bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children
Authors: Anderson B. J. , Holford N. H. G. , Woollard G. A. , Chan P. L. S. 
Published: March 2003

Aims
Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1–2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.
Methods
Concentration‐time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg−1 were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two‐stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model.
Results
Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.2 l h−1 (CV 47%), volume of distribution 67.1 l (CV 58%) and absorption rate constant 0.77 h−1 (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).
Conclusions
Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1–2 h before anticipated pain or fever in children.
Compliance with restrictions on the subsidized use of proton pump inhibitors in Australia
Authors: McManus Peter , Marley John , Birkett Donald J. , Lindner Julie 
Published: March 2003

Aims
To determine among a cohort of patients newly dispensed a prescription for a proton pump inhibitor (PPI) the extent of prior use of other less expensive agents such as antacids and H2‐receptor antagonists as evidence of a ‘stepped care’ approach to peptic ulcer and oesophageal disease.
Methods
A retrospective drug utilization study was conducted within the Pharmaceutical Benefits Scheme (PBS) claims database in Australia. A cohort of social security recipients, who received approval for PPI supply in the month of October 1996, had no prior PPI approval in the previous 18 months and went on to have the drug dispensed, was assembled. This group of ‘new PPI starters’ was then examined for supply of less expensive prescription medicines to treat peptic ulcer and oesophageal disease in the 12 months prior to obtaining their PPI approval.
Results
In a cohort of 4554 defined new PPI users, 1205 (26.5%) showed no use of H2‐receptor antagonists, antacids, cisapride, cytoprotectants or antiregurgitants in the 12 month period prior to commencing the PPI. The major reason for use given by prescribers for PBS supply was ‘severe refractory ulcerating oesophagitis’.
Conclusions
Subsidized supply is currently restricted on cost‐effectiveness grounds to refractory peptic ulcer disease or severe oesophageal disease. Despite this, utilization and epidemiological data suggest that there is widespread leakage of use outside these indications particularly to less severe forms of oesophageal disease. This patient tracking study has shown within the PBS database that around a quarter of the patients are treated directly with a PPI without being prescribed less expensive agents at least in the preceding 12 months.
Stereoselective steady state disposition and action of propafenone in Chinese subjects
Authors: Li Gao , Gong Pei‐Li , Qiu Jun , Zeng Fan‐Dian , Klotz Ulrich 
Published: March 2003

To investigate the steady state disposition and action of racemic propafenone and its enantiomers and the potential for an enatiomer‐enantiomer interaction in Chinese subjects. Eight healthy male Chinese individuals received in a double‐blind, randomized, cross‐over study racemic propafenone (150 mg every 6 h), (S)‐, and (R)‐propafenone (150 mg each every 6 h) and placebo orally for 4 days. During the last dosing interval the plasma concentrations of both enantiomers of propafenone were measured and ECG, blood pressure (MAP) and heart rate were monitored.  Whereas the apparent elimination half‐life (t½,z ), mean residence time (MRT) and time to reach peak concentrations (tmax ) of (S)‐ and (R)‐propafenone were similar and independent of the administered agent, significant differences were observed in the apparent oral clearance (CLO ) of the enantiomers. During dosing with racemic propafenone CLO of (S)‐ and (R)‐propafenone averaged (±s.d.) 1226±751 and 1678±625 ml min−1, respectively (P=0.024). Following the administration of the pure enantiomers CLO of (S)‐propafenone increased (P=0.007) to 2028±959 ml min−1 and that of (R)‐propafenone was reduced (P=0.042) to 1318±867 ml min−1. Both enantiomers and the racemate caused about a 10% increase in the QRS duration (P<0.05) and PR‐interval (P<0.01) when compared with placebo. The increase in maximum exercise heart rate was significantly (P<0.05) attenuated only at 3 h following the administration of the racemate and the S‐enantiomer. MAP and QTC were not affected significantly. These data indicate that the stereoselective disposition of propafenone is similar in Chinese and Caucasian subjects (previously published findings), the (R)‐enantiomer being cleared more rapidly. A similar enantiomer‐enantiomer interaction also occurred. Thus, when the racemate was given, the elimination of (S)‐propafenone was impaired and that of the (R)‐form accelerated compared with single enantiomer administration. The results indicate that dosage adjustments are probably not required in Chinese patients receiving propafenone.
Midazolam effects on prepulse inhibition of the acoustic blink reflex
Authors: Schächinger Hartmut , Müller Beatrice U. , Strobel Werner , Langewitz Wolf , Ritz Rudolf 
Published: March 2003

Aims The eye‐blink response following sudden acoustic noise bursts is part of the startle reflex. The magnitude of the startle response can be attenuated by presentation of a weak stimulus before the ‘startle‐eliciting’ stimulus (prepulse inhibition, PPI). PPI is a stable finding in awake humans but may be altered by anaesthetic drugs. We investigated whether the application of benzodiazepines altered the magnitude of PPI in healthy male volunteers.Methods In an open‐label noncontrolled investigation, the effect of the benzodiazepine agonist midazolam on PPI was assessed in the absence and presence of the antagonist flumazenil. After an initial control period of 60 min three consecutive periods, each of 60 min, with progressively increasing concentrations of midazolam were studied (0.02, 0.06, 0.14 mg kg−1 h−1 ). A final 60 min period during the administration of flumazenil (0.004 mg kg−1 h−1 ) and while the agonist was still present was also studied. Drug was administered intravenuously as a combination of bolus, 50% of total dose and continuous infusion over the 60 min period. Electromyographic (EMG) response of the right orbicularis oculi muscle was used to assess the startle response to noise bursts of 50 ms duration (95 dB(A)). Noise bursts were randomly preceded by nonstartling prepulses (800 Hz sinus, 50 ms duration, 65 dB(A), prepulse to noise interval 120 ms). The magnitude of PPI was calculated by dividing the EMG response to nonprepulsed stimuli by the response to prepulsed stimuli for each individual and period. Eleven subjects participated in the study, two of them were excluded from the statistical analysis because startle responses could not be reliably elicited (final sample size n=9).Results The magnitude of PPI was inversely related to the concentration of midazolam. This relationship was described by a sigmoidal Emax model, giving an Emax of 0.65±0.13, an ED50 of 33.9±10.9 ng ml−1 and gamma of 3.5±1.0. During infusion of flumazenil and in the presence of midazolam, the magnitude of PPI increased by 0.11 (95% CI, 0–0.22, P≤0.04), which is consistent with its mode of action as a benzodiazepine antagonist.Conclusions In healthy male volunteers the magnitude of PPI varies according to agonism and antagonism of benzodiazepine receptors, suggesting that the assessment of PPI may be potentially useful to monitor the sedative effect of benzodiazepines in the clinical setting.
Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers
Authors: Fukuda Tsuyoshi , Yamamoto Isamu , Nishida Yuko , Zhou Qian , Ohno Masako , Takada Kanji , Azuma Junichi 
Published: March 2003

Aims Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O‐desmethylvenlafaxine (ODV). Therefore, the influence of the CYP2D6 genotypes on venlafaxine pharmacokinetics was examined in a Japanese population.Methods Twelve adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotypes were determined by codon 188C/T, 1934G/A, 2938G/A and 4268G/C mutations using endonuclease tests based on PCR and by Xba I‐RFLP analysis. Subjects were categorized into the following 3 groups (n=4 in each group); Group1: CYP2D6*10/*10, *5/*10, Group2: CYP2D6*1/*10, *2/*10 and Group3: CYP2D6*1/*1, CYP2D6*1/*2. Venlafaxine (25 mg, n=6; 37.5 mg, n=6) was administered orally at 09.00 h following an overnight fast. Plasma concentrations of venlafaxine and ODV were monitored by h.p.l.c. for 48 h.Results The Cmax and AUC of venlafaxine were 184% and 484% higher in the group 1 subjects than in the group 3 subjects, and 101% and 203% higher in the group 1 than in the group 2, respectively.Conclusions These results suggest that CYP2D6*10 influences the pharmacokinetics of venlafaxine in a Japanese population.
Effect of troglitazone on plasma lipid metabolism and lipoprotein lipase
Authors: Kobayashi Junji , Nagashima Izumi , Hikita Minoru , Bujo Hideaki , Takahashi Kazuo , Otabe Masako , Morisaki Nobuhiro , Saito Yasushi 
Published: March 2003

Aims To clarify how troglitazone, an insulin‐sensitizing agent, affects lipid metabolism and postheparin plasma lipoprotein lipase (LPL).Methods Fifteen patients (3 male, 12 female) (the average age 62±7 years; the mean body mass index (BMI) 25±3 kg/m2 ) were recruited for this study. The serum lipids and postheparin plasma lipoprotein lipase (LPL) mass before and 4 weeks after oral administration of troglitazone (200 mg day−1 ) were measured. A mouse preadipocyte cell line, 3T3‐L1, was incubated with troglitazone and LPL enzyme protein mass in the culture media was measured by an enzyme linked immunosorbent assay. A reverse transcription polymerase chain reaction (RT‐PCR) using primers specific for the carboxyl terminal 135 amino acid of mouse LPL cDNA was used to evaluate the effect of troglitazone on expression of LPL and Northern blot analysis carried out to determine expression of LPL.Results The average levels before treatment of fasting serum total cholesterol, triglycerides, high density lipoprotein cholesterol, plasma glucose and glycohaemoglobin A1c were 5.6±0.9, 1.8±1.0, 1.5±0.5, 8.1±1.7 mmol l−1 and 7.8±1.6% respectively. Four weeks after treatment, those levels were 5.4±0.9, 1.2±0.3 (P=0.004), 1.6±0.5 (P=0.02) mmol l−1, 7.7±2.3 mmol l−1 and 7.3±0.6% (P=0.01), respectively. The postheparin plasma LPL mass increased from 226±39 to 257±68 ng ml−1 (P=0.03) during that period. The LPL mass in the media of 3T3 L1 cells cultured in the presence of 10, 20 or 30 μm of this compound increased in a dose dependent manner. RT‐PCR revealed that the area of the bands of the RT‐PCR products on 1.5% agarose gel analyzed with NIH image from the cell extracts cultured in the presence of 10 μm troglitazone was significantly larger (P=0.0069) than that in the absence of this compound. Northern blot analysis revealed that in the cultured 3T3‐L1 cells, the expression of LPL was enhanced in the presence of 10 μm troglitazone.Conclusions Troglitazone improves plasma triglyceride‐rich lipoproteins metabolism by enhancing the expression of LPL in adipocytes.
Methadone N‐demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4
Authors: Foster David J. R. , Somogyi Andrew A. , Bochner Felix 
Published: March 2003

Aims To investigate the kinetics of CYP‐mediated N‐demethylation of methadone in human liver microsomes, and examine the role of stereoselectivity and CYP isoforms involved.Methods The kinetics of 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP) formation via N‐demethylation of rac‐, (R)‐ and (S)‐methadone in human liver microsomes prepared from six liver samples were determined by h.p.l.c., and inhibition of metabolic function was studied using isoform‐specific chemical inhibitors and monoclonal antibodies. Microsomes containing expressed CYP3A4, CYP2D6 and CYP2C19 were also used to examine the formation of EDDP.Results The V max, Km, and CLint values for the formation of EDDP from rac‐, (R)‐ and (S)‐methadone were in the ranges of 20–77 nmol mg−1 protein h−1, 125–252 μm, and 91–494 ml h−1 g−1 protein. Km and CLint values for (R)‐ and (S)‐methadone were not statistically significantly different (P >0.05), while V max values for (S)‐methadone were 15% (P=0.045) lower than for (R)‐methadone. Expressed CYP3A4 and CYP2C19 showed similar reaction rates for both (R)‐ and (S)‐methadone, while CYP2D6 did not catalyse this reaction. Selective chemical inhibitors of CYP3A (troleandomycin, ketoconazole) and monoclonal human CYP3A4 antibodies significantly inhibited (P<0.05) the formation of EDDP in a concentration dependent manner by up to 80%. Sulphaphenazole (CYP2C9) also significantly inhibited (P<0.05) EDDP formation (range 14–25%). There were no statistically significant differences in the inhibition observed between the three substrates. Selective inhibitors of CYP1A2 (furafylline), CYP2A6 (coumarin), CYP2C19 ((S)‐mephenytoin), CYP2D6 (quinidine) and CYP2E1 (diethyldithiocarbamic acid sodium salt and monoclonal human CYP2E1 antibodies) had no significant (P >0.05) effect.Conclusions The N‐demethylation of methadone in human liver microsomes is not markedly stereoselective, and is mediated mainly by CYP3A4 with the possible involvement of CYP2C9 and CYP2C19. Thus, the large interindividual variation reported for methadone pharmacokinetics may be due to variability in the expression of these CYP isoforms, and the reported stereoselectivity in the systemic clearance of methadone in vivo is not due to stereoselectivity in N‐demethylation.
Serum concentrations of tramadol enantiomers during patient‐controlled analgesia
Authors: Grond Stefan , Meuser Thomas , Uragg Heinz , Stahlberg Hans J. , Lehmann Klaus A. 
Published: March 2003

Aims
Tramadol, a centrally acting analgesic, is used as a racemate containing 50% of a (+)‐ and 50% of a (−)‐enantiomer. This paper presents the pharmacokinetic results of postoperative patient‐controlled analgesia using (+)‐tramadol, (−)‐tramadol or the racemate.
Methods
Ninety‐eight patients recovering from major gynaecological surgery were treated in a randomised, double‐blind study with (+)‐tramadol, (−)‐tramadol or the racemate. Following an i.v. bolus up to a maximum of 200 mg, patient‐controlled analgesia with demand doses of 20 mg was made available for 24 h. Prior to each demand, the serum concentrations of the enantiomers of tramadol and its metabolite M1 were measured in 92 patients.
Results
The mean concentrations of tramadol during the postsurgery phase were 470±323 ng ml−1, 590±410 ng ml−1 and 771±451 ng ml−1 in the (+)‐, racemate‐ and (−)‐group, respectively ((+) vs (−), P<0.05); the mean concentrations of the metabolite M1 were 57±18 ng ml−1, 84±34 ng ml−1 and 96±41 ng ml−1 in the (+)‐, racemate‐ and (−)‐group, respectively ((+) vs (−) and (+) vs racemate, P<0.05). The mean concentrations of (+)‐tramadol and (+)‐M1 were lower in the racemate‐ than in the (+)‐group (P<0.05), those of (−)‐tramadol and (−)‐M1 were lower in the racemate than in the (−)‐group (P<0.05). In the racemate group, the mean serum concentrations of (+)‐tramadol were higher than those of (−)‐tramadol (P<0.05), whereas the mean serum concentrations of (−)‐M1 were higher than those of (+)‐M1 (P<0.05).
Conclusions
The therapeutic serum concentration of tramadol and M1 showed a great variability. The lowest mean concentrations were measured in the (+)‐group and the highest in (−)‐group. This is in agreement with the clinical finding that (+)‐tramadol is a more potent analgesic than (−)‐tramadol.
A double‐blind, placebo‐controlled investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function
Authors: Hindmarch I. , Shamsi Z. , Stanley N. , Fairweather D. B. 
Published: March 2003

Aims
To assess whether fexofenadine in a range of doses from 80 to 180 mg has any disruptive effects on aspects of psychomotor and cognitive function in comparison with placebo, loratadine and promethazine, an antihistamine known to produce psychomotor and cognitive impairment.
Methods
Twenty‐four healthy volunteers received fexofenadine 80 mg, 120 mg and 180 mg, loratadine 10 mg, promethazine 30 mg (as a positive internal control) and placebo in a six‐way crossover, double‐blind study. Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1.5, 3, 6, 9, 12 and 24 h post dose. The test battery included critical flicker fusion (CFF), choice reaction time (CRT) and assessment of subjective sedation (LARS). Overall levels of activity were monitored by means of wrist mounted actigraphs throughout each of the 24 h experimental periods.
Results
Fexofenadine at all doses tested was not statistically different from placebo in any of the tests used and loratadine did not cause any significant impairment of cognitive function. Significant impairments were found following promethazine. Promethazine caused a significant reduction in CFF threshold and this effect was evident up to 12 h post dose (P<0.05). There was a significant increase in recognition reaction time at 3 and 6 h post promethazine administration, and the drug caused a significant (P<0.002) increase in the percentage of ‘sleep‐like’ activity from actigraph records during the daytime.
Conclusions
Fexofenadine at doses up to 180 mg appears free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the verum control promethazine 30 mg.
Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency
Authors: Greenbaum R. , Zucchelli P. , Caspi A. , Nouriel H. , Paz R. , Sclarovsky S. , O'Grady P. , Yee K.‐F. , Liao W.‐C. , Mangold B. 
Published: March 2003

Aims To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril. Methods Patients with congestive heart failure (CHF, NYHA Class II–IV) and chronic renal insufficiency (creatinine clearance ≤30 ml min−1 ) were randomized to receive fosinopril, enalapril or lisinopril in two parallel‐group studies. In the first study 24 patients were treated with 10 mg fosinopril (n=12 patients) or 2.5 mg enalapril (n=12) every morning for 10 consecutive days. In the second study 31 patients were treated with 10 mg fosinopril (n=16 patients) or 5 mg lisinopril (n=15) every morning for 10 consecutive days. Samples of blood were collected for determination of pharmacokinetic parameters. The area under the curve (AUC) between the first and last days of treatment and the accumulation index (AI) were the primary outcome measures. Results All three angiotensin converting enzyme (ACE) inhibitors exhibited a significant increase in AUC between the first and last days of treatment in both studies. The difference between the AI for fosinoprilat (1.41) and enalaprilat (1.96) was statistically significant (95% CI: 1.05, 1.84). Similarly, the difference between the AI for fosinoprilat (1.21) and lisinopril (2.76) was statistically significant (95% CI: 1.85, 2.69). All three ACE inhibitors completely inhibited serum ACE for 24 h. All treatments were well tolerated. Conclusions Fosinoprilat exhibits significantly less accumulation than enalaprilat or lisinopril in patients with CHF and renal insufficiency, most probably because fosinoprilat is eliminated by both the kidney and liver, and increased hepatic elimination can compensate for reduced renal clearance in patients with kidney dysfunction.
Effects of sibutramine alone and with alcohol on cognitive function in healthy volunteers
Authors: Wesnes K. A. , Garratt C. , Wickens M. , Gudgeon A. , Oliver S. 
Published: March 2003

Aims To investigate the effects of sibutramine in combination with alcohol in a double‐blind, randomised, placebo‐controlled, four‐way crossover study in 20 healthy volunteers. Methods On each study day each volunteer received either: sibutramine 20 mg+0.5 g kg−1 alcohol; sibutramine 20 mg+placebo alcohol; placebo capsules+0.5 g kg−1 alcohol; or placebo capsules+placebo alcohol. Alcohol was administered 2 h following ingestion of the study capsules. During each study day, assessments of cognitive performance were made prior to dosing, and at 3, 4.5, 6 and 10 h post dosing. Blood alcohol concentration was estimated using a breath alcometer immediately prior to each cognitive performance test session. Each study day was followed by a minimum 7 day washout period. Results Alcohol was found to produce statistically significant impairments in tests of attention (maximum impairment to speed of digit vigilance=49 ms) and episodic memory (maximum impairment to speed of word recognition=74 ms). Alcohol also increased body sway (maximum increase 17.4 units) and lowered self rated alertness (maximum decrease 13.6 mm). These effects were produced by an inferred blood alcohol level of 53.2 mg dl−1. Sibutramine was not found to potentiate any of the effects of alcohol. There was a small, yet statistically significant, interaction effect observed on the sensitivity index of the picture recognition task. In this test, the combined effects of sibutramine and alcohol were smaller than the impairments produced by alcohol alone. Sibutramine, when dosed alone, was associated with improved performance on several tasks. Sibutramine improved attention (mean speed of digit vigilance improved by 21 ms), picture recognition speed (improvement at 3=81) and motor control (tracking error at 3 h reduced by 1.58 mm). Also sibutramine improved postural stability (reducing body sway at 3 h by 14.2 units). Adverse events reported were unremarkable and consistent with the known pharmacology of sibutramine and alcohol. Conclusions There was little evidence of a clinically relevant interaction of sibutramine with the impairment of cognitive function produced by alcohol in healthy volunteers. The single statistically significant interaction indicated a reduction, rather than a worsening, of alcohol‐induced impairment when sibutramine is taken concomitantly. Sibutramine when administered alone is associated with improved performance on several tasks.