bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of the initial distribution volume of glucose by an incremental plasma glucose level at 3 min after i.v. glucose in humans
Authors: Hirota Kazuyoshi , Ishihara Hironori , Tsubo Toshihito , Matsuki Akitomo 
Published: March 2003

Aims The initial distribution volume of glucose (IDVG) could be a clinically useful indicator of the central extracellular fluid (ECF) space volume, namely the interstitial fluid volume status of highly perfused organs. In this study, we determined the formula of IDVG using incremental plasma glucose levels after i.v. glucose.Methods One hundred and fifty patients admitted to the general intensive care unit of the University of Hirosaki hospital were entered into this prospective study which was conducted in two stages. In the first stage 300 data points from 100 patients were used to measure the IDVG (3 determinations for each patients). This utilized a one compartment model to describe the incremental plasma glucose decay curve following an intravenous bolus injection of glucose which, in turn, was used to derive the parameters of an equation for IDVG prediction following a single plasma sample. The second stage was a validation of the equation using a separate data set (150 points) from a further 50 patients.Results A one phase exponential decay model was well‐fitted for the IDVG‐postadministration glucose level curve, and indicated that the incremental glucose level at 3 min after i.v. glucose was best‐correlated to the IDVG compared with those at 1, 2, 4, 5 and 7 min postadministration. The formula of the IDVG was obtained from the curve: IDVG=24.44×e−0.0298×ΔGL+2.70, where ΔGL=incremental glucose level at 3 min after i.v. glucose. Another 150 samples showed that the measured‐IDVG from a one compartment model and predicted‐IDVG from the formula were 7.24±1.63 and 7.27±1.52 l, respectively, and that there was a significant correlation between the two IDVGs (r=0.966, P<0.0001).Conclusions Using an incremental glucose level at 3 min after i.v. glucose, we have established the reliable formula for determination of the IDVG which could be a clinically useful indicator of the central ECF volume.
Risk of malformations and other outcomes in children exposed to fluconazole in utero
Authors: Sørensen Henrik Toft , Nielsen Gunnar Lauge , Olesen Charlotte , Larsen Helle , Steffensen Flemming Hald , Schønheyder Henrik C. , Olsen Jørn , Czeizel Andrew E. 
Published: March 2003

Aim
Fluconazole is an active drug systematically used in the oral treatment of vaginal candidiasis and other fungal diseases. We examined the risk of malformations and other birth outcomes following pregnancy related exposures.
Method
From 1 January 1991 to 31 December 1996 we identified 165 women who had taken fluconazole just before or during pregnancy in the Pregnancy Outcome Section of the North Jutland Pharmacoepidemiological Prescription Database, Denmark, which is linked to the Danish Medical Birth Registry. We compared their birth outcomes (malformation, low birth weight and preterm delivery) with the outcomes among 13 327 women who did not receive any prescriptions during their pregnancies.
Results
The prevalence of malformation was 3.3% (four cases) among the 121 women, who had used fluconazole in the first trimester, and 5.2% (697 cases) in offspring to controls (odds ratio: 0.65, 95% confidence limits: 0.24–1.77). Furthermore, we did not find any significantly elevated risk of preterm delivery (odds ratio: 1.17, 95% confidence limits: 0.63–2.17) and low birth weight (odds ratio: 1.19, 95% confidence limits: 0.37–3.79).
Conclusion
The study showed no increased risk of congenital malformations, low birth weight or preterm birth in offspring to women who had used single dose fluconazole before conception or during pregnancy.
The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)‐verapamil in humans
Authors: Sandström Rikard , Knutson Tina W. , Knutson Lars , Jansson Britt , Lennernäs Hans 
Published: March 2003

Aims
The purpose of this human intestinal perfusion study was to investigate the effect of ketoconazole on the jejunal permeability and first‐pass metabolism of (R)‐ and (S)‐verapamil in humans.
Methods
A regional single‐pass perfusion of the jejunum was performed using a Loc‐I‐Gut® perfusion tube in six healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The inlet concentration of (R/S)‐verapamil was 120 mg l−1 in both periods, and ketoconazole was added at 40 mg l−1 in period 2. (R/S)‐verapamil was also administered as a short intravenous infusion of 5 mg, over a period of 10 min. The appearance ratios of the CYP3A formed metabolites (R)‐ and (S)‐norverapamil were also estimated in the outlet jejunal perfusate.
Results
The effective jejunal permeability (Peff) of both (R)‐ and (S)‐verapamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P‐glycoprotein mediated efflux. However, the appearance ratio of both (R)‐ and (S)‐norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of absorption into plasma of (R)‐ and (S)‐verapamil increased despite the low dose of ketoconazole added, indicating an inhibition of the gut wall metabolism of (R/S)‐verapamil by ketoconazole.
Conclusions
Ketoconazole did not affect the jejunal Peff of (R/S)‐verapamil, but it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of verapamil. This might be due to ketoconazole being less potent as an inhibitor of P‐glycoprotein than of CYP3A4 in vivo in humans.
Modification of general practitioner prescribing of antibiotics by use of a therapeutics adviser (academic detailer)
Authors: Ilett Kenneth F. , Johnson Sarah , Greenhill Graham , Mullen Lenette , Brockis Jennifer , Golledge Clayton L. , Reid Donald B. 
Published: March 2003

Aims This was a pilot study of the use of a clinical pharmacist as a therapeutics adviser (academic detailer) to modify antibiotic prescribing by general practitioners. Methods Following a visit by the adviser (March‐May), 112 general practitioners were recruited and randomised to control or active groups. A panel of experts prepared a best practice chart of recommended drugs for upper and lower respiratory tract infections, otitis media and urinary tract infections. The adviser made a 10–15 min visit to each prescriber in the active group (June–July), gave them the chart and discussed its recommendations briefly. Doctors in the control group were not visited nor given the chart. Prescription numbers for all prescribers were obtained from the Commonwealth Health Insurance Commission for the pre(March‐May) and postdetailing (August–September) periods using a three month lag time for data collection. Data for total numbers of prescriptions and for selected individual antibiotics used in these two periods were analysed using nonparametric statistics. Results Prescribing patterns were similar for the control and active groups in the predetailing period. For both groups, there were significant (P<0.03) increases (45% for control and 40% for active) in total number of antibiotic prescriptions in the post compared with the predetailing period. This trend was anticipated on the basis of the winter seasonal increase in respiratory infections. In line with the chart recommendations for first‐line treatment, doctors in the active group prescribed significantly more amoxycillin (P<0.02) and doxycycline (P<0.001) in the post vs predetailing periods. By contrast, doctors in the control group prescribed significantly more cefaclor (P<0.03) and roxithromycin (P<0.03), drugs that were not recommended. The total cost of antibiotics prescribed by doctors in the control group increased by 48% ($37 150) from the preto postdetailing periods. In the same time period, the costs for the active group increased by only 35% ($21 020). Conclusions We conclude that the academic detailing process was successful in modifying prescribing patterns and that it also decreased prescription numbers and costs. Application of the scheme on a nationwide basis could not only improve prescriber choice of the most appropriate antibiotic but also result in a significant saving of health care dollars.
Inhibitory effects of amiodarone and its N‐deethylated metabolite on human cytochrome P450 activities: Prediction of in vivo drug interactions
Authors: Ohyama K. , Nakajima M. , Suzuki M. , Shimada N. , Yamazaki H. , Yokoi T. 
Published: March 2003

Aims
To predict the drug interactions of amiodarone and other drugs, the inhibitory effects and inactivation potential for human cytochrome P450 (CYP) enzymes by amiodarone and its N‐dealkylated metabolite, desethylamiodarone were examined.
Methods
The inhibition or inactivation potency of amiodarone and desethylamiodarone for human CYP activities were investigated using microsomes from B‐lymphoblastoid cell lines expressing CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The in vivo drug interactions of amiodarone and desethylamiodarone were predicted in vitro using the 1+Iu/Ki values.
Results
Amiodarone weakly inhibited CYP2C9, CYP2D6, and CYP3A4‐mediated activities with Ki values of 45.1–271.6 μm. Desethylamiodarone competitively inhibited the catalytic activities of CYP2D6 (Ki=4.5 μm ) and noncompetitively inhibited CYP2A6 (Ki=13.5 μm ), CYP2B6 (Ki=5.4 μm ), and CYP3A4 (Ki=12.1 μm ). The catalytic activities of CYP1A1 (Ki=1.5 μm, α=5.7), CYP1A2 (Ki=18.8 μm, α=2.6), CYP2C9 (Ki=2.3 μm, α=5.9), and CYP2C19 (Ki=15.7 μm, α=4.5) were inhibited by desethylamiodarone with mixed type. The 1+Iu/Ki values of desethylamiodarone were higher than those of amiodarone. Amiodarone inactivated CYP3A4, while desethylamiodarone inactivated CYP1A1, CYP1A2, CYP2B6, and CYP2D6.
Conclusions
The interactions between amiodarone and other drugs might occur via the inhibition of CYP activities by its N‐dealkylated metabolite, desethylamiodarone, rather than by amiodarone itself. In addition, the inactivation of CYPs by desethylamiodarone as well as by amiodarone would also contribute to the drug interactions.
Comparison of the neurokinin‐1 antagonist GR205171, alone and in combination with the 5‐HT3 antagonist ondansetron, hyoscine and placebo in the prevention of motion‐induced nausea in man
Authors: Reid K. , Palmer J. L. , Wright R. J. , Clemes S. A. , Troakes C. , Somal H. S. , House F. , Stott J. R. R. 
Published: March 2003

Aims
In man a neurokinin‐1 (NK1) receptor antagonist has previously been shown to be ineffective in the prevention of motion‐induced nausea. The antiemetic efficacy of NK1 receptor antagonists against chemotherapy‐induced emesis is, however, enhanced when combined with a 5‐HT3 receptor antagonist. Hence the efficacy of the NK1 antagonist GR205171 in combination with the 5‐HT3 antagonist ondansetron (Zofran™) was assessed in motion‐induced nausea.
Methods
GR205171 25 mg i.v., with and without concomitant administration of ondansetron 8 mg i.v., and hyoscine hydrobromide 0.6 mg orally (positive control) were compared with placebo in a model of motion‐induced nausea. The study was performed to a four‐period, randomized, balanced, double‐blind, crossover design in 16 healthy subjects. The end‐point was the exposure to the motion stimulus required to produce moderate nausea in the subjects.
Results
The motion stimulus required to produce moderate nausea was significantly greater for the positive control than placebo (P < 0.001). There was no significant difference between either GR205171 or GR205171 plus ondansetron and placebo (P = 0.648 and 0.342, respectively).
Conclusions
The enhancement of NK1 receptor antagonist antiemetic activity through combination with a 5‐HT3 receptor antagonist is not replicated in motion‐induced nausea.
Effect of P‐glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine
Authors: Drewe Jürgen , Ball Howard A. , Beglinger Christoph , Peng Bin , Kemmler Andreas , Schächinger Hartmut , Haefeli Walter E. 
Published: March 2003

Aims
To investigate the effect of acute P‐glycoprotein inhibition by the multidrug‐resistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G).
Methods
In a double‐blind, three‐way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO2, blood pressure) of morphine were compared with and without acute inhibition ofP‐glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18 healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With the expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h.
Results
The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically significant increase in the AUC and Cmax of M3G (11.8 and 8.3%, respectively). The t½ and tmax were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not significantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (Emax 48 ms, compared with the predose absolute reaction time of 644 ms), which was not detected by the alertness‐drowsiness score, indicating only slight sedation. There was a significant decrease in systolic blood pressure (Emin−9 mmHg), and a trend for a fall in diastolic blood pressure (Emin−14.5 mmHg) and respiratory rate (Emin−1.8 breath·min−1). For all these parameters, the effects of PSC/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a significant increase in PCO2 (Emax 0.69 kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination.
Conclusions
Acute inhibition of P‐glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety‐related pharmacodynamic profile of morphine in a clinically significant manner.
Steady‐state pharmacokinetics of (R)‐ and (S)‐methadone in methadone maintenance patients
Authors: Foster David J. R. , Somogyi Andrew A. , Dyer Kyle R. , White Jason M. , Bochner Felix 
Published: March 2003

Aims  To investigate the steady‐state pharmacokinetics of (R)‐ and (S)‐methadone in a methadone maintenance population.Methods  Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma α1‐acid glycoprotein concentrations were quantified by radial immunoassay.Results  (R)‐methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)‐methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)‐methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)‐methadone, while

(167%) was significantly (P < 0.001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for

, steady‐state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)‐methadone and (S)‐EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%.Conclusions  Steady‐state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose‐plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic‐pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.
Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis
Authors: Mayo Patrick R. , Skeith Kenneth , Russell Anthony S. , Jamali Fakhreddin 
Published: March 2003

Aims  Inflammation reduces hepatic clearance of many drugs with unknown therapeutic consequences. This study was carried out to examine the effect of rheumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of verapamil.Methods  Eight RA patients were age‐ and sex‐matched with eight healthy volunteers. The disease severity was assessed, and ECG, blood pressure and verapamil enantiomers concentrations were measured for 12 h post 80 mg oral verapamil. Serum interleukin‐6 (IL‐6) and nitrite (NO2–) were measured in predose samples.Results  IL‐6 and NO2– concentrations were significantly increased in parallel with disease severity. Oral clearance of both S‐ and R‐verapamil was significantly decreased by RA. While the unbound fraction of S‐ and R‐verapamil decreased by 5 and 7‐fold, respectively, the unbound AUC remained unchanged for the more potent enantiomer, S‐verapamil. AUC of norverapamil enantiomers was increased 2–3‐fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR‐interval was significantly reduced by one fold and the effect on the heart rate and blood pressure did not increase.Conclusions  RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic blood flow. A significant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro‐inflammatory cytokines and/or NO.
Patterns of prescription and drug use in ophthalmology in a tertiary hospital in Delhi
Authors: Biswas Nihar R. , Jindal Sanjay , Siddiquei M. Mairaj , Maini Rajiv 
Published: March 2003

Aims  The present study was carried out to describe the patterns of prescription and drug use in Ophthalmology in out‐patients at Dr Rajendra Prasad (R.P.) Centre for Ophthalmic Sciences of All India Institute of Medical Sciences (A.I.I.M.S.), New Delhi.Methods  Prescriptions of 1017 out‐patients were audited through a specially designed form and analysed for the following: average number of drugs per prescription, duration of treatment (recorded or not), dosage forms prescribed, frequency of administration (recorded or not), number of encounters with antibiotics and percentage of drugs prescribed by generic name.Results  Prescription analysis showed that the average number of drugs per prescription was 3.03. Duration of treatment was recorded for only 26.4% of the drugs prescribed. The maximum number of drugs prescribed were in the form of eye drops (76%), followed by tablets (10.9%), ointments (6.4%), syrups (1%), capsules (0.7%), lotions (0.3%) and injections (0.1%). No dosage form was recorded for 4.6% of the drugs prescribed. The frequency of administration was recorded for only 77.9% of the drugs prescribed. The number of antibiotics prescribed was 1059 which constitutes 34.2% of the total number of drugs prescribed. The percentage of drugs prescribed by generic name was only 35%.Conclusions  The results obtained in this study indicated an awareness of polypharmacy but a high incidence of common prescription writing errors such as not recording the duration of therapy, frequency of administration and dosage form. Moreover prescribing by generic name was also low.
A dose–response study of adrenaline combined with lignocaine 2%: effect on acute postoperative pain after oral soft tissue surgery
Authors: Jorkjend L. , Skoglund L. A. 
Published: March 2003

Aims  The combination of lignocaine and adrenaline may cause more postoperative pain than other types of local anaesthetic agents with comparable clinical efficacy. This study investigates the dose‐response effect of adrenaline added to lignocaine on postoperative pain, when used as local anaesthetic for oral soft tissue surgery.Methods  A controlled, randomized, double‐blind, parallel group study included 195 patients (108 females/87 males) with mean age 49 years (range 26–75 years). The patients were allocated to one of three treatment groups receiving lignocaine 2% (n = 66), lignocaine 2% with adrenaline 1 : 160 000 (n = 63) or lignocaine 2% with adrenaline 1 : 80 000 (n = 66).Results  Lignocaine 2% with adrenaline 1 : 80 000 gave significantly more pain intensity than lignocaine 2% or lignocaine 2% with adrenaline 1 : 160 000. The postoperative pain intensity courses after lignocaine 2% and lignocaine 2% with adrenaline 1 : 160 000 showed a similar pattern except for the time period just after completion of surgery when lignocaine 2% with adrenaline 1 : 80 000 caused less pain.Conclusions  High adrenaline concentrations (1 : 80 000) combined with lignocaine local anaesthetic solution offers no advantage with respect to pain alleviation during the immediate postoperative pain period. High exogenous adrenaline concentrations may play a significant role in enhancing acute postoperative intensity.
Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects
Authors: Lebrun‐Vignes B. , Archer V. Corbrion , Diquet B. , Levron J. C. , Chosidow O. , Puech A. J. , Warot D. 
Published: March 2003

Aims  Itraconazole is a potent inhibitor of CYP3A4 activity and is often used in combination with corticosteroids. Since the latter are partly metabolized by CYP3A4, we studied the interaction between itraconazole, prednisone and methylprednisolone in healthy male subjects.Methods  The effects of 4 days administration of oral itraconazole (400 mg on the first day then 200 mg day−1 for 3 days) on the pharmacokinetics of prednisolone after a single oral dose of prednisone (60 mg) and the pharmacokinetics of methylprednisolone after single oral dose of methylprednisolone (48 mg) were studied in 14 healthy male subjects in a two‐period cross‐over trial. Plasma cortisol concentrations were determined as a pharmacodynamic index.Results  Itraconazole increased the mean area under the methylprednisolone concentration‐time curve from 2773 ng ml−1 h to 7011 ng ml−1 h (P < 0.001) and the elimination half‐life from 3.2 h to 5.5 h (P < 0.001). The pharmacokinetics of prednisolone were unchanged. Cortisol concentrations at 24 h were lower after administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 ng ml−1vs 109 ng ml−1, P < 0.001).Conclusions  Itraconazole increased methylprednisolone concentrations markedly with enhanced suppression of endogenous cortisol secretion, but had no effect on prednisolone pharmacokinetics. The pharmacokinetic interaction between methylprednisolone and itraconazole is probably related to inhibition of hepatic CYP3A4 activity by itraconazole.