subjects usually receive little attention. 2. The profile of several physiological and hormonal parameters was reviewed during the placebo sessions of five double‐ blind phase I studies involving hospitalisation of healthy volunteers for 2 weeks or more. 3. A clear trend towards an increase in heart rate, which culminated at about 10 beats min‐1 at the end of the placebo period was observed, whereas both systolic and diastolic blood pressures remained globally unchanged. 4. Increases in the time to sleep initiation or in asthenia self‐ratings during the placebo sessions suggested poor neuropsychiatric tolerability of experimental conditions in some of the studies. 5. In conclusion, all these data confirm that subjects change during the course of these studies. This is an important reason for conducting phase I studies under double‐ blind placebo‐controlled conditions and to refrain from within‐group comparisons (vs baseline, first‐day effect).
Prolonged half‐life of verapamil in a case of overdose: implications for therapy.
Authors: Buckley CD , Aronson JK
Published: July 2012

After an overdose of verapamil (2.4 g) in a 59‐year‐old man the apparent half‐life of verapamil was prolonged (15 h). The most likely mechanism is rate‐limiting absorption, although changes in clearance and volume of distribution may contribute. As the elimination half‐life of verapamil is increased in overdose, therapy may have to be continued for longer than expected. Moreover since the half‐life of absorption of verapamil in overdose may be prolonged, activated charcoal should be given in repeated doses, even if an ordinary‐release formulation has been taken.
Does luminol chemiluminescence detect free radical scavengers?
Authors: Clapperton M. , McMurray J. , Fisher AC , Dargie HJ
Published: July 2012

Thiol compounds have been reported to abolish hypoxanthine/xanthine oxidase induced luminol chemiluminescence and this effect has been attributed to scavenging of superoxide (O2‐)/(H2O2) produced from hypoxanthine/xanthine oxidase. Yet other workers have reported that thiol compounds have shown little, if any, reactivity towards O2‐/H2O2. The aim of this study was to examine the discrepancy between these two sets of findings further. Captopril (a thiol angiotensin‐converting enzyme (ACE) inhibitor) and MPG (a simple thiol) were observed to abolish hypoxanthine/xanthine oxidase induced chemiluminescence. The reactivity of captopril and MPG towards O2‐/H2O2 was then determined by measurement of thiol oxidation in captopril and MPG after their incubation with hypoxanthine/xanthine oxidase. Incubation (at 10 min, 37 degrees C) with 4 mM hypoxanthine/0.03 u ml‐1 xanthine oxidase resulted in 7% and 20% thiol oxidation in captopril and MPG (at 1 mM) respectively. Captopril and MPG, therefore, appeared to be ineffective scavengers of oxidants produced by hypoxanthine/xanthine oxidase. Captopril and MPG also did not affect urate production or oxygen consumption by xanthine oxidase which indicated that captopril and MPG quench luminol chemiluminescence by a mechanism that excludes the inhibition of xanthine oxidase. Hypoxanthine/xanthine oxidase induced luminol chemiluminescence may, therefore, be an unsuitable method for measuring free radical scavenging activity by drugs.
Lack of effect of pantoprazole on the pharmacodynamics and pharmacokinetics of warfarin [see comments]
Authors: Duursema L. , Muller FO , Schall R. , Middle MV , Hundt HK , Groenewoud G. , Steinijans VW , Bliesath H.
Published: July 2012

Twenty‐six healthy males took part in this double‐blind, randomised, placebo‐controlled, two‐period, cross‐over study. Pantoprazole (40 mg) (test) or placebo (reference) were administered once daily, for 8 days, with a 3 week washout period. A single oral dose of 25 mg warfarin sodium was co‐administered with pantoprazole or placebo on Day 2 of each treatment period. The 90% confidence intervals for the 'test/reference' mean ratios of the excess AUC(0.168 h) of prothrombin time and AUC(0.168 h) of factor VII, and of Cmax, AUC and t1/2 of both R‐ and S‐warfarin fell within the equivalence range of 80% to 125%. These results suggest that pantoprazole does not alter the pharmacokinetics or pharmacodynamics of warfarin.
Effects of peripherally and centrally acting analgesics on somato‐ sensory evoked potentials [see comments]
Authors: Moore UJ , Marsh VR , Ashton CH , Seymour RA
Published: July 2012

1. The effects of aspirin 1000 mg, paracetamol 1000 mg, codeine 60 mg on somatosensory evoked potentials (SEPs) were measured in a four‐way cross‐over study. 2. SEPs were elicited by electrical stimulation of the skin overlying the digital nerve at intensities close to pain threshold. 3. Amplitudes and latencies of both early and late SEPs were recorded, as well as first sensory threshold and subjective pain threshold. 4. None of the study medications affected the amplitude or latency of the late SEP components (100‐250 ms post‐stimulus). The amplitude of early components (15‐30 ms post‐stimulus) was also unaffected, but aspirin shortened the latency 30 min after ingestion. 5. Sensory detection and pain threshold to electrical skin stimulation were also unaffected by any of the study medications despite subjective central effects with codeine.
The psychomotor and cognitive effects of litoxetine in young and middle aged volunteers.
Authors: Fairweather DB , Patat A. , Rosenzweig P. , Curson VH , Dunmore C. , Dubruc C. , Hindmarch I.
Published: July 2012

1. The effects of a range of doses of litoxetine (twice daily for 4 days), a novel specific serotonin re‐uptake inhibitor, were evaluated in young and middle aged volunteers. 2. Psychometric testing was carried out at various time points on days 1 and 4 of each treatment period. The test battery consisted of critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT), Stroop and Sternberg memory scanning tests. Subjective feelings of sleep and sedation were measured by the Leeds Sleep Evaluation Questionnaire (LSEQ) and line analogue rating scales (LARS). 3. Pharmacokinetic profiles were determined from analyses of blood samples taken after the final dose on day 5. 4. Overall, there were few changes in any of the psychometric tests and although the higher doses of litoxetine improved CFF, these effects were weak in that differences could only be detected when the results were pooled against time. 5. The pharmacokinetic profile of litoxetine was very similar in both the young and middle aged subjects, and there was no difference regarding tolerability. 6. There is little evidence from this study to suggest that litoxetine has any intrinsic sedative activity which is likely to interfere with the performance of activities of everyday life.
Pharmacokinetic interaction studies between felbamate and vigabatrin.
Authors: Reidenberg P. , Glue P. , Banfield C. , Colucci R. , Meehan J. , Rey E. , Radwanski E. , Nomeir A. , Lim J. , Lin C. , et al
Published: July 2012

To assess the possible occurrence of pharmacokinetic interactions between the antiepileptic agents felbamate and vigabatrin, two randomized, double‐blind, placebo‐controlled, crossover studies were conducted in healthy male volunteers. In Study I, 18 subjects received oral vigabatrin 1000 mg every 12 h for two 8 days periods with felbamate 1200 mg every 12 h or placebo. In Study II, 18 other volunteers were administered oral felbamate 1200 mg every 12 h for two 8 days periods with vigabatrin 1000 mg every 12 h or placebo. On the eighth day of each treatment period, blood and urine samples were collected over 12 h for determination of the active S(+)‐ and inactive R(−)−vigabatrin enantiomer concentrations (Study I) or felbamate concentrations (Study II). In Study I, the pharmacokinetic parameters of R(−)−vigabatrin were similar during co‐administration with felbamate or placebo. Felbamate produced a 13% increase in AUC(0.12 h) and an 8% increase in urinary excretion of S(+)‐vigabatrin. Although these changes were statistically significant, their magnitude was small. In Study II, the pharmacokinetic parameters of felbamate were similar during concurrent administration with vigabatrin or placebo. These data indicate that there are no clinically relevant pharmacokinetic interactions between felbamate and vigabatrin in man.
Evidence for the polymorphic oxidation of debrisoquine and proguanil in a Khmer (Cambodian) population.
Authors: Wanwimolruk S. , Thou MR , Woods DJ
Published: July 2012

The frequency distributions of the urinary metabolic ratios of debrisoquine and proguanil were measured in a population of unrelated Khmers. Out of 98 Khmer subjects studied, two were identified as poor metabolisers of debrisoquine when a metabolic ratio of 12.6 was used as the cut off point. This represents a prevalence of debrisoquine poor metabolisers of 2.1% (95% confidence interval 0.25‐7.3%) which is similar to other Asian populations. Based on the distribution of the ratio of proguanil to cycloguanil excreted in urine, and using an antimode value of 10, the prevalence of poor metabolisers of proguanil in a Khmer population was estimated to be 18.4% (95% confidence interval 10.9‐28.1%). The frequency of poor metabolisers of proguanil in Khmers was higher than that described for Caucasian populations, but similar to most reported results in Asian populations.
The accumulation of mercaptopurine metabolites in age fractionated red blood cells.
Authors: Rostami‐Hodjegan A. , Lennard L. , Lilleyman JS
Published: July 2012

1. Red blood cells from four children with lymphoblastic leukemia were age fractionated on Percoll density gradients into 'young', 'middle‐ aged' and 'old' cells. 2. The rates of accumulation of the mercaptopurine (MP) metabolites thioguanine nucleotides (TGNs) and methylmercaptopurine nucleotides (MeMPs) were measured in the cell fractions from the start of MP continuing chemotherapy. 3. TGNs and MeMP metabolites were present in all the red cell fractions after 3 days oral MP. There was no significant difference between the metabolite concentrations measured in either young, middle‐aged or old cells (Mann‐Whitney P = 1.0 to 0.12). 4. These observations suggest that MP metabolites do not enter red cells at the stem cell level at the start of therapy. 5. With respect to the monitoring of therapy, these results suggest that the concentration of TGNs after 7 to 10 days MP could be used to predict eventual steady‐state concentrations using a simple model.
Single dose pharmacokinetics, safety and tolerability of MK‐0476, a new leukotriene D4‐receptor antagonist, in healthy volunteers.
Authors: Schoors DF , De Smet M. , Reiss T. , Margolskee D. , Cheng H. , Larson P. , Amin R. , Somers G.
Published: July 2012

MK‐4076 or sodium 1‐(1(R)‐(3‐(2‐(7‐chloro‐2‐quinolinyl)‐(E)‐ ethenyl)phenyl) 3‐(1‐hydroxy‐1‐methylethyl)phenyl)propyl)thio)methyl) cycloproprane) acetate is a novel, potent, and specific LTD4‐receptor antagonist. The safety, tolerability and plasma drug profiles of single oral doses of MK‐0476 (capsules) were evaluated in 18 healthy male volunteers assigned to one of the two parallel 9‐subject panels. Under fasting conditions, increasing single doses of 20 to 800 mg were administered in a first part of the study and in a second part, 200 mg MK‐0476 was given either as a solution, under fasting conditions, or as capsules, after a standard breakfast. All volunteers completed the study. Side effects, reported by the investigator to be related to study drug, were mild and transient. No laboratory abnormalities were noted. In the evaluated dose range of MK‐0476 (20 to 800 mg) the median value of tmax ranged from 2 to 4 h, while the apparent t1/2 value averaged 4 to 5 h. The median tmax value of the 200 mg capsule dose was not significantly different from the median tmax of the 200 mg oral solution dose indicating that neither disintegration nor dissolution is a rate‐limiting step for the absorption of MK‐0476 from capsules. There was a statistically significant increase in the AUC (geometric mean ratio of fed/fast was 2.52 with 95% confidence interval of 1.25, 5.06) and in Cmax (geometric mean ratio of fed/fast was 1.36 with 95% confidence interval of 0.60, 3.04) when MK‐0476 was given together with a breakfast, suggesting an increase in bioavailability.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of intradermal injection of atrial natriuretic peptide.
Authors: Sharara AM , Higham MA , Spanevello A. , Ind PW
Published: July 2012

Atrial natriuretic peptide (ANP) causes mast cell degranulation in rats in vivo and in vitro but is bronchodilator in humans. The aim of this study was to investigate the wheal and flare dose‐response to intradermal injection of alpha‐human ANP in normal humans. Eight normal subjects received five 30 microliters injections containing 1, 10, 39, 78, 117 pmol ANP and one each of normal saline, histamine 675 pmol and substance P 30 pmol. Maximum ANP flare response was greater but not significantly than that to saline at 1.55 +/‐ 0.6 (mean +/‐ s.e. mean) compared with 0.42 +/‐ 0.17 cm2, but much less than to histamine 9.86 +/‐ 0.97 or to substance P 12.5 +/‐ 1.2. Maximum ANP wheal response was significantly greater than that to saline at 0.38 +/‐ 0.08 compared with 0.18 +/‐ 0.05 cm2 (difference between means 0.20, 95% CI 0.05, 0.35), but much less than to histamine 0.75 +/‐ 0.06 or to substance P 1.05 +/‐ 0.08 cm2. No dose‐response to ANP was demonstrated, though responses to the highest dose differed significantly from those to the lowest dose studied. We conclude that human cutaneous responses to ANP differ from those of animals and that the skin is less responsive than other tissues in humans.
The effect of meloxicam on the pharmacokinetics of beta‐acetyl‐digoxin.
Authors: Degner FL , Heinzel G. , Narjes H. , Turck D.
Published: July 2012

The influence of multiple‐dose administration of meloxicam on the pharmacokinetics of oral beta‐acetyl‐digoxin was studied in 12 healthy male volunteers in a randomized double‐blind two‐way crossover study. The primary endpoint, Cminss, was within the accepted range for bioequivalence, as were Cmaxss and AUCss. The 90% confidence interval and the point estimator of 98.7 for Cminss were within the equivalence range of 0.8‐1.25. MRT and tmax were also unchanged, while the elimination rate constant was decreased slightly by 12%, which is of no therapeutic relevance. It is concluded that co‐treatment with meloxicam has no effect on the pharmacokinetics of oral digoxin.
Effects of azapropazone on pain‐related brain activity in human subjects.
Authors: Lotsch J. , Mohammadian P. , Hummel T. , Florin S. , Brune K. , Geisslinger G. , Kobal G.
Published: July 2012

1. The dose‐related effects of azapropazone on (i) event‐related and spontaneous EEG‐activity and (ii) the subjects' pain ratings were investigated using an experimental human pain model based on both chemo‐ somatosensory event‐related potentials (CSSERP) and subjects' pain ratings. 2. Healthy subjects (n = 20) participated in a placebo‐ controlled, randomized, double‐blind, four‐way cross‐over study. Single doses of azapropazone (300 mg, 600 mg and 1200 mg) and placebo were administered intravenously. Each experiment consisted of five sessions (before and 1, 2, 4 and 8 h after administration of the medication). Each session lasted for approximately 40 min. In the first 20 min, pain was induced by short CO2‐stimuli presented to the right nostril (phasic pain; interstimulus interval 30 s) and EEG was recorded from five positions. CSSERPs were obtained in response to painful CO2‐stimuli. In the following 20 min period, tonic pain was induced by a constant stream of dry air introduced in the left nostril. Subjects rated the intensity of both phasic and tonic pain by means of a visual analogue scale. Additionally, a frequency analysis of the spontaneous EEG was performed. 3. Azapropazone reduced the pain‐related CSSERP‐amplitudes at frontal and parietal recording positions. This topographical pattern was observed in previous studies with opioids, while NSAIDs such as flurbiprofen and ketoprofen exerted effects at frontal and central positions. In contrast to other NSAIDs, administration of azapropazone resulted in a reduction of the frequency bands alpha 1, delta and theta of the spontaneous EEG. At the subjective level, analgesic effects of azapropazone were observed in the ratings of tonic pain. 4. Analgesic properties of azapropazone were demonstrated in man. The topographical pattern of the changes in the CSSERPs and the effects on EEG background activity suggest a central component of the analgesic action of azapropazone.
Actions of terfenadine and cimetidine on histamine wheal formation.
Authors: Vere DW
Published: July 2012

1. A Latin square design was used to compare the effects of four masked oral drugs, placebo, cimetidine, terfenadine and cimetidine plus terfenadine, at single standard doses against histamine injected at concentrations of 0.3 mM and 0.074 mM subepidermally in eight healthy volunteers studied at weekly intervals. 2. Wheal growth occurred in three phases, an initial delay, a phase of rapid growth where drugs were effective, and a phase of slow growth where there were no significant drug effects. 3. Terfenadine was an effective antihistamine. 4. The data were consistent with a terfenadine effect continued into the next treatment block. 5. Under these conditions cimetidine apparently reduced the effects of terfenadine during the rapid wheal growth phase both simultaneously and after a week's interval from terfenadine dosing.
Binding of temoporfin to the lipoprotein fractions of human serum.
Authors: Michael‐Titus AT , Whelpton R. , Yaqub Z.
Published: July 2012

The binding of a new photosensitizer, temoporfin, to human serum lipoproteins was investigated. [14C]‐Temoporfin (0.1‐10 micrograms ml‐ 1) was incubated with human serum for 30 min at room temperature or for 20 h at 4 degrees C, prior to stepwise density flotation to separate the lipoprotein fractions. The distribution of the drug was independent of the initial concentration or time and temperature of the incubation. The proportion of temoporfin in each fraction was: very low density lipoprotein 6%, low density lipoprotein 22%, lipoprotein(a) 17%, high density lipoprotein 39% and lipoprotein deficient serum 16%. Autoradiography of agarose gels showed that the drug was associated with the lipoprotein in the fractions. Fractionation of plasma samples collected from a patient after an intravenous infusion of temoporfin revealed a binding profile similar to that obtained in the in vitro study.
Longitudinal variation in food sources and their use by aquatic fauna along a subtropical river in Taiwan
Authors: CHANG HAO‐YEN , WU SHENG‐HAI , SHAO KWANG‐TSAO , KAO WEN‐YUAN , MAA CAN‐JEN W. , JAN RONG‐QUEN , LIU LI‐LIAN , TZENG CHYNG‐SHYAN , HWANG JIANG‐SHIOU , HSIEH HWEY‐LIAN , KAO SHUH‐JI , CHEN YU‐KAI , LIN HSING‐JUH
Published: July 2012

1. River food webs rely on two major food sources: autochthonous primary production within the river and allochthonous organic matter transferred to the river. We characterised the consumer communities and assessed the food sources of dominant consumers along a subtropical mountainous river (the Lanyang River of north‐eastern Taiwan) at the catchment scale from the headwater to the estuary using natural abundances of stable carbon and nitrogen isotopes.

2. The downstream transport of fine particulate organic matter (FPOM) was two orders of magnitude greater than that of coarse particulate organic matter (CPOM). Transport of both materials increased from the headwater and reached a maximum in the midstream reach. CPOM composition exhibited a gradual shift from leaves and branches in the headwater, an area characterised by high canopy cover, to algae in the midstream reaches and marsh plants in the downstream reaches.

3. Consumer communities can be classified into two regional categories: the upland category in the headwater and upstream and midstream reaches and the lowland category comprised of samples from the downstream reach and estuary. The upland category revealed a clear and gradual seasonal shift in community composition, but a seasonal shift was not apparent for the lowland category. Nutrient concentrations and water temperature were the main factors explaining longitudinal and seasonal variations.

4. The use of sources of organic matter by dominant consumers along the Lanyang River was primarily determined by their availability. Riparian C3 plants were the major food sources in the headwater, upstream reach and estuary, but the contribution of periphyton increased in the upper midstream reach where the river flows through an agricultural area. In the lower midstream and downstream reaches, the contribution of riparian C4 plants became dominant.

5. The trophic transfer of organic materials in the Lanyang River may be influenced by the fast current velocity and by sewage nutrient loading in the river, both of which have important implications for predicting how the functioning of subtropical river food webs will respond to human‐related changes in land use.
Difficult clinical challenges in haemophilia: international experiential perspectives
Authors: FORSYTH ANGELA L. , GIANGRANDE PAUL , HAY CHARLES R. M. , KENET GILI , KESSLER CRAIG M. , KNÖBL PAUL N. , LLINÁS ADOLFO , SANTAGOSTINO ELENA , YOUNG GUY
Published: July 2012

Summary.  Haemostasis management in people with haemophilia can present a range of challenges to physicians. Specific challenges that may be encountered relate to regimens for immune tolerance induction, use of central venous access devices, optimizing care of paediatric patients with inhibitors and improving outcomes in acquired haemophilia. There are also challenges related to performing surgery, and the establishment of specialist centres is valuable with regard to this. These challenges are considered in the light of available data, and with perspectives gained from the experience of experts treating patients around the world. Sharing this knowledge may help to improve patient management.
Optimizing joint function: new knowledge and novel tools and treatments
Authors: MONAHAN PAUL E. , DORIA ANDREA S. , LJUNG ROLF , JIMÉNEZ‐YUSTE VICTOR
Published: July 2012

Summary.  Progressive joint destruction resulting from intra‐articular bleeding is the major morbidity affecting patients with haemophilia (PWH), particularly those with inhibitors. Advances in understanding the detrimental processes set in motion by the exposure of joints to bleeding have shaped current management methods. However, to achieve optimal joint health in PWH, in addition to achieving haemostasis at the bleeding vessel, it may be appropriate to explore experimentally other conceptual frameworks. These include the possibilities that markers might help to identify individuals at the risk of more rapid joint deterioration, that clotting factors may have additional local action within tissues, and that outcomes might be improved with therapies that directly address wound healing and inflammation. Joint assessment tools are important. Conventional radiography is frequently used, but given the possibility of subclinical joint bleeds, accurate non‐invasive imaging tools are required to detect soft tissue and cartilage changes. Magnetic resonance imaging and ultrasonography can prove valuable here. New imaging techniques should help to increase understanding of the biological basis of early events in haemophilic arthropathy. The optimal way to measure outcomes in haemophilia is to use several methods – in addition to imaging methods, a 360° approach will use physical, functional and quality‐of‐life instruments. In PWH, inhibitor development complicates treatment of joint bleeds and increases the risk of developing arthropathy. A new therapeutic approach for joint bleeds in inhibitor patients divides treatment into two phases: bleed control, with bypassing agent therapy until bleeding has definitely ceased, followed by regular dosing to prevent rebleeds until synovial recovery is complete.
The clotting system – a major player in wound healing
Authors: MONROE DOUGALD M. , HOFFMAN MAUREANE
Published: July 2012

Summary.  Wound healing involves a complex series of interactions between coagulation, inflammation, angiogenesis, and cellular migration and proliferation. Our laboratory has developed an excisional dermal wound model in mice in order to study some of these processes and to determine how coagulation defects affect wound healing. In contrast to wild type mice, haemophilia B mice typically show delayed healing, signs of bleeding into the wound, and significant wound expansion. The difference in wound size may result from limited fibrin deposition in haemophilic animals and the subsequent inability to anchor the platelet plug to the surrounding tissues, thus allowing wound expansion through oedema. Haemophilic mice also demonstrate impaired wound healing times. However, while pre‐treatment with factor IX or human activated factor VII improves some wound characteristics in haemophilia B animals, the time to wound healing is still delayed and signs of ongoing bleeding are evident. Haemophilic mice also show a deficient initial inflammatory response and increased angiogenesis, which, in turn, leads to increased bleeding: in the absence of robust haemostasis, these fragile, newly sprouted vessels have a tendency to bleed. Taken together, these observations suggest that ongoing haemostasis is necessary for normal wound healing. If this is correct, then optimal wound healing in haemophilia would require therapy until at least the point that vessel formation is stabilized. The goal of such treatment would be to avoid a feedback cycle in which bleeding tends to lead to further bleeding. Once initiated, this cycle may be difficult to control.
Liver transplant outcomes in HIV(+) haemophilic men
Authors: Ragni M. V. , DeVera M. E. , Roland M. E. , Wong M. , Stosor V. , Sherman K. E. , Hardy D. , Blumberg E. , Fung J. , Barin B. , Stablein D. , Stock P. G.
Published: July 2012

Hepatitis C virus infection is the major cause of end‐stage liver disease and the major indication for transplantation (OLTX), including among HIV‐HCV co‐infected individuals. The age of HCV acquisition differs between haemophilic and non‐haemophilic candidates, which may affect liver disease outcomes. The purpose of the study was to compare rates of pre‐ and post‐OLTX mortality between co‐infected haemophilic and non‐haemophilic subjects without hepatocellular cancer participating in the Solid Organ Transplantation in HIV Study (HIV‐TR). Clinical variables included age, gender, race, liver disease aetiology, BMI, antiretroviral therapy, MELD score, CD4 +  cell count, HIV RNA PCR and HCV RNA PCR. Time to transplant, rejection and death were determined. Of 104 HIV‐HCV positive subjects enrolled, 34 (32.7%) underwent liver transplantation, including 7 of 15 (46.7%) haemophilic and 27 of 89 (30.3%) non‐haemophilic candidates. Although haemophilic subjects were younger, median 41 vs. 47 years, P = 0.01, they were more likely than non‐haemophilic subjects to die pre‐OLTX, 5 (33.3%) vs. 13 (14.6%), P = 0.03, and reached MELD = 25 marginally faster, 0.01 vs. 0.7 years, P = 0.06. The groups did not differ in baseline BMI, CD4, detectable HIV RNA, detectable HCV RNA, time to post‐OLTX death (P = 0.64), graft loss (P = 0.80), or treated rejection (P = 0.77). The rate of rejection was 14% vs. 36% at 1‐year and 36% vs. 43% at 3‐year, haemophilic vs. non‐haemophilic subjects, respectively, and post‐OLTX survival, 71% vs. 66% at 1‐year and 38% vs. 53% at 3‐year. Despite similar transplant outcomes, pretransplant mortality is higher among co‐infected haemophilic than non‐haemophilic candidates.
The effect of different ternary mixtures of sodium phosphates on hardness of processed cheese spreads
Authors: Buňka František , Doudová Lucie , Weiserová Eva , Kuchař Dalibor , Michálek Jaroslav , Slavíková Štěpánka , Kráčmar Stanislav
Published: July 2012

The aim of this study was to describe the dependence of hardness of processed cheeses on the proportion of disodium hydrogenphosphate (DSP), tetrasodium diphosphate (TSPP) and/or sodium salts of polyphosphate (POLY) in ternary mixtures of emulsifying salts. The samples were observed during a 30‐day storage period (at 6 °C). On the second day of storage, hardness of the samples with the individual DSP, TSPP or POLY were in the range of 1.65–1.83 N, 2.42–2.81 N and 5.98–6.53 N, respectively. Within zero or a very low proportion of POLY in the mixture, hardness of the processed cheeses increased rapidly (up to 14 N) at a specific ratio of DSP to TSPP in range of 1:1–3:4. Hardness of the samples containing the above‐mentioned specific ratio was decreasing with the rising content of POLY (up to 60%) in the ternary mixtures. Within the prevailing content of POLY in the ternary mixtures (more than 60%), the phenomenon of a specific ratio of DSP to TSPP was no longer observed. With the increasing storage period (up to 30 days), hardness of the processed cheeses was slightly rising (in range of 2–4 N).
Chemical and sensory characteristics of meat from Nellore and Crioulo Lageano breeds
Authors: Mitterer‐Daltoé Marina L. , Petry Fabiane C. , Wille Daniele F. , Treptow Rosa O. , Martins Vera M. V. , Queiroz Maria I.
Published: July 2012

This study aimed to describe and differentiate Crioulo Lageano and Nellore beef using chemical and sensory characteristics. Twenty‐four cattle were divided into two groups as follows: Nellore (12) and Crioulo Lageano (12). Six types of cuts were analysed: topside, rum cap, eye round, tenderloin, sirloin and rib eye. The Crioulo cuts had a higher (P ≤ 0.05) percentage of fat compared with the Nellore cuts with the exception of the sirloin and rib eye where no significant differences were found. Moreover, breed type influenced collagen variation. The total colour difference parameter indicated a significant colour difference between meats from the different breeds. A quantitative descriptive analysis showed differences in sensory attributes between breeds and cuts. The breed type had a significant effect on the fibre residue, bitter taste, chewiness and fat residue. According to the principal component analysis, certain sensory attributes provided 48.8% of the information about the Crioulo meat.
Computer‐ and web‐based interventions to promote healthy eating among children and adolescents: a systematic review
Authors: Hamel Lauren M. , Robbins Lorraine B.
Published: July 2012

Aims

To: (1) determine the effect of computer‐ and web‐based interventions on improving eating behavior (e.g. increasing fruit and vegetable consumption; decreasing fat consumption) and/or diet‐related physical outcomes (e.g. body mass index) among children and adolescents; and (2) examine what elements enhance success.

Background

Children and adolescents are the heaviest they have ever been. Excess weight can carry into adulthood and result in chronic health problems. Because of the capacity to reach large audiences of children and adolescents to promote healthy eating, computer‐ and web‐based interventions hold promise for helping to curb this serious trend. However, evidence to support this approach is lacking.

Design

Systematic review using guidelines from the Cochrane Effective Practice and Organisation of Care Group.

Data sources

The following databases were searched for studies from 1998–2011: CINAHL; PubMed; Cochrane; PsycINFO; ERIC; and Proquest.

Review methods

Fifteen randomized controlled trials or quasi‐experimental studies were analysed in a systematic review.

Results

Although a majority of interventions resulted in statistically significant positive changes in eating behavior and/or diet‐related physical outcomes, interventions that included post intervention follow‐up, ranging from 3–18 months, showed that changes were not maintained. Elements, such as conducting the intervention at school or using individually tailored feedback, may enhance success.

Conclusion

Computer‐ and web‐based interventions can improve eating behavior and diet‐related physical outcomes among children and adolescents, particularly when conducted in schools and individually tailored. These interventions can complement and support nursing efforts to give preventive care; however, maintenance efforts are recommended.