bluuebunny/crossref_metadata_2025_split huggingface dataset:
Topical penetration of commercial salicylate esters and salts using human isolated skin and clinical microdialysis studies
Authors: Cross Sheree E. , Anderson Chris , Roberts Michael S. 
Published: March 2003

Aims
The penetration of active ingredients from topically applied anti‐inflammatory pharmaceutical products into tissues below the skin is the basis of their therapeutic efficacy. There is still controversy as to whether these agents are capable of direct penetration by diffusion through the tissues or whether redistribution in the systemic circulation is responsible for their tissue deposition below the application site.
Methods
The extent of direct penetration of salicylate from commercial ester and salt formulations into the dermal and subcutaneous tissue of human volunteers was determined using the technique of cutaneous microdialysis. We also examined differences in the extent of hydrolysis of the methylester of salicylate applied topically in human volunteers and in vitro skin diffusion cells using full‐thickness skin and epidermal membranes.
Results
The present study showed that whilst significant levels of salicylate could be detected in the dermis and subcutaneous tissue of volunteers treated with the methylsalicylate formulation, negligible levels of salicylate were seen following application of the triethanolamine salicylate formulation. The tissue levels of salicylate from the methylsalicylate formulation were approx. 30‐fold higher than the plasma concentrations.
Conclusion
The absorption and tissue concentration profiles for the commercial methylsalicylate formulation are indicative of direct tissue penetration and not solely redistribution by the systemic blood supply.
The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross‐over study with extensive and quinidine‐induced poor metabolizers
Authors: Wilder‐Smith Clive H. , Hufschmid Edith , Thormann Wolfgang 
Published: March 2003

Aims
Dihydrocodeine is metabolized to dihydromorphine via the isoenzyme cytochrome P450 2D6, whose activity is determined by genetic polymorphism. The importance of the dihydromorphine metabolites for analgesia in poor metabolizers is unclear. The aim of this study was to assess the importance of the dihydromorphine metabolites of dihydrocodeine in analgesia by investigating the effects of dihydrocodeine on somatic and visceral pain thresholds in extensive and quinidine‐induced poor metabolizers.
Methods
Eleven healthy subjects participated in a double‐blind, randomized, placebo‐controlled, four‐way cross‐over study comparing the effects of single doses of placebo and slow‐release dihydrocodeine 60 mg with and without premedication with quinidine sulphate 50 mg on electrical, heat and rectal distension pain tolerance thresholds. Plasma concentrations and urinary excretion of dihydrocodeine and dihydromorphine were measured.
Results
In quinidine‐induced poor metabolizers the plasma concentrations of dihydromorphine were reduced between 3 and 4 fold from 1.5 h to 13.5 h after dosing (P<0.005) and urinary excretion of dihydromorphine in the first 12 h was decreased from 0.91% to 0.28% of the dihydrocodeine dose (P<0.001). Dihydrocodeine significantly raised the heat pain tolerance thresholds (at 3.3 h and 5 h postdosing, P<0.05) and the rectal distension defaecatory urge (at 3.3 h and 10 h postdosing, P<0.02) and pain tolerance thresholds (at 3.3 h and 5 h postdosing, P<0.05) compared with placebo. Premedication with quinidine did not change the effects of dihydrocodeine on pain thresholds, but decreased the effect of dihydrocodeine on defaecatory urge thresholds (at 1.5 h, 3.3 h and 10 h postdosing, P<0.05).
Conclusions
In quinidine‐induced poor metabolizers significant reduction in dihydromorphine metabolite production did not result in diminished analgesic effects of a single dose of dihydrocodeine. The metabolism of dihydrocodeine to dihydromorphine may therefore not be of clinical importance for analgesia. This conclusion must however, be confirmed with repeated dosing in patients with pain.
Pharmacokinetic variability and strategy for therapeutic drug monitoring of saquinavir (SQV) in HIV‐1 infected individuals
Authors: Regazzi Mario B. , Villani Paola , Maserati Renato , Cocchi Laura , Giacchino Roberto , Burroni Daniela , Rettani Mauro 
Published: March 2003

Aims To investigate the pharmacokinetic profile of the protease inhibitor saquinavir (SQV) after multiple doses in HIV‐positive patients and to evaluate the possibility of predicting total body exposure of SQV from concentrations determined at single time points.Methods Twenty HIV‐positive patients on steady‐state treatment with SQV (Hard‐Gel‐Capsule, Invirase®) were enrolled in this study. Serial blood samples were obtained during a dosing interval. SQV plasma concentrations were determined by high performance liquid chromatography (h.p.l.c.) and pharmacokinetic parameters were determined by noncompartmental techniques.Results There was a marked interindividual variability in SQV pharmacokinetic parameters with a 11‐fold variability in total systemic exposure to SQV, as expressed by AUC(0,8h) values (range: 268–3009 ng ml−1 h, CV: 69%). The oral clearance shows an interindividual CV of 75%. A strong correlation (r=0.94) was found between SQV plasma concentration at 3 h (C3 h ) and AUC(0,8h).Conclusions This study shows that C3 h is a good predictor for total body exposure of SQV and might be useful to predict SQV disposition in HIV‐positive patients on steady‐state treatment.
Systemic availability of budesonide after nasal administration of three different formulations: pressurized aerosol, aqueous pump spray, and powder
Authors: Thorsson  , Borgå  , Edsbäcker  
Published: March 2003

The present study was undertaken to determine the absolute systemic availability of budesonide from three different devices for nasal administration: pressurized aerosol, aqueous pump spray, and powder. Sixteen healthy, non‐smoking, volunteers participated in this open, randomized, and crossover study. All subjects received budesonide as an intravenous dose of 400 μg, and as three, single‐dose, intranasal administrations: pressurized aerosol 800 μg, aqueous pump spray 400 μg, and powder 800 μg. Blood was sampled for 10 h after each administration and budesonide was assayed in plasma by liquid chromatography plus mass spectrometry.  The mean [95% CI] systemic availability of budesonide with reference to the metered dose was: 13 [10; 15]%, 29 [23; 37]%, and 20 [16; 23]%, and the maximum plasma concentration (Cmax ) was attained at (tmax ) 2.0, 0.7, and 0.4 h after administration for the pressurized aerosol, aqueous pump spray, and powder, respectively. The uptake of budesonide was more rapid and more complete, and the systemic availability of the drug was significantly higher from the aqueous pump spray and powder than from the pressurized aerosol.
The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing
Authors: Begg Evan J. , Robson Richard A. , Saunders Darren A. , Graham Garry G. , Buttimore Rona C. , Neill Alister M. , Town G. Ian 
Published: March 2003

Aims To examine the pharmacokinetics of ciprofloxacin and fleroxacin in plasma and sputum of patients with an acute exacerbation of chronic bronchitis or bronchiectasis following the first dose and again during the third day of treatment. Methods Twelve patients, aged >35 years, with acute infective exacerbation of bronchitis or bronchiectasis were allocated randomly to treatment with either fleroxacin 400 mg daily or ciprofloxacin 500 mg twice daily in an open, parallel group design. Plasma and sputum were collected during the first and third days of treatment. The time course of concentrations in sputum was modelled assuming that it acted as a negligibly small compartment of distribution. Results The mean sputum to plasma ratios of both ciprofloxacin and fleroxacin were approximately 1 on both days 1 and 3. Peak concentrations of ciprofloxacin in sputum were achieved 1.6 (95% CI on mean difference 0.8–2.3) and 1.2 (0.4–1.9) h later than in plasma on day 1 and day 3, respectively (mean difference±95% confidence interval). For fleroxacin, the corresponding delay in time to peak concentrations was less marked and not significant. Fleroxacin accumulated in plasma (accumulation index 1.52±0.07) and sputum (accumulation index 1.79±0.39) from day 1 to day 3. Accumulation did not occur for ciprofloxacin because the dose interval (12 h) was considerable longer than its half life (3–4 h). Conclusions The sputum to plasma ratio of ciprofloxacin and fleroxacin is approximately 1. The time to peak concentrations of ciprofloxacin in sputum is slightly delayed compared with plasma. Fleroxacin accumulates over time in both plasma and sputum consistent with its longer half‐life.
Effectiveness of delayed activated charcoal administration in simulated paracetamol (acetaminophen) overdose
Authors: Yeates P. J. A. , Thomas S. H. L. 
Published: March 2003

Aims Oral activated charcoal is used to treat drug overdose and is effective at reducing drug absorption when administered within 1 h of drug ingestion. There are fewer data on efficacy when the delay is longer, as is the case in most drug overdoses. This study investigated the efficacy of activated charcoal at preventing paracetamol (acetaminophen) absorption after simulated overdose when administration was delayed between 1 and 4 h. Methods An open randomized‐order four‐way crossover study was performed in healthy volunteers comparing the effect of activated charcoal 50 g on the absorption of 3 g paracetamol tablets when administered after an interval of 1, 2 or 4 h or not at all. Plasma paracetamol concentrations were measured over 9 h after paracetamol ingestion using h.p.l.c. and areas under the curve between 4 and 9 h (AUC(4,9 h)) calculated as a measure of paracetamol absorption. Results Activated charcoal significantly reduced paracetamol AUC(4,9 h)when administered after 1 h (mean reduction 56%; 95% Confidence intervals 34, 78; P<0.002) or 2 h (22%; 6, 39; P<0.03) but not after 4 h (8%; −8, 24). When administered after 1 h activated charcoal reduced individual plasma paracetamol concentrations significantly at all times between 4 and 9 h after paracetamol administration. Administration at 2 or 4 h had no significant effect. Conclusions These results in healthy volunteers cannot be extrapolated directly to poisoned patients. However, they provide no evidence of efficacy for activated charcoal when administered after an interval of more than 2 h.
Effect of caffeine on clozapine pharmacokinetics in healthy volunteers
Authors: Hägg Staffan , Spigset Olav , Mjörndal Tom , Dahlqvist Rune 
Published: March 2003

Aims To assess the effects of caffeine on the pharmacokinetics of clozapine in healthy volunteers. Methods This was an open label randomized crossover study in 12 nonsmoking healthy male volunteers. The subjects received a single oral dose of 12.5 mg clozapine in each phase with or without concomitant intake of caffeine (mean dose: 550 mg day−1, range: 400–1000 mg day−1 ). Serum concentrations of clozapine and its metabolites desmethyl‐clozapine and clozapine‐N‐oxide were measured during a 48 h period in each phase. In addition, serum concentrations of caffeine and the metabolite paraxanthine were monitored. Results A 19% increase in mean clozapine AUC(0,∞) (P=0.05) and a 14% decrease of mean oral clearance of clozapine were observed during concomitant intake of caffeine (P=0.05) compared with intake of only clozapine. Statistically significant decreases of mean ratios between AUC(0,12h) for desmethyl‐clozapine and AUC(0,12h) for clozapine (−18%), and between AUC(0,12h) for clozapine‐N‐oxide and AUC(0,12h) for clozapine (−23%) were observed during the caffeine phase (P=0.03 and 0.02, respectively). Oral clearance of clozapine and the ratio AUC(0,12h) for desmethyl‐clozapine/AUC(0,12h) for clozapine were correlated with the paraxanthine/caffeine ratio in serum after intake of caffeine (rs=0.62; P=0.03 and rs=0.77; P=0.003, respectively). Conclusions These results suggest that caffeine in daily doses of 400–1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals.
Pharmacokinetics and pharmacodynamics of R‐ and S‐gallopamil during multiple dosing
Authors: Gross Annette S. , Eichelbaum Michel , Mörike Klaus , Mikus Gerd 
Published: March 2003

Aims Using a stable isotope technique we investigated the pharmacokinetics and pharmacodynamics of gallopamil after administration of 50 mg pseudoracemic gallopamil every 12 h for 7 doses (72 h). Methods Six male healthy volunteers were studied. After the seventh dose the pharmacokinetics and pharmacodynamics were assessed. Serum levels of gallopamil were measured by gas chromatography/mass spectrometry. Effects of gallopamil were measured by ECG recording. Results The apparent oral clearances (R: 4.8 l min−1 (95% CI: 2.9–6.8); S: 5.5 l min−1 (95% CI: 2.5–8.5)) and half‐lives (R: 6.2 h; S: 7.2 h) of R‐ and S‐gallopamil were similar (P >0.05). The serum protein binding (fu R: 0.035 (95% CI: 0.026–0.045); S: 0.051 (95% CI: 0.033–0.069)) and the renal elimination (% of dose R: 0.49%; S: 0.71%) were enantioselective. Gallopamil had a potent effect on the PR interval (% prolongation 35.7% (95% CI: 14.0–57.3)). No changes in other electrocardiographic or cardiovascular parameters were observed. Conclusions The pharmacokinetics and bioavailability of the racemic drug gallopamil are not stereoselective at steady‐state and are therefore not substantially altered compared with the single dose administration of gallopamil.
The effect of staggered dosing of sucralfate on oral bioavailability of sparfloxacin
Authors: Kamberi Marika , Nakashima Hajime , Ogawa Keita , Oda Naomi , Nakano Shigeyuki 
Published: March 2003

Aims To investigate the effect of sucralfate on sparfloxacin absorption when administered concurrently or at strategically spaced dosing times designed to avoid the potential interaction. Methods The study was a four‐way crossover design where eight healthy Japanese volunteers were randomized to one of four treatment sequences at entry. A 300 mg dose of sparfloxacin was administered alone for treatment A (control). Treatments B, C and D included sucralfate 1.5 g every 12 h for five doses. For treatment B, the fifth dose of sucralfate was administered concurrently with sparfloxacin 300 mg. For treatment C, 300 mg sparfloxacin was given 2 h prior to the fifth dose of sucralfate. Treatment D consisted of sparfloxacin 300 mg given 4 h prior to the fifth dose of sucralfate. Blood and urine samples were collected at predetermined time intervals for 72 h. Sparfloxacin concentrations in plasma and urine and the concentrations of sparfloxacin metabolite in urine were determined by high performance liquid chromatography assays. Results Sucralfate administrated concurrently with sparfloxacin decreased the mean AUC(0,∞) of sparfloxacin 2‐fold (P<0.001) and the mean Cmax 2.1‐fold (P<0.001) compared with sparfloxacin alone. When sucralfate was administrated 2 h after sparfloxacin, the mean AUC(0,∞) was decreased 1.5‐fold (P<0.01) and the mean Cmax 1.4‐fold (P<0.01). Sucralfate did not alter the extent of absorption of sparfloxacin when it was given 4 h after the administration of sparfloxacin. The relative bioavailabilities for treatments B, C and D were 0.50 (95% CI: 0.35–0.65), 0.64 (95% CI: 0.51–0.77), and 0.92 (95% CI: 0.81–1.03), respectively, relative to sparfloxacin alone. The mean percentage of the sparfloxacin dose recovered in urine was significantly lower after sparfloxacin was administered with sucralfate than after sparfloxacin was administered alone or 2 h before the sucralfate dose (P<0.001). Treatments B, C and D were demonstrated to be equivalent to treatment A in the rate of absorption. The tmax, CLr and t1/2 were not significantly affected by sucralfate. The metabolism of sparfloxacin was not altered in the presence of sucralfate. Conclusions Oral administration of sucralfate with sparfloxacin or 2 h after sparfloxacin, decreased the extent of sparfloxacin absorption. When both drugs are to be administered together, sucralfate should be administered 4 h after sparfloxacin, allowing thus sufficient time for sparfloxacin absorption prior to the sucralfate dose and thereby minimizing the chance of a significant interaction.
Comparative oral bioavailability of azimilide dihydrochloride in the fed and fasted states
Authors: Corey Alfred E. , Agnew Jeffrey R. , Valentine Suzanne N. , Nesbitt John D. , Wagner Dan L. , Powell James H. , Thompson Gary A. 
Published: March 2003

Aims
This study investigated the relative oral bioavailability of azimilide dihydrochloride following administration in the fed (high‐fat meal) and fasted states.
Methods
This was a single‐dose, randomized, two‐way crossover study in 30 healthy, Caucasian, male subjects. Following oral administration, blood samples were collected over 27 days and analysed for azimilide using h.p.l.c. with u.v. detection. Pharmacokinetic parameters were determined using ‘noncompartmental’ analysis and compared using an ANOVA and 90% or 95% confidence intervals.
Results
The extent of absorption was equivalent in the fed and fasted states (ratio = 96.2%; 90% CI=90.5%−102.4%). However, Cmax was decreased 19% following a high‐fat meal (ratio=81.4%; 90% CI= 76.2%−87.0%). No difference in tmax or t½,z was observed.
Conclusions
Azimilide dihydrochloride may be orally administered to patients without regard to the prandial state.
Pharmacokinetics of bambuterol during oral administration of plain tablets and solution to healthy adults
Authors: Rosenborg, Johan , Larsson Per , Nyberg Lars 
Published: March 2003

Aims
The pharmacokinetics of orally administered bambuterol were investigated in healthy adult subjects, with particular regard to time to steady state, pharmacokinetic linearity, intraindividual variability for the parent drug and its active β2‐adrenergic metabolite terbutaline and bioequivalence between tablet and solution.
Methods
Twenty‐six healthy Caucasian subjects were included and 23 (12 women) completed this open, randomised, crossover study. Racemic bambuterol hydrochloride was administered orally as 10 mg, 20 mg, and 10 + 20 mg tablets, and as a solution once daily for 2 weeks at about 19.00 h. Plasma concentrations and urinary recoveries of bambuterol and terbutaline were measured after single doses and during repeated treatments.
Results
Absorption of bambuterol was biphasic. The initial rate could not be assessed directly, but it was faster than that during the second phase where absorption was rate‐limiting for elimination (mean terminal half‐life: 16 h). Steady‐state AUC(0,24 h) of bambuterol, reached within 1 week, was not dose‐linear. Mean terminal half‐life of terbutaline was 22 h and steady‐state was reached within one week of bambuterol treatment. Contrary to bambuterol, overall pharmacokinetics of terbutaline indicated dose‐linearity. Day‐to‐day intraindividual variation in AUC(0,24 h) of terbutaline, 15% with the tablet, was half that of bambuterol. Urine data indicated that intraindividual variability was slightly smaller with the solution. Tablets were bioequivalent with the solution with regard to terbutaline (90% confidence interval: 87–100%).
Conclusions
With oral bambuterol steady state was reached within 1 week. Regarding generated terbutaline, pharmacokinetics judged to be were linear, intraindividual variability of AUC at steady state was on average 15% with the tablet, and tablets were bioequivalent with the solution.
Single‐ and multiple‐dose pharmacokinetics of ziprasidone in healthy young and elderly volunteers
Authors: Wilner K. D. , Tensfeldt T. G. , Baris B. , Smolarek T. A. , Turncliff R. Z. , Colburn W. A. , Hansen R. A. 
Published: March 2003

Aims  To compare the pharmacokinetics of ziprasidone in healthy young (18–45 years) men and women, and healthy elderly ( ≥ 65 years) men and women.Methods  Eight young men, 11 young women, 8 elderly men and 8 elderly women were given oral ziprasidone 40 mg day− 1, in two evenly divided daily doses, for 7 days, followed by a single 20 mg dose on day 8. Serum samples were collected immediately before the morning dose on days 1–8, for up to 12 h after dosing on day 1 and for up to 96 h after dosing on day 8. The resulting data were used to derive pharmacokinetic parameters of ziprasidone in each age and gender group.Results  Steady‐state serum concentrations of ziprasidone were achieved within 2–3 days. The steady‐state pharmacokinetics of ziprasidone, determined 8 days after the initiation of treatment, were similar in the young men, elderly men and young women. Assessment of gender effects by analysis of variance revealed statistically significant differences in Cmax (85 vs 69 ng ml− 1) and tmax (3.19 vs 4.81 h) but no differences in AUC(0,12 h) or λz. Assessment of age effects by analysis of variance revealed statistically significant differences in AUC(0,12 h) (560 vs 465 ng  ml− 1 h), Cmax (85 vs 69 ng ml− 1) and λz (0.126 vs 0.197 l h− 1) but no difference in tmax. Assessment of age and gender effects by analysis of covariance, with body weight as the covariate, did not reveal any significant differences. The mean t½,z in the young men, young women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 h, respectively. Standard deviations of the means for the pharmacokinetic parameters for the elderly women tended to be large.Conclusions  The influence of age and gender on the pharmacokinetics of ziprasidone is not clinically significant.