bluuebunny/crossref_metadata_2025 huggingface dataset:
A cross‐over comparison of the anti‐clotting effects of three low molecular weight heparins and glycosaminoglycuronan.
Authors: Stiekema JC , Van Griensven JM , Van Dinther TG , Cohen AF
Published: July 2012

1. The anti‐clotting effects after intravenous administration of three low molecular weight (LMW) heparins, Fragmin (KABI 2165), Fraxiparine (CY 216), Clexane (PK 10169) and the LMW mixture of glycosaminoglycuronans Orgaran (Org 10172) were compared in a randomized cross‐over study in 12 healthy male volunteers. 2. The time courses of the anti‐Xa activity of Fragmin, Fraxiparine and Clexane (five subjects) were best fitted by a monoexponential function and had comparable half‐lives of 1.9 h, 2.3 h and 2.8 h, respectively. The time courses of the anti‐Xa activity of Orgaran and Clexane (four subjects) were described by a biexponential function with terminal half‐lives of 56.8h and 27.7 h, respectively. They were longer than those of Fraxiparine and Fragmin. Orgaran injection was associated with a significantly smaller 'clearance' (0.8 +/‐ 0.2 l h‐1) of the plasma anti‐Xa activity compared with Fragmin (2.0 +/‐ 0.5), Fraxiparine (1.7 +/‐ 0.5) and Clexane (1.6 +/‐ 0.5). 3. In comparison with the three LMW heparins, the terminal half‐life of plasma anti‐IIa activity after Orgaran was longer and the 'clearance' of Orgaran was lower than that after Clexane. The area under the curve of the plasma anti‐IIa activity after administration of Orgaran was negligible compared with that obtained after injection of the LMW heparins. 4. Orgaran caused the smallest and Fragmin the greatest prolongation of the activated partial thromboplastin time (Orgaran 5.8 +/‐ 1.2 s vs Fragmin 18.5 +/‐ 5.2 s) and the thrombin clotting time (Orgaran 2.9 +/‐ 1.7 s vs Fragmin 47.8 +/‐ 0.9 s).(ABSTRACT TRUNCATED AT 250 WORDS)
The passage of cloxacillin into cerebrospinal fluid in the absence of meningitis.
Authors: Schievink HI , Mattie H. , Thomeer RT , Van Strijen E.
Published: July 2012

1. Eleven patients undergoing lumbar discectomy received cloxacillin by continuous i.v. infusion, starting before the operation. During the operation several blood samples and one CSF sample were taken. 2. Mean rate constants describing the passive transfer of drug from plasma to CSF (kp) and the largely active transfer in the opposite direction (kCSF) were estimated. 3. In some subjects the CSF albumin quotient, defined as the ratio between the albumin concentration in CSF and in plasma times 1000, was slightly elevated (up to 23) which caused a significant increase in the value of kp. 4. The estimate of mean kp for healthy individuals was 0.065 h‐1, which corresponds to a half‐life of 10 h. The estimate of mean kCSF was 2.10 h‐1. This predicts a steady‐ state CSF drug concentration which is 3% of the unbound plasma drug concentration. 5. There was a significant lag between the time courses of plasma and CSF drug concentrations, presumably reflecting the time for drug to move from the choroid plexus to the lumbar sampling site. 6. Four other patients received cloxacillin for prophylactic or therapeutic reasons by continuous i.v. infusion. In three of those patients the albumin quotient was normal or slightly elevated and the steady‐state CCSF/Cu ratio was similar to the predicted normal value. 7. These findings indicate that eradicating staphylococci from CSF in cases of meningitis with a low degree of inflammation may be difficult.
Acute and subchronic effects of the H1‐histamine receptor antagonist ebastine in 10, 20 and 30 mg dose, and triprolidine 10 mg on car driving performance.
Authors: Brookhuis KA , de Vries G. , de Waard D.
Published: July 2012

1. The effects of a new antihistamine, ebastine (10, 20 and 30 mg), on several parameters of driving performance in actual traffic were studied in 15 healthy male volunteers. Subjects were treated for 5 days, and their driving performance tested on day 1 and day 5. The study was double‐blind, placebo controlled and included the antihistamine triprolidine (10 mg sustained release) as an active drug control. 2. General tolerability was good except in one case following the reference compound triprolidine. No significant changes in driving performance were found with the new antihistamine ebastine at any dosage, on day 1 or day 5. Triprolidine (10 mg) significantly increased both the amount of weaving and the delay in following speed manoeuvres of a leading car, compared with placebo. 3. The results suggest that ebastine in doses up to 30 mg may be relatively safe for use by those who drive motor vehicles while under medication. The results do not warrant such a conclusion for triprolidine 10 mg.
Disposition of the enantiomers of hydroxychloroquine in patients with rheumatoid arthritis following multiple doses of the racemate.
Authors: McLachlan AJ , Tett SE , Cutler DJ , Day RO
Published: July 2012

In eight patients with rheumatoid arthritis receiving racemic hydroxychloroquine, blood and urine concentrations of the enantiomers of hydroxychloroquine and its major metabolites were measured each month over the first 6 months of therapy. Plasma concentrations of hydroxychloroquine enantiomers were measured in five of these patients. In all patients, the blood concentration of (R)‐hydroxychloroquine exceeded that of the (S)‐enantiomer, the mean (R)/(S) ratio being 2.2 (range 1.6‐2.9). A similar excess of (R)‐hydroxychloroquine was found in the plasma, the mean (R)/(S) ratio being 1.6 (range 1.2‐1.9). The mean enantiomer blood concentration ratio (R)/(S) for the metabolite desethylhydroxychloroquine was 0.45 (range 0.34‐0.58) and for desethylchloroquine it was 0.56 (range 0.35‐0.86) suggesting stereoselective metabolism of hydroxychloroquine. (S)‐ hydroxychloroquine had a mean (+/‐ s.d.) renal clearance from blood of 41 +/‐ 11 ml min‐1, approximately twice that of (R)‐hydroxychloroquine. The predicted unbound renal clearance was also higher for (S)‐ hydroxychloroquine. The clinical implications of enantioselective disposition of hydroxychloroquine are currently not known.
Zidovudine pharmacokinetics in zidovudine‐induced bone marrow toxicity.
Authors: Barry M , Howe JL , Back DJ , Swart AM , Breckenridge AM , Weller IV , Beeching N , Nye F
Published: July 2012

1. The major adverse effect of zidovudine (ZDV) is haematological toxicity which results in anaemia and granulocytopenia. The aim of the present study was to investigate if HIV‐positive patients developing erythroid aplasia/hypoplasia are exposed to higher plasma concentrations of ZDV owing to impaired hepatic metabolism to the major metabolite, 3'‐azido‐3'‐deoxy‐5'‐beta‐D‐glucopyranuronosylthymidine (GZDV). 2. Twelve HIV‐positive male patients were studied, six having developed bone marrow aplasia/hypoplasia within the first 6 months of ZDV therapy. Each of the patients exhibiting toxicity were matched for age, weight, risk factors for HIV infection and disease stage with patients who had no evidence of early bone marrow toxicity. 3. ZDV was administered orally in doses of 3‐10 mg kg‐1 and blood samples taken at intervals to 6 h. Urine was collected over the whole 6 h period. ZDV and GZDV were assayed by h.p.l.c. 4. There were no significant differences in the pharmacokinetic parameters between the two groups of patients. For patients with early bone marrow toxicity the elimination half‐life of ZDV was 1.10 +/‐ 0.16 h with an oral clearance of 2752 +/‐ 1031 ml min‐1 compared with values of 1.06 +/‐ 0.18 h and 2843 +/‐ 730 ml min‐1 seen in the control group. Similarly there was no significant difference in the pharmacokinetics of GZDV or the urinary ratio of GZDV to ZDV. 5. Therefore, despite the fact that ZDV toxicity to haematopoietic progenitor cells has been previously shown to be dose related, there was no indication from this study that it is directly related to plasma concentrations of ZDV.
A double‐blind, placebo‐controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients.
Authors: McKee PJ , Blacklaw J , Forrest G , Gillham RA , Walker SM , Connelly D , Brodie MJ
Published: July 2012

1. The effect of carbamazepine (CBZ), sodium valproate (VPA) and phenytoin (PHT) on the pharmacokinetics of oxcarbazepine (OXC) was explored in three groups of 12 epileptic patients taking one of these drug as monotherapy. 2. Each patient took a single 600 mg dose of OXC followed 7 days later by 3 weeks' treatment with OXC 300 mg thrice daily and matched placebo in random order. 3. Seven untreated patients, acting as controls, were prescribed the single OXC dose and 3 weeks' active treatment only. 4. In those patients completing the study, the area under the concentration‐time curve (AUC) at steady‐state for hydroxycarbazepine (OHCZ), the active metabolite of OXC, was significantly lower in the CBZ‐treated group than in controls (P < 0.05). 5. No other differences in AUCs or elimination half‐lives for OHCZ were found between treated and untreated patients following single or multiple OXC dosing. 6. Median AUCs of CBZ, VPA and PHT during a dosage interval did not differ significantly after treatment with OXC and placebo. 7. Ten patients completing the study complained of side‐ effects during treatment with OXC compared with one taking placebo (P < 0.01). 8. There were no important changes in cognitive function testing during administration of OXC compared with placebo. 9. Standard doses of OXC can be given as add‐on therapy in epileptic patients receiving CBZ, VPA or PHT without producing a clinically relevant pharmacokinetic interaction.
Clinical pharmacology and therapeutics in undergraduate medical education in the UK: the future.
Authors: Walley T , Bligh J , Orme M , Breckenridge A
Published: July 2012

1. Changes in undergraduate medical education will involve the development of a core curriculum of material of essential knowledge and of the skills for self directed learning both as a student and a postgraduate. A survey of departments or individuals teaching clinical pharmacology and therapeutics was conducted to consider what a core curriculum in these subjects might contain and how changes in the school curriculum would affect teaching in the future. 2. A questionnaire was developed based on an American consensus statement on the core curriculum in clinical pharmacology and therapeutics. Freetext answers were encouraged. Twenty‐seven medical schools were surveyed; 21 (78%) replied. 3. Items of core knowledge (as defined by the American statement) were generally rated important or very important. The most important were considered to be (in order): prescribing for the elderly, management of overdose and adverse drug reactions. All of these were widely taught (85‐100%). The least important items were the efficacy and toxicity of nonprescription drugs (taught by 35%) and the process of drug development and approval (taught nevertheless by 95%). 4. Core skills were generally rated less important, and less often taught. It was felt by many respondents that these skills, as defined, were excessively detailed for British undergraduates and more appropriate for postgraduate education. 5. Core attitudes were rated as being of intermediate importance, but not widely taught as it was felt that these could best be inculcated by example rather than formal teaching. Again, many felt that these attitudes were inappropriate for a UK core curriculum.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibitory effects of calcium antagonists on alpha‐adrenoceptor‐ mediated contraction in the human internal mammary artery.
Authors: He GW , Acuff TE , Ryan WH , Yang CQ , Douthit MB , Bowman RT , Mack MJ
Published: July 2012

1. The internal mammary artery has become a preferred coronary bypass graft. Sympathomimetic amines are spasmogens for vasospasm and calcium antagonists are frequently administered drugs perioperatively. The effect of calcium antagonists on alpha‐adrenoceptor‐mediated contraction depends on the subtype of alpha‐adrenoceptor and the type of origin of vascular smooth muscle. This study was designed to investigate the effect of calcium antagonists on alpha‐adrenoceptor‐ mediated contraction in the IMA. 2. Human IMA segments taken from 22 patients undergoing IMA—coronary artery bypass grafting were mounted in an organ bath under the physiological pressure determined from their own length‐tension curves. 3. Three ring segments were allocated into three groups. One served as a control and the others were treated with clinically related concentrations of nifedipine (20 or 200 nM) for 25 min before concentration‐contraction curves to alpha 1‐adrenoceptor agonist methoxamine (MO) or full alpha‐adrenoceptor agonist noradrenaline (NA) were established. 4. In separate experiments, the concentration‐relaxation curves to nifedipine were established in the IMA rings precontracted with MO (30 microM) or NA (10 microM). Glyceryl trinitrate (GTN, 3 microM) was added to further relax the vessels. 5. Pretreatment with nifedipine (200 nM) only slightly inhibited the MO‐ (1.74 +/‐ 0.32 vs 2.88 +/‐ 0.56 g) or NA‐ (2.43 +/‐ 0.66 vs 3.60 +/‐ 0.82 g) induced contraction without statistical significance (P > 0.05). 6. On the other hand, nifedipine only caused 34.49% relaxation in the MO‐precontracted and 24.39% relaxation in the NA‐precontracted IMAs. In contrast, GTN caused 76.16% (against MO, P < 0.05) or 92.22% (against NA, P < 0.0001) relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
Population genetics of the angiotensin‐converting enzyme in Chinese.
Authors: Lee EJ
Published: July 2012

A genetic polymorphism exists for the angiotensin‐converting enzyme (ACE) gene which accounts for 44% of the variance of circulating ACE activity in a normal Caucasian population. The presence or absence of a 250 bp fragment in intron 16 of the gene serves as a marker for this polymorphism. One hundred and eighty‐nine normal Chinese subjects were genotyped and phenotyped for this ACE polymorphism. The frequencies of the deletion and insertion alleles among Chinese are 0.3 and 0.7 respectively, indicating a much higher prevalence of the insertion allele than had been reported among Caucasians.
Do cholesterol‐lowering agents affect brain activity? A comparison of simvastatin, pravastatin, and placebo in healthy volunteers.
Authors: Harrison RW , Ashton CH
Published: July 2012

1. The effects of simvastatin and pravastatin on measures of central nervous system activity were investigated in a double‐blind, placebo‐ controlled, randomised crossover study. 2. Twenty‐five healthy volunteers sequentially took 40 mg day‐1 simvastatin, 40 mg day‐1 pravastatin or placebo for 4 weeks, separated by a 4‐6 week washout phase. 3. CNS measures included EEG evoked potentials, power spectral analysis, Leeds Sleep Questionnaire, Hospital Anxiety Depression (HAD) Scale, and Digit Symbol Substitution Test (DSST); biochemical measures included plasma cholesterol, liver enzymes (gamma‐GT, AST, ALT) and creatine kinase. 4. Mean cholesterol concentrations with both drugs were significantly lower than with placebo, and the cholesterol‐ lowering effect was greater with simvastatin. There were no significant differences between treatment in EEG evoked potentials, HAD Scale, or DSST scores. On the sleep measure, subjects reported significantly greater difficulty in getting to sleep while on simvastatin than on pravastatin, but neither score differed from placebo. No significant correlations were observed between sleep ratings and either plasma cholesterol concentrations or EEG evoked potentials. 5. The study showed that, while both drugs reduced plasma cholesterol concentrations, neither exerted significant effects, compared with placebo, on EEG evoked potentials, mood, sleep, or cognitive performance after 4 weeks of chronic administration in healthy volunteers.
The acute effects of a single dopamine infusion in elderly patients with congestive cardiac failure.
Authors: Robinson T , Gariballa S , Fancourt G , Potter J , Castleden M
Published: July 2012

1. Dopamine (DA) at low doses (2.5 micrograms kg‐1 min‐1) produces a measurable increase in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in young healthy subjects and has a therapeutic effect in younger patients with congestive cardiac failure (CCF). In elderly healthy subjects, DA increases ERPF but does not increase GFR in all subjects. 2. To determine the potential therapeutic use of DA in elderly subjects with CCF, we studied 17 patients (5 male) aged 79.9 years (range 68 to 93 years) admitted to hospital for inpatient treatment of CCF resistant to diuretic and angiotensin converting enzyme inhibitor therapy. The effects of a single infusion DA at 2.5 micrograms kg‐1 min‐1 on GFR and ERPF were assessed in a double‐blind, placebo controlled prospective study. 3. There were no significant differences in GFR or ERPF between control and DA. A reduction in GFR was seen in some patients. 4. DA at low dosage was not shown to benefit elderly patients with resistant CCF, and in some patients was detrimental. Higher doses or a combination with other inotropes may be necessary for a renal effect in elderly patients.
Comparative effects of angiotensin II on Doppler parameters of left and right heart systolic and diastolic blood flow.
Authors: Lipworth BJ , Dagg KD
Published: July 2012

1. The purpose of the study was to investigate the effects of angiotensin II on Doppler parameters of right ventricular systolic and diastolic blood flow, and to compare these with effects on the left heart, in normal subjects. 2. Pulsed‐wave Doppler measurements were made in eight normal volunteers: after a 30 min control i.v. infusion of dextrose, after 30 min stepwise infusions of angiotensin II (2, 4 and 6 ng kg‐1 min‐1), and finally 30 min after stopping the 6 ng kg‐1 min‐1 dose of angiotensin II. Aortic (Ao) and pulmonary (Po) systolic ejection parameters, as well as mitral (Mi) and tricuspid (Tc) diastolic filling parameters were measured. 3. Ao and Po maximal velocity were both significantly reduced by angiotensin II, whereas there were significant opposite effects on Ao (reduced) and Po (increased) mean acceleration. There was a dose‐related fall in Po acceleration time with angiotensin II, whilst Ao acceleration time remained unchanged. 4. Mi and Tc early diastolic filling velocities were not significantly altered by angiotensin II compared with baseline, although there was a significant rebound increase in both Mi and Tc early filling after cessation of angiotensin II infusion. Mi and Tc pressure half‐times were not significantly changed. 5. In conclusion, angiotensin II produced changes in Po ejection parameters consistent with a pressor response in the pulmonary vascular bed. Neither right nor left ventricular diastolic filling were directly affected by angiotensin II. The differential effects of angiotensin II on Po and Ao ejection parameters might be due to inherent differences in basal pulmonary and systemic vascular tone.
Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group.
Authors: Detry JM , Sellier P , Pennaforte S , Cokkinos D , Dargie H , Mathes P
Published: July 2012

1. Trimetazidine has a direct anti‐ischaemic effect on the myocardium without altering the rate x pressure product or coronary blood flow. 2. The effects of trimetazidine (20 mg three times daily) were compared with those of propranolol (40 mg three times daily) in a double‐blind parallel group multicentre study in 149 men with stable angina. 3. Reproducibility of exercise performance was verified during a 3 week run‐in placebo washout period. All patients had > 1 mm ST‐depression on exercise test. 4. After 3 months, similar anti‐anginal efficacy was observed between the trimetazidine (n = 71) and propranolol (n = 78) groups. No significant differences were observed between trimetazidine and propranolol as regards anginal attack rate per week (mean difference P‐TMZ: 2; 95% CI: ‐4.4, 0.5) and exercise duration (mean difference P‐TMZ: 0 s; 95% CI: ‐33, 34) or time to 1 mm ST segment depression (mean difference P‐TMZ: 13 s; 95% CI: ‐24, 51). Heart rate and rate x pressure product at rest and at peak exercise remained unchanged in the trimetazidine group but significantly decreased with propranolol (P < 0.001 in all cases). With both drugs there was a trend to decreased ischaemic episodes in the 46% patients who experienced ambulatory ischaemia on Holter monitoring. Six patients stopped trimetazidine and 12 propranolol. Of these, five in each group were withdrawn because of deterioration in cardiovascular status. 5. The results suggest that trimetazidine and propranolol at the doses studied have similar efficacy in patients with stable angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of liver disease and food on plasma MEGX concentrations.
Authors: Pritchard‐Davies R , Gross AS , Shenfield GM
Published: July 2012

Plasma monoethylglycinexylidide (MEGX) concentrations were measured in 15 healthy controls (age 23‐46 years) and 12 patients with biopsy proven cirrhosis (age 34‐70 years) 30 min after 1 mg kg‐1 intravenous lignocaine. Mean (+/‐ s.d.) MEGX concentrations were 57 +/‐ 33 ng ml‐1 in the controls compared with 21 +/‐ 18 ng ml‐1 in the cirrhotics (P < 0.05), but there was overlap in the range of concentrations. MEGX concentrations were inversely correlated with age, but not disease severity, in the cirrhotic patients (r = 0.62, P = 0.04) but not in the control subjects. In a second study 20 healthy subjects were given 1 mg kg‐1 intravenous lignocaine on two occasions; either fed or fasted, and samples taken at 15, 30 and 60 min after dosage. MEGX concentrations were not significantly different at any time within either day or between fed and fasted study days. There was no correlation with age. The plasma lignocaine concentration at 15 min was significantly higher fed than fasted (2.88 +/‐ 2.44 and 1.82 +/‐ 0.96 micrograms ml‐1, P = 0.01). Measurement of plasma MEGX after i.v. lignocaine is a useful test of liver function and may be performed in fed or fasted subjects. It is reproducible within an individual but is not specific for cirrhosis and appears age‐related in liver disease.
The pharmacokinetics of quinapril and quinaprilat in patients with congestive heart failure.
Authors: Begg EJ , Robson RA , Ikram H , Richards AM , Bammert‐Adams JA , Olson SC , Posvar EL , Reece PA , Sedman AJ
Published: July 2012

The pharmacokinetics of quinapril and its active metabolite quinaprilat were studied in 12 patients with congestive heart failure (CHF) after multiple oral doses of 10 mg quinapril twice daily. Six patients had an ejection fraction of < 35% and six had an ejection fraction between 35%‐ 50%. Increases in the apparent elimination half‐life and in AUC(0, 12h) values of quinaprilat were associated with smaller ejection fractions, decreased creatinine clearance, and increased patient age. Comparison with data from age‐matched controls having comparable renal function suggests that creatinine clearance is the major determinant of quinaprilat clearance. CHF per se appears to have minimal effect. Dosing of quinapril in patients with CHF should be based on their renal function.
Isolated circulatory response to intravenous administration of the ACE inhibitor enalaprilat.
Authors: Boldt J , Knothe C , Schindler F , Stertmann WA , Hempelmann G
Published: July 2012

The isolated vascular effects of intravenous administration of the angiotensin converting enzyme (ACE) inhibitor enalaprilat were investigated. Thirty male patients undergoing cardiopulmonary bypass (CPB) were studied. According to a randomized sequence, 0.04 mg kg‐1 enalaprilat (low‐dose, n = 10), 0.08 mg kg‐1 (high‐dose, n = 10) enalaprilat or saline solution as placebo (control group, n = 10) was given as an i.v. bolus during CPB. Changes in mean arterial pressure (MAP) and venous reservoir (RV) of the extracorporeal circulation were studied as indices of arterial resistance and venous capacitance. Mean arterial blood pressure (MAP) and peripheral vascular resistance (SVR) were significantly more reduced in the high‐dose enalaprilat group (MAP: ‐36 mm Hg after 9 min; SVR: ‐836 dyn s cm‐5) than in the low‐dose group (MAP: ‐13 mm Hg after 10 min). Volume of the reservoir (RV) decreased in both enalaprilat treated groups indicating additional (dose‐dependent) venous pooling effects of the substance (low‐dose: ‐ 300 ml; high‐dose: ‐520 ml; control group: ‐100 ml). Skin capillary blood flow measured by laser Doppler flowmetry (LDF) increased after injection of 0.04 mg kg‐1 enalaprilat, whereas it decreased significantly when MAP fell markedly in patients treated with high‐dose enalaprilat. I.v. enalaprilat had dose‐dependent vasodilating properties in the arterial and venous vessel system indicating reduction in pre‐ and afterload. Microcirculation in both enalaprilat treated groups improved as long as reduction in blood pressure was not limited.
Interactive effects of indomethacin, angiotensin II and frusemide on renal haemodynamics and natriuresis in man.
Authors: Motwani JG , Struthers AD
Published: July 2012

The responses of renal haemodynamic and natriuretic indices to the oral prostaglandin synthetase inhibitor indomethacin (200 mg), to infused angiotensin II (1 ng min‐1 kg‐1) and to the combination of the two were studies in placebo‐controlled fashion in eight normal male subjects both prior to and following administration of intravenous frusemide (20 mg). As compared with placebo, angiotensin II infusion alone caused significant reductions in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.001 vs placebo) but had no effect on glomerular filtration rate. The only change observed in these parameters with indomethacin alone was a small but significant reduction in urine flow rate (P < 0.005 vs placebo). As compared with the effects of angiotensin II alone, indomethacin pre‐treatment followed by angiotensin II infusion led to much greater falls in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.0001 vs placebo) associated with a significant reduction in glomerular filtration rate (P < 0.0001) not observed with angiotensin II alone. Frusemide administration at the midpoint of each study limb resulted in each case in a prompt 15 to 20 fold increase in natriuresis. The renal haemodynamic and natriuretic effects of angiotensin II, indomethacin and their combination were not qualitatively different from those observed in the pre‐frusemide phase. Our findings provide a clear demonstration in man of the important homeostatic role of renal prostaglandins in preserving renal function, particularly glomerular filtration, under conditions of elevated circulating angiotensin II.
Decreased plasma protein binding of valproate in patients with acute head trauma.
Authors: Anderson GD , Gidal BE , Hendryx RJ , Awan AB , Temkin NR , Wilensky AJ , Winn HR
Published: July 2012

1. One hundred and ten plasma samples were obtained from 50 patients treated with valproate for prophylaxis of post‐traumatic head injuries. The samples were selected to include a wide range of albumin concentrations and were assayed for free and total valproate concentrations. Valproate binding parameters were determined from the Scatchard equation for one binding site using reweighted least squares analysis. 2. Plasma albumin concentrations were measured in 130 patients with head trauma. They started to decrease immediately after trauma, reaching a minimum at 5‐7 days of approximately 24% of baseline value and did not return to normal until 1 month. 3. The free fraction of valproate varied six to seven‐fold as albumin concentration ranged from 1.5 to 4.8 g 100 ml‐1 (218‐696 mumol l‐1). The mean association constant for binding (Ka) was 0.008 mumol l(‐1) and the mean number of binding sites (N) was 2.0. There values were similar to those reported for valproate in otherwise healthy patients with epilepsy. 4. Because of saturable protein binding of valproate, hypoalbuminaemia may necessitate the monitoring of free valproate concentrations to avoid toxicity when valproate is used in patients with acute head injury.
Influence of endothelium and surgical preparation on responses of human saphenous vein and internal thoracic artery to angiotensin II.
Authors: Barker JE , Anderson J , Treasure T , Piper PJ
Published: July 2012

1. The saphenous vein (SV) and internal thoracic artery (ITA) are the most commonly used conduits for coronary artery bypass surgery (CABS). The ITA shows better long term patency than the SV, at least in part due to their different responses to agonists, as well as physical differences between the ITA and SV at the time of grafting. 2. Angiotensin II (A II), a potent endogenous vasoconstrictor circulates at augmented levels during and after CABS, but little is known about the effects of A II on the SV and ITA. 3. We studied the contractile effects of A II on SV and ITA as intact rings from a heterogeneous group of patients undergoing CABS. Two groups of SV samples were studied; freshly excised SV (FSV) with no further manipulation and SV that had been surgically prepared for use as a bypass conduit (PSV). We also assessed the function of the endothelium in FSV, PSV and ITA, by measuring the relaxation of preconstricted rings to bradykinin. In some tissues endothelial presence was examined histologically. 4. Surgical preparation of SV affected the contractile ability of the smooth muscle, as PSV contracted less than FSV to potassium chloride (KCl, 90 mM) (P < 0.0001). Loss of endothelial function was seen in 25% of FSV, 50% of PSV and 33% of ITA. 5. A II caused concentration dependent contractions in all rings, over the same concentration range (1 nM‐100 nM). In rings of FSV the presence of functional endothelium attenuated the response, median values with endothelium being less than half that without endothelium (P < 0.0007, at 100 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
Colchicine concentration in leukocytes of patients with familial Mediterranean fever.
Authors: Chappey O , Niel E , Dervichian M , Wautier JL , Scherrmann JM , Cattan D
Published: July 2012

Free and total plasma, granulocyte and mononuclear cell colchicine concentrations were measured by radioimmunoassay in 30 patients with familial Mediterranean fever treated with colchicine 0.5 to 2 mg day‐1. Colchicine concentrations showed a large intersubject variability in plasma (0.13‐1.75 ng ml‐1), granulocytes (4 to 64 ng/10(9) cells), and mononuclear cells (11.4 to 57.6 ng/10(9) cells). Whereas unbound and total plasma colchicine concentrations were well correlated, no correlation was found between total or free plasma and granulocyte or mononuclear cell colchicine concentrations and dose of administered colchicine. In contrast, total or free plasma and granulocyte or mononuclear cell colchicine concentrations were correlated using a hyperbolic function indicating saturable colchicine distribution in both leukocyte populations.
Lack of pharmacokinetic interaction between vinpocetine and oxazepam.
Authors: Storm G , Oosterhuis B , Sollie FA , Visscher HW , Sommer W , Beitinger H , Jonkman JH
Published: July 2012

The influence of multiple doses of vinpocetine (10 mg three times daily) on the steady state plasma concentrations of oxazepam (10 mg three times daily) was studied in 16 healthy subjects. The mean (+/‐ s.d.) AUC (ng ml‐1h‐1) of oxazepam over 24 h during combined treatment was 4716 +/‐ 2296 and for oxazepam treatment alone it was 4737 +/‐ 2448 (95% confidence intervals for ratio of means = 95.4‐103.7%). The degree of plasma protein binding of oxazepam was 98.11 +/‐ 0.32% and was not affected by vinpocetine. Independent of vinpocentine treatment a significant diurnal change in the plasma binding of oxazepam was observed; the free drug fraction was 20% higher during the night than during the day. Cmax and AUC values based on total oxazepam in plasma were 10% lower during the night. The results indicate a lack of influence of vinpocetine on oxazepam kinetics. Diurnal changes in the plasma binding of oxazepam probably have no clinical consequences.
Formation and elimination of sulphamethoxazole hydroxylamine after oral administration of sulphamethoxazole.
Authors: Van der Ven AJ , Mantel MA , Vree TB , Koopmans PP , Van der Meer JW
Published: July 2012

The formation and elimination of sulphamethoxazole hydroxylamine in relation to the pharmacokinetics of the parent compound and its N4‐ acetyl metabolite were investigated in six healthy subjects after a single oral dose of 800 mg sulphamethoxazole. The apparent half‐lives of sulphamethoxazole and its metabolites were approximately 10 h, indicative of formation rate‐limited metabolism. The mean residence time of the hydroxylamine metabolite was 5.5 +/‐ 1.5 h. The renal clearance of sulphamethoxazole hydroxylamine was 4.39 +/‐ 0.91 l h‐1. The urinary recovery of sulphamethoxazole accounted for 16.5 +/‐ 5.5% of the dose, N4‐acetyl‐sulphamethoxazole for 46.2 +/‐ 6.6% and the hydroxylamine metabolite for 2.4 +/‐ 0.8%. The remaining 35% of the dose was unaccounted for. Acetylator phenotype was determined using sulphadimidine. The renal excretion of sulphamethoxazole hydroxylamine was 1.9 +/‐ 0.9% in slow acetylators (n = 3) and 2.8 +/‐ 0.3% in fast acetylators (n = 3); for N4‐acetyl‐sulphamethoxazole the values were 48 +/‐ 6% and 44 +/‐ 8%, respectively. Sulphamethoxazole is metabolized, although to a limited extent, to a hydroxylamine metabolite. This metabolite may be important for the pathogenesis of adverse reactions.
Clinical pharmacology, physiology and pathophysiology of superficial veins‐1.
Authors: Aellig WH
Published: July 2012

1. Venous resistance contributes very little to total peripheral resistance; more than half of the total blood volume, however, is contained in the extrathoracic veins. Owing to marked differences between venous and arterial anatomy and physiology, studies on veins and arteries usually require different methodological approaches. Whereas for arteries the most relevant parameters are resistance, pressure and flow, for veins volume and compliance are most important. For studies of general aspects of the peripheral circulatory system, venous occlusion plethysmography is probably the most useful method. The determination of both the rate of rise in limb volume and the total volume rise after inflating a proximally applied occlusion cuff to a subdiastolic pressure permits the concomitant estimation of both arterial flow and venous compliance. 2. Studies of direct pharmacological or physiological effects on veins, interactions of various pharmacological or physiological stimuli, or pathophysiological changes in venous responsiveness have been facilitated by the development of investigational techniques relying on direct measurements of the compliance of single human veins in vivo. One of these, relying on the use of a linear variable differential transformer (LVDT) for determining changes in the compliance of superficial veins at a standardized congestion pressure, has been found very suitable for the practical application in both patients and healthy subjects. 3. Physiological studies were carried out on the effect of age, exercise, temperature, and the menstrual cycle on venous compliance and venous responsiveness to various stimuli. In addition, interindividual variability in venous responsiveness in monozygotic and dizygotic twins and in unrelated subjects was investigated, and studies on the function of the endothelium were carried out in man in vivo. 4. Pathophysiological studies using this technique were reported from patients with hypertension, orthostatic hypotension, myocardial infarction, varicosis, cystic fibrosis, asthma, diabetes, systemic sclerosis, and cluster headache. 5. Clinical pharmacological studies represent a most important field for the use of this method. Studies were carried out on the effects of a large number of constrictor and dilator agents, and also on drug interactions on human veins in vivo. Venoconstriction was observed after local administration of alpha‐ adrenoceptor and 5‐HT‐receptor agonists, ergot derivatives, angiotensinogen, angiotensin I and II, and several prostaglandins. 6. Owing to the low venous tone present under effects can usually be quantified only on veins e.g. noradrenaline or 5‐hydroxytryptamine. Under these conditions dilatation was observed after the administration of beta‐adrenoceptor agonists, cholinergic (muscarinic) agonists, nitrates, calcium antagonists, bradykinin, substance P and several prostaglandins.
The pharmacokinetics and pharmacodynamics of quinine in the diabetic and non‐diabetic elderly.
Authors: Dyer JR , Davis TM , Giele C , Annus T , Garcia‐Webb P , Robson J
Published: July 2012

1. Quinine is a front‐line antimalarial drug but is prescribed most commonly in nonmalarious countries for cramps. Postural hypotension, hearing loss and hyperinsulinaemic hypoglycaemia occur in malaria and overdose but little is known of quinine kinetics and toxicity in the elderly. 2. We studied 12 non‐insulin‐dependent diabetics and 10 non‐ diabetic controls aged 51‐79 years. Subjects attended on two occasions > 7 days apart. On each test day, subjects were given a 600 Cal meal at 18.00 h (0 h) and, on one occasion, quinine sulphate 600 mg at 22.00 h (4 h). Venous blood samples for glucose, insulin and quinine assay were drawn pre‐prandially and then regularly over the next 38 h. Supine and erect blood pressures were taken and audiometry was performed at 4, 6, 8 and 14 h. A one‐compartment open pharmacokinetic model was fitted to serum quinine concentrations. 3. Absorption and elimination half‐times, volume of distribution and oral clearance of quinine were comparable in the two groups (P > 0.2) and there was a mean absorption lag‐time of approximately 1 h. Basal and immediate post‐prandial (< 4 h) serum glucose and insulin concentrations on both test days were similar in the diabetics and also in the non‐diabetics, but quinine produced a mean reduction in serum glucose of 1.0 mmol l‐1 from 3‐5 h post‐dose in both groups without affecting serum insulin concentrations. Quinine administration did not alter postural blood pressure changes or produce significant hearing loss in either group.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of bradykinin‐induced vasodilation in human forearm vasculature by icatibant, a potent B2‐receptor antagonist.
Authors: Cockcroft JR , Chowienczyk PJ , Brett SE , Bender N , Ritter JM
Published: July 2012

1. The effect of icatibant (D‐Arg‐[Hyp3, Thi5, D‐Tic7, Oic8] bradykinin) a potent B2‐kinin receptor antagonist, was studied on bradykinin‐induced vasodilation in the human forearm. 2. Eight healthy normotensive men were studied in a rising dose random‐placebo controlled study. Placebo and icatibant (20, 50 and 100 micrograms kg‐1 i.v.) were administered double‐blind. Forearm blood flow was measured by venous occlusion plethysmography during rising dose brachial artery infusions of bradykinin (10‐3,000 ng min‐1) 60‐90 min after placebo or icatibant. 3. Plasma concentrations of icatibant fell exponentially following each of three doses, up to the final measurement. Elimination half‐lives calculated from linear regression of the mean data were 25, 27 and 29 min after 20, 50 and 100 micrograms kg‐1 doses respectively. 4. Icatibant inhibited the effect of bradykinin (P < 0.001 at each dose of icatibant) in a dose‐dependent manner. Bradykinin (100 ng min‐1) increased mean blood flow in the infused arm by 238 +/‐ 31% when infused following placebo, by 112 +/‐ 21% after icatibant 20 micrograms kg‐1, by 71 +/‐ 14% after icatibant 50 micrograms kg‐1 and by 48 +/‐ 9% after icatibant 100 micrograms kg‐1. 5. These results demonstrate that icatibant antagonises B2‐receptor mediated vasodilation in human forearm resistance vessels. The findings provide a quantitative basis for future studies of the role of bradykinin in the response to angiotensin converting enzyme inhibitors and in circulatory disease.
At equipotent doses, isradipine is better tolerated than amlodipine in patients with mild‐to‐moderate hypertension: a double‐blind, randomized, parallel‐group study.
Authors: Hermans L , Deblander A , de Keyser P , Scheys I , Lesaffre E , Westelinck KJ
Published: July 2012

1. The objective of this double‐blind parallel‐group study was to compare the tolerability of isradipine and amlodipine, specifically, the side‐effects known to be related to the use of dihydropyridine calcium antagonists. 2. A total of 205 patients with mild‐to‐moderate essential hypertension were randomized to receive either the sustained‐ release (SRO) formulation of isradipine (n = 103) or amlodipine (n = 102), both at dosages of 5 mg once daily. Blood pressure measurements were taken at the end of the dosing interval to assess the antihypertensive efficacy of the two drugs. 3. Adverse reactions were assessed in two ways: a) spontaneously reported adverse events were recorded and investigated in depth for severity, duration, relation to the study drug, and outcome; b) a questionnaire was used to elicit specific adverse reactions known to be related to the use of dihydropyridine calcium antagonists which were evaluated for severity, duration, relation to the study drug, and outcome. 4. After 6 weeks of active treatment, both isradipine and amlodipine reduced mean sitting systolic/diastolic blood pressure: from 165.1/100.1 to 145.2/89.7 mm Hg with isradipine; and from 164.1/100.6 to 145.7/90.5 mm Hg with amlodipine. There was no difference in antihypertensive effect between isradipine and amlodipine (95% CI: ‐3.73 to 4.73 and ‐1.89 to 3.49 for differences in systolic and diastolic blood pressure, respectively). 5. The number of patients spontaneously reporting adverse events was significantly higher (P = 0.02; 95% CI: 3.1 to 26.7%) with amlodipine (33.3%) than with isradipine (18.4%).(ABSTRACT TRUNCATED AT 250 WORDS)
Disappearance kinetics of solutes from synovial fluid after intra‐ articular injection.
Authors: Owen SG , Francis HW , Roberts MS
Published: July 2012

1. Five rheumatoid patients with a knee joint effusion participated in the study. An aqueous solution (0.1 to 0.2 ml) containing paracetamol, salicylate, diclofenac and [125I]‐albumin was injected into a given joint to yield target concentrations of approximately 20 micrograms ml‐ 1 for diclofenac, salicylate and paracetamol and 10(8) counts ml‐1 for [125I]‐albumin. 2. Paracetamol, salicylate and diclofenac were analysed in synovial fluid by h.p.l.c. [125I]‐albumin was analysed using gamma counting. 3. The clearances (+/‐ s.d.) obtained for the solutes were [125I]‐albumin (0.0053 +/‐ 0.0019 l h‐1), diclofenac (0.0096 +/‐ 0.0061 l h‐1), salicylate (0.024 +/‐ 0.022 l h‐1) and paracetamol (0.055 +/‐ 0.041 l h‐1). The corresponding fractions unbound of these solutes in synovial fluid were 0.0, < or = 0.01, 0.34 +/‐ 0.09 and 0.85 +/‐ 0.10, respectively. 4. Diffusion of unbound solute through the synovium is estimated to account for (+/‐ s.d.) 0.52 +/‐ 0.08, 0.87 +/‐ 0.06 and 0.99 +/‐ 0.01 of the total clearance of diclofenac, salicylate and paracetamol from the joint space, respectively. The remaining proportion of clearance is accounted for by efflux of solute bound to albumin. 5. An expression for the ratio of synovial fluid to total plasma concentrations after systemic administration was developed to include both diffusion of unbound solute and albumin flux. Most solutes appear to satisfy the conditions in which this expression reduces to the limiting case where the unbound concentration of the solute is identical in the synovial fluid and plasma under steady state conditions.
Adenosine modulation of neurotransmission in penile erection.
Authors: Chiang PH , Wu SN , Tsai EM , Wu CC , Shen MR , Huang CH , Chiang CP
Published: July 2012

1. Adenosine inhibited the noradrenaline‐induced contraction of rabbit corpus cavernosum in a dose‐dependent manner. The effect of adenosine was greater in intact corpus cavernosa than in endothelium‐denuded preparations. This finding indicates that the relaxing effect of adenosine is partially endothelium‐dependent and involved in the release of endothelium‐derived relaxing factors. 2. Adenosine and its analogues relaxed the noradrenaline‐induced contractile response as well as inhibited the transmural nerve induced contraction with the potency order: NECA > R‐PIA > adenosine. These data indicate that adenosine can modulate both the non‐adrenergic non‐cholinergic and adrenergic neurotransmission. DMPX, an adenosine antagonist selective for the A2 receptors, abolished the electrically elicited relaxation. However, CGS 21680, selective for A2a receptor, had no effect on relaxation. Therefore, adenosine receptors involved in the modulation of neurotransmission in rabbit corpus cavernosum appear to be A2b subtype. 3. Adenosine also induced an increase in human cavernosal arterial velocity and resistive index measured by colour duplex sonography. The combination of adenosine and 10 micrograms prostaglandin E1 was more effective in resistive index and erection grade than 20 micrograms prostaglandin E1 alone. Our results suggest that adenosine seems to be an important neuromodulator for penile erection and can be an effective and alternative combination in the treatment of impotence.
Lansoprazole does not affect the bioavailability of oral contraceptives.
Authors: Fuchs W , Sennewald R , Klotz U
Published: July 2012

The effects of the proton pump inhibitor lansoprazole on the bioavailability of a low‐dose oral contraceptive (OC), containing 0.03 mg ethinyloestradiol (EE) and 0.15 mg levonorgestrel (LNG), were investigated. Twenty‐four healthy females (aged 19‐35 years; weight 60.6 +/‐ 7.1 kg) participated in a multiple‐dose, placebo‐controlled, randomized two‐way cross‐over study. All subjects received the OC over 2 full menstrual cycles from day 1 to day 21 separated by a drug‐free interval of 7 days. Lansoprazole (60 mg day‐1) or placebo was coadministered for 3 weeks each. Plasma concentrations of EE and LNG were determined by GC‐MS. The 90% confidence intervals for ratios of Cmax and AUC after log transformation of both EE and LNG ranged between 91 and 111%, indicating that lansoprazole did not affect the bioavailability of EE and LNG.
False‐positives in spontaneous reporting: should we worry about them?
Authors: Begaud B , Moride Y , Tubert‐Bitter P , Chaslerie A , Haramburu F
Published: July 2012

Spontaneous reporting remains the most used and, undoubtedly, the most cost‐effective approach for the identification of adverse drug reactions (ADRs). Most of the limitations of this method are well recognised but the possibility of receiving false‐positive reports of coincidental drug‐event associations has received little attention. In this paper we propose a method based on the Poisson distribution for computing the maximum number of reports of an ADR that could be expected to be reported coincidentally. Three parameters are required: (i) the background risk of the event in the reference population, (ii) the total number of patients treated with the drug considered and, (iii) the proportion of cases that have been reported to the pharmacovigilance system. For most empirical situations occurring in the post‐marketing surveillance setting, the expected number remains low and only a maximum of one to three cases could be accepted as possibly coincidental. For rare adverse events such as agranulocytosis or toxic epidermal necrolysis, coincidental associations are so unlikely that a number of reports greater than three constitutes a strong warning and requires further investigation. These findings suggest that for rare events, reports of coincidental drug‐event associations are too unlikely to be considered as an important limitation of spontaneous reporting.