bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of medigoxin and digoxin in the control of atrial fibrillation.
Authors: Coburn P. , Kongola GM , Mawer GE
Published: July 2012

1 Medigoxin (Lanitop) 300 microgram/day and digoxin (Lanoxin) 500 microgram/day were compared in cross‐over studies on healthy volunteers and on patients with uncontrolled atrial fibrillation. Serum glycoside concentrations were measured by radioimmunoassay and ventricular rates by ECG. The two regimens appeared to be therapeutically equivalent. 2 The mean serum glycoside concentration in the steady state and the rate at which this state was attained were similar with both drug regimens in the healthy volunteer group. The between‐subject variation in serum glycoside concentration was not significantly less during medigoxin administration. 3 The renal clearance of serum glycoside was much lower during medigoxin administration both in healthy volunteers and in patients. This was not due to a difference in serum protein binding. The relatively small dosage requirement for medigoxin was attributed partly to a lower clearance rate and partly to more nearly complete absorption. 4 During the first 2 weeks of the patient study there was a substantial rise in mean serum glycoside concentration and a corresponding fall in ventricular rate. This was attributed to more consistent self‐administration of digoxin. The subsequent change to medigoxin had no further effect on mean glycoside concentration, ventricular rate or frequency of ventricular ectopic beats. 5. An attempt to compare the onset of the ventricular rate response to a single oral dose of medigoxin with that to digoxin gave inconclusive results.
Comparison of a new microcrystalline dicoumarol preparation with warfarin under routine treatment conditions.
Authors: Lockner D. , Paul C.
Published: July 2012

1 To determine whether two different oral anticoagulants show difference under routine clinical conditions, 71 patients were randomized to treatment with Apekumarol, a microcrystalline dicoumarol preparation, and 72 patients to treatment with warfarin. 2 During the inpatient phase of treatment both drug groups remained for about 94% of their treatment time within prothrombin value limits of 5‐25% (Simplastin A). No statistically significant difference was found between the drugs. 3 While under outpatient care, both drug groups remained for about 80% of their treatment time within prothrombin value limits of 5‐25%. No statistically significant difference was found between the drugs. 4 The intensity of control and number of prothrombin‐ determinations did not differ significantly between the groups. 5 Variations in the daily dose did not differ significantly between the groups. 6 The mean daily dose could not be correlated to mean body weight. 7 The mean daily dose decreased with age for the male patients taking warfarin, not for the female patients. There was no such decrease for either male or female patients taking Apekumarol. An additional 137 patients who at the time of the trial were under routine treatment with warfarin were also studied with regard to mean daily dose, age and sex. In this additional group the mean daily dose could be correlated with age in both males and females. 8 No difference between Apekumarol and warfarin could be demonstrated when tested under routine clinical conditions according to the design of the present study. Sensitivity for warfarin, but not for Apekumarol, seems to increase with age, this sensitivity has been demonstrated in both sexes.
CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients.
Authors: Sotaniemi EA , Rautio A , Backstrom M , Arvela P , Pelkonen O
Published: July 2012

1. The in vitro hepatic metabolism of lignocaine to monoethylglycinexylide (MEGX) is mediated by CYP3A4 and that of coumarin to 7‐hydroxycoumarin (7OHC) by CYP2A6. We investigated the usefulness of monitoring serum MEGX concentrations (after 1 mg kg‐1 lignocaine i.v.) and urinary 7OHC excretion (after 5 mg coumarin p.o.) to reflect liver function in patients with liver (n = 36), kidney (n = 12) and epileptic (n = 12) disease and in control subjects (n = 20). The extent of liver disease was assessed using measurements of serum aminoterminal propeptide (PIIINP) and Child‐Pugh grades. 2. Serum concentrations of MEGX were decreased in severe (4.6 +/‐ 3.0 s.d. ng ml‐ 1), moderate (19.1 +/‐ 11.6 s.d. ng ml‐1) and mild (32.8 +/‐ 14.2 s.d ng ml‐1) liver disease as compared with controls (53.4 +/‐ 15.8 s.d ng ml‐1). The excretion of 7OHC over 2 h was decreased in severe (18.0 +/‐ 10.3 s.d % of dose) and moderate (34.2 +/‐ 15.6 s.d %), but not in mild (49.7 +/‐ 19.0 s.d %) liver disease as compared with that in controls (56.2 +/‐ 11.6%). 3. In epileptic patients the urinary recovery of 7OHC was increased (2 h value 69.5 +/‐ 13.2 s.d %) suggesting enzyme induction. In contrast, serum MEGX concentration were low (40.0 +/‐ 14.1 s.d ng ml‐1), possibly due to competition for CYP3A4 between lignocaine and antiepileptic drugs. 4. In patients with kidney disease serum MEGX concentration (56.5 +/‐ 26.1 s.d ng ml‐1) was similar to that in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Reproducibility of angiotensin converting enzyme inhibitor induced cough: a double‐blind randomised study.
Authors: Charlon V , Dollow S , Fidel J , Hoglund C , Honkanen T , Kobrin I , McEwan J , McInnes G , Viskoper JR , Woo KS , et al
Published: July 2012

1. The reproducibility of angiotensin converting enzyme inhibitor induced cough was examined in a double‐blind cross over study in patients previously shown to have exhibited this side effect. 2. Ninety‐ seven patients who had experienced angiotensin converting enzyme inhibitor cough within the last 2 years were challenged with enalapril 20 mg daily for 4 weeks to establish eligibility. Eighty‐eight of 97 (91%) patients experienced a repeat of their cough symptoms. Sixty‐four patients entered the double‐blind part of the study where they were treated with enalapril 20 mg and a renin inhibitor for up to 4 weeks in random order. These periods were separated by a minimum 4 week placebo wash out. 3. Of 59 evaluable patients who received enalapril a second time, 37 (62.7%) experienced cough again. Of 62 patients on the renin inhibitor 16 (25.8%) experienced cough, however as it was not equi‐ efficacious to enalapril no valid comparison could be made. 4. Angiotensin converting enzyme inhibitor cough is not reproducible within patients, as other factors are involved in the aetiology. Objective testing with blinded assessment together with symptom reporting, would give a more accurate measure of the incidence, and mechanism of this side effect.
Pharmacokinetics and pharmacodynamics of roxatidine in patients with renal insufficiency.
Authors: Gladziwa U , Wagner S , Sieberth HG , Klotz U
Published: July 2012

1. Roxatidine acetate, a new histamine H2‐receptor antagonist, was administered in the evening (75 mg p.o.) to eight patients with renal insufficiency (CLCR 8‐17 ml min‐1) for 12 days and plasma drug concentrations were measured. 2. Ambulatory intragastric pH was monitored following the last dose and values were compared with those on day 1 when all patients received a placebo. 3. The terminal elimination half‐life (mean +/‐ s.d.) of roxatidine was 10.8 +/‐ 2.4 h and its oral clearance was 178 +/‐ 43 ml min‐1. 4. During roxatidine treatment gastrin levels increased slightly (median 189 vs 289 ng l‐1) and the hyperparathyroid status of the patients was almost normalized (parathyroid hormone levels: median 199 vs 132 ng l‐1). 5. The mean latency to a gastric pH of at least 4 was 4.3 +/‐ 1.4 h. The duration of action (intragastric pH > 4) was 10.6 +/‐ 3.9 h. 6. As in a pilot study with six patients (CLCR < or = 17 ml min‐1) the recommended dosage regimen (75 mg 48 h‐1) was unable to maintain gastric pH > 4 for more than 6 h, daily nocturnal intake of 75 mg roxatidine acetate appears appropriate to elevate gastric pH > 4 for a sufficient period of time.
The effect of levcromakalim (BRL 38227) on bladder function in patients with high spinal cord lesions.
Authors: Komersova K , Rogerson JW , Conway EL , Lim TC , Brown DJ , Krum H , Jackman GP , Murdoch R , Louis WJ
Published: July 2012

The effects of the potassium channel opener levcromakalim (BRL 38227) 7.5 micrograms kg‐1 were examined on urodynamic variables and blood pressure during inflow and voiding cystometry in six high spinal cord lesion patients. Levcromakalim administration significantly increased the duration of bladder contraction (197 +/‐ 128 s to 267 +/‐ 167 s, P < 0.05) and also reduced blood pressure (126 +/‐ 13/67 +/‐ 9 mm Hg to 104 +/‐ 25/52 +/‐ 12 mm Hg) but was without effect on other urodynamic parameters. Because of concerns about hypotensive responses, further studies involving higher doses of levcromakalim should be considered only if the drug was administered intravesically.
Twenty‐four hour efficacy of two dose levels of a once daily sustained‐ release diltiazem formulation in stable angina: a placebo‐controlled trial. The Dildurang Study Group.
Authors: Frances Y , Gagey S , Stalla‐Bourdillon A
Published: July 2012

1. This placebo‐controlled study assessed once daily sustained‐release (SR) diltiazem, 200 and 300 mg, in 182 stable angina patients with positive exercise test. 2. Exercise testing was performed at baseline after a 7 day placebo run‐in period, and repeated after 7 days of treatment, 25.0 +/‐ 0.1 h postdose. 3. Diltiazem (200 and 300 mg) produced respectively a 68% and a 64% decrease in weekly angina episodes, and placebo a 15% decrease (P < 0.05). Similarly, both dose levels produced a 70% decrease in nitroglycerin consumption, whereas no difference was obtained with placebo (P < 0.01). The increase in time to ischaemic threshold was significantly superior for 200 mg and 300 mg diltiazem when compared with placebo (75.2 and 91.5 s respectively vs 47.0 s) (P < 0.05); increase in time to anginal threshold was also significantly greater for diltiazem when compared with placebo (84.6 and 85.9 s respectively vs 43.9 s) (P < 0.05). 4. Only one patient experienced worsening of angina and had to be withdrawn from the study. 5. This study demonstrates 200 and 300 mg SR diltiazem is effective when given once‐a‐day in the prophylaxis of stable exertional angina. This once daily formulation should improve patients' compliance and comfort.
The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects.
Authors: Batty KT , Davis TM , Ilett KF , Dusci LJ , Langton SR
Published: July 2012

1. The mechanism of the interaction between ciprofloxacin and theophylline was investigated in nine healthy subjects. 2. Subjects were given a single oral dose of theophylline (3.4 mg kg‐1), before and after 60 h of ciprofloxacin therapy at a dose of 500 mg twice daily. 3. Ciprofloxacin reduced the oral clearance of theophylline by 19% (‐7.73 +/‐ 6.42 ml kg‐1 h‐1 (95% confidence limits ‐12.66, ‐2.79)). Some subjects (group A, n = 4) showed little decrease in clearance (mean 4.4%; ‐1.6 +/‐ 0.7 ml kg‐1 h‐1 (‐2.6, 0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; ‐12.7 +/‐ 3.7 ml kg‐1 h‐1 (‐ 17.2, ‐8.1)). 4. Comparing groups A and B, the decrease in oral clearance of theophylline in group B could not be ascribed to differences in the AUC of ciprofloxacin. Group A subjects showed only slight inhibition of 1‐demethylation (‐12.8 +/‐ 5.5% (‐21.5, ‐4.0)), while group B subjects showed a significantly greater inhibition of 1‐ demethylation (‐49.9 +/‐ 9.8% (‐62.1, ‐37.7)), 3‐demethylation (‐44.8 +/‐ 8.6% (‐55.4, ‐34.1)) and 8‐hydroxylation (‐27.0 +/‐ 3.7% (‐31.6, ‐ 22.4)). 5. The results suggest that inter‐individual variability in the inhibition of theophylline metabolism by ciprofloxacin can be attributed to inter‐individual differences in the level of CYP1A2 expression and/or in the degree of inhibition of hepatic CYP1A2 and CYP3A4. 6. The interaction between ciprofloxacin and theophylline can be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Serum drug concentrations after oral administration of paracetamol to patients with surgical resection of the gastrointestinal tract.
Authors: Ueno T , Tanaka A , Hamanaka Y , Suzuki T
Published: July 2012

Serum concentrations of paracetamol were measured at 30, 60, 120 and 180 min after oral administration of a solution of 1500 mg paracetamol in normal subjects (n = 32) (Group A) and in patients with total gastrectomy (Roux‐en‐Y reconstruction) (n = 5) (Group B), distal partial gastrectomy (Billroth I reconstruction) (n = 7) (Group C), pylorus preserving pancreatoduodenectomy (Billroth I type reconstruction) (n = 12) (Group D), and short bowel syndrome (n = 5) (Group E). In Group B, the dose was delivery directly into the jejunum 20 cm distal to the duodenojejunal flexure. The highest serum drug concentrations were observed in the 30 min sample in Groups B and C and in the 120 min sample in Groups A, D, and E. Mean (+/‐ s.d.) concentrations at these times were 18.90 +/‐ 1.55 micrograms ml‐1 (Group B), 12.89 +/‐ 2.12 micrograms ml‐1 (Group C), 11.12 +/‐ 3.16 micrograms ml‐1 (Group A), 9.78 +/‐ 2.85 micrograms ml‐1 (Group D), and 4.89 +/‐ 1.96 micrograms ml‐1 (Group E), respectively. We conclude that in patients with normal intact gastrointestinal tract, most of a dose of oral paracetamol is absorbed from the jejunum distal to the duodenojejunal flexure.
Comparison of non‐invasive methods for the assessment of haemodynamic drug effects in healthy male and female volunteers: sex differences in cardiovascular responsiveness.
Authors: Wolzt M , Schmetterer L , Rheinberger A , Salomon A , Unfried C , Breiteneder H , Ehringer H , Eichler HG , Fercher AF
Published: July 2012

1. The study was performed to determine the sensitivity and short‐term and day‐to‐day variability of a novel technique based on laser interferometry of ocular fundus pulsations and of non‐invasive methods for the quantification of haemodynamic drug effects. An additional aim was to assess sex differences in haemodynamic responsiveness to cardiovascular drugs in male and female healthy volunteers. 2. Ten males and nine females (age range 20‐33 years) were studied in a double‐ blind, randomized, cross‐over trial. Simultaneous measurements from systemic haemodynamics, laser interferometry of ocular fundus pulsations, systolic time intervals from mechanocardiography, a/b ratio from oxymetric fingerplethysmography and Doppler sonography of the radial artery were used to describe the haemodynamic effects of cumulative, stepwise increasing intravenous doses of phenylephrine, isoprenaline, sodium nitroprusside and of placebo. 3. Laser interferometry detected the isoprenaline‐effects at the lowest dose level of 0.1 micrograms min‐1 with a high signal‐to‐noise ratio. The reproducibility of measurements under baseline was high, no changes were observed after systemically effective doses of phenylephrine or sodium nitroprusside. Systolic time intervals were sensitive and specific for isoprenaline‐induced effects, PEP and QS2c‐measurements had high reproducibility. Fingerplethysmography proved a sensitive measurement for the detection of the vasodilating effects of sodium nitroprusside, but was not specific, and showed low reproducibility. Measurements from Doppler sonography had lower reproducibility and sensitivity compared with the other applied methods. 4. There was a significant sex difference for several of the haemodynamic parameters under baseline conditions; however, the responsiveness to the drugs under study was not different, when drug effects were expressed as %‐ change from the baseline. 5. Laser interferometry is a valuable non‐ invasive, highly sensitive and specific approach for the detection of pulse pressure changes. A battery of non‐invasive tests appears useful for the characterization of cardiovascular drugs. Gender differences may not pose a relevant problem for the study of acute haemodynamic effects of cardiovascular drugs.
Comparison of the pharmacokinetics and pharmacodynamics of oral doses of perindopril in normotensive Chinese and Caucasian volunteers.
Authors: Critchley JA , Tomlinson B , Resplandy G
Published: July 2012

1. The pharmacokinetics of perindopril and perindoprilat and the hormonal and haemodynamic responses following a single oral dose were studied in 12 Chinese and 10 Caucasian healthy, normotensive volunteers on two occasions. Perindopril was given on the first occasion as a 4 mg dose and then after at least 10 days as a weight‐adjusted dose of 4 mg/70 kg. Plasma was sampled for assay of perindopril, perindoprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE activity. Urine was collected for perindopril and perindoprilat assay. A radioimmunoassay technique was used to measure the prodrug and its active metabolite. 2. The time to maximum concentration (tmax) for perindopril was shorter for the Chinese group after the 4 mg dose (median 0.5, range 0.5‐1.5 h vs median 1.0, 0.5‐1.5 h P < 0.05) and also tended to be shorter after the weight‐adjusted dose (median 0.5, range 0.5‐1.0 h vs median 1.0, range 0.5‐3.0 h). Cmax and AUC tended to be higher after the 4 mg dose in the Chinese group who had a lower body weight than the Caucasians. 3. The tmax of perindoprilat tended to be shorter for both doses and there was a tendency towards a higher Cmax after the 4 mg dose in the Chinese group but there was no statistically significant difference between the two groups. 4. There were no differences in the levels of PRA, plasma AI, plasma aldosterone or the degree of ACE‐inhibition for either dose in the two ethnic groups. 5. Blood pressure was measured at intervals up to 24 h post‐dose in both the supine and standing positions. Perindopril reduced blood pressure acutely with respect to the pre‐dose level with good tolerability in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Cytochrome P4502D6 genotype does not determine response to clozapine.
Authors: Arranz MJ , Dawson E , Shaikh S , Sham P , Sharma T , Aitchison K , Crocq MA , Gill M , Kerwin R , Collier DA
Published: July 2012

1. The atypical antipsychotic drug clozapine, used in the treatment of resistant schizophrenia, is metabolized partly by the hepatic cytochrome P450 enzyme CYP2D6. Two phenotypes with respect to the activity of the enzyme are recognized (extensive metabolisers (EM) and poor metabolisers (PM)), resulting from allelic variation in the gene, CYP2D6. 2. Genotype was determined in 123 schizophrenic patients currently being treated with clozapine, in order to determine if EM or PM status influences response to this drug. Patients were divided into responders and non‐responders using the Global Assessment Scale, and genotyped for the A and B poor metaboliser mutations by digesting PCR products with HpaII or BstNI. 3. Fifty‐nine patients were heterozygous for allele B and for allele A. Eight patients were determined as poor metabolisers since they were homozygous either for A and B. Poor metabolisers were equally distributed between responders and nonresponders and no correlation between CYP2D6 alleles and response to clozapine was found. 4. The results are consistent with recent findings showing that CYP1A2, rather than CYP2D6, is the major enzyme responsible for the metabolism of clozapine.
Method specificity of the auscultatory estimates of the inodilatory reduction of diastolic blood pressure based on Korotkoff IV and V criteria.
Authors: De Mey C
Published: July 2012

1. Non‐invasive measurements of blood pressure (BP) are method‐specific estimates of actual blood pressure. The agreement of the auscultatory Korokoff V ('disappearance' of sound, kv) and Korokoff IV ('sound muffling' kiv) cut‐off points in measuring diastolic blood pressure (DBP) was evaluated in healthy subjects in the presence of various controlled inodilatory interventions. 2. Eating (n = 8), 10 min i.v. infusion of 1 microgram min‐1 isoprenaline and adrenaline (n = 12), p.o. administration of 40 mg of the PDE‐III inhibitors isomazole and meribendan (n = 18) and p.o. administration of 1200 mg celiprolol (n = 15) caused evident chrono‐inodilatory responses: average HR increases of 7, 19, 10, 17, 17 and 8 beats min‐1, estimated CO increases of 1.6, 4.5, 2.3, 1.9, 2.6 and 1.8 1 min‐1 and average shortening of QS2c of 18, 41, 8, 37, 42 and 9 ms for food, isoprenaline, adrenaline, isomazole, meribendan and celiprolol, respectively. 3. In general, there was good agreement between DBPkV and DBPkIV measurements before the administration of the inodilatory treatments (bias DBPkV‐DBPkIV: 1‐ 2 mm Hg) but the extent of inodilatory DBP reduction (‐8, ‐6, ‐10, ‐2, ‐ 7 and ‐8 mm Hg according to DBPkIV for food, isoprenaline, adrenaline, isomazole, meribendan and celiprolol, respectively) was substantially overestimated when based on Korotkoff‐V rather than ‐IV (bias DBPkV‐ DBPkIV in estimating the inodilatory effect on DBP: ‐8, ‐12, 1, ‐13, ‐ 12 and ‐7 mm Hg for food, isoprenaline, adrenaline, isomazole, meribendan and celiprolol, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of captopril on the human foetal placental circulation: an interaction with bradykinin and angiotensin I.
Authors: de Moura R , Lopes MA
Published: July 2012

1. The mechanism underlying the foetal toxicity induced by captopril is not well understood. Since bradykinin and angiotensin II appear to be important in the regulation of the placental circulation, experiments were performed to assess the effects of captopril on the vascular actions of these peptides on the human foetal placental circulation. 2. Full‐term human placentas, obtained from normal pregnancy, were perfused with a modified Tyrode solution bubbled with O2 using a pulsatile pump. The placental perfusion pressure was measured with a Statham pressure transducer and recorded continuously on a Hewlett‐ Packard polygraph. 3. Bradykinin (0.1, 0.3 and 1.0 nmol) injected into the placental arterial circulation produced an increase in placental perfusion pressure in all experiments. This effect of bradykinin was significantly inhibited by indomethacin (3 × 10(‐7) M). 4. Captopril (10(‐7) M) significantly potentiated the pressor effect of bradykinin on the human placental circulation (n = 6). This effect of captopril was reversed by indomethacin (3 × 10(‐7) M). 5. Angiotensin I (n = 6) and angiotensin II (n = 6), injected into the placental arterial circulation, both produced dose‐dependent increases in placental perfusion pressure. The dose‐response curves to angiotensin I (n = 6) were significantly displaced to the right by captopril in a concentration‐dependent manner. 6. We suggest that the toxic effects of captopril on the foetus, rather than reflecting an inhibition of angiotensin II formation, may instead be related to a potentiation of the vasoconstrictor effect of bradykinin on the foetal placental circulation, thereby reducing blood flow and causing foetal damage. The reasons for this are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in children with HIV infection.
Authors: Gibb D , Barry M , Ormesher S , Nokes L , Seefried M , Giaquinto C , Back D
Published: July 2012

The pharmacokinetics of zidovudine (ZDV) and dideoxyinosine (ddI) were investigated following administration alone and in combination to children with symptomatic HIV disease. The children were studied on three separate occasions and received ZDV 200 mg m‐2, ddI 100 mg m2 or a combination of ZDV 200 mg m‐2 plus ddI 100 mg m‐2. The administration of ddI did not significantly alter ZDV pharmacokinetics. The area under the curve (AUC) was 14.2 +/‐ 4.9 and 15.8 +/‐ 7.2 mumol l‐1 h and elimination half‐life (t1/2, z) was 1.4 +/‐ 0.4 and 1.2 +/‐ 0.2 h in the absence and presence of ddI respectively. The peak concentration (Cmax), time to peak (tmax) and apparent oral clearance (CL/F) were also unchanged. The administration of ZDV had no significant effect on ddI Cmax, tmax, t1/2,z, or CL/F, however the AUC was reduced by 19% (5.9 +/‐ 2.9 to 4.8 +/‐ 2.7 mumol l‐1 h; P < 0.05). This study suggests that ZDV and ddI may be co‐administered to children with symptomatic HIV disease without concern of a clinically relevant pharmacokinetic drug interaction.
Factors affecting the absolute bioavailability of nifedipine.
Authors: Rashid TJ , Martin U , Clarke H , Waller DG , Renwick AG , George CF
Published: July 2012

1. Nifedipine was administered to eight volunteers (seven Caucasian, one East Asian of Chinese origin) as a single 10 mg capsule orally and as 2.5 mg intravenously. The pharmacokinetics were determined under fasting conditions and following 200 ml double strength grapefruit juice taken orally both 2 h before and at the time of dosing. 2. In a separate study, the pharmacokinetics of nifedipine were defined in eight South Asian volunteers (with both parents originating from the Indian subcontinent) following 10 mg nifedipine orally and 2.5 mg intravenously. 3. The administration of grapefruit juice did not alter the pharmacokinetics of intravenous nifedipine, but resulted in a significantly increased area under the plasma concentration‐time curve (AUC) (191 +/‐ 59 c.f. 301 +/‐ 95 ng ml‐1 h, P < 0.05) and bioavailability (0.63 +/‐ 0.18 c.f. 0.86 +/‐ 0.15, P < 0.05) following oral nifedipine. The elimination half‐life was unchanged by administration of grapefruit juice and there was no evidence of decreased formation of the nitropyridine first‐pass metabolite. 4. The AUC of nifedipine after intravenous administration was significantly higher in South Asian subjects than in Caucasians (146 +/‐ 39 c.f. 74 +/‐ 18 ng ml‐1 h, P < 0.002). This was due to a lower systemic clearance in the South Asians which was 50% of that in the Caucasians. The half‐life was markedly prolonged in South Asians (4.1 +/‐ 1.9 c.f. 1.7 +/‐ 0.5 h, P < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetic and pharmacodynamic analysis of a novel leukotriene biosynthesis inhibitor, MK‐0591, in healthy volunteers.
Authors: Uematsu T , Kanamaru M , Kosuge K , Hara K , Uchiyama N , Takenaga N , Tanaka W , Friedman BS , Nakashima M
Published: July 2012

1. The pharmacokinetic and pharmacodynamic properties of a novel 2‐ indolealkanoic acid derivative (MK‐0591), a potent inhibitor of leukotriene biosynthesis, were investigated in healthy male Japanese volunteers. Single oral doses of 50, 125, 250 and 500 mg and multiple oral doses of 125 mg twice daily for 9.5 days and 250 mg once daily for 10 days were administered. 2. After the single‐dose administration following overnight fasting, Cmax and AUC of MK‐0591 in plasma increased in a dose‐dependent manner, while elimination half‐life remained constant (11.2‐13.2 h) irrespective of dose. Food intake decreased Cmax and AUC by 71% and 68%, respectively, at a dose of 250 mg. With respect to multiple‐dose administration before meals, there were no significant differences in the pharmacokinetic parameters between the first and last days, indicating a lack of significant accumulation of MK‐0591 in plasma. Urinary recovery as the unchanged form was negligible throughout the study. 3. Ionophore‐stimulated production of leukotriene B4 (LTB4) in blood ex vivo was inhibited significantly from 1 h until 12 to 48 h after single‐dose administration as compared with predose value. In parallel, the urinary excretion of endogenous leukotriene E4 (LTE4) was significantly decreased from 4 to 8 h until 48 to 72 h after drug administration. Reduction of ionophore‐stimulated LTB4 biosynthesis and urinary excretion of LTE4 following single administration of MK‐0591 was statistically significant as compared with placebo group, and the duration of inhibition of LTB4 biosynthesis was dose‐related.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics of ketoprofen enantiomers after different doses of the racemate.
Authors: Geisslinger G , Menzel S , Wissel K , Brune K
Published: July 2012

The pharmacokinetics of the enantiomers of ketoprofen after oral administration of 12.5 mg, 25 mg and 50 mg and i.v. administration of 50 mg racemic ketoprofen to 24 healthy subjects were investigated. The AUC values of R‐ (r2 = 0.929) and S‐ketoprofen (r2 = 0.930) were proportional to dose. The absolute bioavailability of the 50 mg oral dose was 84.5 (s.d. 20.6) % and 81.4 (18.0) % for R‐ketoprofen and S‐ ketoprofen, respectively. With the exception of AUC values no dose dependent differences in pharmacokinetic parameters were observed. However, the R‐enantiomer had higher AUC, lower clearance data and higher Cmax values than the S‐form after oral administration. The results suggest that stereochemical and pharmacokinetic considerations cannot explain the lack of dose response observed with ketoprofen doses below 50 mg.
Marked enhancement by rifampicin and lack of effect of isoniazid on the elimination of quinine in man.
Authors: Wanwimolruk S , Kang W , Coville PF , Viriyayudhakorn S , Thitiarchakul S
Published: July 2012

The effect of rifampicin and isoniazid pretreatment on the pharmacokinetics of quinine after a single oral dose (600 mg quinine sulphate) was studied in nine healthy young Thai male volunteers using a three‐way randomized crossover design. Subjects were studied over three 2 day periods, during which they received no pretreatment, or pretreatment with daily 600 mg p.o. rifampicin for 2 weeks, or isoniazid 300 mg p.o. daily for 1 week, prior to quinine administration. The mean (+/‐ s.d.) clearance (CL/F) of quinine coadministered with rifampicin (0.87 +/‐ 0.35 1 h‐1 kg‐1) was significantly greater than that of quinine alone (0.14 +/‐ 0.05 1 h‐1 kg‐1). The mean difference in clearance from the control treatment was 0.73 1 h‐1 kg‐1, with 95% confidence interval (C.I.) of 0.48 to 0.98. The unbound clearance (CLu/F) of quinine, which reflects the activity of the drug‐metabolizing enzymes, was considerably greater (6.9‐fold) in subjects when rifampicin was coadministered with quinine than that of quinine alone (6.9 +/‐ 3.6 vs 1.0 +/‐ 0.5 1 h‐1 kg‐1; the 95% C.I. for the mean difference was 3.3 to 8.5). The mean elimination half‐life of quinine when coadministered with rifampicin (5.5 +/‐ 3.0 h) was significantly shorter than when quinine was given alone (11.1 +/‐ 3.0 h; the 95% C.I. for the mean difference was ‐8.6 to ‐2.6). In contrast to rifampicin, pretreatment for 1 week with 300 mg oral isoniazid had no significant effects on the pharmacokinetics of quinine.(ABSTRACT TRUNCATED AT 250 WORDS)
Method specificity of non‐invasive blood pressure measurement: oscillometry and finger pulse pressure vs acoustic methods.
Authors: de Mey C , Schroeter V , Butzer R , Roll S , Belz GG
Published: July 2012

1. The agreement of blood pressure measurements by stethoscope auscultation (SBPa, DBPa‐IV and DBPa‐V), oscillometry (Dinamap; SBPo, and DBPo) and digital photoplethysmography (Finapres; SBPf, and DBPf) with the graphical analysis of the analogue microphone signals of vascular wall motion sound (SBPg and DBPg) was evaluated in eight healthy subjects in the presence of responses to the intravenous infusion of 1 microgram min‐1 isoprenaline. 2. In general, there was good agreement between the SBP/DBP‐measurements based on auscultatory Korotkoff‐I‐ and IV‐criteria and the reference method; the average method difference in estimating the isoprenaline responses for SBPa‐ SBPg was: ‐1.1, 95% CI: ‐5.4 to 3.1 mm Hg with a within‐subject between‐ method repeatability coefficient (REP) of 11.6 mm Hg and for DBPa‐IV‐ DBPg: 3.5, 95% CI: ‐0.5 to 6.5 mm Hg, REP: 11.5 mm Hg. The ausculatation of Korotkoff‐V substantially overestimated the isoprenaline induced reduction of DBP: method difference DBPa‐V‐DBPg: ‐ 11.3, 95% CI: ‐17.8 to ‐4.7 mm Hg, REP: 31.8 mm Hg. 3. Oscillometry yielded good approximations for the SBP response to isoprenaline (average method difference SBPo‐SBPg: ‐2.9, 95% CI: ‐9.0 to 3.3 mm Hg, REP: 17.6 mm Hg) but was poorly sensitive with regard to the DBP responses: method difference DBPo‐DBPg: 6.5, 95% CI: ‐1.3 to 14.3 mm Hg, REP: 25.7 mm Hg. 4. Whilst the finger pulse pressure agreed well with regard to DBP (method difference for the DBP responses to isoprenaline: DBPf‐DBPg: 1.8, 95% CI: ‐5.1 to 8.6 mm Hg, REP: 18.5 mm Hg) it was rather unsatisfactory with regard to SBP (method difference SBPf‐SBPg: ‐14.1, 95% CI: ‐28.2 to ‐0.1 mm Hg, REP: 49.9 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiopulmonary interactions of salbutamol and hypoxaemia in healthy young volunteers.
Authors: Kiely DG , Cargill RI , Lipworth BJ
Published: July 2012

1. Nebulised salbutamol is frequently used in the treatment of asthma and chronic obstructive pulmonary disease. Its effects on the cardiovascular system have been extensively investigated although as yet little is known concerning its effects on the pulmonary circulation, particularly during hypoxaemia. We have therefore examined the effects of nebulised salbutamol on pulmonary haemodynamics to see if it modifies hypoxic pulmonary vasoconstriction. 2. Eight healthy normal volunteers were studied on two separate occasions. After resting to achieve baseline haemodynamics patients were randomised to receive 5 mg salbutamol or placebo via a nebuliser. They were restudied after 30 min and then rendered hypoxaemic by breathing an N2/O2 mixture to achieve an SaO2 of 75‐80%. Doppler echocardiography was used to measure mean pulmonary artery pressure (MPAP), cardiac output (CO) and hence pulmonary vascular resistance (PVR). 3. Treatment with salbutamol significantly increased MPAP during normoxaemia and hypoxaemia compared with placebo at 12.0 +/‐ 1.2 vs 8.0 +/‐ 0.7 mm Hg and 28.6 +/‐ 0.9 vs 25.2 +/‐ 1.0 mm Hg, respectively (P < 0.05). Salbutamol caused a significant increase in heart rate compared with placebo and effects were additive to those of hypoxia at 74 +/‐ 2 vs 67 +/‐ 3 beats min‐1 during normoxaemia and 84 +/‐ 3 vs 77 +/‐ 4 beats min‐1 during hypoxaemia, respectively (P < 0.05). Whilst systemic vascular resistance fell in response to salbutamol, PVR was unchanged by salbutamol during either normoxaemia or hypoxaemia. Cardiac output was increased by salbutamol and by hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma concentrations and effects of salbutamol administered orally to patients with cystic fibrosis.
Authors: Demnati R , Michoud MC , Jeanneret‐Grosjean A , Ong H , Du Souich P
Published: July 2012

1. To test whether cystic fibrosis (CF) altered the kinetics and dynamics of oral salbutamol, 11 patients with CF (19‐33 years old; five females; FEV1: 37 +/‐ 12% of predicted value) and 10 healthy volunteers (20‐41 years old; five females; FEV1: 99 +/‐ 14% of predicted value) received orally 4 mg salbutamol. 2. The estimated pharmacokinetic parameters of salbutamol in patients with CF were identical to those in healthy subjects. For instance, peak plasma concentrations of salbutamol were 10.5 +/‐ 2.6 (mean +/‐ s.d.) and 10.2 +/‐ 2.9 ng ml‐1 (NS), and the area under salbutamol plasma concentrations as a function of time (AUC (0, 7 h)) was 43.0 +/‐ 9.3 ng ml‐1 h and 43.3 +/‐ 12.7 ng ml‐1 h (NS) in CF patients and in healthy subjects, respectively. Since on a mg kg‐1 dose basis, CF patients received a dose 28% greater than healthy subjects, this lack of differences implies a decrease in the amount of salbutamol absorbed, or alternatively, an increase in both clearance and volume of distribution of salbutamol. 3. Salbutamol did not elicit bronchodilation in CF patients, but increased heart rate from 77 +/‐ 2 to 103 +/‐ 3 beats min‐1 (P < 0.05). 4. Salbutamol decreased plasma potassium concentrations from 4.5 +/‐ 0.1 to 3.8 +/‐ 0.1 mmol l‐1 in the CF group (P < 0.05) and from 4.1 +/‐ 0.2 to 3.4 +/‐ 0.1 mmol l‐1 in the controls (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Age and gender related changes in stereoselective pharmacokinetics and pharmacodynamics of verapamil and norverapamil.
Authors: Gupta SK , Atkinson L , Tu T , Longstreth JA
Published: July 2012

1. Pharmacokinetics and pharmacodynamics of R‐ and S‐verapamil and R‐ and S‐norverapamil were studied at steady state following administration of 180 mg verapamil delivered by a controlled‐release gastrointestinal therapeutic system (COER‐verapamil). 2. Of the 30 young (19 to 43 years) and 30 elderly subjects (65 to 80 years) enrolled, approximately half of each age group were women; all subjects were healthy and none were smokers. 3. Mean R‐ and S‐verapamil and R‐ and S‐norverapamil Cmax, Cmin, and AUC values for elderly subjects were 1.2 to 2.2 times greater than those for young subjects; these differences were statistically significant at P < 0.05. Median tmax values for young and elderly subjects were not significantly different for any enantiomer. The mean half‐life values of R‐ and S‐verapamil for elderly subjects were approximately 20 h compared with approximately 13 h for young subjects, respectively. The mean half‐life values of R‐ and S‐norverapamil for elderly subjects were approximately 31 h and 20 h, respectively, compared with approximately 19 h and 21 h for young subjects, respectively. 4. In both age groups, the mean plasma verapamil concentrations of each enantiomer were higher for women than for men at all time points. 5. Mean arterial pressure (MAP) had a significant correlation to R‐ (r2 = 0.86) and S‐verapamil (r2 = 0.87) concentration values that was not influenced by either gender or age of the patient. Change in PR‐interval also had a significant correlation to R‐ and S‐verapamil concentration values. However, the sensitivity of the response to changes in R‐ and S‐verapamil concentration values in elderly subjects was about 1/5 of that in younger subjects.
An unequal cross‐over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype.
Authors: Panserat S , Mura C , Gerard N , Vincent‐Viry M , Galteau MM , Jacoz‐Aigrain E , Krishnamoorthy R
Published: July 2012

1. The study of the CYP2D genotype and phenotype of a Caucasian family revealed that a XbaI‐9 kb allele was associated with the poor metabolizer phenotype. 2. A Polymerase Chain Reaction (PCR)‐based assay showed that the previously described mutations D6A and D6B are not associated with the XbaI‐9 kb allele. 3. To explore the molecular basis of the poor metabolizer phenotype associated with the XbaI‐9 kb allele, complete sequencing of the nine exons and intron‐exon boundaries of the CYP2D6 gene was undertaken after amplification by PCR. 4. All the exons were successfully amplified using CYP2D6 gene‐specific primers except exon 1 which required a combination of CYP2D7 gene‐specific 5' primer and a CYP2D6 gene‐specific 3' primer. 5. Sequence data derived from this amplified product revealed that the XbaI‐9 kb allele corresponds to a novel rearrangement of the locus. This involved a deletion of an approximately 20 kilobase (kb) DNA segment generating a hybrid 5' CYP2D7/CYP2D6 3' gene. 6. The chimeric gene is non‐functional presumably due to an insertion in exon 1 (characteristic of the exon 1 of the CYP2D7 gene) which causes a shift in the reading frame with premature termination of translation.
Evaluation of the central effects of alcohol and caffeine interaction.
Authors: Azcona O , Barbanoj MJ , Torrent J , Jane F
Published: July 2012

1. The dynamic and kinetic interactions of alcohol and caffeine were studied in a double‐blind, placebo controlled, cross‐over trial. Treatments were administered to eight healthy subjects in four experimental sessions, leaving a 1 week wash‐out period between each, as follows: 1) placebo, 2) alcohol (0.8 g kg‐1), 3) caffeine (400 mg) and 4) alcohol (0.8 g kg‐1) + caffeine (400 mg). 2. Evaluations were performed by means of: 1) objective measures: a) psychomotor performance (critical flicker fusion frequency, simple reaction time and tapping test), b) long latency visual evoked potentials ('pattern reversal'); 2) subjective self‐rated scales (visual analogue scales and profile of mood states); 3) caffeine and alcohol plasma concentration determinations. 3. The battery of pharmacodynamic tests was conducted at baseline and at +0.5 h, +1.5 h, +2.5 h, +4 h and +6 h. An analysis of variance was applied to the results, accepting a P < 0.05 as significant. The plasma‐time curves for caffeine and alcohol were analysed by means of model‐independent methods. 4. Results obtained with caffeine in the objective measures demonstrated a decrease in simple reaction time and an increase in the amplitude of the evoked potentials; the subjects' self‐ratings showed a tendency to be more active. Alcohol increased simple reaction time and decreased amplitude of the evoked potentials, although the subjects rated themselves as being active. The combination of alcohol + caffeine showed no significant difference from placebo in the objective tests; nevertheless, the subjective feeling of drunkenness remained. The area under the curve (AUC) for caffeine was significantly higher when administered with alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)
Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.
Authors: Aasmundstad TA , Xu BQ , Johansson I. , Ripel A. , Bjorneboe A. , Christophersen AS , Bodd E. , Morland J.
Published: July 2012

1. The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture Cosylan were investigated in 10 healthy subjects. 2. The median urinary recovery of ethylmorphine and measured metabolites was 77% over 48 h. The median tmax of unchanged ethylmorphine was 45 min, and the terminal elimination t1/2 was 2 h. Ethylmorphine‐6‐glucuronide was found to be the major metabolite. 3. Two subjects had significantly lower urinary recovery (0.48 h) of morphine and morphine‐glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MRO) and partial metabolic clearances (CLmO) for O‐deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine type. 4. Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five homozygote (wt/wt) and five heterozygote subjects. Two subjects phenotypically classified as poor metabolisers were genotypically CYP2D6A/wt and CYP2D6D/wt, respectively. 5. Serum and urine samples taken more than 8 and 24 h after administration of ethyl‐morphine respectively, contained morphine and morphine‐ glucuronides, but no ethylmorphine, ethylmorphine‐6‐glucuronide or (serum only) norethylmorphine. Norethylmorphine could be detected after hydrolysis of urine samples in all subjects. The urinary recovery of the active metabolites morphine and morphine‐6‐glucuronide after administration of ethylmorphine varied by a factor of 9 between individuals. 6. The wide variation in recovery of morphine and morphine‐ glucuronides after oral administration of ethylmorphine could not be explained simply by a difference in CYP2D6 genotype. Constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administration of ethylmorphine. Norethylmorphine should be included in urine assays for opiates in forensic toxicology, and no firm conclusions about the source of morphine are possible based on serum samples obtained more than 24 h after drug administration.
Urinary recovery and kinetics of sulphamethoxazole and its metabolites in HIV‐seropositive patients and healthy volunteers after a single oral dose of sulphamethoxazole.
Authors: van der Ven AJ , Vree TB , van Ewijk‐Beneken Kolmer EW , Koopmans PP , van der Meer JW
Published: July 2012

1. The urinary excretion of sulphamethoxazole and its metabolites was compared between healthy volunteers and HIV‐seropositive patients in order to get a better understanding of why HIV seropositives are more predisposed to idiosyncratic toxicity of sulphonamides. 2. A single 800 mg oral dose of sulphamethoxazole was administered to seven healthy volunteers and seven asymptomatic HIV seropositives without previous use of sulphonamides. 3. Urine was collected for 4 days and drug analysis was by h.p.l.c. 4. No difference was observed between seropositive and seronegative individuals in the urinary recovery of sulphamethoxazole, N4‐acetyl‐, 5‐hydroxy‐, N4‐acetyl‐5‐hydroxy‐ sulphamethoxazole and the N1‐glucuronide conjugate. However the recovery of the hydroxylamine metabolite of sulphamethoxazole was significantly lower in the HIV seropositives (0.50 +/‐ 0.51 vs 2.23 +/‐ 0.85%; 95% CI on the difference, ‐0.90 to ‐2.55; P = 0.0006). 5. Sulphamethoxazole hydroxylamine may be a factor in the susceptibility of HIV infected individuals to sulphonamides.
Evaluation of cardiac beta 1‐adrenergic sensitivity with dobutamine in healthy volunteers.
Authors: Pousset F. , Chalon S. , Thomare P. , Diquet B. , Lechat P.
Published: July 2012

1. Evaluation of cardiac beta 1‐adrenergic sensitivity in heart failure should provide instructive therapeutic as well as prognostic information. We set up a non‐invasive test in healthy volunteers to evaluate beta 1‐adrenergic reactivity using dobutamine as a preferential agonist. 2. The range of i.v. bolus doses was 3.2 to 12.2 micrograms kg‐1. The test was well tolerated. The parameters that were most sensitive and best correlated to dobutamine doses were systolic blood pressure and the rate‐corrected electromechanical systole (QS2i). The reproducibility of the test over 48 h and over 1 month was satisfactory for most parameters, with a mean variation coefficient ranging from 9 to 26%, and was better for QS2i than for heart rate. 3. Slope of log dose‐response for heart rate and QS2i was similar with dobutamine and with isoprenaline, corresponding to stimulation of the same type of beta‐adrenergic receptors (beta 1‐subtype). This result was obtained despite a higher vagal stimulation with dobutamine. We conclude that the left ventricular contractile response assessed by QS2i provided the best parameter for evaluation of beta 1‐adrenergic cardiac effects either with dobutamine or with isoprenaline. 4. In heart failure patients such a dobutamine test should allow separation of altered contractility and beta‐adrenergic desensitization, since alteration of inotropic response to dobutamine should depend on both altered contractile function and adrenergic desensitization but heart rate response should only depend on the latter phenomenon.
The axial distribution of nicotine content along hair shaft as an indicator of changes in smoking behaviour: evaluation in a smoking‐ cessation programme with or without the aid of nicotine chewing gum.
Authors: Uematsu T. , Mizuno A. , Nagashima S. , Oshima A. , Nakamura M.
Published: July 2012

1. Hair samples were obtained from subjects at the end of a 6 month smoking‐cessation programme carried out with (n = 16) or without (n = 10) the aid of nicotine chewing gum. The axial distribution of nicotine along the hair shaft was determined and compared both with the self‐ report of smoking behavior and with the concentration of carbon monoxide (CO) in expired air measured at 1 month intervals. 2. A gradual decrease in nicotine content along the hair shaft corresponded to the decrease in self‐reported number of cigarettes smoked daily in both the nicotine chewing‐gum treated and untreated subjects and with the clinical assessment of abstinence. 3. There was reasonable agreement between the CO content of expired air, the self‐reported number of cigarettes smoked daily and the axial distribution of nicotine in 22 of 26 subjects. In the other four subjects there was an apparent disagreement between the CO content of expired air and the other parameters. 4. This study showed that, as a routine marker of smoking status, hair analysis may be preferable to repeated CO measurements since only a single sample at the end of an abstinence programme might be sufficient. However, one problem is that nicotine may dissociate slowly from melanin to limit the ability to mark a sudden cessation of smoking. Also, some nicotine in hair might be attributable to nicotine adsorbed to the outside of hair.