bluuebunny/crossref_metadata_2025_split huggingface dataset:
The influence of drug input rate on the development of tolerance to frusemide
Authors: Wakelkamp Monique , Alván Gunnar , Scheinin Harry , Gabrielsson Johan 
Published: March 2003

Understanding the impact of drug input rate on its pharmacokinetic‐pharmacodynamic relationship may lead to a more optimal drug therapy. The aim of the present study was to investigate the influence of the rate of administration on tolerance development to frusemide, by giving the drug at four different infusion rates. Eight healthy volunteers were given 10 mg of frusemide on four different occasions, as a constant‐rate intravenous infusion during 10, 30, 100 and 300 min, respectively. Urinary volume and contents of frusemide and sodium were measured in samples collected over 8 h. The four different infusion rates systematically influenced the frusemide excretion rate versus diuretic and natriuretic response relationship. Counter‐clockwise hysteresis occurred for the most rapid infusion rate, whereas a progressive clockwise hysteresis was observed for the slower infusions, indicating development of tolerance. For each subject, diuresis and natriuresis were modeled for all four treatments simultaneously, using a feedback tolerance model. It was not possible to describe the data using a model without tolerance. The time course of tolerance development showed remarkable differences between the infusion rates. The intensity of maximum tolerance development was significantly less for the slowest infusion rate compared with the more rapid infusions and it appeared significantly later. However, no differences in diuretic or natriuretic response were found between the treatments. The direction of the hysteresis loop is dependent on the input rate of frusemide. After the administration of a single low dose of frusemide, the time course of tolerance, rather than the integrated time course of tolerance, is influenced by the drug input rate.
Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine
Authors: Sachse Christoph , Brockmöller Jürgen , Bauer Steffen , Roots Ivar 
Published: March 2003

Aims The cytochrome P450 enzyme CYP1A2 metabolises several drugs and carcinogens. We wanted to determine how much of the variability of CYP1A2 activity is explained by a newly discovered gene polymorphism in intron 1.Methods A single nucleotide polymorphism in intron 1 of the CYP1A2 gene at position 734 downstream of the first transcribed nucleotide was identified by DNA sequence analysis. The functional significance of this C/A polymorphism was assessed in 185 healthy Caucasian non‐smokers and in 51 smokers by genotyping and phenotyping using caffeine (100 mg oral dose).Results Out of the total sample, 46% were homozygous for the variant A, 44% were heterozygous, and 10% were homozygous for the variant C. The ratio of 1,7‐dimethylxanthine (17X) plus 1,7‐dimethyluric acid divided by caffeine in 0–5 h urine samples from 185 non‐smokers did not differ significantly between the three CYP1A2 genotypes. In the 51 smokers, analysis of variance revealed significant differences in the 5 h plasma 17X/caffeine ratios between the genotypes (P=0.008, F‐test). The mean ratio was 1.37 in carriers of the A/A genotype, 0.88 in heterozygotes and 0.82 in carriers of C/C. The mean difference between the A/A and C/A groups was 0.48 (95% confidence interval 0.15–0.81; P=0.01).Conclusions The A/A genotype, which may represent a CYP1A2 high inducibility genotype, may either be a direct cause of increased CYP1A2 activity, or be genetically linked to polymorphisms conferring high inducibility. Further studies are needed to define the role of this polymorphism on the pharmacokinetics of drugs metabolised by CYP1A2 and in the activation of carcinogens.
The efficacy of a novel adenosine agonist (WAG 994) in postoperative dental pain
Authors: Seymour  , Hawkesford  , Hill  , Frame  , Andrews  
Published: March 2003

Aims To determine the comparative efficacy of a new novel adenosine agonist (WAG 994) in postoperative pain after third molar surgery.Methods One hundred and twenty‐two patients with postoperative pain after third molar surgery were randomised in a placebo double‐blind trial with an active control group. In the early postoperative period patients received either a single dose of WAG 994 1 mg, ibuprofen 400 mg or matched placebos. Pain intensity score was recorded on serial visual analogue scales over a 6 h investigation period. Similarly, pain relief was completed on a 4 point categorical scale at each evaluation point. Patients had access to escape analgesic and if these were taken, the time and dosage were recorded. A sparse sampling technique was used to investigate the relationship between analgesic effects and plasma concentrations of WAG 994.Results All three treatment groups were matched for various demographic variables. For all efficacy measures, WAG 994 was not significantly different from placebo (P >0.05), whereas ibuprofen 400 mg was significantly superior to placebo (P<0.001). No significant relationships (P<0.05) were found between WAG 994 pharmacokinetic variables and efficacy measures.Conclusion WAG 994, an adenosine agonist, did not show efficacy in the management of postoperative pain after third molar surgery. Although this pain responds well to nonsteroidal anti‐inflammatory drugs, it appears to be resistant to compounds that interact with purinergic receptors.
Effect of activated charcoal alone or given after gastric lavage in reducing the absorption of diazepam, ibuprofen and citalopram
Authors: Lapatto‐Reiniluoto O. , Kivistö K. T. , Neuvonen P. J. 
Published: March 2003

Aims
The efficacy of activated charcoal alone, and gastric lavage followed by charcoal in reducing the absorption of diazepam, ibuprofen and citalopram was studied in healthy volunteers.
Methods
In a randomized cross‐over study with three phases, nine healthy volunteers were administered single oral doses of 5 mg diazepam, 400 mg ibuprofen and 20 mg citalopram, taken simultaneously after an overnight fast. Thirty minutes later, the subjects were assigned to one of the following treatments: 200 ml water (control), 25 g activated charcoal as a suspension in 200 ml water or gastric lavage followed by 25 g charcoal in suspension given through the lavage tube. Plasma concentrations of diazepam, ibuprofen and citalopram were determined up to 10 h.
Results
The AUC(0,10 h) of diazepam was reduced by 27% (P<0.05) by both charcoal alone and charcoal combined with lavage. The increase in plasma diazepam concentration from 0.5 h onwards was prevented by both interventions (P≤0.05), whereas the Cmax of diazepam was not significantly affected by either treatment. The AUC(0, 10 h) of ibuprofen was reduced by 49% (P<0.05) after the combination treatment and by 30% (P<0.05) after charcoal alone, but there was no significant difference between these two treatments. Both charcoal alone and the combination treatment were equally effective in preventing the increase in plasma ibuprofen from 0.5 h onwards (P<0.01). The Cmax of ibuprofen was reduced by 45% (P<0.05) and by 21% (P=NS), respectively. The AUC(0,10 h) of citalopram was reduced by 51% (P<0.05) after both charcoal alone and charcoal combined with lavage, and the Cmax by 52% (P<0.05) and 54% (P<0.05), respectively. The increase in plasma citalopram concentration from 0.5 h onwards was reduced by about 50% (P<0.01) by both interventions.
Conclusions
Activated charcoal alone and charcoal combined with lavage showed similar efficacy in preventing the absorption of diazepam, ibuprofen and citalopram. These results suggest that gastric lavage needs not be routinely performed before administration of charcoal.
Polypharmacy in a general surgical unit and consequences of drug withdrawal
Authors: Kennedy J. M. , Van Rij A. M. , Spears G. F. , Pettigrew R. A. , Tucker I. G. 
Published: March 2003

Aims  To identify drug usage/withdrawal in surgical patients and the relative risk this imposes on postoperative surgical complications.Methods  A prospective survey of patients’ medicines, oral intake (food/fluids/ medicines) and postoperative complications was carried out in the General Surgical Unit, Dunedin Hospital, Dunedin, New Zealand.Results  One thousand and twenty‐five general surgical patients aged ≥ 16 years, were entered into the study. Half of the patients were taking medicines unrelated to surgery. On average these patients received 9 different drugs (range 1–47) from a selection of 251, of which 21% were released in the last 10 years. The mean number of these drugs taken increased with age, vascular surgery and other major procedures. The majority of patients (53%) were taking drugs for cardiovascular problems. Only 8% of admissions were on the drugs more traditionally recognized to be of importance to the surgery, i.e. steroids and diabetic therapy. With respect to risk, taking a drug unrelated to surgery was associated with an increased relative risk of a postoperative complication by 2.7 (95% C.I. 1.76–4.04) compared with those who were not taking any drug. Cardiovascular drugs contributed significantly to this risk; when they were excluded from analysis, the risk dropped to 1.8 (95% C.I. 1.14–2.93). Death may be more common in those taking ACE inhibitors. Drug withdrawal and complications were analysed and as the time without medicines increased (range 1–42 days) so did the complication rate (χ2 = 14.7, DF = 2, P = 0.007). Of those patients who were taking a cardiovascular medicine and were without their normal medicines for a period of time postoperatively, 12% suffered a cardiac complication.Conclusions  Many patients admitted to a general surgical ward, are taking medicines unrelated to surgery. Drug therapy unrelated to surgery is a useful predictor for increased postoperative complications and one for which preventive action can be taken. This study provides evidence that withdrawal of regular medicines may add significant risk to the surgery and further complicate outcome. The longer patients were without their regular medicines the more nonsurgical complications they suffered. Reintroduction of patients’ regular medicines early in their postoperative course may decrease morbidity and mortality in‐patients.
Within‐ and between‐subject variations in pharmacokinetic parameters of ethanol by analysis of breath, venous blood and urine
Authors: Norberg Å. , Gabrielsson J. , Jones A. W. , Hahn R. G. 
Published: March 2003

Aims To evaluate the prerequisites for using ethanol dilution to estimate total body water, we studied the within‐ and between‐subject variation in the parameter estimates of a two‐compartment model for ethanol pharmacokinetics with parallel Michaelis‐Menten and first‐order renal elimination. Because sampling of breath might be preferable in some clinical situations the parameter estimates derived from breath and venous blood were compared.Methods On two occasions, ethanol 0.4 g kg−1was given by intravenous infusion to 16 volunteers after they had fasted overnight. The proposed model was fitted by means of nonlinear regression to concentration‐time data measured in the breath, venous blood and urine during 360 min. The model contained six parameters:VmaxandKm(Michaelis‐Menten elimination constants), CLd(intercompartmental distribution parameter),VCandVT(volumes of the central and tissue compartment, respectively) and CLR(renal clearance). The volume of distribution,Vss, was calculated as the sum ofVCandVT.Results The mean ± total s.d. of the parameter estimates derived from blood data wereVmax95 ± 25 mg min−1,Km27 ± 19 mg l−1, CLd809 ± 232 ml min−1,VC14.5 ± 4.3 l,VT21.2 ± 4.4 l, CLR3.6 ± 2.0 ml min−1andVss35.8 ± 4.3 l. The variation within subjects amounted to 3%, 9%, 21%, 21%, 17%, 26% and 2%, respectively, of the total variation. Breath samples were associated with a similar or lower variation than blood, both within and between subjects. About 1.5% of the infused ethanol was recovered in the urine.Conclusions The low within‐subject variation of the key parameterVss(only 2%) suggests that ethanol dilution analysed by the pharmacokinetic model applied here may be used as an index of the total body water. Breath samples yielded at least as good reproducibility in the model parameters as venous blood.
Validation of the diagnosis of venous thromboembolism in general practice database studies
Authors: Lawrenson R. , Todd J.‐C. , Leydon G. M. , Williams T. J. , Farmer R. D. T. 
Published: March 2003

Aims
The study was conducted to determine whether the method for selecting cases of venous thromboembolism (VTE) from general practice databases significantly affected the findings of an epidemiological study.
Methods
Cases of VTE were identified from the UK General Practice Research Database (GPRD) by searching for codes for deep vein thrombosis (DVT) and pulmonary embolism (PE). These had to be supported by evidence of anticoagulation and be exposed to a combined oral contraceptive (COC) at the time of the event. Additional information about the event was sought from general practitioners who were requested to complete a questionnaire and to supply anonymised copies of hospital letters and discharge summaries.
Results
Of the 285 cases identified from the GPRD, additional information was available for 177 VTE events. This information showed that 84% of those events were supported by hospital investigations or a death certificate. Using only verified cases, rather than all GPRD identified events, did not alter the results of the epidemiological study.
Conclusions
The GPRD provides information of sufficiently high quality to allow valid epidemiological research of VTE events. Excluding cases without a database record of hospital admission would lead to valid events being overlooked, and an under‐estimate of the disease incidence.
Constriction to ETB receptor agonists, BQ‐3020 and sarafotoxin S6c, in human resistance and capacitance vessels in vivo
Authors: Strachan Fiona E. , Crockett Thomas R. , Mills Nicholas L. , Gray Gillian A. , Webb David J. 
Published: March 2003

Aims
The aim of the study was to examine the effects of the ETB receptor selective agonists sarafotoxin S6c (SFTX6c) and BQ‐3020 on the forearm resistance and capacitance vessels in healthy subjects in vivo.
Methods
The local response to intra‐arterial or intravenous infusion of SFTX6c (5 pmol min−1) or BQ‐3020 (50 pmol min−1) was assessed, on separate occasions, in eight healthy men (aged 20–28 years). Data (mean ± s.e.mean) were examined by
anova. Results are expressed as percentage change from baseline at 90 min.
Results
SFTX6c and BQ‐3020 reduced forearm blood flow, following local intra‐arterial infusion (−25 ± 7% and −27 ± 7%, respectively; P < 0.001) and reduced hand vein diameter, following local intravenous infusion (−30 ± 8% and −16 ± 7%, respectively; P < 0.001).
Conclusions
We have shown that locally active infusions of the selective ETB receptor agonists SFTX6c and BQ‐3020 cause arterial constriction and venoconstriction in healthy human blood vessels in vivo. These results indicate that ETB receptor stimulation may mediate vasoconstriction in humans.
A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children
Authors: Anderson Brian J. , Woollard Gerald A. , Holford Nicholas H. G. 
Published: March 2003

Aims
The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants.
Methods
Infants in their first 3 months of life (n = 30) were randomised to sequentially receive one of three paracetamol formulations (dose 30–40 mg kg−1) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10–16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n = 221) and age‐related pharmacokinetic changes investigated.
Results
Population pharmacokinetic parameter estimates and their coefficients of variation (CV%) for a one compartment model with first order input, lag time and first order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h−1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half‐life of 1.9 days from 120 l 70 kg−1 at birth to 69.9 l 70 kg−1 by 14 days. Clearance increased from birth (4.9 l h−1 70 kg−1) with a half‐life of 3.25 months to reach 12.4 l h−1 70 kg−1 by 12 months. The absorption half‐life (tabs) for the oral preparation was 0.13 (154%) h with a lag time (tlag) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were tabs 1.34 (90%) h, tlag 0.14 h (31%) and tabs 0.65 (63%) h, tlag 0.54 h (31%), respectively. The tabs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively.
Conclusions
Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l−1 in approximately 50% subjects can be achieved by a dose from 45 mg kg−1 day−1 at birth and up to 90 mg kg−1 day−1 in 5‐year‐old children. A reduced dose of 75 mg kg−1 day−1 in an 8‐year‐old child is sufficient because clearance is a nonlinear function of weight.
Intravenous diltiazem and CYP3A‐mediated metabolism
Authors: Masica Andrew L. , Azie Nkechi E. , Brater D. Craig , Hall Stephen D. , Jones David R. 
Published: March 2003

Aims
To study whether intravenous diltiazem, a calcium channel blocker commonly prescribed for hypertension and stable angina, is an inhibitor of the CYP3A enzymes by using oral lovastatin, an HMG Co‐A reductase inhibitor, as a substrate.
Methods
Ten healthy volunteers were studied in a randomized two‐way crossover design. The two arms were 1) administration of a 20 mg dosage of lovastatin orally and 2) administration of a 20 mg dosage of lovastatin orally 1 h after an intravenous loading dosage and constant infusion of diltiazem. Blood samples were collected up to 25 h in order to quantify lovastatin and diltiazem concentrations in the separated serum. Lovastatin and diltiazem concentrations were quantified by GC‐MS and h.p.l.c., respectively.
Results
Intravenous diltiazem did not significantly affect the oral AUC, Cmax, t½, or tmax of lovastatin.
Conclusions
These data suggest that the interaction of lovastatin with diltiazem does not occur systemically and is primarily a first‐pass effect. Thus, drug interactions with diltiazem may become evident when a patient is moved from intravenous to oral dosing.
Relative bioavailability of salbutamol to the lung following inhalation when administration is prolonged
Authors: Silkstone V. L. , Tomlinson H. S. , Corlett S. A. , Chrystyn H. 
Published: March 2003

Aims  Urinary salbutamol post‐inhalation has been shown to be an index of lung deposition. The possibility of using the urinary method for prolonged periods of inhalation (such as nebulized therapy) has been evaluated.Methods  On separate study days volunteers received salbutamol 5 × 100 µg via either oral administration (ORAL), oral with 5 g oral charcoal (ORAL + C), inhaled from a metered dose inhaler (MDI) or MDI plus 5 g oral charcoal (MDI + C). Each dose was separated by 2 min, i.e. administration time of 8 min. Urine samples were provided at 0, 30, 40, 60 and 120 min postdose. Also seven subjects inhaled 5×100 µg doses from the MDI on five separate occasions and provided urine 0–30 min post dose.Results  No salbutamol was detected in urine samples following ORAL + C. The mean (s.d.) amounts of salbutamol excreted in the urine in the first 30 min post ORAL, MDI and MDI + C were 0.42 (0.55), 11.01 (3.77) and 11.60 (3.68) µg, respectively. The ratio of urinary salbutamol following MDI and MDI + C to ORAL in the 0–30 min collection period was 26.2 and 27.8, and between 30 and 40 min postdose was 5.1 and 4.7, respectively. There was no difference between urinary salbutamol over the first 30 min following MDI and MDI + C with a mean ratio (90% confidence interval) of 95.6 (84.0, 107.2). The mean (s.d.) coefficient of variation for the 30 min urinary salbutamol elimination following inhalation of 5 × 100 µg doses from the MDI by seven subjects (on 5 separate study days) was 9.4 (2.3) %.Conclusions  The 30 min urinary salbutamol method can be used for an inhalation period of up to 8 min to identify the relative bioavailability to the lung. Samples taken after this time period are affected by excretion of the oral absorbed fraction. Most nebulisers deliver their dose within this administration time.
The pharmacokinetics of trinitroglycerin and its metabolites in patients with chronic stable angina
Authors: Hashimoto Satoru , Yamauchi Eiko , Kobayashi Atsuko , Shigemi Kenji , Tsuruta Hiroshi , Yamashita Tomomitsu , Tanaka Yoshifumi 
Published: March 2003

Aims
To study the pharmacokinetics of trinitroglycerin (GTN) and its four metabolites in angina patients during their transient use of transdermal GTN tape following intravenous administration of GTN.
Methods
Four patients received a GTN tape following intravenous administration of 0.1 µg kg−1 min−1 GTN, and the other four patients received two GTN tapes following intravenous administration of 0.2 µg kg−1 min−1 GTN.
Results
Plasma concentrations of GTN in both groups during tape application showed a slight decrease for the hour after the application of the tape and then were con‐ stant for 24 h. In contrast, the concentrations of dinitroglycerins (GDNs) and mononitroglycerins (GMNs) depended on the duration of previous intravenous administration of GTN. Neither significant cardiovascular changes nor undesirable complications were observed during the study.
Conclusions
The results suggest that appropriate replacement of intravenous GTN administration with transdermal tape application could maintain a therapeutic GTN level.