bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of a defender on run‐up velocity and ball speed when crossing a football
Authors: Orth Dominic , Davids Keith , Araújo Duarte , Renshaw Ian , Passos Pedro
Published: July 2012

This study evaluated effects of defensive pressure on running velocity in footballers during the approach to kick a stationary football. Approach velocity and ball speed/accuracy data were recorded from eight football youth academy participants (15.25, SD=0.46 yrs). Participants were required to run to a football to cross it to a receiver to score against a goal‐keeper. Defensive pressure was manipulated across three counterbalanced conditions: defender‐absent (DA); defender‐far (DF) and defender‐near (DN). Pass accuracy (percentages of a total of 32 trials with 95% confidence limits in parenthesis) did not significantly reduce under changing defensive pressure: DA, 78% (55–100%); DF, 78% (61–96%); DN, 59% (40–79%). Ball speed (m·s−1) significantly reduced as defensive pressure was included and increased: DA, 23.10 (22.38–23.83); DF, 20.40 (19.69–21.11); DN, 19.22 (18.51–19.93). When defensive pressure was introduced, average running velocity of attackers did not change significantly: DA versus DF (m·s−1), 5.40 (5.30–5.51) versus 5.41 (5.34–5.48). Scaling defender starting positions closer to the start position of the attacker (DN) significantly increased average running velocity relative to the DA and DF conditions, 5.60 (5.50–5.71). In the final approach footfalls, all conditions significantly differed: DA, 5.69 (5.35–6.03); DF, 6. 22 (5.93–6.50); DN, 6.52 (6.23–6.80). Data suggested that approach velocity is constrained by both presence and initial distance of the defender during task performance. Implications are that the expression of kicking behaviour is specific to a performance context and some movement regulation features will not emerge unless a defender is present as a task constraint in practice.
The science–policy interface: the role of scientific assessments—UK National Ecosystem Assessment
Authors: Watson Robert Tony
Published: July 2012

This paper discusses the science–policy interface, emphasizing the role of evidence and scientific assessments. It then presents the key findings from the UK National Ecosystem Assessment (NEA), which provided much of the evidence for the Natural Environment White Paper for England as a case study. It also influenced the development of the biodiversity strategy for England. The NEA demonstrates the importance of a multi-disciplinary team of experts to prepare and peer review assessments and the importance of input from funding agencies and relevant stakeholder groups in co-designing and reviewing. Much of the text and all of the figures in the NEA section are taken from the Synthesis Report of the NEA, which I drafted as co-chair of the NEA.

1
The pharmacokinetics of Casodex enantiomers in subjects with impaired liver function
Authors: COCKSHOTT I. D. , SOTANIEMI E. A. , COOPER K. J. , JONES D. C.
Published: July 2012

Casodex is a novel non‐steroidal antiandrogen being developed for the treatment of prostatic cancer. The antiandrogenic activity is predominantly in the R(–) enantiomer with little, if any, activity in the S(+) enantiomer.

The pharmacokinetics of the enantiomers of Casodex have been investigated over 28 days following a single oral dose of Casodex (50 mg) to 10 male subjects with histologically verified liver cirrhosis or fatty liver with fibrosis. Ten age matched male subjects with normal hepatic function served as a control group.

For both groups plasma concentrations of (S)‐Casodex were lower than those for (R)‐Casodex; this difference was about 10‐fold at early time points and increased to about 25‐fold by 24 h after dosage.

The kinetics of (R)‐Casodex were similar in subjects with and without liver disease (Cmax: 750 vs 848 ng ml−1; tmax: 24 − 30 h; t1/2;: 7.40 vs 7.22 days; AUC: 182 vs 225μg ml−1 h).

The kinetics of (S)‐Casodex could not be described in the majority of subjects; in the remainder the mean terminal phase half‐life for both groups was less than 1 day.
Trough concentrations of cyclosporine in blood following administration with grapefruit juice
Authors: DUCHARME MURRAY P. , PROVENZANO ROBERT , DEHOORNE‐SMITH MICHELLE , EDWARDS DAVID J.
Published: July 2012

Components of grapefruit juice have been shown to inhibit CYP3A4 activity, the enzyme involved in cyclosporine metabolism. Eleven medically stable patients (seven males, four females) receiving cyclosporine following kidney transplantation were instructed to take their usual dose of cyclosporine with water for 1 week (Phase 1), with grapefruit juice (8 ounces) for 1 week (Phase 2) and again with water for 1 week (Phase 3). Trough blood samples were obtained at the end of each phase for measurement of cyclosporine concentration using a specific monoclonal whole blood radioimmunoassay. Cyclosporine trough concentrations averaged 116.9 ± 51.6 ng ml−1 in the first phase, 145.3 ± 44.7 ng ml−1 with grapefruit juice (P < 0.05 compared with the first and third phases) and 111.2 ± 56.1 ng ml−1 in the third phase. Cyclosporine concentrations increased in 8 of 11 patients when given with grapefruit juice (mean increase 32%; range −4 to 97%) and declined in 10 of 11 when subjects resumed taking cyclosporine with water (mean decrease 27%). These results suggest that grapefruit juice increases trough concentrations of cyclosporine in blood, possibly by inhibiting pre‐hepatic gut wall metabolism, and could be useful in optimizing therapy with this drug.
Stereoselective sulphate conjugation of salbutamol in humans: comparison of hepatic, intestinal and platelet activity.
Authors: Walle UK , Pesola GR , Walle T
Published: July 2012

1. The oral bioavailability of the beta 2‐adrenoceptor agonist salbutamol has been proposed to be stereoselective, presumably due to presystemic sulphate conjugation. In the present study we examined the stereochemistry of the sulphation reaction in vitro using human tissue preparations. 2. Sulphation of salbutamol was studied with partially purified hepatic M and P form phenol sulphotransferases (PSTs), 100,000 g cytosol of jejunal mucosa and platelet homogenate. The cosubstrate PAP35S was used as the sulphate donor. The acceptor substrate was either (+)‐, (‐)‐or (+/)‐salbutamol. 3. Sulphation was catalyzed by the M form PST of the liver but not the P form. The sulphation efficiency (Vmax/Km) was 11.9‐fold greater for the (‐)‐ than for the (+)‐ enantiomer, due entirely to a lower apparent Km for (‐)‐salbutamol, 103 microM, than for (+)‐salbutamol, 1394 microM. 4. Sulphation by the jejunal mucosa (n = 3) was very similar to that of the M form PST with the efficiency being 9.8‐fold greater for the (‐)‐enantiomer and apparent Km values 95 microM and 889 microM for (‐)‐ and (+)‐ salbutamol, respectively. 5. Sulphation by the platelet (n = 3) was also very similar to that of the M form PST with the efficiency being 9.9‐fold greater for the (‐)‐enantiomer and apparent Km values 141 microM and 1190 microM for (‐)‐ and (+)‐salbutamol, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Non‐steroidal anti‐inflammatory drugs and hypertension in the elderly: a community‐based cross‐sectional study.
Authors: Johnson AG , Simons LA , Simons J , Friedlander Y , McCallum J
Published: July 2012

1. Whether non‐steroidal anti‐inflammatory drug (NSAID) usage in the elderly elevates blood pressure or antagonises the blood pressure‐ lowering effect of antihypertensive medication is presently unknown. The primary aims of this study were to estimate the prevalence of NSAID usage, to evaluate the prescription of NSAIDs for arthritis and to determine whether NSAID usage was an independent predictor of hypertension in a large elderly community. 2. All non‐institutionalised elderly (> 60 years) residents of Dubbo, NSW who attended for a baseline assessment were enrolled (1237 males, 1568 females). A questionnaire was administered and blood pressure was measured according to the Prineas protocol. The frequency of NSAID usage was determined, with stratification by age, sex, blood pressure group and history of arthritis. 3. NSAID usage was 26% overall (females 28%, males 23%), increased with age and was higher in females than males for every age group studied. Amongst patients with a past history of 'arthritis', 45% were using NSAIDs. Twelve percent were taking NSAIDs and antihypertensive medication concurrently, constituting the population at risk of an adverse drug‐drug interaction. Employing a multiple logistic regression model which adjusted for several confounders in the cross‐sectional analysis, NSAID usage significantly predicted the presence of hypertension (odds ratio: 1.4, 95% confidence interval: 1.1‐1.7) with an attributable risk of 29%. 4. Amongst non‐ institutionalised elderly persons, NSAID usage may be an independent risk factor for hypertension. Considering the substantial consumption of NSAIDs by elderly patients, physicians should review their NSAID prescribing patterns for this community group.
Receptor occupancy in lumbar CSF as a measure of the antagonist activity of atenolol, metoprolol and propranolol in the CNS.
Authors: Kaila T , Marttila R
Published: July 2012

1. The antagonist activity of atenolol, metoprolol and propranolol in the CNS was estimated by determining the extent to which the drugs occupy animal beta 1‐ and beta 2‐receptors in CSF ex vivo at the time of lumbar puncture. 2. Five CSF and plasma samples were obtained 4 h after drug intake from subjects treated for hypertension with atenolol, 100 mg once daily and five from subjects treated with metoprolol, 50 mg three times daily. Twenty‐four samples were obtained 1, 2, 4 or 12 h after drug intake from subjects receiving a single 40 mg dose of propranolol. 3. The receptor occupancy in the samples was determined by adding beta 1‐receptors of rabbit lung and beta 2‐receptors of rat reticulocytes into the samples and labeling the receptors with a nonselective beta‐adrenoceptor antagonist, (‐)‐[3H]‐CGP‐12177. 4. Atenolol and metoprolol occupied, as expected, larger fractions of beta 1‐ than beta 2‐receptors in CSF and plasma samples. The receptor fraction occupied by atenolol in CSF was significantly (P < 0.05) lower than that occupied by metoprolol. The differences in occupancy between the drugs in plasma, however, were not statistically significant. 5. Propranolol occupied larger fractions of beta 2‐ than beta 1‐receptors in the samples. Although propranolol concentrations in CSF were only 1/20‐1/40 of those in plasma, the receptor occupancy of propranolol in CSF was similar to that in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Presenting clinical pharmacology and therapeutics: a problem based approach for choosing and prescribing drugs.
Authors: De Vries TP
Published: July 2012

As a guide to the rational choice and prescribing of drugs a normative (ideal) problem‐solving model has been developed. This model combines medical problem solving and decision analysis, practical medical aspects, and pharmacological facts and basic principles. It consists of a set of actions or steps: determine the goal for treatment, choose a (drug) treatment, start drug treatment, monitor the results, draw conclusions, determine further action, and stop, alter or continue treatment. All steps require several kinds of skills. The cognitive skills needed include the correct use of pharmacological facts and basic principles in the framework of the whole problem‐solving process.
The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function.
Authors: Movin‐Osswald G , Boelaert J , Hammarlund‐Udenaes M , Nilsson LB
Published: July 2012

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in an open study with three parallel groups. Twenty‐one patients with severely impaired (ClCr < 25 ml min‐1), moderately impaired (ClCr 25‐50 ml min‐1) and normal (ClCr > 65 ml min‐1) renal function were evaluated. A single oral dose of remoxipride hydrochloride 100 mg was administered, and blood and urine were collected over 48 h. Concentrations of remoxipride and metabolites were measured by h.p.l.c. 2. In patients with severely decreased renal function, the AUC and Cmax of remoxipride were increased significantly, and t1/2 was prolonged, as compared with the control patients. The renal clearance and urinary recovery of the unchanged drug were significantly diminished. 3. The unbound fraction of remoxipride in plasma was decreased in patients with renal failure, in association with a disease‐related increase in alpha 1‐acid glycoprotein. In spite of a 25% recovery of unchanged drug in the urine in patients with normal renal function, the AUC of unbound drug was twice as high in patients with severely impaired renal function. 4. A strong correlation between creatinine clearance and renal drug clearance was observed indicating a direct relationship between kidney function and the renal clearance of remoxipride. 5. Remoxipride was the predominant compound in plasma as well as in urine in patients with severely decreased as well as normal renal function. In patients with severely decrease renal function, remoxipride and all five pharmacologically inactive metabolites showed increased peak plasma concentrations, delayed tmax, increased AUC, prolonged half‐lives and decreased renal clearance.
Cicaprost, an orally active prostacyclin analogue: its effects on platelet aggregation and skin blood flow in normal volunteers.
Authors: Belch JJ , McLaren M , Lau CS , Mackay IR , Bancroft A , McEwen J , Thompson JM
Published: July 2012

1. Prostacyclin (PGI2) and its analogues may be useful in peripheral vascular disease. However, most have to be given intravenously due to their metabolic instability. 2. We have investigated the pharmacological effects of cicaprost, a synthetic PGI2 analogue which is metabolically stable and bioavailable after oral administration, in eight healthy male volunteers. 3. This was a double‐blind, placebo‐ controlled, cross‐over study. The volunteers were given either placebo, 5 micrograms, 7.5 micrograms or 10 micrograms cicaprost (at 09.00 h, 14.00 h, 19.00 h and again at 09.00 h the following day) on four separate occasions each 14 days apart. 4. Platelet aggregation induced by collagen and ADP in platelet rich plasma (PRP) and whole blood were measured prior to and 1 h after the trial medication. Laser Doppler flowmetry measured skin blood flow on the face before and after medication. 5. There was a statistically significant dose relationship in the inhibition of platelet aggregation induced by 2 microM ADP and 0.4 microgram ml‐1 collagen in PRP and 2 microM ADP and 0.6 microgram ml‐1 collagen in whole blood by cicaprost (P = 0.008, P = 0.34, P = 0.011 and P = 0.036, respectively). The threshold dose was 7.5 micrograms. Attenuation of anti‐platelet effects was seen with the 14.00 h and 19.00 h doses. This may be due to a decrease in absorption after meals or to the development of tachyphylaxis. 6. Similar dose dependent effects of cicaprost on skin blood flow were also found (P = 0.01 and P = 0.006 for maximum output signal and red blood cell flux, respectively). The threshold dose was 7.5 micrograms. 7. In conclusion, cicaprost has significant anti‐platelet and vasodilatory effects when given in doses of 7.5 micrograms and 10 micrograms three times a day in healthy male volunteers.
R‐verapamil: pharmacokinetics and effects on PR interval, blood pressure and heart rate.
Authors: Ahmed JH , Godden J , Meredith PA , Elliott HL
Published: July 2012

1. This study in healthy normotensive male volunteers investigated the pharmacokinetics and the effects on electrocardiographic PR interval, blood pressure and heart rate of single oral doses of the single isomer R‐verapamil (250, 500 and 1000 mg) in comparison to placebo and 240 mg racemic verapamil. 2. After 500 and 1000 mg R‐verapamil there were significant prolongations in PR interval, maximal at 1‐2 h after dosing and coincident with peak plasma drug concentrations, but these were not significantly different from the maximum prolongation obtained with 240 mg racemic verapamil. 3. After 1000 mg R‐verapamil there was a significant hypotensive effect, particularly on standing. 4. Single doses of 500 and 1000 mg R‐verapamil produced peak plasma drug concentrations in the range 1000‐3000 ng ml‐1. If this concentration range is appropriate for adjuvant cancer chemotherapy it can be predicted that similar steady state concentrations will occur with a dosage regimen of 300 mg 3 times daily.
Bioavailability and absorption kinetics of nicotine following application of a transdermal system.
Authors: Gupta SK , Benowitz NL , Jacob 3rd P , Rolf CN , Gorsline J
Published: July 2012

1. The absolute bioavailability and absorption kinetics of nicotine were investigated in 13 healthy adult male smokers following single and multiple applications of a nicotine transdermal system (NTS), designed to release nicotine at an approximate rate of 1.5 mg h‐1 over 24 h. The absorption of nicotine from the single NTS application was calculated with reference to a simultaneous intravenous infusion (i.v.) of deuterium‐labelled nicotine. 2. The mean input time (MIT) and mean absorption time (MAT) for nicotine following application of NTS for 24 h were 7.7 and 4.2 h, respectively. 3. Following NTS removal, the mean apparent nicotine elimination half‐life was 2.8 h, compared with 2.0 h following i.v. nicotine, reflecting continued absorption of nicotine following NTS removal. 4. The mean amount of nicotine absorbed from the NTS after the 24 h application was 20.9 mg, which represents about 68% of the amount released from the system; the remaining 32% was lost from the system during daily activities. 5. The ratio of AUC values for the metabolite cotinine relative to nicotine was similar whether nicotine was administered transdermally or intravenously. 6. Following i.v. administration, the mean nicotine clearance was 72 l h‐1 (coefficient of variation 29%). Since coefficients of variation in AUC values following NTS and i.v. treatments were similar, transdermal administration of nicotine was not associated with increased interindividual variability in plasma nicotine concentrations. 7. No significant changes were seen in the pharmacokinetics of nicotine between single and multiple applications of NTS. 8. As expected from the higher total plasma nicotine concentrations, the incidence of adverse effects was higher following simultaneous intravenous and transdermal administration of nicotine. The most frequently reported systemic side effects were nervousness and headache: mild itching was the most frequent topical effect.
Double dummy comparison between once and twice daily dosing with modified‐release carbamazepine in epileptic patients.
Authors: McKee PJ , Blacklaw J , Carswell A , Gillham RA , Brodie MJ
Published: July 2012

1. Fourteen patients with refractory epilepsy on a twice daily regimen of modified‐release carbamazepine (CBZ‐MR. Tegretol Retard. Ciba Pharmaceuticals) completed a balanced, double‐blind, double dummy, random order, crossover comparison of 8 weeks treatment with once (o.d.) and twice daily (b.d.) dosing. In order to obtain a profile of serum CBZ concentrations over 24 h on once daily dosing, patients were randomised to taking it in the morning (o.d. a.m.) or evening (o.d. p.m.) for 4 weeks. Each treatment was taken with a placebo of the other and total tablet numbers were matched. Blood sampling was undertaken 0, 2, 4, 6, 8, 10, 12 and 24 h after the morning tablets at the end of each 4 week treatment period. 2. Overall, trough serum drug concentrations (Cmin) were lower with once daily dosing (Cmin: b.d. 7.5 mg l‐1, o.d. 6.5 mg l‐1, P < 0.05, 95% CI of the difference ‐1.3 to ‐ 0.1), but no significant differences were found in average (Cav) or peak (Cmax) concentrations, AUC values or fluctuations in CBZ concentrations. 3. Pharmacokinetic parameters for CBZ 10.11 epoxide, the active metabolite of CBZ did not differ significantly between the dosage schedules. 4. Seizure control was similar during once and twice daily dosing with CBZ‐MR (median seizures/month (range): b.d. 1 (0‐ 14.5), o.d. 0.5 (0‐11), NS, 95% CI of the difference ‐1.8 to + 0.25). 5. There were no differences in psychomotor performance between the treatment periods. 6. More patients (n = 11) preferred treatment (P < 0.05) with once daily than twice daily dosing (n = 3) with CBZ‐MR. 7. Once daily dosing with CBZ‐MR should be possible in the majority of patients receiving the drug as monotherapy.
Steady state serum concentrations of pravastatin and digoxin when given in combination.
Authors: Triscari J , Swanson BN , Willard DA , Cohen AI , Devault A , Pan HY
Published: July 2012

Pravastatin is an HMG CoA reductase inhibitor used in the treatment of hypercholesterolaemia. The steady state pharmacokinetics of pravastatin (20 mg) and digoxin (0.2 mg) were evaluated in 18 healthy male subjects following the administration of each drug alone or in combination for 9 days. Serum and urine were collected for up to 48 h after the ninth dose in this open, randomized 3‐way crossover study. Digoxin concentrations were measured by radioimmunoassay, and pravastatin and its metabolites. SQ 31,906 and SQ 31,945 were measured by GC‐MS. Digoxin and pravastatin pharmacokinetics were unchanged following combined administration. Combination therapy with pravastatin and digoxin is unlikely to expose patients to additional risk compared with pravastatin alone.
Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone.
Authors: Wu D. , Otton SV , Sproule BA , Busto U. , Inaba T. , Kalow W. , Sellers EM
Published: July 2012

1. In microsomes prepared from three human livers, methadone competitively inhibited the O‐demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty‐two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O‐demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme.
Effect of an inhaled histamine H3‐receptor agonist on airway responses to sodium metabisulphite in asthma.
Authors: O'Connor BJ , Lecomte JM , Barnes PJ
Published: July 2012

Histamine H3‐receptor agonists inhibit excitatory neuro‐transmission in human and guinea‐pig airways. Since neural bronchoconstriction may be important in asthma we have studied the effect of a specific H3‐ receptor agonist R‐alpha‐methylhistamine (alpha MeHA) on bronchoconstriction induced by the inhaled irritant sodium metabisulphite (MBS) in six mild asthmatic subjects in a randomised double‐blind crossover study. Subjects received either alpha MeHA, 10 mg (as a chloride salt) or matched placebo (P) and were then challenged with doubling concentrations of MBS (0.3‐80 mg ml‐1) nebulised from a dosimeter at 5 min intervals with measurement of specific airway conductance (sGaw) and FEV1 at 2 and 4 min respectively after each inhalation. There was no effect of alpha MeHA on baseline airway calibre and the log concentrations of MBS required to lower sGaw by 50% (log PC50) and FEV1 by 20% (log PC20) were not significantly different after alpha MeHA when compared with placebo, suggesting that selective stimulation of airway H3‐receptors does not inhibit MBS‐induced bronchoconstriction.
The effects of anti‐hypertensive medication on learning and memory.
Authors: Powell J. , Pickering A. , Wyke M. , Goggin T.
Published: July 2012

1. The aim of the study was to investigate whether there were differential effects of three different anti‐hypertensive medications (cilazapril, atenolol, nifedipine) on cognitive function. 2. A sub‐ group of patients participating in a large clinical trial of these three drugs, randomly allocated between the three drug conditions, received cognitive assessment at two points before the commencement of treatment and then after 12 and 24 weeks of treatment. Seventy‐six patients began treatment, and 55 completed the full course. 3. Tests of learning and memory were designed specially for the study, with a different but comparable version administered on each assessment occasion, in a fixed order. 4. No significant differences between drug groups were found in any index of learning or memory, at any testing occasion. The results were the same whether or not treatment non‐ completers were included in the analysis.
CNS‐related performance and haemodynamics of metoprolol‐Oros and propranolol after single and 3 days dosing in healthy volunteers.
Authors: van Steveninck AL , Pieters MS , Schoemaker HC , Breimer DD , Cohen AF
Published: July 2012

1. The effects of metoprolol‐Oros 14/190 once daily, propranolol 80 mg twice daily and temazepam 10 mg once daily on central nervous system (CNS) related performance and haemodynamic variables were evaluated in a double‐blind, randomized, placebo controlled, crossover study in 12 healthy volunteers. Drugs were administered for 3 consecutive days except for temazepam, which was administered on days 1 and 3 only. Treatment effects were evaluated at 0, 2, 5 and 8 h on days 1 and 3. 2. Neither beta‐adrenoceptor blocker had significant effects in a battery of tests after single or 3 days dosing. Temazepam caused a decrease in saccadic peak velocity of 37.4 degrees s‐1 (95% CI: 6.0, 68.9) at 2 h and an increase of auditory reaction times of 11.5 ms (0.2, 22.8) at 8 h on day 1. No significant effects of temazepam were detected on day 3. 3. Both beta‐adrenoceptor blockers reduced exercise heart rate. Peak effects were measured at 2 h 40 min after propranolol but not metoprolol‐Oros (difference, day 1:20 (11, 29) beats min‐1, day 3:13 (8, 19) beats min‐1). Both beta‐adrenoceptor blockers significantly reduced baseline exercise heart rate on day 3. Compared with day 1, metoprolol‐Oros caused larger reductions of exercise heart rate at all times on day 3. 4. Metoprolol‐Oros and propranolol caused similar reductions of systolic‐ and diastolic blood pressure on days 1 and 3. Temazepam caused a small reduction in diastolic blood pressure at 5 h 40 min on day 1 but was otherwise devoid of haemodynamic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma concentrations and urinary excretion of histamine after inhalation and subcutaneous injection of histamine.
Authors: Murdoch RD , Youlten LJ , Williams AJ , Howland K.
Published: July 2012

1. Increased histamine concentrations are found in the plasma and urine following allergen challenge in allergic subjects. This study compared a controlled challenge with clinically relevant doses of inhaled and injected histamine, as indicative of an allergic response, in an attempt to validate the use of urinary histamine or 1‐methylhistamine measurements as an objective, non‐invasive diagnostic test. 2. Inhalation of histamine produced peripheral vasodilation, increased heart rate, a fall in partial expiratory flow rate (pEFR) and blood pressure, ‘tight chest’ and cough. Subcutaneous injection produced vasodilation and headache but no change in heart rate or blood pressure. 3. Plasma histamine concentrations were similar in the two studies. Inhalation of increasing doses of histamine through a nebuliser (output 0.13 ml min‐1) resulted in an increase from a mean of 0.30 to 1.65 ng ml‐1, with return towards baseline within 20 min. Injection of 1 mg histamine s.c. produced an increase from 0.32 to 1.4 ng ml‐1 within 5 min, remaining above 1 ng ml‐1 for 30 min. 4. There was a significant increase of 15.2 ng mg‐1 creatinine in urinary histamine concentration following the injection of histamine (P = 0.04) and an increase of 11.4 ng mg‐1 creatinine when histamine was given by inhalation (P = 0.18). Histamine excretion rate increased by 108 ng min‐ 1 (P = 0.04) after inhalation and by 37.2 ng min‐1 (P = 0.09) after injection. Urinary 1‐methylhistamine concentrations were significantly raised following both histamine inhalation (+ 238 ng mg‐1 creatinine; P = 0.013) and injection (+ 180 ng mg‐1 creatinine; P = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
Interactions among primaquine, malaria infection and other antimalarials in Thai subjects.
Authors: Edwards G. , McGrath CS , Ward SA , Supanaranond W. , Pukrittayakamee S. , Davis TM , White NJ
Published: July 2012

1. The pharmacokinetics of rac‐primaquine (45 mg base) and its principal plasma metabolite, carboxyprimaquine have been investigated in healthy Thai adults prior to and following a single oral dose of mefloquine (10 mg kg‐1). 2. Primaquine was rapidly absorbed, attaining peak plasma concentrations (median and range) of 167 (113‐532) micrograms l‐1 in 2 (1‐4) h. Thereafter, concentrations declined rapidly with an apparent terminal half‐life of 6.1 (1.7‐16.1) h and an oral clearance (CLpo) of 33.1 (17.6‐49.3) l h‐1. Administration of mefloquine had no effect on the values of any of these parameters at the 5% level of significance [Cmax 229 (114‐503) micrograms l‐1; tmax 3 (2‐4) h; t1/2,z 3.9 (1.7‐13.5) h; CLpo 34.0 (21.7‐49.0) l h‐1]. 3. The carboxylic acid metabolite of primaquine achieved maximum concentrations (median and range) of 890 (553‐3634) micrograms l‐1 at 6 (3‐16) h. Thereafter, plasma concentrations of carboxyprimaquine declined to 346 (99‐918) micrograms l‐1 at 24 h. AUC (0,24 h) was 12737 (6837‐27388) micrograms l‐1 h. Administration of mefloquine had no effect on the plasma concentrations of this metabolite [Cmax 1035 (174‐ 3015) micrograms l‐1; tmax 8 (2‐24) h; AUC(0,24) 13471 (2132‐17863) micrograms l‐1 h]. 4. The effect of falciparum malaria and treatment with quinine (10 mg salt kg‐1 p.o.) on the pharmacokinetics of primaquine (45 mg base p.o.) has been investigated in adult Thai patients during and after infection with falciparum malaria.(ABSTRACT TRUNCATED AT 250 WORDS)
Patients' attitudes to participation in clinical trials.
Authors: Bevan EG , Chee LC , McGhee SM , McInnes GT
Published: July 2012

1. In order to assess attitudes of patients to participation in therapeutic trials 197 patients underwent structured interviews conducted by a single observer. Of these patients 66 were previous or current participants in clinical trials (group A), 12 had declined participation in a trial (group B), and 119 had never been invited to participate in research (group C). 2. In group A, 62% stated their motivation for participation was to help others and 39% to improve their own treatment, but in 38% participation was to comply with the doctor's request. Two‐thirds of group C patients would or might participate in a future hypothetical trial; of these more than half (57%) would do so to help others, and 42% to improve their own treatment. 3. Of the 12 patients who had declined entry into a study (group B) three did not want to alter their current therapy, three had insufficient time to participate in the particular trial, and in three cases relatives objected to their participation. Group C patients who stated they would not participate in trials gave being too ill (22%), not wanting to change treatment (22%), and fear of side‐effects (17%) as the commonest reasons for declining. 4. In group A, 83% felt they had adequate time to consider their participation. Nearly two‐thirds of patients (60%) would have liked written information to retain for reference, whereas only 38% were provided with information in this form. Over half of these patients (54%) disliked no aspect of the study in which they participated. Venepuncture and other uncomfortable procedures were least popular.(ABSTRACT TRUNCATED AT 250 WORDS)
The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials.
Authors: Roderick PJ , Wilkes HC , Meade TW
Published: July 2012

The proven benefit of aspirin in the secondary prevention of cardiovascular disease and its possible value in primary prevention must be weighted against its potential hazards. This paper is an overview of the gastrointestinal toxicity of aspirin, its most serious complication after intracerebral haemorrhage. Information on toxicity has been drawn only from randomised trials, thus avoiding the potential biases of observational studies. All randomised placebo controlled trials listed in the Anti‐platelet Trialists Collaboration where a direct aspirin‐placebo comparison was possible were included. Twenty‐ one trials were included, all but one of secondary prevention. There were over 75,000 person years of aspirin exposure. The pooled odds ratios for categories of gastrointestinal bleeding (e.g. haematemesis, melaena) were between 1.5‐2.0; fatal bleeds were very rare. The risk of peptic ulcers was 1.3 and of upper gastrointestinal symptoms 1.7. These risks were lower than those found in observational studies. Attributable disease rates are also presented. For haematemesis for example they varied from 0.2‐1.0 per 1000 person years. Toxicity was dose related. Aspirin does have significant gastrointestinal toxicity, although this is rarely fatal. More recent work has demonstrated the efficacy of low doses of aspirin (75 mg daily) but there is limited information yet available on its toxicity.
The effect of L‐leucine on the absorption of levodopa, studied by regional jejunal perfusion in man.
Authors: Lennernas H. , Nilsson D. , Aquilonius SM , Ahrenstedt O. , Knutson L. , Paalzow LK
Published: July 2012

1. A new method for perfusing a 10 cm segment of jejunum in humans has been used in seven subjects to study the effect of the amino acid L‐ leucine (40 mM) on the intestinal absorption of levodopa (2.5 mM). The tube contains six channels and has two inflatable balloons, which enable a perfusion of a closed and defined segment of the proximal small intestine. 2. L‐leucine decreased the intestinal absorption of levodopa from 40 +/‐ 19 to 21 +/‐ 15% but was without effect on the absorption of antipyrine, benserazide and D‐glucose. 3. We confirm that levodopa is absorbed by the active transport system normally responsible for the absorption of large neutral amino acids (LNAA) in humans. Oral absorption by passive diffusion, probably by the paracellular route, might also occur for levodopa in the proximal part of the small intestine.
Comparison of the effect of oral sulphasalazine, sulphapyridine and 5‐ amino‐salicylic acid on the in vivo antibody response to oral and systemic antigen.
Authors: Sheldon P. , Pell P.
Published: July 2012

1. Mice, whose drinking water contained sulphasalazine, sulphapyridine or 5‐amino‐salicylic acid, received an antigenic challenge by cholera toxin administered either orally or systemically. 2. Sulphasalazine treated mice made less specific antibody of IgA class provided the antigen also was administered orally (P = 0.009 for days 7‐28). When the antigen was administered systemically, there was a vigorous anti‐ cholera toxin antibody response of IgG class, and a lesser IgM but only a weak IgA response. The effect of sulphasalazine in this case was confined to the IgG response, which was significantly suppressed on day 28 (P = 0.008). 3. Sulphapyridine and 5‐amino salicylic acid had no significant effect on the anti‐cholera toxin (CT) responses of all three classes. 4. It therefore appears that in this model, only sulphasalazine is capable of influencing the humoral immune system, the antibody class affected depending on the route of entry of antigen. This may have implications for conditions such as rheumatoid arthritis and chronic inflammatory bowel disease, for which sulphasalazine has been found useful.
Diazepam effects on the performance of healthy subjects are not enhanced by treatment with the antihistamine ebastine.
Authors: Mattila MJ , Aranko K. , Kuitunen T.
Published: July 2012

1. We have given 12 healthy subjects the H1‐antihistamine ebastine (20 mg) or placebo in a randomized double‐blind and crossover study for 1 week each. The subjects were tested for drug effects on day 6 of each period, and for interactions of ebastine with oral 15 mg diazepam (DZ) on day 7. On both days, the testing runs were at baseline and 1.5, 3, 4.5 and 6 h after intake. 2. The performance was evaluated both objectively (digit symbol substitution, flicker fusion, Maddox wing, simulated driving, body balance) and subjectively (visual analogue scales, questionnaires). Venous blood was sampled daily during the maintenance and during each testing round for the assay of plasma carebastine (the active metabolite of ebastine) by high pressure liquid chromatography and plasma diazepam by radioreceptor assay. Three‐way ANOVA, paired t‐test, Wilcoxon rank sign test and Fisher's fourfold table test were used for data analysis. 3. Plasma carebastine reached steady levels from day 3 onwards. The mean concentrations in the morning were 82 micrograms l‐1 on day 6 and 85 micrograms l‐1 on day 7. The rise (+ 150%) in plasma carebastine after an extra 20 mg ebastine was not modified by DZ. Ebastine did not affect performance objectively or subjectively, yet borderline drowsiness was recorded during the first 3 h. On day 7, plasma DZ concentrations peaked (mean 480 micrograms l‐1) at 1.5 h after the intake. DZ produced impaired performance in various objective tests, and drowsiness, weakness, clumsiness, mental slowness and poor performance were reported on visual analogue scales.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans.
Authors: Ohtawa M. , Takayama F. , Saitoh K. , Yoshinaga T. , Nakashima M.
Published: July 2012

1. The pharmacokinetics and biochemical efficacy of losartan, an orally active nonpeptide angiotensin II (AII) receptor antagonist, were evaluated in healthy male volunteers after single and multiple oral administration. 2. Plasma and urinary concentrations of losartan and its active metabolite, E‐3174, were determined by a specific high performance liquid chromatographic (h.p.l.c.) method. 3. Plasma concentrations of losartan were proportional to dose over the range of 25 to 200 mg and the terminal half‐lives (t1/2,z) ranged from 1.5 to 2.5 h. The mean values of Cmax and AUC0‐infinity increased in a dose‐ dependent manner. 4. Plasma concentrations of E‐3174 were higher than those of losartan at all dose levels. The values of Cmax and AUC0‐ infinity for E‐3174 were approximately 2 and 5‐8 times higher than those for losartan, respectively. Also the value of t1/2,z was 2 times longer than that of losartan. 5. After multiple dosing for 7 days, the pharmacokinetics of losartan and E‐3174 each did not change significantly between day 1 and day 7. 6. Plasma renin activity (PRA) and plasma concentrations of AII increased markedly at all dose levels. Plasma aldosterone levels were slightly reduced, but a similar decrease was also observed with placebo. 7. No clinically significant adverse reaction was observed in any of the volunteers during either study. Blood counts, routine laboratory tests, urine analyses, and electrocardiograms were also not modified by losartan. 8. Losartan appears to be a potent orally active angiotensin II antagonist with a relatively long duration of action.
Haemodynamic and hormonal responses to oral enalapril in salt depleted normotensive man.
Authors: MacFadyen RJ , Elliott HL , Meredith PA , Reid JL
Published: July 2012

A combination of dietary sodium restriction (40 mmol day‐1) and frusemide pretreatment has been used to activate the renin angiotensin system (RAS) in order to characterise the haemodynamic and hormonal responses to enalapril in young normotensives. Enalapril significantly reduced supine blood pressure with a mean maximum fall of 19 +/‐ 7.6, compared with 6.5 +/‐ 6.8 mm Hg with placebo. Similar but greater responses were seen in erect blood pressure. Mean maximal plasma ACE inhibition (78 +/‐ 5.7%) was associated with a significant increase in PRA from 5.2 +/‐ 2.1 ngAI ml‐1 h‐1 to a peak of 29.1 +/‐ 6 ngAI ml‐1 h‐ 1. This simple well tolerated regimen produced consistent RAS activation and gave readily measurable falls in blood pressure following enalapril. This model may be used to undertake detailed assessments of ACE inhibition, renin inhibition and angiotensin receptor blockade.
Potentiation of the hypoglycaemic response to glipizide in diabetic patients by histamine H2‐receptor antagonists.
Authors: Feely J. , Collins WC , Cullen M. , el Debani AH , MacWalter RS , Peden NR , Stevenson IH
Published: July 2012

In a randomised placebo controlled study, two groups of six maturity onset diabetic patients stabilised on glipizide were given cimetidine (400 mg) or ranitidine (150 mg) 3 h before a standardised meal. In comparison with placebo, both cimetidine and ranitidine significantly reduced the post‐prandial rise in blood glucose by a mean of 40% and 25% respectively producing glucose levels of less than 3 mmol l‐1 (lowest 1.5 mmol l‐1) in four patients. Both drugs also significantly increased plasma glipizide AUC by approximately 20%. Caution should be exercised when initiating treatment with H2‐receptor antagonists in diabetics receiving sulphonylurea hypoglycaemic agents.
Effects of physiological and pharmacological variation of sympathetic nervous system activity on plasma non‐esterified fatty acid concentrations in man.
Authors: Barbe P. , Galitzky J. , Riviere D. , Senard JM , Lafontan M. , Garrigues M. , Berlan M.
Published: July 2012

1. The consequence of the sympatholytic effect of clonidine (alpha 2‐ adrenoceptor agonist) was compared with the effect of a physiological inhibition of sympathetic nervous system activity (change from upright to supine position) on plasma catecholamine and non‐esterified fatty acid (NEFA) concentrations in overnight fasting healthy men. 2. Clonidine (150 micrograms orally) administered in upright position induced a significant reduction of plasma noradrenaline and NEFA concentrations. A change from upright to supine position which provoked a more marked decrease in plasma noradrenaline concentrations induced a weak increase in plasma NEFA concentrations. 3. The modification of plasma NEFA and catecholamine concentrations brought about by standing up was studied after placebo or yohimbine (alpha 2‐adrenoceptor antagonist) administration. With placebo, standing up promotes a 100% increase in plasma noradrenaline concentrations (measured 5 and 15 min after rising) and a weak transient decrease in plasma NEFA concentrations (5 min after rising). In the supine position, yohimbine increased plasma noradrenaline and NEFA concentrations by about 100% and 55% respectively. Standing after yohimbine administration promoted large increases in plasma noradrenaline and NEFA concentrations. 4. These results indicate that a reduction of sympathetic nervous activity is not associated with a decrease of plasma NEFA concentrations and argue for a role of alpha 2‐adrenoceptors in the NEFA mobilization from adipose tissue after sympathetic nervous system activation in man.
The use of a three compartment in vitro model to investigate the role of hepatic drug metabolism in drug‐induced blood dyscrasias.
Authors: Tingle MD , Park BK
Published: July 2012

1. N‐hydroxylation is thought to be an essential step in the haemotoxicity of dapsone (DDS). To investigate both metabolism‐ dependent and cell‐selective drug toxicity in vitro we have developed a three‐compartment system in which an hepatic drug metabolizing system is contained within a central compartment separated by semipermeable membranes from compartments containing mononuclear leucocytes (MNL) and red blood cells (RBC). 2. Metabolism of dapsone (100 microM) by rat liver microsomes resulted in toxicity to RBC cells (47.3 +/‐ 2.1% methaemoglobin), but there was no significant toxicity toward MNL (3.7 +/‐ 1.3% cell death) compared with control values (1.6 +/‐ 0.9%). However, when RBC were replaced with buffer in the third compartment there was significantly greater (P < 0.001) white cell toxicity (17.6 +/‐ 0.6% cell death), demonstrating the protection of MNL by RBC. Metabolism of dapsone by human liver microsomes again resulted in RBC toxicity (12.5 +/‐ 3.3% methaemoglobin) but no significant MNL toxicity (2.9 +/‐ 0.8% cell death). Replacement of RBC resulted in a significant (P < 0.001) increase in MNL toxicity (6.5 +/‐ 0.7% cell death). Addition of synthetic dapsone hydroxylamine (30 microM) in the absence of a metabolizing system and with no RBC in the third compartment resulted in significant (P < 0.001) toxicity toward MNL (43.36 +/‐ 5.82% cell death) compared with control (1.8 +/‐ 1.1%). The presence of RBC in the third compartment resulted in a significant (P < 0.001) decrease in MNL toxicity (17.6 +/‐ 2.2% cell death), with 40.1 +/‐ 3.7% methaemoglobin in the RBC.(ABSTRACT TRUNCATED AT 250 WORDS)
L‐arginine infusion has no effect on systemic haemodynamics in normal volunteers, or systemic and pulmonary haemodynamics in patients with elevated pulmonary vascular resistance.
Authors: Baudouin SV , Bath P. , Martin JF , Du Bois R. , Evans TW
Published: July 2012

1. The evidence that the infusion of L‐arginine, the precursor of endothelium‐derived relaxing factor (EDRF)/nitric oxide (NO), may reduce systemic blood pressure, via the generation of intracellular cyclic guanosine‐3,5‐monophosphate(cGMP), in normotensive volunteers is controversial. In the first part of the study we investigated the effect of an L‐arginine infusion on systemic blood pressure and plasma cGMP in healthy volunteers. 2. Patients with systemic sclerosis have widespread endothelial damage which, by reducing the release of NO, could contribute to the raised pulmonary vascular resistance (PVR) often found in this condition. We hypothesised that if there were a failure of NO synthesis this might be overcome by infusing L‐arginine into the pulmonary artery, thereby lowering PVR. In the second part of the study we investigated the effect of L‐arginine infusion on systemic and pulmonary haemodynamics, and on plasma cGMP levels in patients with pulmonary hypertension and systemic sclerosis. 3. L‐arginine (500 mg kg‐ 1) was infused over 30 min into five normotensive volunteers and five patients with systemic sclerosis and pulmonary hypertension. Blood pressure, heart rate and skin temperature were measured non‐invasively in the volunteers and systemic and pulmonary haemodynamics recorded via radial artery cannulae and balloon‐tipped, flow directed, pulmonary artery catheters in the patients with systemic sclerosis. 4. L‐arginine had no significant effect on blood pressure, heart rate or skin temperature in the normotensive volunteers nor on systemic or pulmonary haemodynamics in the systemic sclerotic group. Cyclic‐GMP levels did not significantly change in either group.(ABSTRACT TRUNCATED AT 250 WORDS)