bluuebunny/crossref_metadata_2025 huggingface dataset:
Drugs and human memory: effects of low doses of nitrazepam and hyoscine on retention.
Authors: Jones DM , Jones ME , Lewis MJ , Spriggs TL
Published: July 2012

1 The effects of diazepam (5 mg) and hyoscine hydrobromide (0.3 mg) were assessed in two memory tasks: short‐term retention of digit strings and the free recall of items from categorizable lists. 2 One hundred and two healthy subjects were tested in an independent‐groups design. Subjects were assigned randomly to either placebo, diazepam or hyoscine groups. Treatments were administered orally under double‐blind conditions. 3 The short‐term retention of digits was impaired to an equivalent degree and locus for both drugs (P less than 0.05). This effect was ascribed to the action on primary memory. 4 The drugs produced no significant effects on the recall of categorizable lists either in terms of the number of words recalled or the cohesiveness of categorical recall. 5 These results demonstrate that drugs of different pharmacological actions produce isomorphic psychological deficits in memory and that 'anti‐memory' effects on one task should not be extrapolated to all aspects of memory.
The effect of enzyme induction on diazepam metabolism in man.
Authors: Ohnhaus EE , Park BK , Colombo JP , Heizmann P
Published: July 2012

1 The elimination and metabolism of diazepam in man was investigated following the induction of the liver microsomal enzyme system by antipyrine. 2 Seven healthy volunteers were given 1200 mg antipyrine as an inducing agent for a period of 14 days. Before and after the induction period the elimination of diazepam and desmethyldiazepam was measured in the plasma by gaschromatography. As parameters of liver microsomal enzyme activity, antipyrine elimination and gamma‐glutamyl‐ transpeptidase in the plasma, D‐glucaric acid and 6‐beta‐ hydroxycortisol urinary excretion were measured on both occasions. 3 Following the induction period most parameters of microsomal enzyme activity measured were significantly changed indicating an increase of the microsomal enzyme system. The elimination of diazepam was significantly altered having a half‐life of 37 h before and 18 h afterwards combined with a significant increase in total body clearance after the induction period, although the volume of distribution remained unaltered. The formation of the main metabolite N‐ desmethyldiazepam was not changed, but its elimination was increased having a half‐life of 139 or 58 h respectively. 4 The elimination of unchanged diazepam and desmethyldiazepam is significantly increased by the induction of the liver microsomal enzyme system using antipyrine as an inducing agent in healthy volunteers, which might be important under certain clinical conditions.
Bioavailability and disposition of metoprolol and hydrochlorothiazide combined in one tablet and of separate doses of hydrochlorothiazide.
Authors: Jordo L , Johnsson G , Lundborg P , Persson BA , Regardh CG , Ronn O
Published: July 2012

1. The plasma levels and the urinary excretion of hydrochlorothiazide (HCT) have been studied after administration of single doses of 12.5 and 25 mg of the drug in solution and in combination with 100 mg of the selective beta 1‐adrenoreceptor antagonist metoprolol in a rapidly dissolving tablet. 2. Metoprolol did not significantly influence the bioavailability or the time‐course of HCT. 3. HCT had no significant effect on the time‐course or the plasma levels of metoprolol. The average half‐life, 4.4 +/‐ 0.9 h, is about the same as previously observed for separate doses of this drug. 4. It seems unlikely that repeated doses of the combination product studied will lead to biopharmaceutic or pharmacokinetic interactions of clinical importance.
N‐Methyl‐benzylamine, a metabolite of pargyline in man.
Authors: Pirisino R , Ciottoli GB , Buffoni F , Anselmi B , Curradi C
Published: July 2012

1. N‐methyl‐benzylamine was identified in human urine and plasma after the administration of pargyline in man. This metabolite was identified by thin layer chromatography mobility, gas chromatographic retention time and mass spectrum relative to authentic N‐methyl‐benzylamine. 2. [14C]‐N‐methyl‐benzylamine, together with a small amount of [14C]‐ benzylamine, was formed in vitro from [14C]‐pargyline when this was incubated with human and rat liver microsomes. 3. The urinary excretion rates of pargyline and its metabolite have also been described.
Concentration effect studies with oral metoclopramide.
Authors: Bateman DN , Kahn C. , Davies DS
Published: July 2012

1 The effects of single oral doses of 10 mg and 20 mg metoclopramide have been compared to placebo in six normal male volunteers. 2 The drug did not significantly increase the rate of gastric emptying as measured by ethanol absorption. 3 Sedation during the absorption of ethanol was only observed 1 h after the 20 mg oral dose of metoclopramide (P less than 0.05). 4. Akathisia, a central nervous system side effect of metoclopramide, occurred only in subjects who had peak plasma concentrations above 100 ng/ml. 5 It has not been possible to define a concentration‐effect relationship for the action of metoclopramide on the stomach and comparison with previous results after intravenous dosing suggests that the route of administration is of major importance in determining the action of this drug.
Effects of subjects' sex, and intake of tobacco, alcohol and oral contraceptives on plasma phenytoin levels.
Authors: De Leacy EA , McLeay CD , Eadie MJ , Tyrer JH
Published: July 2012

1. Steady state plasma phenytoin levels in 210 epileptic patients were studied by computerized analysis of covariance to determine whether the subject's sex, alcohol intake, tobacco smoking or use of oral contraceptives influenced the relation between plasma drug level and drug dose. 2. Sex, tobacco smoking and alcohol usage had no statistically significant effect. There was a trend towards higher phenytoin levels relative to drug dose in oral contraceptive users. 3. This finding prompted an additional study of plasma phenytoin levels in 40 oral contraceptive users and 135 aged matched non‐users. Analysis of covariance again showed higher plasma phenytoin levels relative to drug dose in users of oral contraceptives (P = 0.061). 4. This finding raised the possibility that the relation between plasma phenytoin level and drug dose differed between males and females who did not use oral contraceptives. However, when the relation between plasma phenytoin levels and drug dose was compared in 159 females who did not use oral contraceptives and 101 males (both groups aged 15 to 70 years) no statistically significant difference was found.
Cross‐over study of the efficacy of four beta 2‐sympathomimetic bronchodilator aerosols
Authors: Madsen BW , Tandon MK , Paterson JW
Published: July 2012

1 Bronchodilator efficacy of four beta 2‐sympathomimetic aerosols, fenoterol, orciprenaline, salbutamol and terbutaline has been compared in nine patients with chronic stable reversible airways obstruction using a double‐blind placebo controlled cross‐over design. Two puffs of each agent were given on two separate occasions to each of the patients and the forced expiratory volume in one second (FEV1) and the vital capacity (VC) were measured before and 30, 90, 150 and 210 min after administration. 2 Multivariate analysis of the data at 30 min showed FEV1 and VC in these patients to be so highly correlated that they could be considered as a single variable. 3 When absolute change in VC at 30 min was used as the response criterion, efficacy of the four drugs was significantly better than placebo (P < 0.01). It was not possible to rank all four drugs in order of effectiveness; fenoterol and salbutamol were significantly better than terbutaline and orciprenaline (P < 0.01) but this was complicated by a significant interaction effect between drugs and patients (P < 0.01). 4 Similar results were obtained when absolute and relative changes in FEV1 and VC and area under the curve were used as response variables. 5 The study demonstrates that important individual differences in patient response may be concealed if only average drug effects are considered.
Studies on the bronchodilator, tremorogenic, cardiovascular and hypokalaemic effects of fenoterol dry powder in asthma
Authors: BAUER K. G. , KAIK B. , SERTL K. , KAIK G. A.
Published: July 2012

The airway and tremor response and cardiovascular and hypokalaemic effects of single and cumulative doses of fenoterol given by dry powder capsules (DPC) and by metered dose inhaler (MDI) were studied in asthmatics in two randomized, crossover trials.

Single doses of fenoterol DPC and MDI (0.2 mg, 0.4 mg), investigated in 24 subjects, produced similar, dose‐dependent increases in FEV1. Fenoterol DPC caused less tremor response and less hypokalaemic effects than fenoterol MDI.

Cumulative doses of fenoterol DPC and MDI (0.2, 0.6, 1.4, 3.0, 6.2 mg), investigated in 12 subjects, produced a comparable bronchodilatation (mean maximum increase in FEV1 was 0.53 ± 0.06/0.52 ± 0.08 1 for DPC/MDI) and a similar, dose‐dependent rise in heart rate (35 ± 3.81/41 ± 2.25 beats min−1). The rise in tremor and the fall in plasma potassium were smaller after DPC than after MDI. The mean maximum changes were 51.58 ± 6.41/95.83 ± 6.75 cm s−2 for tremor and −0.68 ± 0.09/−0.96 ± 0.10 mmol 1−1 for potassium.

Our findings may result from a difference in the pharmacokinetics of the dry powder and the aerosol formulation, particularly differences in distribution and absorption.

In conclusion, fenoterol DPC used in low therapeutic doses (0.2, 0.4 mg), is preferable to the MDI. Fenoterol DPC used as rescue medication in high cumulative doses, do not suggest a greater safety margin than the MDI and the same restrictions should be considered for the fenoterol dry powder formulation as suggested for the MDI.
Circulatory effects of the PDE‐inhibitors piroximone and enoximone
Authors: BOLDT J. , KNOTHE Ch. , ZICKMANN B. , SCHINDLER E. , STERTMANN W. A. , HEMPELMANN G.
Published: July 2012

The isolated circulatory response to intravenous application of the phosphodiesterase (PDE) inhibitors piroximone and enoximone was studied.

In a randomized sequence of 30 male patients undergoing elective aortocoronary bypass grafting either piroximone (0.5 mg kg−1; n = 10) or enoximone (0.5 mg kg−1; n = 10) were given during steady state of cardiopulmonary bypass (CPB). A group in which NaCl was given as a placebo served as a control (n = 10).

MAP was reduced by piroximone (maximum −23 mm Hg) and enoximone (maximum — 18 mm Hg), whereas it increased in the control (+20 mm Hg). Volume of the extracorporeal circuit indicating venous pooling decreased more pronouncedly in the enoximone patients (–440 ml) than in the piroximone group (–300 ml).

Laser Doppler flows (LDFs) increased in both PDE‐III inhibitor groups with the higher and longer increase in the enoximone‐treated patients (LDF‐forehead maximum +44%, LDF‐forearm maximum +33%). Piroximone‐induced increase in both LDFs was less pronounced with respect to both time and degree (LDF‐forehead maximum +30%, LDF‐forearm +12%).

Oxygen consumption (VO2) was significantly higher in the PDE‐III inhibitor‐treated than in the control patients.

Piroximone and enoximone showed significant vasodilatory properties at the arterial and venous side (= ‘venous pooling’), from which patients with heart failure would profit.

Vasodilation could be observed for a longer period and was more pronounced in the enoximone‐treated than in the piroximone patients. Alterations in capillary skin blood flow measured by laser Doppler technique gave evidence for an improvement in nutritive microcirculation, which was slightly more pronounced in the enoximone patients.
Stereoselective pharmacokinetics of pazinaclone, a new non‐benzodiazepine anxiolytic, and its active metabolite in healthy subjects
Authors: HUSSEIN Z. , MULFORD D. J. , BOPP B. A. , GRANNEMAN G. R.
Published: July 2012

Serum and urine concentrations of enantiomers of pazinaclone (DN‐2327) and an active metabolite MII, were measured after single and twice daily oral doses of 4 and 8 mg racemic drug to healthy subjects.

The kinetics of rac‐pazinaclone and rac‐MII were dose‐independent and no unchanged drug was recovered in urine.

The terminal elimination half‐lives of the drug isomers were similar (about 10.5 h), but mean steady‐state values of AUC were twofold higher for the S‐isomer than those of the antipode (e.g., 8 mg dose: 127 vs 69 ng ml−1 h). However, the corresponding AUC values based upon unbound drug were similar (5.71 vs 5.73 ng ml−1 h) indicating no stereoselectivity in intrinsic metabolic clearance.

The terminal elimination half‐lives of 5‐ and R‐MII were similar to those of parent compound indicating that the elimination of these metabolites is formation rate‐limited.

The R:S‐ratio for the AUCs of MII was 4:1. Both enantiomers were excreted in the urine mainly as glucuronide conjugates, with stereoselectivity toward 5‐MII.

Since only the S‐enantiomers of DN‐2327 and MII bind to the benzodiazepine receptor, further measurements of drug effect in patients should be related to combine serum concentrations of the S‐enantiomers of both parent drug and MII.
Single and multiple dose pharmacokinetics of lansoprazole in elderly subjects
Authors: FLOUVAT B. , DELHOTAL‐LANDES B. , COURNOT A. , DELLATOLAS F.
Published: July 2012

Plasma concentrations of lansoprazole and of its sulphone, sulphide and 5‐hydroxylated metabolites were determined after oral administration of a single 30 mg dose and after 7 days of treatment with a daily 30 mg dose in 12 elderly subjects (mean age 83 years). Results after a single dose were compared with those from a historical control group of 18 young subjects (mean age 23 years). Mean values of AUC after single dose were 2668 ng ml−1 h in the young subjects and 5216 ng ml−1 h in the elderly (P < 0.05). Mean t1/2;z values in young and elderly subjects were 1.4 h and 2.9 h, respectively (P < 0.001). Plasma concentrations of the metabolites were similar in both groups. However, the hydroxylated metabolite of the sulphone was detected only in elderly subjects. Steady state plasma concentrations of lansoprazole were reached after 3 days of dosing with lansoprazole. The accumulation ratio was 1.31 in the elderly subjects.
Cigarette smoking enhances the elimination of quinine
Authors: WANWIMOLRUK S. , WONG S. M. , COVILLE P. F. , VIRIYAYUDHAKORN S. , THITIARCHAKUL S.
Published: July 2012

The pharmacokinetics of a single dose (600 mg) of quinine sulphate were examined in a group of non‐smokers (n = 10) and in heavy cigarette smokers (n = 10). The mean (± s.d.) oral clearance of quinine in smokers (0.189 ± 0.075 1 h−1 kg−1) was significantly greater than in non‐smokers (0.107 ± 0.0451 h−1 kg−1, P < 0.01). The unbound clearance of quinine which reflects activity of the drug‐metabolizing enzyme, was considerably greater (1.5‐fold) in the smokers than in the non‐smoker subjects. The mean elimination half‐life of quinine in smokers was 7.5 ± 1.4 (s.d.) h, significantly shorter (P < 0.005) than the mean value in non‐smokers (12.0 ± 3.1 h). These results suggest that cigarette smoking enhances the elimination of quinine. The clinical significance of these findings is unknown but they indicate the need for caution in the administration of quinine to patients who are heavy cigarette smokers.
Human studies on abecarnil a new beta‐carboline anxiolytic: safety, tolerability and preliminary pharmacological profile.
Authors: Duka T , Schutt B , Krause W , Dorow R , McDonald S , Fichte K
Published: July 2012

1. Abecarnil (isopropyl‐6‐benzyloxy‐4‐methoxymethyl‐beta‐carboline‐3‐ carboxylate), a beta‐carboline with high affinity for benzodiazepine receptors, was tested in healthy male subjects; single doses of abecarnil were given in five dosage levels (1 mg, 5 mg, 10 mg, 20 mg, 40 mg) and in a multiple dose study in four dosage levels (15 mg, 30 mg, 60 mg, 90 mg day‐1) for 7 days. On two days following multiple dose treatment, placebo was given in single‐blind conditions (follow‐up). In each dosage level, in both studies drug was given to 10 subjects (7: verum, 3: placebo). 2. Safety and tolerability were evaluated by changes in vital signs, incidence and severity of adverse reactions and biochemical and haematological screening. Drug effects were estimated utilizing a bipolar visual analogue scale (poles: 'sleepy'‐'alert') and a psychomotor task, the digit symbol substitution task. The pharmacokinetics of single and multiple doses were also determined in the multiple dose study. 3. Abecarnil was generally well tolerated. In the single dose study the most frequently reported side effects associated with abecarnil at high doses (20 and 40 mg) were dizziness, unsteady gait, and lack of concentration. A decrement in performance on the digit symbol substitution task was also observed in the two high dosage groups 20 mg and 40 mg. Evaluation of visual analogue scale ratings did not reveal a sedative effect even at higher doses. 4. In the multiple dose study the most frequently reported side effects during the treatment period were dizziness, unsteady gait, and lack of concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetics, tolerability and pharmacodynamics of tucaresol (589C80; 4[2‐formyl‐3‐hydroxyphenoxymethyl] benzoic acid), a potential anti‐sickling agent, following oral administration to healthy subjects.
Authors: Rolan PE , Parker JE , Gray SJ , Weatherley BC , Ingram J , Leavens W , Wootton R , Posner J
Published: July 2012

1. Tucaresol (589C80; 4[2‐formyl‐3‐hydroxyphenoxymethyl] benzoic acid) interacts stoichiometrically with haemoglobin to increase oxygen affinity. By decreasing the proportion of insoluble deoxy sickle haemoglobin at capillary oxygen concentrations, tucaresol may be of therapeutic benefit in sickle cell anaemia. 2. In this study, which involved the first administration to man, the pharmacokinetics and pharmacodynamics of tucaresol were studied in healthy male volunteers following oral doses of 200‐3600 mg. 3. Peak drug concentrations in plasma and erythrocytes were linearly related to dose; mean (s.d.) values were 95.8 (26.1) and 1035 (67) micrograms ml‐1, respectively, at the highest dose. Median tmax in plasma was 6.5 h and in erythrocytes 24.5 h, when approximately 60% of the administered dose was in the target tissue. Plasma drug concentrations fell biexponentially with commencement of the apparent terminal elimination phase at approximately 24 h. The terminal elimination half‐life from plasma increased with dose (r = 0.77; P < 0.0001) from 133‐190 h at 400 mg to a mean (s.d.) of 289 (30) h at 3600 mg. Erythrocyte drug concentrations declined mono‐exponentially with a half‐life that was always shorter than the apparent terminal half‐life in plasma: overall mean (95% CI) of t1/2 erythrocyte/t1/2 plasma ratio was 0.57 (0.53, 0.61). The erythrocyte AUC/plasma AUC ratio increased with dose (r = 0.67; P < 0.001). 4. The proportion of haemoglobin modified to a form with high oxygen affinity (%MOD) increased in a dose‐related manner above doses of 800 mg reaching 19‐26% after the 3600 mg dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of angiotensin converting enzyme with enalapril maleate in infants with congestive heart failure.
Authors: Dutertre JP , Billaud EM , Autret E , Chantepie A , Oliver I , Laugier J
Published: July 2012

We studied the inhibition of angiotensin converting enzyme (ACE) in eight infants with congestive heart failure (CHF) poorly controlled with digoxin and diuretics, treated orally with 0.25 mg kg‐1 enalapril maleate once a day. Baseline ACE activities were compared between these infants and control children without CHF or ACE inhibitor. Except for one infant who vomited, inhibition of ACE activity was 75.5 +/‐ 12.2%, 75.5 +/‐ 10.5% and 51.7 +/‐ 12.2%, at 4, 12 and 24 h after drug intake respectively. There was no correlation between postnatal age and inhibition of ACE activity. In infants with CHF, mean baseline ACE activity was significantly higher than in control infants (36.4 +/‐ 7.2 mu ml‐1 vs 26.9 +/‐ 6.9 mu ml‐1, P < 0.05). These results were very similar to those seen in adults.
Variability in the stereoselective disposition of ibuprofen in patients with rheumatoid arthritis.
Authors: Geisslinger G , Stock KP , Loew D , Bach GL , Brune K
Published: July 2012

1. Patients suffering from rheumatoid arthritis received oral doses of 600 mg racemic ibuprofen (n = 25; RAC) or 400 mg (S)‐ibuprofen (n = 25; S‐IBU) in a double‐blind, randomized parallel‐group study. 2. The pharmacokinetic parameters of (S)‐ibuprofen were not statistically different between treatments (P > 0.05). Comparing (S)‐ and (R)‐ ibuprofen within the group receiving the racemate significantly higher Cmax (20.3 +/‐ 5.3 vs 17.7 +/‐ 4.4 micrograms ml‐1; P < 0.02; 95% confidence interval for differences (CI): 0.5‐4.6), AUC (86.2 +/‐ 23.5 vs 67.6 +/‐ 26.6 micrograms ml‐1 h; P < 0.001; CI: 9.5‐27.6), mean residence time (4.5 +/‐ 1.1 vs 4.1 +/‐ 1.2 h; P < 0.01; CI: 0.1‐0.6) and renal clearance (0.8 +/‐ 0.6 vs 0.0 +/‐ 0.0 ml min‐1; P < 0.001; CI: 0.5‐1.0) values were observed for the (S)‐enantiomer. 3. No difference was found (P > 0.05) between treatments in the percentage of the dose recovered in the urine as (R)‐ or (S)‐ibuprofen plus metabolites (S‐IBU: 80.2 +/‐ 8.47 vs RAC: 74.1 +/‐ 14.0%). 4. Interindividual variation in the pharmacokinetics of (S)‐ibuprofen following administration of the racemate was similar to that following the administration of the single isomer suggesting that chiral inversion is not a major factor contributing to variability in the disposition of this drug.
The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril.
Authors: Macdonald NJ , Sioufi A , Howie CA , Wade JR , Elliott HL
Published: July 2012

1. Eighteen healthy, normotensive subjects (nine young and nine elderly) participated in a double‐blind, 3‐way, crossover study to compare aspects of the pharmacokinetics and pharmacodynamics of single oral doses of 10 mg benazepril, 10 mg enalapril and placebo. 2. The hypotensive effect was similar after both drugs but the absolute reductions were greater in the elderly who had higher initial levels of blood pressure. 3. The AUCs for both benazeprilat and enalaprilat were higher in the elderly but by a significantly greater amount for enalaprilat (+ 113% vs 40%; P < 0.01). 4. The AUCs for both drugs tended to be highest in subjects with the lowest creatinine clearance. 5. The changes in kinetics and dynamics observed in the elderly after benazepril are qualitatively similar to those with other ACE inhibitors. The clinical significance of the quantitative differences requires further investigation.
Effects of interferon‐alpha monotherapy on hepatic drug metabolism in cancer patients.
Authors: Israel BC , Blouin RA , McIntyre W , Shedlofsky SI
Published: July 2012

1. The influence of interferon‐alpha (IFN alpha) on the clearances of theophylline (TH), antipyrine (AP) and hexobarbitone (HB) was studied in seven cancer patients given IFN alpha as their only treatment. In addition, IFN alpha effects on drug clearance were correlated with changes in serum inflammatory cytokines and acute phase proteins. 2. A 'baseline' study was performed by administering an oral drug 'cocktail' of TH (150 mg), AP (250 mg) and HB (250 mg) with saline injected simultaneously and again 24 h later. One week later, an 'acute' study was performed at the initiation of IFN alpha therapy, 3 × 10(6) units injected with the drug cocktail and again 24 h later. After 2 weeks of IFN alpha treatment three times per week, a 'chronic' study was performed with IFN alpha injected the day prior to, simultaneously with, as well as 24 h after the drug cocktail. 3. Plasma samples were collected over 48 h and the clearances of TH, AP and HB were estimated. Serum samples were collected at various times for the measurement of tumor necrosis factor (TNF), interleukin‐1 (IL‐1), interleukin‐6 (IL‐ 6), C‐reactive protein (C‐RP) and alpha 1‐acid glycoprotein (AGP). 4. IFN alpha caused a 33% decrease in the oral clearance of TH during the chronic study compared with baseline (P < or = 0.05). Although IFN alpha inhibited TH clearance by 16% during the acute study and AP clearance by 20‐21% during both acute and chronic studies, these changes did not reach statistical significance. IFN alpha caused minimal changes in HB clearance. There were no chronic effects of IFN alpha on serum cytokines or acute phase proteins. 5. The findings confirm that the most commonly used dose of IFN alpha inhibits the hepatic clearance in humans of some but not all drugs and that this inhibition persists during IFN alpha therapy. Because inhibition was not associated with increases in serum cytokines or acute phase proteins, the mechanism by which IFN alpha inhibits cytochrome P450 activities in vivo does not appear to involve inflammatory mediators such as TNF. IL‐1 or IL‐6.
Therapeutic consultation: a necessary adjunct to independent drug information.
Authors: Rodriguez C. , Arnau JM , Vidal X. , Laporte J.R.
Published: July 2012

1. A therapeutic consultation service was implemented in 1984 to complement other methods of information and education on drug therapy for prescribers. 2. Up to 1991, 1,620 enquiries were received, 65% from our hospital and an increasing proportion from primary care (10%), other hospitals (6%), family planning centres (4%), and other sources (14%). 3. More than two‐thirds (67%) were consultative enquiries, as opposed to demands for factual information, which needed knowledge of medical aspects of the case and clinical expertise. 4. 85% of enquiries were answered with a written report including relevant references and as conclusive as possible recommendations. 5. More discussion of therapeutic consultation is needed, and aspects for discussion are suggested.
Evening vs morning isradipine sustained release in essential hypertension: a double‐blind study with 24 h ambulatory monitoring.
Authors: Fogari R. , Malacco E. , Tettamanti F. , Gnemmi AE , Milani M.
Published: July 2012

A randomized, double‐blind, placebo controlled study evaluated the effects on 24 h ambulatory blood pressure (ABP) of isradipine sustained release (I‐SRO) administered once daily, in the morning (AM) or in the evening (PM). Eighteen uncomplicated essential hypertensives (10 men, mean age 55 +/‐ 6 years) with casual sitting DBP 96‐110 mm Hg received, according to a triple‐way crossover design, I‐SRO 5 mg AM, or 5 mg PM, or placebo for 4 weeks. A 24 h ABP monitoring (Spacelabs 90207) was carried out at the end of each treatment. Twenty‐four hour BP was 145.3/89.8 mm Hg after randomized placebo. AM and PM I‐SRO significantly reduced 24 h BP, by 13.7/8.7 and 12.9/8.2 mm Hg respectively. Daytime (07.00 h‐23.00 h) BP significantly decreased by 15.0/9.7 mm Hg with AM and 13.2/8.7 mm Hg with PM regimen; night‐time BP (23.00 h‐07.00 h) significantly decreased by 11.6/7.1 and 12.3/7.4 mm Hg, respectively. Nocturnal nadir BP values were 132.6/78.1 after randomized placebo, 120.9/71.4 after AM I‐SRO and 121.0/72.4 mm Hg after PM I‐SRO. Morning peak BP values were 154.6/96.9, 139.5/87.6 and 137.5/85.5 mm Hg, respectively. Mean BP values in the early morning hours (i.e. between 03.00 h and 08.00 h) were significantly decreased by 12.1/7.3 mm Hg after AM and 14.3/7.9 mm Hg after PM intake. No significant differences were detected in the BP lowering effect of the two I‐SRO regimens.(ABSTRACT TRUNCATED AT 250 WORDS)
The bioavailability of digoxin from three oral formulations measured by a specific h.p.l.c. assay.
Authors: Cohen AF , Kroon R. , Schoemaker HC , Breimer DD , Van Vliet‐Verbeek A. , Brandenburg HC
Published: July 2012

1. We have studied the absolute bioavailability of three oral formulations of digoxin, 1.0 mg, in 12 young healthy volunteers in a four way randomised cross‐over study using an intravenous control. 2. Digoxin tablets (250 micrograms), liquid filled digoxin capsules (100 micrograms) and an experimental enteric‐coated capsule (100 micrograms) were evaluated. In vitro dissolution at pH 1 demonstrated extensive hydrolytic breakdown of digoxin from the tablets and capsules but not from the enteric‐coated capsules. 3. Serum ‘digoxin’ concentrations were measured by fluorescence polarization immunoassay (FPI). The systemic availability (+/‐ s.d.) of the capsules was 70.5 +/‐ 11.3%, and that of the tablets 71.5 +/‐ 8.6%. Drug was less available from the enteric‐coated capsules (62.1 +/‐ 10.3%) measured with FPI. These results were reflected in the urinary drug recoveries measured by FPI. 4. By contrast, there were no differences in urinary recovery of unchanged digoxin between any of the oral treatments, when this was measured by h.p.l.c. The cross‐reactivity of immunoassays for metabolites of digoxin may produce artefactual results and the optimal pharmaceutical formulation for digoxin remains to be determined.
Stereoselective disposition of (+/‐)‐sotalol at steady‐state conditions.
Authors: Fiset C. , Philippon F. , Gilbert M. , Turgeon J.
Published: July 2012

The objective of this study was to assess, under steady‐state conditions, the stereoselective disposition of (+/‐)‐sotalol in man. In all patients studied (n = 7) values of oral clearance (137 +/‐ 51 ml min‐1), renal clearance (96 +/‐ 42 ml min‐1) and nonrenal clearance (41 +/‐ 25 ml min‐1) of (−)−sotalol were greater than those for (+)‐sotalol (123 +/‐ 45 ml min‐1, 89 +/‐ 39 ml min‐1 and 34 +/‐ 23 ml min‐1, respectively; P < 0.05, Student's paired t‐test). Binding to plasma proteins was greater for (+)‐sotalol (38 +/‐ 9% vs 35 +/‐ 9% for the (−)−enantiomer; P < 0.05) such that unbound oral clearance (+)/(‐) ratio (0.95 +/‐ 0.06) and unbound renal clearance (+)/(‐) ratio (0.97 +/‐ 0.06) were not stereoselective. In contrast, estimated unbound nonrenal clearance, which represents approximately 25% of the total unbound clearance of the drug, was greater for the (−)−enantiomer (64 +/‐ 42 ml min‐1) compared with (+)‐sotalol (57 +/‐ 42 ml min‐1; P < 0.05). The difference in the pharmacokinetics of sotalol enantiomers is mainly related to stereoselectivity in plasma protein binding.
The effects of a peripherally selective alpha 2‐adrenoceptor antagonist, MK‐467, on the metabolic and cardiovascular response to exercise in healthy man.
Authors: Sciberras DG , Reed JW , Elliott C , Blain PG , Goldberg MR
Published: July 2012

1. A double‐blind, placebo controlled study has been conducted to investigate the consequences of i.v. treatment with MK‐467, a peripherally selective alpha 2‐adrenoceptor antagonist in exercising healthy male subjects. In particular, the effects on blood pressure, heart rate, circulating catecholamines (noradrenaline (NA) and adrenaline (A)), insulin, glucose and free fatty acids (FFA) were determined. 2. Exercise produced increases in catecholamines, blood pressure and heart rate. FFA increased at the start of the exercise but then declined as exercise progressed. 3. MK‐467 significantly increased NA, in a dose‐dependent manner, before and during exercise without altering A. Blood pressure and heart rate were not affected by drug treatment. 4. The insulin and FFA response to exercise was significantly enhanced by MK‐467 although glucose was unaltered by drug. 5. It is concluded that both pre‐ and post‐junctional peripheral alpha 2‐receptors play an important role in the metabolic response to exercise in man.
Pharmacokinetics of artemether after oral administration to healthy Thai males and patients with acute, uncomplicated falciparum malaria.
Authors: Na Bangchang K , Karbwang J , Thomas CG , Thanavibul A , Sukontason K , Ward SA , Edwards G
Published: July 2012

1. The pharmacokinetics of artemether were investigated (a) in six healthy male Thai volunteers after single 200 mg oral doses and (b) in eight male Thai patients with acute uncomplicated falciparum malaria after an initial 200 mg oral dose followed by 100 mg at 12 h then 100 mg daily for 4 days. 2. In the healthy subjects, median (range) maximum plasma concentrations of artemether of 118 (112‐127) ng ml‐1 were reached at 3 (1‐10) h. Thereafter, drug concentrations declined monoexponentially with a median (range) t1/2.z of 3.1 (1.0‐9.6) h. The median (range) AUC and MRT values were 1.10 (0.33‐4.44) micrograms ml‐1 h and 8.3 (3.5‐20.8) h. The median Cmax value of dihydroartemisinin, an active metabolite, was 379 (162‐702) mg ml‐1 at 6 (2‐12) h. Its median AUC value was 6.6 (0.83‐38.7) micrograms ml‐1 h; the apparent t1/2.z was 10.6 (4.7‐19.2) h and the median MRT value was 16.0 (5.0‐41.0) h. 3. In the patients, a higher Cmax value of parent drug than those observed in healthy subjects (median and range of 231 (116‐411) ng ml‐ 1), was reached at 3 (1‐3) h after the first dose. Steady state was reached after the third dose (24 h) and concentrations fluctuated over the range of 36‐60 ng ml‐1. The respective median (range) values of AUC and t1/2.z were 5.8 (3.76‐12.9) micrograms ml‐1 h and 4.2 (2.5‐5.3) h.(ABSTRACT TRUNCATED AT 250 WORDS)
A comparison of the antinociceptive effects of imipramine, tramadol and anpirtoline [see comments]
Authors: Hummel T , Hummel C , Friedel I , Pauli E , Kobal G
Published: July 2012

The pain relieving properties of imipramine (100 mg orally), tramadol (150 mg orally), and anpirtoline (60 mg orally) were compared in 16 healthy subjects in a cross‐over, double‐blind, randomized, and placebo‐ controlled study. Anpirtoline exhibits analgesia which is possibly mediated via serotoninergic pathways, whereas tramadol exerts its effects at opioid receptors. The pain‐relieving effect of the tricyclic antidepressant imipramine may involve both serotoninergic and opioid mechanisms. Chemo‐somatosensory event‐related potentials (CSSERP) were recorded after painful stimulation of the nasal mucosa with carbon dioxide. Subjects rated the perceived intensity of the stimuli by means of a visual analogue scale. In addition, acoustically evoked responses were recorded, the spontaneous EEG was analyzed in the frequency domain, the subjects' vigilance was assessed in a tracking task, and side effects of the drugs were monitored. Anpirtoline and tramadol produced a decrease of both CSSERP amplitudes and subjective estimates of pain, the effects of the former compound being greater. In contrast, after administration of imipramine no change of CSSERP amplitudes could be detected, whereas the subjective estimate of pain intensity decreased significantly. This was accompanied by a significant decrease of arousal indicating that pain relief produced by acute administration of imipramine was primarily related to its sedation action. The analgesic properties of anpirtoline were demonstrated in man. Tramadol was characterized as a week opioid analgesic. In contrast, imipramine appeared to produce its pain‐relieving effects predominantly by non‐ specific actions. It is hypothesized that different analgesics may change ERP sources in a drug‐specific manner.
Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers.
Authors: Geisslinger G , Lotsch J , Menzel S , Kobal G , Brune K
Published: July 2012

Plasma concentrations of the enantiomers of flurbiprofen were measured following oral administration of (S)‐flurbiprofen 50 mg and (R)‐ flurbiprofen 50 mg and 100 mg to sixteen healthy subjects. Chiral inversion did not occur to a measurable extent. Significantly higher values of AUC (55.2 +/‐ 17.0 vs 44.6 +/‐ 11.2 micrograms ml‐1h) elimination half‐life (5.6 +/‐ 1.4 vs 4.0 +/‐ 1.0 h) and mean residence time (7.5 +/‐ 1.6 vs 5.7 +/‐ 1.2 h) were observed after 50 mg (S)‐ flurbiprofen as compared with 50 mg (R)‐flurbiprofen. With the exception of Cmax and AUC values pharmacokinetic data for the 50 mg and the 100 mg dose of (R)‐flurbiprofen did not differ significantly. The data are of clinical relevance if (R)‐flurbiprofen also has analgesic activity in humans and is to be developed as an analgesic.
Influence of sex‐steroid hormones on the regulation of lymphocyte beta 2‐adrenoceptors during the menstrual cycle.
Authors: Wheeldon NM , Newnham DM , Coutie WJ , Peters JA , McDevitt DG , Lipworth BJ
Published: July 2012

1. Up to 40% of female asthmatic subjects suffer a premenstrual deterioration in their condition which may be ameliorated by progesterone supplementation, although the mechanism responsible for this phenomenon is not understood. In vitro studies have shown that female sex‐steroid hormones potentiate the bronchorelaxant effect of isoprenaline, whilst in vivo it has been shown that females exhibit greater sensitivity of systemic beta 2‐adrenoceptor responses. 2. The aim of the present study was to determine whether cyclical alterations in beta 2‐adrenoceptor expression, occurring under the influence of ovarian sex‐steroid hormones, may offer an explanation for these findings. In vitro parameters of lymphocyte beta 2‐adrenoceptor function were investigated in nine normal female subjects (aged 24 +/‐ 2 years) during the follicular (day 2‐4) and luteal (day 21‐23) phases of their menstrual cycle, and results were compared with those of nine age‐matched healthy male controls studied at the same time intervals. 3. In female subjects there were significant increases in serum concentrations of oestradiol (3.3‐fold) and progesterone (10.6‐fold) between the follicular and luteal phases of the menstrual cycle, whereas no changes occurred in males. 4. In females during the luteal phase, the increase in sex‐steroid hormones was mirrored by an increase in lymphocyte beta 2‐adrenoceptor density (Bmax) and in maximal cyclic AMP response to isoprenaline (Emax), which were significantly higher than in male subjects. Mean differences (95% CI) between male and female subjects on visit 2 were 1.09 (0.49 to 1.69) fmol/10(6) cells (P = 0.001) for Bmax, and 3.42 (0.80 to 6.04) pmol/10(6) cells (P = 0.02) for Emax.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorption of ipsapirone along the human gastrointestinal tract.
Authors: Fuhr U , Staib AH , Harder S , Becker K , Liermann D , Schollnhammer G , Roed IS
Published: July 2012

Isapirone‐HCl (5 mg) was administered orally, rectally and locally, by a remote control drug delivery device (HF‐capsule) into different segments of the gastrointestinal tract, to four young healthy male adults. The relative systemic bioavailability of the drug from the colon and rectum was 2‐3‐fold greater than that from the upper gastrointestinal tract. This supports a rationale for a prolonged‐ release formulation.
A novel index for expressing exposure of the infant to drugs in breast milk.
Authors: Ito S , Koren G
Published: July 2012

1. We present a novel index for expressing the exposure of the infant to drugs in breast milk, which unifies two independent factors: a pharmacokinetic parameter, drug clearance, and a physiochemical parameter, i.e. milk‐to‐maternal plasma drug concentration ratio (M/P ratio). 2. During breast‐feeding by a woman receiving therapeutic doses of a drug at steady state this index is given by: Exposure index = A × (M/P ratio)/CLI where A is a coefficient (10 ml kg‐1 min‐1) and CLI is drug clearance in the infant (ml kg‐1 min‐1). 3. This equation indicates a hyperbolic relationship between drug clearance and the exposure level of the breast‐fed infant at a given M/P ratio of drug, emphasizing the importance of drug clearance as a determinant of infant exposure.
Reproducibility of non‐invasive measurement and of short‐term variability of blood pressure and heart rate in healthy volunteers.
Authors: Dimier‐David L , Billon N , Costagliola D , Jaillon P , Funck‐Brentano C
Published: July 2012

1. Spectral analyses of blood pressure and heart rate oscillations are increasingly used to assess the influences of diseases and drugs on the autonomic nervous system. Such influences can only be interpreted in view of the spontaneous variability of these oscillations. We therefore studied the reproducibility of power spectral analyses of blood pressure and heart rate fluctuations measured by a non‐invasive finger plethysmographic method in 24 healthy volunteers. 2. Intra‐observer reproducibility was assessed from measurements obtained on 3 consecutive days and 1 month later in each subject. Inter‐observer reproducibility was assessed by comparing measurements made by two observers on one occasion. 3. There was no significant difference in standard haemodynamic and spectral analysis parameters (low frequency: 60‐130 mHz and high frequency: respiration rate +/‐ 30 mHz) measured on 3 consecutive days and 1 month later in each subject. The standard deviation of differences between systolic blood pressure or heart rate oscillations on different occasions was in the 150‐200 and 50‐100 mm Hg Hz‐1/2 or beats min‐1 Hz‐1/2 range for low frequency and high frequency oscillations respectively. Similar results were found when inter‐ observer reproducibility was considered. 4. From these results, we derived a sample‐size table giving the number of subjects to be included in studies of cross‐over or parallel design in order to detect a non‐random difference in spectral analysis parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes.
Authors: Kerry NL , Somogyi AA , Bochner F , Mikus G
Published: July 2012

1. The enzyme kinetics of dextromethorphan O‐demethylation in liver microsomes from three extensive metabolisers (EM) with respect to CYP2D6 indicated high (Km1 2.2‐9.4 microM) and low (Km2 55.5‐307.3 microM) affinity sites whereas microsomes from two poor metabolisers (PM) indicated a single site (Km 560 and 157 microM). Similar differences were shown for 3‐methoxymorphinan O‐demethylation to 3‐ hydroxymorphinan (Km 6.9‐9.6 microM in EM subjects; Km 307 and 213 microM in PM subjects). 2. Dextromethorphan O‐demethylation was inhibited competitively by quinidine (Ki 0.1 microM), rac‐perhexiline (Ki 0.4 microM), dextropropoxyphene (Ki 6 microM), rac‐methadone (Ki 8 microM), and 3‐methoxymorphinan (Ki 15 microM). These compounds were also potent inhibitors of 3‐methoxymorphinan O‐demethylation with IC50 values ranging from 0.02‐12 microM. Anti‐LKM1 serum inhibited both dextromethorphan and 3‐methoxymorphinan O‐demethylations in a titre‐ dependent manner. 3. The Michaelis‐Menten constant for dextromethorphan N‐demethylation to 3‐methoxymorphinan (Km 632‐977 microM) and dextrorphan N‐demethylation to 3‐hydroxymorphinan (Km 1571‐4286 microM) did not differ between EM and PM microsomes. These N‐demethylation reactions were not inhibited by quinidine and rac‐methadone or LKM1 antibodies. 4. Dextromethorphan and 3‐methoxymorphinan are metabolised by the same P450 isoform, CYP2D6, whereas the N‐demethylation reactions are not carried out by CYP2D6.
The pharmacokinetics of chloroquine in healthy Thai subjects and patients with Plasmodium vivax malaria.
Authors: Na‐Bangchang K , Limpaibul L , Thanavibul A , Tan‐Ariya P , Karbwang J
Published: July 2012

The pharmacokinetics of chloroquine (CQ) and desethylchloroquine (DECQ) were studied in seven male Thai patients with P. vivax malaria and seven healthy male Thais, after the standard oral dosage regimen of CQ (a total dose of 1500 mg given over 3 days). All patients showed a rapid initial response to the treatment with median (range) values of fever and parasite clearance times of 13.7 (2‐47) and 58 (33‐38) h, respectively. In the patients, the median range Cmax value was significantly higher (1547 (996‐2446) vs 838 (656‐1587) ng ml‐1), and AUC(0,28d) was greater (281 (250‐515) vs 122 (103‐182) micrograms ml‐1 h). In addition, the median (AUC(0,28d) of DECQ was significantly greater (170 (72‐265) vs 77 (49‐140) micrograms ml‐1 h). The AUC(0,28d) ratio of DECQ to CQ in patients was significantly higher than that in healthy subjects (0.67 (0.43‐0.90) vs 0.51 (0.29‐0.61)).
Effect of NG‐monomethyl‐L‐arginine on kinin‐induced vasodilation in the human forearm.
Authors: Cockcroft JR , Chowienczyk PJ , Brett SE , Ritter JM
Published: July 2012

1. We compared effects of NG‐monomethyl‐L‐arginine (L‐NMMA), an NO synthase inhibitor, on vasodilator responses to intra‐arterial infusion of bradykinin and substance P in the human forearm. 2. Bradykinin (100 pmol min‐1) increased forearm blood flow when infused into the brachial artery of eight healthy male volunteers, from 2.8 +/‐ 0.2 (mean +/‐ s.e. mean) to 9.3 +/‐ 1.0 ml min‐1 per 100 ml forearm volume. 3. Co‐ infusion of L‐NMMA (2 mumol min‐1 and 4 mumol min‐1) with bradykinin (100 pmol min‐1) for 6 min produced respectively a 9 +/‐ 14% and 42 +/‐ 14% inhibition (compared with L‐NMMA vehicle) in the response to bradykinin. 4. Substance P (1 pmol min‐1) when infused into the brachial artery of a further eight male subjects increased forearm blood flow from 3.4 +/‐ 0.2 to 6.3 +/‐ 0.7 ml min‐1 100 ml‐1. 5. Co‐ infusion of L‐NMMA (2 mumol min‐1 and 4 mumol min‐1) with substance P (1 pmol min‐1) for 6 min produced respectively a 27 +/‐ 8% and 70 +/‐ 13% inhibition (compared with L‐NMMA vehicle) in the response to substance P. 6. These results demonstrate that vasodilator responses to both bradykinin and substance P are mediated in part via the L‐ arginine/NO pathway. Bradykinin and substance P may be useful agonists with which to study endothelial function in this vascular bed.
Stereoselective disposition of ibuprofen enantiomers in infants.
Authors: Rey E , Pariente‐Khayat A , Gouyet L , Vauzelle‐Kervroedan F , Pons G , D'Athis P , Dubois MC , Murat I , Lassale C , Goehrs M , et al
Published: July 2012

The pharmacokinetics of the enantiomers of ibuprofen were investigated after oral administration of a single 7.6 +/‐ 0.3 mg kg‐1 dose of the racemate in 11 infants. Mean (+/‐ s.d.) half‐lives were 1.6 +/‐ 0.5 h for S(+) and 1.5 +/‐ 0.5 h for R(‐) and mean (+/‐ s.d.) AUC values were 31.5 +/‐ 14.3 mg l‐1 h for S(+) and 36.6 +/‐ 13.8 mg l‐1 h for R(‐). Since plasma concentrations of the active S(+)‐isomer were lower than those reported in adults, a higher dosage might be required in infants.