bluuebunny/crossref_metadata_2025 huggingface dataset:
The pharmacokinetics of teniloxazine in healthy subjects and patients with hepatic cirrhosis.
Authors: Orlando R , Benvenuti C , Mazzo M , Palatini P
Published: July 2012

The single‐dose and steady‐state pharmacokinetics of teniloxazine, an investigational drug with antidepressant and anti‐anoxic properties, were compared in 12 healthy volunteers and 12 cirrhotic patients, following oral administration of 80 mg teniloxazine maleate every 12 h for 7 days. In healthy volunteers, an increase in oral clearance, CLo (from a mean (s.d.) value of 14.6 (3.9) to 18.0 (6.6) ml min‐1 kg‐1; mean % ratio between the two values (95% CI), 123 (94‐151)) and a significant shortening of t 1/2 (from 6.2 (2.7) to 4.8 (1.4) h; mean % ratio (95% CI), 78 (58‐98)) were observed upon repeated administration, suggesting autoinduction of teniloxazine metabolism. In cirrhotic patients, the pharmacokinetic parameters of teniloxazine remained essentially invariant with time. Compared with normal subjects, CLo was about halved in cirrhotic patients, whereas t 1/2 was more than doubled. As a consequence of these modifications, the multiple‐dose regimen resulted in a two‐fold mean drug accumulation in cirrhotic patients, compared with virtually no accumulation in healthy volunteers. Although no adverse events were noted in either study group, it is suggested that maintenance doses for patients with liver dysfunction should initially be at the lower end of the therapeutic range.
The effect of amoxycillin on salivary nitrite concentrations: an important mechanism of adverse reactions?
Authors: Dougall HT , Smith L , Duncan C , Benjamin N
Published: July 2012

Broad spectrum antibiotics are known to predispose towards oral candidiasis and gastroenteritis. Oral nitrite synthesis by commensal bacteria may be important in protecting the mouth and lower intestine from pathogenic organisms, including Candida albicans. The effect of 2 days administration of the broad spectrum antibiotic amoxycillin on salivary nitrite concentration, following a 200 mg potassium nitrate oral load, was studied in 10 healthy volunteers. The Cmax fell by 40% and the AUC was reduced by 1227 microM h (43%, 95% CI 273, 2181, P < 0.006) in the antibiotic treated group when compared with control. These findings suggest that destruction of nitrate reductase containing bacteria in the mouth by antibiotics may explain an increased incidence of infection with Candida and other pathogens.
Management of hypertension in the elderly: attitudes of general practitioners and hospital physicians.
Authors: Ford GA , Asghar MN
Published: July 2012

1. The attitudes of general practitioners and hospital physicians to the management of hypertension in the elderly, were examined by responses to a postal questionnaire distributed within the Northern Region, concerning the management of a healthy 75 year old male non‐ smoker with sustained diastolic or isolated systolic hypertension. 2. Two hundred and fourteen (64%) general practitioners and 127 (70%) hospital physicians responded to the questionnaire. General practitioners stated they would most commonly measure to the nearest 2 mm Hg (47%) as compared with nearest 5 mm Hg (61%) by physicians; P < 0.05. When measuring diastolic blood pressure 16% general practitioners and 31% physicians would use phase IV sounds; P < 0.01. 3. Median levels of hypertension, confirmed by repeated readings, at which antihypertensive therapy would be commenced were similar: 180 (150‐ 230)/100(90‐120) mm Hg vs 180 (150‐200)/100 (90‐120) mm Hg; median (range). The stated use of non‐pharmacological methods to lower blood pressure before starting drug therapy was similar (74% vs 63%). General practitioners were more likely to prescribe a thiazide diuretic (70% vs 54%) and less likely to prescribe a calcium channel blocker (14% vs 28%) as first line therapy; data for diastolic hypertension, P < 0.001. 4. Considerable variation exists amongst both general practitioners and physicians in their stated assessment and management of a healthy elderly non‐smoking male with sustained hypertension. General practitioners and physicians have similar stated thresholds for treating hypertension but differ in their choice of first line therapy. (ABTRACT TRUNCATED AT 250 WORDS)
The antimalarial drug halofantrine is bound mainly to low and high density lipoproteins in human serum.
Authors: Cenni B , Meyer J , Brandt R , Betschart B
Published: July 2012

1. The major serum proteins which bind halofantrine were identified by size exclusion chromatography. In addition, the binding affinity of halofantrine to human erythrocytes and serum proteins was measured by an erythrocyte partitioning technique. The influence of serum‐drug binding on the distribution of halofantrine in whole blood was estimated by simulating several disease‐related changes in the levels of the most important binding proteins. 2. The chromatographic resolution of serum preincubated with halofantrine allowed a quantitative analysis of binding to low density lipoproteins, high density lipoproteins, alpha 1‐acid glycoprotein and albumin using the erythrocyte partitioning technique. Very low density lipoproteins did not bind halofantrine to a significant extent. 3. In whole blood halofantrine is bound to serum proteins (83%) and to erythrocytes (17%). Low density lipoproteins (affinity constant nKP = 44.4 l g‐1) and high density lipoproteins (nKP = 14.4 l g‐1) were the most important binding proteins in serum. alpha 1‐acid glycoprotein (nKP = 4.39 l g‐1) and albumin (nKP = 0.27 l g‐1) had relatively low binding affinities. 4. The concentration of serum proteins influences both the fraction of unbound drug and the fraction of drug associated with the erythrocytes. Changes in serum protein concentrations often encountered in malaria are likely to increase both the unbound fraction and the fraction bound to the erythrocytes.
Influence of metabolites on protein binding of verapamil enantiomers.
Authors: Johnson JA , Akers WS
Published: July 2012

This study investigated the effect of verapamil metabolites on R‐ and S‐ verapamil protein binding in plasma samples collected from subjects prior to rac‐verapamil dosing and following single dose and steady state rac‐verapamil dosing. In vitro studies of the effects of norverapamil, D617 and D620 on R‐ and S‐verapamil protein binding were also performed. Protein binding of R‐ and S‐verapamil was unchanged following single and multiple doses of rac‐verapamil as compared with protein binding in pre‐dose samples. In vitro, norverapamil had no effect on R‐ and S‐verapamil protein binding up to 1000 ng ml‐1. Norverapamil 5000 ng ml‐1 caused a 30% increase in free fraction of both R‐ and S‐verapamil. D617 and D620 concentrations up to 5000 ng ml‐ 1 had no effect on R‐ and S‐verapamil protein binding. We conclude the metabolites of verapamil have no clinically significant effect on R‐ and S‐verapamil protein binding.
A placebo controlled comparison of the effects of metoprolol and celiprolol on echo‐Doppler measurements of cardiovascular function in normal volunteers.
Authors: Silke B , Thompson A , Leitch A , Riddell JG
Published: July 2012

1. This study used a continuous‐wave echo‐Doppler method (Exerdrop) to investigate the effects of beta‐adrenoceptor antagonism and partial agonism on cardiovascular responses at rest and during dynamic exercise. 2. A double‐blind, randomised, placebo controlled comparison of metoprolol (50 mg) and celiprolol (200 mg) was undertaken in nine normal volunteers; single oral doses of medication were administered at weekly intervals. Rest and exercise (supine bicycle) haemodynamics were assessed at 0, 2, 4, 6 and 8 h following dosing. 3. Before dosing and after placebo, the aortic flow velocity, acceleration and velocity integral increased progressively during exercise, as did heart rate, blood pressure and cardiac output. 4. Following metoprolol 50 mg, heart rate was significantly reduced without change in systolic or diastolic blood pressure. Echo‐Doppler peak acceleration and velocity decreased at rest. On exercise, heart rate and systolic blood pressure fell significantly; the increase in acceleration was significantly blunted compared with placebo (a decrease of 15.2% at rest and 22.9% at 75 watts; P < 0.01 vs placebo). Peak velocity fell significantly by 75 watts exercise. 5. Celiprolol 200 mg at rest significantly increased systolic blood pressure, peak acceleration and velocity. On exercise celiprolol, in contrast to metoprolol, did not reduce peak acceleration or peak velocity; however exercise heart rate and systolic blood pressure were significantly reduced. The difference between celiprolol and metoprolol in respect of peak acceleration persisted over the 8 h of the study. 6. These differences between metoprolol and celiprolol are compatible with the partial agonism of celiprolol.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine receptor‐induced cyclic AMP generation and inhibition of 5‐ hydroxytryptamine release in human platelets.
Authors: Cooper JA , Hill SJ , Alexander SP , Rubin PC , Horn EH
Published: July 2012

1. We have assessed the effects of adenosine receptor agonists and antagonists on collagen‐induced 5‐hydroxytryptamine (5‐HT) release and cyclic AMP generation in human platelets. 2. 5'‐N‐ ethylcarboxamidoadenosine (NECA) and CGS 21680 elicited accumulations of cyclic AMP with mean EC50 values of 2678 and 980 nM, respectively. The maximal response to CGS 21680 was approximately half that of the response to 10 microM NECA. 3. NECA and CGS 21680 inhibited collagen‐ induced 5‐hydroxytryptamine release with mean EC50 values of 960 and 210 nM, respectively. The maximal response to CGS 21680 was approximately 25% of the response to 10 microM NECA. 4. The A1/A2a‐ selective adenosine receptor antagonist PD 115,199 was more potent as an inhibitor of NECA‐elicited responses than the A1‐selective antagonist DPCPX with calculated Ki values of 22‐32 nM and > 10 microM, respectively. 5. In the presence of a cyclic AMP phosphodiesterase inhibitor, the effects of CGS 21680 on cyclic AMP accumulation and 5‐HT release were enhanced to levels similar to those elicited by 10 microM NECA. In the absence of phosphodiesterase inhibition, CGS 21680 did not antagonise the effects of NECA. Furthermore, endogenous adenosine did not contribute to the effects of CGS 21680 when phosphodiesterase was inhibited. 6. We conclude that an A2a adenosine receptor appears to be involved in the NECA‐elicited increases in cyclic AMP levels and inhibition of 5‐HT release in human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of arterio‐venous haemofiltration on teicoplanin elimination.
Authors: Hillaire‐Buys D , Peyriere H , Lobjoie E , Bres J , Ossart M , Despaux E
Published: July 2012

The pharmacokinetics of teicoplanin infused for 30 min at a dose of 6 mg kg‐1 was studied in 11 infected patients under continuous arterio‐ venous haemofiltration (CAVH). Serum teicoplanin levels were assayed by h.p.l.c. over 24 h. After 0.5 h, i.e. at the end of the infusion, the mean plasma concentration was 49.6 +/‐ 15.1 mg l‐1. At the last sampling time (24 h), the mean concentration was 2.6 +/‐ 1.0 mg l‐1. The concentration of teicoplanin was determined in the haemofiltrates. The percentage of the administered dose recovered in the haemofiltrate was low: less than 1% for seven patients, between 1.8 and 3.7% for three patients and 7% for one patient. CAVH patients should be given teicoplanin using the same dosage regimens as previously described for patients with renal impairment.
Systemic effects of S‐nitroso‐glutathione in the human following intravenous infusion.
Authors: Ramsay B , Radomski M , de Belder A , Martin JF , Lopez‐Jaramillo P
Published: July 2012

Nitric oxide (NO) is a potent vasodilator and inhibitor of platelet aggregation. At present the clinical use of NO donors as inhibitors of platelet activation is limited by their concomitant hypotensive effect. The new NO donor S‐nitroso‐glutathione (GSNO) has a significant antiplatelet effect at doses that cause only a small decrease in blood pressure in rats. We have examined the antiplatelet and vasodilator properties of this nitrosothiol following systemic intravenous infusion in the human. GSNO was administered intravenously to 10 normal females of reproductive age noting changes in blood pressure, pulse and reported side effects. Ex vivo platelet aggregation to ADP was then performed in a platelet‐ionized calcium lumiaggregometer on blood samples taken both before and after the infusions. Side effects such as headache or palpitations occurred only in two subjects at the highest infusion rate of 250 micrograms min‐1. Blood pressure and pulse did not vary significantly during the study. Ex vivo platelet aggregation in response to ADP was significantly reduced by the infusion. These results suggest that GSNO is a more potent inhibitor of platelet activation than it is a vasodilator and therefore potentially represents a more clinically useful NO donor than has so far been available where an anti‐thrombotic effect is required.
Influence of basal nitric oxide secretion on cardiac function in man.
Authors: Clarkson PB , Lim PO , MacDonald TM
Published: July 2012

1. Nitric oxide is recognised as an important biological mediator, which is thought to be involved in cardiovascular homeostasis. The purpose of this study was to investigate the effects of basal nitric oxide synthesis on cardiac function in man, by blocking nitric oxide synthesis with NG‐monomethyl‐L‐arginine (L‐NMMA). 2. Eight normal volunteers were studied on two separate occasions. Measurements of heart rate, blood pressure and echocardiographic indices of left ventricular systolic and diastolic function were made at baseline on each day and every 20 min during incremental infusion of L‐NMMA (0.1, 0.2, 0.5, 1.0 and 2.0 mg kg‐1 h‐1) or placebo. 3. A trend towards reduction in heart rate was observed with L‐NMMA infusion although this did not reach statistical significance, whereas significant increases in both systolic blood pressure (at 2.0 mg kg‐1 h‐1) and systemic vascular resistance index (at 0.5 mg kg‐1 h‐1) were seen. 4. L‐NMMA infusion caused significant reductions in stroke distance and cardiac index, although there was no change in the ratio of end systolic wall stress/end systolic volume index (an afterload independent index of left ventricular systolic performance). 5. The isovolumic relaxation time significantly increased with L‐NMMA infusion, together with a significant reduction in the 'E' wave flow velocity integral. Reductions in both peak E/A ratio and E/A flow velocity integral ratio were also seen, although these failed to reach statistical significance. 6. In conclusion, the basal generation of nitric oxide in man appears to maintain a vasodilated state, and modifies left ventricular diastolic filling parameters.
An investigation into the direct and indirect venoconstrictor effects of endothelin‐1 and big endothelin‐1 in man.
Authors: Haynes WG , Moffat S , Webb DJ
Published: July 2012

1. Endothelin‐1 is a potent endothelium‐derived vasoconstrictor peptide that is generated through cleavage of its precursor big endothelin‐1 by 'endothelin converting enzyme' (ECE) in resistance vessels, including those of the forearm vascular bed. In some animal tissues, but not in resistance vessels of healthy human subjects, endothelin‐1 appears to potentiate the actions of the sympathetic nervous system. We examined whether ECE activity is present in human hand veins and whether endothelin‐1 or big endothelin‐1 potentiate sympathetically mediated venoconstriction. 2. Six healthy subjects received dorsal hand vein infusion of local, non‐systemic doses of endothelin‐1 (5 pmol min‐1), big endothelin‐1 (50 pmol min‐1) and, as a control, sodium chloride (0.9%; w/v) for 90 min. Vein diameter was measured using the Aellig displacement technique. Sympathetically mediated venoconstriction was elicited using the single deep breath reflex. 3. Endothelin‐1 caused a progressive decrease in hand vein diameter, by 49% at 90 min (95% confidence intervals [CI]: ‐68 to ‐30%; P = 0.0001). Vein diameter did not change significantly after 90 min infusion of big endothelin‐1 (+3%; CI: ‐11 to +17%; P = 0.0007 vs endothelin‐1; P = 0.40 vs baseline) or sodium chloride (+2%; CI: ‐12 to +16%; P = 0.0002 vs endothelin‐1; P = 0.60 vs baseline). Venoconstriction to deep breath was not potentiated by endothelin‐1. 4. These results suggest that, in contrast to the situation in forearm resistance vessels, there is little or no local ECE activity in human hand veins and that endothelin does not potentiate sympathetic responses in these cutaneous capacitance vessels.
Detection of autoantibodies directed against human hepatic endoplasmic reticulum in sera from patients with halothane‐associated hepatitis.
Authors: Kitteringham NR , Kenna JG , Park BK
Published: July 2012

1. Previous studies have demonstrated the presence of antibodies to trifluoroacetylated hepatic proteins (TFA‐proteins) in sera from patients with the severe form of halothane‐associated hepatitis (halothane hepatitis). The TFA‐proteins are produced via cytochrome P450‐mediated metabolism of halothane to the reactive species TFA‐ chloride. 2. To investigate the presence of autoantibodies (which recognize various non‐TFA‐modified human hepatic polypeptides) in patients with halothane hepatitis immunoblotting experiments were performed using microsomal fractions prepared freshly from livers of five different (halothane‐free) tissue donors. Blots were developed using 15 well‐characterised sera from patients with halothane hepatitis. 3. Autoantibodies to human hepatic polypeptides were detected in most, but not all, of the patients' sera. The pattern of antibody reactivity varied markedly between sera. Although no common pattern of antibody recognition was observed, polypeptides of molecular mass between 60 and 80 kDa were the predominant targets. A similar protein recognition pattern was seen when each positive serum was tested against the five individual human liver samples. 4. Such autoantibodies were not detected in sera from 16 normal human blood donors, but were detected in three of six sera from patients exposed to halothane without developing hepatitis. 5. The autoantibodies are thought to arise in patients exposed to halothane as a consequence of a halothane‐induced immune response to chemically‐modified proteins. Such antibodies could contribute to the complex pathological processes involved in halothane hepatitis.
Modelling the market uptake of new drugs following listing for subsidy in Australia. A report from the Drug Utilisation Subcommittee of the Australian Pharmaceutical Benefits Advisory Committee.
Authors: Birkett DJ , McManus P
Published: July 2012

The market uptake of five drugs following subsidy listing in Australia during the period 1990 to 1992 has been modelled using the sigmoid Emax model for drug‐receptor binding. Utilisation trends for simvastatin, omeprazole, budesonide, fluoxetine and moclobemide in defined daily dose (DDD) per 1000 population per day were smoothed by expressing as rolling annual averages. The results indicate good fits of the model to the data except for omeprazole, with good estimates of uptake rate and eventual maximum utilisation. Substantial differences between the drugs occurred in uptake rate which may be related to public education campaigns on asthma and coronary heart disease occurring during the release period. The very slow uptake of omeprazole relative to other drugs is likely to be due to restrictions on subsidised use. Modelling the market uptake rate and eventual utilisation of new drugs is useful as an aid to regulatory, quality use of medicines and financial decisions and allows comparisons between drugs to investigate factors important in market uptake.
Use of 24 h ambulatory ECG recordings in the assessment of new chemical entities in healthy volunteers.
Authors: Stinson JC , Pears JS , Williams AJ , Campbell RW
Published: July 2012

1. Ambulatory (24 h) cardiac monitoring (ACM) is frequently used to screen healthy volunteers before inclusion in trials of new chemical entities in man. We analysed 156 consecutive ACM recordings in 'healthy' volunteers (on no medication). 2. Only 20 (13%) of the recordings showed normal sinus rhythm throughout. 3. Supraventricular ectopics were the commonest abnormality (83%). Ventricular ectopics occurred in 11%; ventricular tachycardia (unsustained) in 2% and sinus pauses in 6.5%. One volunteer was found to be in atrial fibrillation throughout. 4. The data indicate that when ACM recordings are performed in the assessment of the effects of experimental drugs, guidelines are needed to assess 'normality' to suggest when cardiological investigation is needed and to assign causality of the arrhythmia to the new chemical entity. 5. Proposed guidelines are presented.
A double‐blind, placebo controlled study of the effect of the specific histamine H1‐receptor antagonist, terfenadine, in chronic severe asthma.
Authors: Wood‐Baker R. , Smith R. , Holgate ST
Published: July 2012

1. The characteristic changes seen in asthma are widely regarded as being caused by local mediator release in the airways, with histamine the first putative mediator in asthma to be identified. 2. We performed a double‐blind, randomised, placebo‐controlled crossover trial of the effect of 4 weeks treatment with terfenadine 120 mg twice daily in chronic severe asthma. 3. Forty‐two subjects (20 male and 22 female) completed the 10 week study. 4. Terfenadine had no significant treatment effect on the primary efficacy variables measured. Mean (95% CI) measurements for terfenadine vs placebo treatment periods were 1.5 vs 1.5 (‐0.3, 0.3) l for FEV1, 259 vs 260 (‐42, 40) l min‐1 for morning PEF and 0.8 vs 0.8 (‐0.3, 0.3) for global symptom scores. 5. Bronchodilator use and sleep disturbance, the secondary efficacy variables studied, showed an improvement during terfenadine treatment but this only reached statistical significance for the number of times subjects awoke from sleep (P = 0.04). 6. There was a similar frequency of minor adverse effects reported during placebo (13.6%) and terfenadine (16.7%) treatments. 7. Addition of the potent and specific histamine H1‐receptor antagonist terfenadine to maintenance asthma treatment had no significant therapeutic benefit in this group of chronic severe asthmatics.
Lack of effect of gender and oral contraceptive steroids on the pharmacokinetics of (R)‐ibuprofen in humans.
Authors: Knights KM , McLean CF , Tonkin AL , Miners JO
Published: July 2012

The effects of gender and oral contraceptive steroids on the pharmacokinetics of (R)‐ibuprofen were studied in groups of healthy adult males, females and oral contraceptive steroid (OCS) using females. The values of AUC, CLpo, t1/2 and Vss, app did not differ significantly between the groups. Similarly, the percentage unbound of (R)‐ibuprofen in pooled plasma from the three groups was not statistically different. Since chiral inversion is the major determinant of (R)‐ibuprofen clearance in humans, it may be inferred from these data that gender and OCS have little or no effect on conversion of (R)‐ibuprofen to the pharmacologically active S‐ enantiomer. Moreover, it is unlikely that hormonal factors influence the activity of the human hepatic long‐chain fatty‐acid:CoA ligase, the enzyme mediating the rate limiting step of (R)‐ibuprofen inversion.
The spontaneous reporting of adverse drug reactions by nurses.
Authors: Hall M. , McCormack P. , Arthurs N. , Feely J.
Published: July 2012

In an attempt to improve the low reporting rate of adverse drug reactions (ADR) we examined the potential for hospital nurses to report ADRs through a spontaneous 'yellow card' system. Over 14 months 100 cards were received (compared with 28 cards from doctors). Although reports from doctors for the same period were of a more substantial nature, nurses nevertheless reported many life threatening (17%) or moderately severe (76%) reactions. Nurses identified uncertainty concerning their role and deficient in‐service education on drug therapy as major constraints in their participation. Given their unique position in drug administration and recording observations on patients, we believe that nurses could contribute significantly and in a complementary fashion to the spontaneous reporting of adverse reactions.
Pharmacokinetic‐pharmacodynamic interaction between the COMT inhibitor tolcapone and single‐dose levodopa.
Authors: Dingemanse J. , Jorga K. , Zurcher G. , Schmitt M. , Sedek G. , Da Prada M. , Van Brummelen P.
Published: July 2012

1. Single oral doses of the catechol‐O‐methyltransferase (COMT) inhibitor tolcapone (10‐800 mg) or placebo were administered simultaneously with a dose of levodopa/benserazide 100/25 mg to seven sequential groups of six healthy male subjects in a two‐way crossover study. 2. Plasma concentrations of tolcapone, its metabolite 3‐O‐ methyltolcapone, levodopa and 3‐O‐methyldopa (3‐OMD) were determined in conjunction with COMT activity in erythrocytes. 3. The drug combination was well tolerated at all dose levels and there were no signs indicative of an increase in dopaminergic stimulation. 4. Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes in parallel with a dose‐dependent decrease in the formation of 3‐OMD. Tolcapone increased the area under the concentration‐time curve and elimination half‐life of levodopa. The maximum effects were obtained at a dose of about 200 mg when both parameters increased approximately twofold. The drug had no influence on the maximum concentration of levodopa. 5. Tolcapone was rapidly absorbed and eliminated with, on average, a tmax of 1.5 h and a t1/2 of 2.3 h. The drug showed dose‐proportional pharmacokinetics, in contrast to 3‐O‐methyltolcapone whose formation was relatively decreased at higher doses. 6. Plasma concentrations of tolcapone correlated with inhibition of COMT activity in erythrocytes and suppression of 3‐OMD levels, but not with changes in levodopa pharmacokinetics.
Cardiorespiratory effects of continuous i.v. administration of the ACE inhibitor enalaprilat in the critically ill.
Authors: Boldt J. , Muller M. , Heesen M. , Harter K. , Hempelmann G.
Published: July 2012

1. Cardiorespiratory effects of long‐term, continuous i.v. administration of the ACE inhibitor enalaprilat were studied. 2. Forty‐ five consecutive critically patients suffering from trauma or postoperative complications were randomly separated into three groups (15 patients in each group) receiving either 0.25 mg h‐1 or 0.50 mg h‐1 enalaprilat, respectively, or saline solution as placebo (= control group). The infusion was continued for 5 days. 3. Haemodynamic and respiratory parameters were intensively monitored on admission to the intensive care unit (= 'baseline' values) and daily during the next 5 days. 4. Mean arterial blood pressure (MAP) decreased significantly only in the enalaprilat‐treated patients, whereas heart rate (HR) remained unchanged in these patients. 5. Pulmonary capillary wedge pressure (PCWP) and pulmonary artery pressure (PAP) were decreased by enalaprilat (0.50 mg h‐1: PAP (mean +/‐ s.d.) decreased from 28.0 +/‐ 4.1 to 24.0 +/‐ 3.0 mm Hg) and remained significantly lower than in the control group. In the untreated control group, cardiac index (CI), oxygen consumption (VO2I) and oxygen delivery (DO2I) significantly decreased, which was blunted by enalaprilat infusion. Oxygen extraction (O2‐extr) increased in both enalaprilat groups (0.25 mg h‐1: from 26.1 +/‐ 5.5 to 30.4 +/‐ 4.0%; 0.50 mg h‐1: 25.2 +/‐ 5.6 to 30.9 +/‐ 4.4%) and decreased in the control patients. 6. Right ventricular haemodynamics improved by enalaprilat infusion (0.50 mg h‐1: RVEF increased from 40.0 +/‐ 3.5 to 45.5 +/‐ 4.0%). Lactate plasma concentrations decreased in the group with 0.50 mg h‐1 enalaprilat (from 1.9 +/‐ 1.0 to 1.3 +/‐ 0.3 mg dl‐1) and increased in the control patients. 7. Continuous infusion of the ACE inhibitor enalaprilat exerted beneficial cardiorespiratory effects in the critically ill. The widespread common risk of altered perfusion with decreased CI, DO2, VO2, O2‐extr and increased lactate concentration was blunted by enalaprilat infusion. 8. Although 0.5 mg h‐1 enalaprilat was most effective, a dose of 0.25 mg h‐1 also showed beneficial haemodynamic effects in the critically ill.
The effects of selective serotonin reuptake inhibitors and their metabolites on S‐mephenytoin 4'‐hydroxylase activity in human liver microsomes.
Authors: Kobayashi K. , Yamamoto T. , Chiba K. , Tani M. , Ishizaki T. , Kuroiwa Y.
Published: July 2012

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S‐mephenytoin 4'‐hydroxylation activities in human liver microsomes were studied. The 4'‐hydroxylation of S‐ mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 microM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug‐drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.
Pharmacokinetics of quinine in chronic liver disease.
Authors: Auprayoon P. , Sukontason K. , Na‐Bangchang K. , Banmairuroi V. , Molunto P. , Karbwang J.
Published: July 2012

The pharmacokinetics of quinine were investigated in a) six healthy male Thai subjects, and b) nine male Thai patients with a moderate degree of chronic liver disease, after a single oral dose of 600 mg quinine sulphate. tmax and t1/2.2 were significantly prolonged in patients (median [range] tmax 2 [1‐5] vs 1.6 [0.8‐2] h; t1/2,z 23.4 [17.4‐41.7] vs 9.7 [7.8‐17.2] h), and Vz/F was significantly larger (median [range] 4.21 [2.33‐15.87] vs 2.78 [1.49‐3.38] 1 kg‐1). Median (range) concentration of the plasma unbound Qn fraction collected from the patients at 4 h after drug administration was 17 (8.4‐17.8)% of total drug concentration.
Where are we at with point‐ of‐ care testing in haematology?
Authors: Briggs Carol , Kimber Simon , Green Laura
Published: July 2012

Point‐of‐care testing (POCT) in haematology has continued to grow in popularity and uptake throughout the world. The increasing demand to reduce the turnaround time of test results, coupled with rapid improvements in technology, have led to the development of several devices that are designed for use in different clinical settings, with the hope of improving patient care. The most used POCT in haematology is measurement of haemoglobin concentration. Other POCT devices (used primarily in developing countries) for malaria screening and CD4+ T‐lymphocytes for quantification of human‐immunodeficiency‐virus are becoming the cornerstone for the diagnosis and management of these disorders. New devices are also available for red cell indices, white blood cell count and platelets. In this review clinical studies that validate the use of such devices will be discussed, as well as the advantages and disadvantages of POCT in haematology. A disadvantage of POCT is a lack of training, poor standardization in obtaining blood samples and insufficient internal/external quality assessment. As there is every reason to expect that POCT use will increase in all pathology disciplines, including haematology, it is imperative that systems are put in place to oversee these issues.
Chronobiology of blood pressure: emerging implications of melatonin
Authors: Simko Fedor
Published: July 2012

Eur J Clin Invest 2012; 42 (11): 1252–1254
Phenolic compounds in fruits – an overview
Authors: Haminiuk Charles W. I. , Maciel Giselle M. , Plata‐Oviedo Manuel S. V. , Peralta Rosane M.
Published: July 2012

Phenolic compounds are secondary metabolites widely found in fruits, mostly represented by flavonoids and phenolic acids. The growing interest in these substances is mainly because of their antioxidant potential and the association between their consumption and the prevention of some diseases. The health benefits of these phytochemicals are directly linked to a regular intake and their bioavailability. Studies have shown the importance of the regular consumption of fruits, especially for preventing diseases associated with oxidative stress. In the present review, the most recent articles dealing with polyphenols in fruits are reviewed, focusing on their occurrence, main methods of extraction, quantification and antioxidant assays. In addition, the health benefits and bioaccessibility/bioavailability of phenolic compounds in fruits are addressed.
Improving antioxidant activities of whey protein hydrolysates obtained by thermal preheat treatment of pepsin, trypsin, alcalase and flavourzyme
Authors: Lin Suju , Tian Weina , Li He , Cao Jiankang , Jiang Weibo
Published: July 2012

Antioxidant activity of whey protein concentrate (WPC) hydrolysates was evaluated. Hydrolysates were obtained by pepsin, trypsin, alcalase and flavourzyme enzymatic reaction and preheat treatment of 95 °C for 5 or 10 min. The degree of hydrolysis (DH) was determined by 2,4,6‐trinitrobenzene sulphonic acid method, and antioxidant properties were determined by three spectrophotometric methods: ferricyanide method, ferric reducing/antioxidant power assay and diphenyl‐picryl hydrazinyl radical‐scavenging activity. For all the enzymes, briefly preheat treatment (95 °C/5 min) increased DH of WPC. Alcalase hydrolysates showed the highest antioxidant activity by three methods. The changes in antioxidant activity was coincidental with the changes in DH (R2 = 0.988). Hydrolysates analysed by polyacrylamide gel electrophoresis and high performance liquid chromatography indicated that the α‐La was hydrolysed completely by pepsin, trypsin and alcalase and was resistant to flavourzyme to some extent; β‐lactoglobulin was only completely hydrolysed by trypsin and alcalase. Results indicated that antioxidant activity of hydrolysates was greatly related to the exposure of amino acid residues.
Antimicrobial activity of chitosan‐based films against Salmonella typhimurium and Staphylococcus aureus
Authors: Rodríguez‐Núñez Jesús R. , López‐Cervantes Jaime , Sánchez‐Machado Dalia I. , Ramírez‐Wong Benjamin , Torres‐Chavez Patricia , Cortez‐Rocha Mario O.
Published: July 2012

The antibacterial effect of polyamide 6/66‐chitosan blend and chitosan‐coated plastic films was compared to chitosan films and chitosan solution, against Salmonella typhimurium and Staphylococcus aureus. The chitosan films did not show inhibition halos; however, contact inhibition was observed. During the tests, the films absorbed moisture, increasing of the diameter discs in relation to the concentration of the chitosan for both microorganisms at least 31%. Chitosan plastic film coating (bilayer system) showed only contact inhibition, without increase in contact area. The films from polyamide 6/66‐chitosan blend had no antibacterial activity. The highest inhibitory effect resulted from a chitosan solution at 1000 and 2000 ppm for S. typhimurium and S. aureus, respectively. The results of this study showed that the antimicrobial activity was lessened when the chitosan was combined with the plastic matrix because of the absence of contact inhibition, and the best activity was obtained with films prepared by casting of chitosan solution.
Before empowerment: residents' memories of the role of the housemother in diaconal residential care settings in Germany 1945–1995
Authors: HÄNDLER‐SCHUSTER D. , SCHULZ M. , BEHRENS J.
Published: July 2012

Accessible summary

In German institutions for people with mental illness, some woman lived and worked as ‘housemothers’. In the 20th century, they played a very important role. This paper is based on interviews with people who lived in these institutions and looks at their experiences of a place where carers and people with mental illness lived together.

Housemothers often spent decades living and working in the institutions. There are three main phases to their development: (1) ‘Setting out as bride: borrowed power and domination’; (2) ‘Realizing one's potential as a housemother: applied power and domination’; and (3) ‘Leaving the housemother function: lost power and domination’.

The findings show that the housemothers often felt that they did not get enough recognition for what they did from the deacons. Deacons in Germany are ministers in the Protestant Church who also have special training in social care. Housemothers did not just do housework; they were also caregivers who played a decisive role in resource‐oriented care. The concepts of power and domination are very important here.

The historical concept of houseparents helps us understand the current discussion about new forms of residential care homes and psychiatric care.

In the 20th century, houseparent families represented a significant resource in the long‐term care of people with mental illnesses and physical disabilities in diaconical care settings in Germany. In theory, such families could therefore be understood as a type of institutional family: groups which occasionally use familial patterns of reciprocity but are not themselves families. As little empirical material on life in institutional families existed, a qualitative study was undertaken to explore the experiences of contemporary witnesses, particularly those who had experienced the duties and responsibilities of housemothers in the second half of the 20th century. This paper has combined the experiences of residents (n= 8) and biological children of houseparents (n= 5) from a qualitative study (n= 42). The qualitative study took a grounded theory approach, with the phenomena of power and domination forming the central category. The findings show that life in houseparent families of the time was shaped by rules which the family members had to obey. This study explores a highly controversial area which is of great relevance for current mental health nursing practice: the power relations in diaconal families. This demonstrates the importance of integrating autonomy and empowerment into everyday communal life and contributes to professional nursing practice.
IL28B genetic variation and hepatitis C virus–specific CD4+ T‐cell responses in anti‐HCV‐positive blood donors
Authors: Bes M. , Sauleda S. , Campos‐Varela I. , Rodriguez‐Frias F. , Casamitjana N. , Homs M. , Piron M. , Quer J. , Tabernero D. , Guardia J. , Puig L. , Esteban J. I.
Published: July 2012

Summary.  Epidemiological, viral and host factors are associated with the outcome of hepatitis C virus (HCV) infection, and strong host immune responses against HCV favour viral clearance. Recently, genome‐wide association studies have shown a strong correlation between single‐nucleotide polymorphisms (SNPs) near the interleukin‐28B (IL28B) gene and spontaneous or treatment‐induced HCV clearance. We have investigated whether protective IL28B genetic variants are associated with HCV‐specific T‐cell responses among Spanish blood donors. The rs12979860 IL28B haplotype was determined in 69 anti‐HCV‐positive blood donors (21 HCV RNA negative and 48 HCV RNA positive) and 30 seronegative donors. In all cases, HCV‐specific CD4+ T‐cell responses to HCV recombinant proteins (core, NS3 and NS3 helicase) were assessed by ex vivo interferon‐γ ELISpot assay. The rs12979860‐CC genotype was highly overrepresented in donors with spontaneous HCV clearance when compared to those with chronic infection (76.2%vs 29.2%, P < 0.001; odds ratio, 7.77; 95% confidence interval, 2.4–25.3, P < 0.001). HCV‐specific CD4+ T‐cell responses were detected in 16 (76.2%) spontaneous resolvers especially towards nonstructural proteins, but with no correlation with IL28B genotype. Chronic individuals had a significantly lower overall T‐cell response again irrespective of IL28B genotype. When spontaneous resolvers and chronic individuals were stratified according to their IL28B genotype, significantly stronger T‐cell responses were only observed among those with non‐CC haplotypes. Although the protective rs12979860 IL28B CC genotype is associated with spontaneous HCV clearance, stronger CD4+ T‐cell responses towards NS3 were only evident among those with non‐CC haplotypes.
Endogenous cellular prion protein regulates contractility of the mouse ileum
Authors: MARTIN G. R. , ALVAREZ A. L. , BASHASHATI M. , KEENAN C. M. , JIRIK F. R. , SHARKEY K. A.
Published: July 2012

Background  Cellular prion protein (PrPC) is expressed in the enteric nervous system (ENS), however, its physiological role has not been identified. Studies suggest that PrPC can function as a metal‐binding protein, as absence of the protein has been linked to altered copper metabolism and atypical synaptic activity. Because copper is known to modulate smooth muscle relaxation, we tested the hypothesis that PrPC deficiency would alter intestinal contractility.

Methods  We examined electrically evoked ileal contractility in Prnp−/− or wild type littermate mice and the effects of copper or copper chelation. PrPC expression was studied in whole mount ileal preparations of mice and guinea pigs by immunohistochemistry.

Key Results  Relative to wild type mice, ileal tissues of Prnp−/− mice exhibited reduced electrical field stimulation (EFS)‐evoked contractility. Furthermore, EFS‐induced relaxation, as a percentage of that induced by a nitric oxide donor, was enhanced. Addition of a copper donor to the organ bath increased, whereas the addition of a copper chelator inhibited, nitric oxide donor‐induced ileal relaxation in Prnp−/− mice. PrPC was expressed on nerve fibers or terminals, and some cell bodies in the myenteric and submucosal plexuses of wild type mice. PrPC colocalized with a neuron‐specific ectonucleotidase, nucleoside triphosphate diphosphohydrolase 3 (NTPDase3), but to only a limited extent with GFAP, a marker of enteric glia. Guinea pigs expressed PrPC in nerve fibers or terminals and enteric glia in the myenteric and submucosal plexuses.

Conclusions & Inferences  Our findings suggest that PrPC, which is abundant in the ENS, has a role in the regulation of ileal contractility.
Mitochondrial DNA deletions and depletion within paraspinal muscles
Authors: Campbell G. R. , Reeve A. , Ziabreva I. , Polvikoski T. M. , Taylor R. W. , Reynolds R. , Turnbull D. M. , Mahad D. J.
Published: July 2012

G. R. Campbell, A. Reeve, I. Ziabreva, T. M. Polvikoski, R. W. Taylor, R. Reynolds, D. M. Turnbull and D. J. Mahad (2013) Neuropathology and Applied Neurobiology39, 377–389

Mitochondrial DNA deletions and depletion within paraspinal muscles

Aims: Although mitochondrial abnormalities have been reported within paraspinal muscles in patients with axial weakness and neuromuscular disease as well as with ageing, the basis of respiratory deficiency in paraspinal muscles is not known. This study aimed to determine the extent and basis of respiratory deficiency in paraspinal muscles from cases undergoing surgery for degenerative spinal disease and post mortem cases without a history of spinal disease, where age‐related histopathological changes were previously reported. Methods: Cervical and lumbar paraspinal muscles were obtained peri‐operatively from 13 patients and from six post mortem control cases (age range 18–82 years) without a neurological disease. Sequential COX/SDH (mitochondrial respiratory chain complex IV/complex II) histochemistry was performed to identify respiratory‐deficient muscle fibres (lacking complex IV with intact complex II activity). Real‐time polymerase chain reaction, long‐range polymerase chain reaction and sequencing were used to identify and characterize mitochondrial DNA (mtDNA) deletions and determine mtDNA copy number status. Mitochondrial respiratory chain complex subunits were detected by immunohistochemistry. Results: The density of respiratory‐deficient fibres increased with age. On average, 3.96% of fibres in paraspinal muscles were respiratory‐deficient (range 0–10.26). Respiratory deficiency in 36.8% of paraspinal muscle fibres was due to clonally expanded mtDNA deletions. MtDNA depletion accounted for further 13.5% of respiratory deficiency. The profile of immunohistochemically detected subunits of complexes was similar in respiratory‐deficient fibres with and without mtDNA deletions or mtDNA depletion. Conclusions: Paraspinal muscles appeared to be particularly susceptible to age‐related mitochondrial respiratory chain defects. Clonally expanded mtDNA deletions and focal mtDNA depletion may contribute towards the development of age‐related postural abnormalities.
Interaction of xylem and phloem during exudation and wound occlusion in Cucurbita maxima
Authors: ZIMMERMANN MATTHIAS R. , HAFKE JENS B. , VAN BEL AART J. E. , FURCH ALEXANDRA C. U.
Published: July 2012

Collection of cucurbit exudates from cut petioles has been a powerful tool for gaining knowledge on phloem sap composition without full notion of the complex exudation mechanism. Only few publications explicitly mentioned that exudates were collected from the basal side of the cut, which exudes more copiously than the apical side. This is surprising since only exudation from the apical side is supposedly driven by phloem pressure gradients. Composition of carbohydrates and pH values at both wounding sides are equal, whereas protein concentration is higher at the basal side. Apparently, exudation is far more complex than just the delivery of phloem sap. Xylem involvement is indicated by lower protein concentrations after elimination of root pressure. Moreover, dye was sucked into xylem vessels owing to relaxation of negative pressure after cutting. The lateral water efflux from the vessels increases turgor of surrounding cells including sieve elements. Simultaneously, detached parietal proteins (PP1/PP2) induce occlusion of sieve plates and cover wound surface. If root pressure is strong enough, pure xylem sap can be collected after removal of the occlusion plug at the wound surface. The present findings provide a mechanism of sap exudation in Cucurbita maxima, in which the contribution of xylem water is integrated.
The cost‐effectiveness of immunotherapy for respiratory allergy: a review
Authors: Simoens S.
Published: July 2012

This article reviews the international literature on the cost‐effectiveness of immunotherapy for respiratory allergy. Included studies conducted an economic evaluation of immunotherapy for allergic rhinoconjunctivitis, allergic conjunctivitis, allergic rhinitis, asthma or allergic rhinitis in combination with asthma. Although there were few economic evaluations and these suffered from methodological shortcomings, the evidence appears to support the cost‐effectiveness of immunotherapy as compared with pharmacotherapy for allergic rhinoconjunctivitis, subcutaneous immunotherapy as compared with pharmacotherapy for allergic rhinitis and immunotherapy as compared with pharmacotherapy for allergic rhinitis and asthma. One economic evaluation suggested that immunotherapy as compared with pharmacotherapy is unlikely to be cost‐effective for asthma. The questions of the cost‐effectiveness of sublingualvssubcutaneous immunotherapy and of the cost‐effectiveness of immunotherapy for allergic conjunctivitis have not been resolved to date. The cost‐effectiveness of immunotherapy depends on the duration of the clinical benefit of immunotherapy following treatment cessation, and on the break‐even point of cumulative costs between immunotherapy and pharmacotherapy. There is a need for economic evaluations based on high‐quality prospective and long‐term clinical studies comparing immunotherapy with pharmacotherapy in real‐life practice and comparing sublingual with subcutaneous immunotherapy.
Intensive educational course in allergy and immunology
Authors: Elizalde A. , Perez E. E. , Sriaroon P. , Nguyen D. , Lockey R. F. , Dorsey M. J.
Published: July 2012

A one‐day intensive educational course on allergy and immunology theory and diagnostic procedure significantly increased the competency of allergy and immunology fellows‐in‐training.