bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil
Authors: Tracy Timothy S. , Korzekwa Kenneth R. , Gonzalez Frank J. , Wainer Irving W.
Published: March 2003

Aims The present study was conducted to evaluate metabolism of the enantiomers of verapamil and norverapamil using a broad range of cytochrome P450 isoforms and measure the kinetic parameters of these processes.

Methods Cytochrome P450 cDNA‐expressed cells and microsomes from a P450‐expressed lymphoblastoid cell line were incubated with 40 μm concentrations of R‐ or S‐verapamil and R‐ or S‐norverapamil and metabolite formation measured by h.p.l.c. as an initial screening. Those isoforms exhibiting substantial activity were then studied over a range of substrate concentrations (2.5–450 μm ) to estimate the kinetic parameters for metabolite formation.

Results P450s 3A4, 3A5, 2C8 and to a minor extent 2E1 were involved in the metabolism of the enantiomers of verapamil. Estimated Km values for the production of D‐617 and norverapamil by P450 s 3A4 and 3A5 were similar (range=60–127 μm ) regardless of the enantiomer of verapamil studied while the Vmax estimates were also similar (range=4–8 pmol min−1 pmol−1 P450). Only nominal production of D‐620 by these isoforms was noted. Interestingly, P450 2C8 readily metabolized both S‐ and R‐verapamil to D‐617, norverapamil and PR‐22 with only slightly higher Km values than noted for P450s 3A4 and 3A5. However, the Vmax estimates for P450 2C8 metabolism of S‐ and R‐verapamil were in general greater (range=8–15 pmol min−1 pmol−1 P450) than those noted for P450 s 3A4 and 3A5 with preference noted for metabolism of the S‐enantiomer. Similarly, P450 s 3A4, 3A5 and 2C8 also mediated the metabolism of the enantiomers of norverapamil with minor contributions by P450 s 2D6 and 2E1. P450s 3A4 and 3A5 readily formed the D‐620 metabolite with generally a lower Km and higher Vmax for S‐norverapamil than for the R‐enantiomer. In contrast, P450 2C8 produced both the D‐620 and PR‐22 metabolites from the enantiomers of norverapamil, again with stereoselective preference seen for the S‐enantiomer.

Conclusions These results confirm that P450s 3A4, 3A5 and 2C8 play a major role in verapamil metabolism and demonstrate that norverapamil can also be further metabolized by the P450s.
Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion
Authors: Aswania  , Corlett  , Chrystyn
Published: March 2003

Aims To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler.

Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross‐over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method.

Results No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) μg, 10.4 (10.9) μg and 83.7 (71.1) μg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P<0.01) with 32.9 (14.5) μg, 61.2 (28.3) μg and 305.6 (82.3) μg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) μg, 49.3 (18.1) μg and 184.9 (98.4) μg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h.

Conclusions The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body following inhalation. Because of the lack of difference between the INH and INHC in the first 0.5 h, the use of activated charcoal is not necessary when this method is used to compare the relative lung bioavailability of different products or techniques.
Pharmacokinetics and haemodynamics of candesartan cilexetil in hypertensive patients on regular haemodialysis
Authors: Pfister Marc , Schaedeli Franziska , Frey Felix J. , Uehlinger Dominik E.
Published: March 2003

Aims The pharmacokinetic profile of candesartan cilexetil might be altered in patients with end‐stage renal disease (ESRD). No data are available about the pharmacokinetics and haemodynamics of the angiotensin II receptor antagonist candesartan cilexetil in ESRD patients on regular haemodialysis (HD).

Methods We performed a repeated dose study (8 mg candesartan cilexetil once daily) in eight male HD patients over a treatment period of 5 days with an additional observation period of 3 days.

Results Pharmacokinetic analysis with nonlinear mixed effects modeling (NONMEM) over the whole treatment period revealed a dependency of the volume of distribution on body weight and of the metabolic clearance on age and body weight in the studied population. No significant drug elimination by HD was observed. The estimated metabolic and intercompartmental clearances were 83 ml min−1 (CV 39%) and 9.9 ml min−1, respectively. The unexplained random variability of the final two compartment model was 30%. In one patient with adult polycystic kidney disease oral clearance decreased during the observation period, attributable to a significant increase in bioavailability. Maximum observed changes in blood pressure were −50/−27±14/8 mmHg on day 5 with haemodialysis therapy as compared with changes in blood pressure of −14/−12±14/8 mmHg on day 1 without haemodialysis treatment. The observed maximum decrease in systolic blood pressure correlated with the amount of ultrafiltration during the HD session on day 5 (r=0.70, P<0.05). In two patients, one of whom was binephrectomized, severe hypotensive episodes were observed during this HD session.

Conclusions HD does not influence the elimination kinetics of candesartan. The observed inter‐ and intraindividual variability of oral clearance and the pronounced influence of HD‐induced volume contraction on the haemodynamic effects of candesartan makes it mandatory to carefully monitor HD patients treated with candesartan cilexetil.
The nasal airways response in normal subjects to oxymetazoline spray: randomized double‐blind placebo‐controlled trial
Authors: Bickford Larissa , Shakib Sepehr , Taverner David
Published: March 2003

Aims The effects of a single dose of oxymetazoline nasal spray on nasal patency have been compared with placebo using three separate measuring systems in normal subjects.

Methods The study was a placebo‐controlled, randomised double‐blind crossover trial. Subjects without ear, nose or throat disease and with resting nasal airways resistance >0.15 Pa s cm−3 were selected so that a fall in airways resistance could be detected. Nasal airways resistance (NAR) was measured by NR6–2 rhinomanometer. Acoustic rhinometry (SR‐2000 rhinometer) provided the sum of the minimum cross‐sectional areas (tMCA) and volume (tVOL) of the left and right nasal cavities. Symptoms of congestion were assessed on a visual analogue scale (CON, range 0–100). Measurements were made for 60 min before and for 120 min after bilateral administration of oxymetazoline nasal spray (0.9 mg) or placebo (0.9% saline). Crossover occurred 7–21 days later. Results for all measures were analysed as change from average baseline value by trapezoidal AUC, and statistical significance was tested by 2‐way anova.

Results NAR, tMCA, tVOL and CON did not change after placebo, but NAR and CON fell and tMCA and tVOL increased significantly at all timepoints after oxymetazoline. NAR_AUC, tVOL_AUC, tMCA_AUC were significantly different between placebo and oxymetazoline (P<0.001) as was CON_AUC (P=0.012). The day‐to‐day intraindividual repeatability of baseline NAR tMCA and tVOL was <10%.

Conclusions Normal subjects can be used to detect the effects of nasally vasoactive drugs with a variety of complementary systems, with the advantages of easy subject recruitment and low variability.
Auditory and electroencephalographic effects of midazolam and α‐hydroxy‐midazolam in healthy subjects
Authors: Hotz Michel A. , Ritz Rudolf , Linder Lilly , Scollo‐Lavizzari Giuseppe , Haefeli Walter E.
Published: March 2003

Aims Whereas cortical EEG effects of benzodiazepines are well characterized, information about benzodiazepine effects in other areas of the central nervous system is sparse. This study investigated the action of midazolam and its active metabolite α‐hydroxy‐midazolam on different parts of the auditory pathway in six healthy volunteers in a randomized, double‐blind, three‐way cross‐over study.

Methods Acoustically evoked short (SLP) and middle (MLP) latency potentials, transitory evoked otoacoustic emissions (TEOAE), and EEG power spectra were analysed after short i.v. injections of placebo, or 0.15 mg kg−1 midazolam, or α‐hydroxy‐midazolam, respectively.

Results All subjects fell asleep during the 4 min infusion of active drug. SLP showed a significant transient increase of Jewett wave V 10 min after injection for midazolam and α‐hydroxy‐midazolam while the latency of wave I was unchanged. Both benzodiazepines induced a marked and long‐lasting MLP amplitude decrease for 240 min with slow recovery over the following 360 min. No changes of TEOAE were observed. In agreement with earlier reports, increases in EEG beta activity and decreases in alpha activity were observed after administration of either drug.

Conclusions Systemically administered benzodiazepines modulate the auditory pathway above the level of the cochlea. While SLP changes were closely associated with sedation and high plasma benzodiazepine concentrations, MLP effects persisted for hours after sedation even at low benzodiazepine plasma levels. Evoked potentials may therefore be more sensitive than EEG as a tool to monitor benzodiazepine effects.
Dramatic inhibition of amiodarone metabolism induced by grapefruit juice
Authors: Libersa, Christian C. , Brique Serge A. , Motte Kokou B. , Caron Jacques F. , Guédon‐moreau Laurence M. , Humbert Luc , Vincent A. , Devos Patrick , Lhermitte Michel A.
Published: March 2003

Aims  Grapefruit juice increases blood concentrations of many drugs metabolized by CYP3A. Amiodarone is metabolized by CYP3A to N‐desethylamiodarone (N‐DEA). The aim of this study was to determine amiodarone kinetics when administrated with and without grapefruit juice.

Methods  Eleven healthy adult volunteers took part in a single sequence, repeated‐measures design study. Each subject, who had been evaluated 6 months previously for amiodarone pharmacokinetics, was given a single oral dose of amiodarone (17 mg kg−1) with three glasses of 300 ml of grapefruit juice on the same day.

Results  Grapefruit juice completely inhibited the production of N‐DEA, the major metabolite of amiodarone, in all subjects and increased the area‐under‐the‐curve (AUC) and maximum concentration of amiodarone (Cmax) by 50% and 84%, respectively, as compared with the control period during which water had been administrated instead of grapefruit juice (AUC: 35.9 ± 14.3 vs 23.9 ± 11.2 µg ml−1 h, P < 0.005 and Cmax: 3.45 ± 1.7 vs 1.87 ± 0.6 µg ml−1, P < 0. 02, respectively) (means ± s.d.). This inhibition of N‐DEA production led to a decrease in the alterations caused by amiodarone on PR and QTc intervals.

Conclusions  Grapefruit juice dramatically alters the metabolism of amiodarone with complete inhibition of N‐DEA production. These results are in agreement with in vitro data pointing to the involvement of CYP3 A in the metabolism of amiodarone and suggests that this interaction should be taken into account when prescribing this antiarrhythmic drug.
Lack of adherence to lipid‐lowering drug treatment. A comparison of utilization patterns in defined populations in Funen, Denmark and Bologna, Italy
Authors: Larsen John , Vaccheri Alberto , Andersen Morten , Montanaro Nicola , Bergman Ulf
Published: March 2003

Aims The objective was to explore differences in lipid‐lowering drug (LLD) prescribing in Italy and Denmark.

Methods We used two geographical areas with computerized drug prescription records in defined populations, one in Funen, Denmark with 500 000 inhabitants, the other in Bologna, Italy with 400 000 inhabitants. Prescriptions for patients who had purchased a LLD from 1994 until 1996 were retrieved as well as coprescriptions of antidiabetic and cardiovascular drugs as markers for diabetes and cardiovascular disease. Only patients surviving and remaining in the area were included. Compliance was defined as percentage of DDDs purchased divided by the number of days within the time window. The limit between good and poor compliance was set at 82%.

Results In Bologna, LLD consumption measured in DDD increased by 41% and in Funen by 129%. Annual prevalence increased from 36.9 to 46.3 users/1000 inhabitants from 1994 to 1996 and from 3.2 to 6.6 users/1000 inhabitants in Bologna and Funen, respectively. From 1995 to 1996, the incidence of use decreased slightly in Bologna from 19.3 to 18.8/1000 inhabitants/year, whereas in Funen the incidence increased from 1.8 to 2.3/1000 inhabitants/year. In Bologna 48% and in Funen 91% of users persisted with treatment for 2 years or longer. In Bologna, 7% and in Funen 45% were good compliers. In Bologna, 61% and in Funen, 72% received other drugs indicating cardiovascular or diabetic comorbidity.

Conclusions Patterns of use differed substantially between the two areas. In contrast with Funen, where long‐term use was common, Bologna LLD use was sporadic. Based on a higher rate of coprescription, LLDs seemed to be used for secondary prevention to a higher extent in Funen than in Bologna. In Funen it appeared that the correct patients, but an insufficient number of them, were being treated adequately according to guidelines. The higher discontinuation rate of lipid lowering drugs in the Bologna area indicates that a large proportion of patients use these drugs for too short a period of time to benefit from treatment. Since society’s health care resources are limited it is difficult to justify public funding of these medications without at the same time giving appropriate attention to these problems.
Validation of a population pharmacokinetic model for adjunctive lamotrigine therapy in children
Authors: Chen Chao
Published: March 2003

Aims
This analysis was performed to validate a previously developed population pharmacokinetic model for lamotrigine in order to establish a basis for dosage recommendations for children.

Methods
(a) The importance of the covariates in the final model was confirmed using the model validation dataset. Population and individual (Bayesian estimate) pharmacokinetic parameters were estimated using both the initial model, which included none of the covariates, and the final model. Accuracy and precision of parameter estimation and of concentration prediction were compared between the two models. (b) The performance in predicting the validation concentrations by the final model parameters obtained previously from the model development dataset was assessed. (c) The parameters of the final model were refined using a dataset combining both the development and validation data.

Results
Prediction performance of the final pharmacostatistical model was superior to that of the initial model. The results of the validation confirmed that concomitant antiepileptic drugs that increased or reduced lamotrigine clearance in adults had similar effects in children. The validation also verified the linear relationship between weight and clearance. The previously seen small sex effect on clearance was found statistically insignificant.

Conclusions
The current analysis confirmed the previous findings. To achieve the same concentrations, children receiving enzyme‐inducing antiepileptic drugs without valproate require higher doses than those receiving valproate; and heavier children require higher doses.
Effects of a medicine review and education programme for older people in general practice
Authors: Lowe Catherine J. , Raynor David K. , Purvis John , Farrin Amanda , Hudson Jocelyn
Published: March 2003

Aims
To determine whether a medicine review and education programme influences the compliance and knowledge of older people in general practice.

Methods
Older people taking at least three medicines were randomly allocated to a control or intervention group. Both groups received three visits from a clinical pharmacist:

Visit 1: Assessment and patients' medicines rationalized in intervention group.

Visit 2: Intervention group given medicines education.

Visit 3: Knowledge and compliance in both groups assessed by structured questionnaire

Results
Compliance in the intervention group was 91.3%, compared with 79.5% in the control group (P < 0.0001). The number of intervention group patients correctly understanding the purpose of their medicines increased from 58% to 88% on the second visit, compared with 67% to 70% in the control group (P < 0.0005).

Conclusions
A general practice based medication review and education programme improved medicine compliance and knowledge of older people in the short term.
Effects of policosanol treatment on the susceptibility of low density lipoprotein (LDL) isolated from healthy volunteers to oxidative modification in vitro
Authors: Menéndez Roberto , Más Rosa , Amor Ana MA. , González Rosa MA. , Fernández Julio C. , Rodeiro Idania , Zayas Mirta , Jiménez Sonia
Published: March 2003

Aims
The aim of this study was to investigate the effect of policosanol on the susceptibility of LDL‐C to in vitro lipid peroxidation in human healthy volunteers.

Methods
The effect of policosanol (5 and 10 mg day−1) on LDL‐C oxidation was studied in a double‐blind, randomized, placebo‐controlled trial conducted in 69 subjects. LDL‐C samples isolated at baseline and after 8 weeks were subjected to in vitro tests of LDL‐C oxidation. We tested the susceptibility of LDL‐C to lipid peroxidation in a cell‐free system by the addition of copper ions as well as in a more physiological system, macrophage‐mediated oxidation.

Results
At baseline all groups were well matched regarding all variables. After 8 weeks of therapy policosanol administered at 5 and 10 mg, significantly and in a dose‐dependent manner increased the lag phase of conjugated diene generation (mean ± s.d.) from 83.79 ± 29.16 min to 94.90 ± 25.50 min (5 mg day−1) and from 82.74 ± 17.16 min to 129.89 ± 35.71 min (10 mg day−1), while in the placebo group LDL‐C oxidation did not change significantly. Policosanol (10 mg day−1), but not placebo, significantly decreased the rate of conjugated diene generation. Comparison with placebo after therapy also showed significant differences. Macrophage mediated‐oxidation was also inhibited by policosanol as evident by measuring thiobarbituric acid reactive substances (TBARS). Policosanol (10 mg day−1) significantly lowered malondialdehyde (MDA) generation from 8.50 ± 0.91 to 5.76 ± 1.01 nmol mg−1 protein. Comparison with placebo after 5 and 10 mg day−1 showed significant differences. Policosanol significantly lowered total cholesterol by 10.5% (5 mg day−1) and 12.4% (10 mg day−1) and LDL‐C by 16.7% and 20.2%, respectively. Also, policosanol (10 mg day−1) increased HDL‐C by 15.2%. Five subjects withdrew from the study, none because of adverse experiences. No clinical or blood biochemical drug‐related disturbances were found.

Conclusions
The present study demonstrated that policosanol administered within its therapeutic dosage for lowering cholesterol (5 and 10 mg day−1), decreased the susceptibility of LDL‐C to lipid peroxidation in vitro.
In vitro evaluation of potential in vivo probes for human flavin‐containing monooxygenase (FMO): metabolism of benzydamine and caffeine by FMO and P450 isoforms
Authors: Lang Dieter H. , Rettie Allan E.
Published: March 2003

Aims
To determine the FMO and P450 isoform selectivity for metabolism of benzydamine and caffeine, two potential in vivo probes for human FMO.

Methods
Metabolic incubations were conducted at physiological pH using substrate concentrations of 0.01–10 m
m with either recombinant human FMOs, P450s or human liver microsomes serving as the enzyme source. Products of caffeine and benzydamine metabolism were analysed by reversed‐phase h.p.l.c. with u.v. and fluorescence detection.

Results
CYP1A2, but none of the human FMOs, catalysed metabolism of caffeine. In contrast, benzydamine was a substrate for human FMO1, FMO3, FMO4 and FMO5. Apparent Km values for benzydamine N‐oxygenation were 60 ± 8 µm, 80 ± 8 µm, > 3 m
m and > 2 m
m, for FMO1, FMO3, FMO4 and FMO5, respectively. The corresponding Vmax values were 46 ± 2 min−1, 36 ± 2 min−1, < 75 min−1 and < 1 min−1. Small quantities of benzydamine N‐oxide were also formed by CYPs 1A1, 1A2, 2C19, 2D6 and 3A4.

Conclusions
FMO1 and FMO3 catalyse benzydamine N‐oxygenation with the highest efficiency. However, it is likely that the metabolic capacity of hepatic FMO3 is a much greater contributor to plasma levels of the N‐oxide metabolite in vivo than is extrahepatic FMO1. Therefore, benzydamine, but not caffeine, is a potential in vivo probe for human FMO3.
Research Methods in Human Cardiovascular Pharmacology edited by Dr S. Maxwell and Prof. D. Webb Flow‐mediated dilatation
Authors: Raitakari Olli T. , Celermajer David S.
Published: March 2003

Arterial endothelial dysfunction is one of the key early events in atherogenesis, preceding structural atherosclerotic changes. It is also important in the late stages of obstructive atherosclerosis, predisposing to constriction and/or thrombosis. Endothelial function can be measured in coronary arteries and in the periphery by measuring vasomotor function after intra‐arterial infusion of pharmacologic substances which enhance the release of endothelial nitric oxide. The disadvantage of these methods is their invasive nature, which generally makes them unsuitable for studies involving asymptomatic subjects. For this reason, noninvasive tests of endothelial function have been developed. In the most widely used of these, an ultrasound‐based method, arterial diameter is measured in response to an increase in shear stress, which causes endothelium‐dependent dilatation. Endothelial function assessed by this method correlates with invasive testing of coronary endothelial function, as well as with the severity and extent of coronary atherosclerosis. This noninvasive endothelial function testing has provided valuable insights into early atherogenesis, as well as into the potential reversibility of endothelial dysfunction by various strategies, including pharmacological agents (lipid lowering, ACE inhibition), l‐arginine, antioxidants and hormones.
Benzydamine N‐oxidation as an index reaction reflecting FMO activity in human liver microsomes and impact of FMO3 polymorphisms on enzyme activity
Authors: Störmer Elke , Roots Ivar , Brockmöller Jürgen
Published: March 2003

Aims  The role of flavin containing monooxygenases (FMO) on the disposition of many drugs has been insufficiently explored. In vitro and in vivo tests are required to study FMO activity in humans. Benzydamine (BZD) N‐oxidation was evaluated as an index reaction for FMO as was the impact of genetic polymorphisms of FMO3 on activity.

Methods
 BZD was incubated with human liver microsomes (HLM) and recombinant enzymes. Human liver samples were genotyped using PCR‐RFLP.

Results

 BZD N‐oxide formation rates in HLM followed Michaelis‐Menten kinetics (mean Km = 64.0 µm, mean Vmax= 6.9 nmol mg−1 protein min−1; n = 35). N‐benzylimidazole, a nonspecific CYP inhibitor, and various CYP isoform selective inhibitors did not affect BZD N‐oxidation. In contrast, formation of BZD N‐oxide was almost abolished by heat treatment of microsomes in the absence of NADPH and strongly inhibited by methimazole, a competitive FMO inhibitor. Recombinant FMO3 and FMO1 (which is not expressed in human liver), but not FMO5, showed BZD N‐oxidase activity. Respective Km values for FMO3 and FMO1 were 40.4 µm and 23.6 µm, and respective Vmax values for FMO3 and FMO1 were 29.1 and 40.8 nmol mg−1 protein min−1. Human liver samples (n = 35) were analysed for six known FMO3 polymorphisms. The variants I66M, P135L and E305X were not detected. Samples homozygous for the K158 variant showed significantly reduced Vmax values (median 2.7 nmol mg−1 protein min−1) compared to the carriers of at least one wild type allele (median 6.2 nmol mg−1 protein min−1) (P < 0.05, Mann–Whitney‐U‐test). The V257M and E308G substitutions had no effect on enzyme activity.

Conclusions

 BZD N‐oxidation in human liver is mainly catalysed by FMO3 and enzyme activity is affected by FMO3 genotype. BZD may be used as a model substrate for human liver FMO3 activity in vitro and may be further developed as an in vivo probe reflecting FMO3 activity.
The pharmacokinetics of methadone in HIV‐positive patients receiving the non‐nucleoside reverse transcriptase inhibitor efavirenz
Authors: Clarke Susan M. , Mulcahy Fiona M. , Tjia John , Reynolds Helen E. , Gibbons Sara E. , Barry Michael G. , Back David J.
Published: March 2003

Aims  Methadone is predominantly metabolized by cytochrome P450 3A4 and the non nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is a recognized inducer of this enzyme. We evaluated the pharmacokinetics of methadone in the presence and absence of efavirenz when administered to HIV infected patients with a history of injection drug use (IDU).

Methods  Eleven patients on stable methadone maintenance therapy, due to commence antiretroviral therapy (ART), participated in this study. Steady state methadone kinetic profiles were obtained on two occasions 0, 1, 2, 3, 4, 5, 6, 7, 8 and 24 h post dosing. Following centrifugation, separated plasma was heated at 58 °C for 30 min to inactivate HIV and stored at −80 °C until methadone analysis by high performance liquid chromatography.

Results  When combined with efavirenz there was a marked decrease in the maximum plasma concentration (Cmax) of methadone from 689 (range 212–1568) to 358 (range 205–706) ng ml−1, P = 0.007 : 95% confidence interval (CI) 112–549. The mean area under the methadone concentration curve 0–24 h (AUC(0,24 h)) was also significantly reduced from 12341 (range 3682–34147) to 5309 (range 2430–10349) ng ml−1 h in the presence of efavirenz, P = 0.012 : 95% CI 1921–12143. Nine patients described symptoms of methadone withdrawal and received a dose increase. Although methadone AUC(0,24 h) was reduced by over 50% following efavirenz the mean increase in methadone dose required was 22% (range 15–30 mg).

Conclusion  The inclusion of the NNRTI efavirenz in once daily ART for HIV patients with a history of IDU receiving methadone maintenance results in a significant reduction in methadone plasma concentrations mediated by enzyme induction. It is important to distinguish efavirenz neurological effects which were observed between days 1–5 of therapy from symptoms of methadone withdrawal which occurred from day 8 onwards. The dose of methadone was adjusted by increments of 10 mg to counteract the efavirenz inducing effect.
Cost of prescribed NSAID‐related gastrointestinal adverse events in elderly patients
Authors: Rahme Elham , Joseph Lawrence , Kong Sheldon X. , Watson Douglas J. , LeLorier Jacques
Published: March 2003

Aims It is well established that nonsteroidal anti‐inflammatory drugs (NSAIDs) have gastrointestinal (GI) side‐effects. However, the cost of health care resources spent on preventing and managing these side‐effects is not clear. The objective of this study was to estimate the direct cost of NSAID‐related GI events in an elderly population.

Methods
From the Régie de l'assurance‐maladie du Québec (RAMQ) database, we obtained medical, pharmaceutical and demographic records of a 10% random sample (n = 49 033) of seniors who, between January 1, 1993 and December 31, 1997, had a dispensed prescription of a NSAID. Patients who did not have any GI events during the year prior to their first dispensed prescription were included in the cohort. All patients were followed‐up for 2 years. The daily direct Canadian dollar costs of GI events that were incurred by these patients while they were on NSAID therapy were compared with those of GI events that were incurred by these same patients while they were not on NSAID therapy. The difference in these daily costs was attributed to NSAIDs.

Results A total of 12 082 new NSAID users were included in the study. Two hundred and seventeen (1.8%) were hospitalized for GI‐related problems; of these, 130 (60%) had their GI hospitalization as their first GI event; 3257 (27.0%) used gastroprotective agents (GPAs), and 857 (26.3%) took GPAs without any apparent prior GI symptoms; 801 (6.6%) had GI diagnostic tests; and 661 (5.5%) died. The average direct costs of GI side‐effects per patient‐day on NSAIDs were 3.5 times higher than those of a patient‐day not on NSAIDs. The direct cost of GI side‐effects per patient‐day on NSAIDs was $1.34, of which more than 70% ($0.94) was attributed to GI events resulting from NSAID treatment.

Conclusions Approximately one Canadian dollar was added to patient costs for every day he/she was on NSAID therapy. Safer therapies and appropriate patient risk management may potentially reduce NSAID‐related health care resource use.
The effect of anastrozole on the single‐dose pharmacokinetics and anticoagulant activity of warfarin in healthy volunteers
Authors: Yates R. A. , Wong J. , Seiberling M. , Merz M. , März W. , Nauck M.
Published: March 2003

Aims  The aims of this study were to determine the effects of the nonsteroidal, selective aromatase inhibitor, anastrozole, at steady‐state concentrations, on the pharmacokinetics and pharmacodynamics of warfarin, and to assess whether or not anastrozole alone has any anticoagulant activity.

Methods  This was a randomized, double‐blind, placebo‐controlled, two‐way crossover trial conducted at a single centre. The study comprised two treatment periods of 11 days, separated by a 3 week washout. Healthy male volunteers (n = 16, median age 28.5 years) were randomized to receive either anastrozole (7 mg loading dose on day 1, followed by 1 mg daily on days 2–11) in the first treatment period and placebo in the second treatment period, or vice versa. In addition to their randomized treatment, all volunteers received a single dose of 25 mg warfarin on day 3 of each treatment period. Blood samples for pharmacokinetic and pharmacodynamic assessment were taken at frequent intervals during each treatment period. The safety of volunteers was monitored throughout the study.

Results  Administration of anastrozole resulted in no clinically significant changes in the pharmacokinetics of either R‐ or S‐warfarin compared with placebo for AUC (ng ml−1 h) (glsmean, R‐warfarin; anastrozole 93619.9, placebo 91127.91, 95%CI 0.988–1.068; S‐warfarin; anastrozole 57129.21, placebo 55676.34, 95%CI 0.979–1.076), CL/F (ml min−1) (glsmean, R‐warfarin; anastrozole 2.23, placebo 2.29, 95%CI 0.937–1.012; S‐warfarin; anastrozole 3.65, placebo 3.74, 95%CI 0.929–1.021) and t1/2 (h) (lsmean, R‐warfarin; anastrozole 55.40, placebo 55.15, 95%CI−2.083–2.592; S‐warfarin; anastrozole 39.38, placebo 40.98, 95%CI−6.189–2.996). In addition, anastrozole had no clinically significant effect on the pharmacodynamic effects of warfarin, as assessed 240 h after warfarin dosing by measurement of prothrombin time (s) (glsmean, anastrozole 11.56, placebo 11.31, 95%CI 0.987–1.059), thrombin time (s) (glsmean, anastrozole 19.06, placebo 18.75, 95%CI 0.980–1.054) activated partial thromboplastin time (s) (glsmean, anastrozole 29.94, placebo 29.74, 95%CI 0.968–1.047) and factor VII (%) (glsmean, anastrozole 97.81, placebo 107.26, 95%CI 0.821–1.012). Anastrozole alone had no effect on these indicators of the clotting process.

Conclusions  Overall, there was no evidence to suggest that anastrozole has any clinically relevant effects on the pharmacokinetics of warfarin. Anastrozole had no effect on clotting mechanisms or on the pharmacodynamic activity of warfarin, as assessed by prothrombin time, thrombin time, activated partial thromboplastin time, and factor VII.
A single dose of methadone inhibits cytochrome P‐4503A activity in healthy volunteers as assessed by the urinary cortisol ratio
Authors: Boulton David W. , Arnaud Philippe , DeVane C. Lindsay
Published: March 2003

Aims  To examine the effect of a single oral dose of methadone on cytochrome P450 (CYP) 3A activity using the urinary 6β‐hydroxycortisol to cortisol ratio (UCR) as a marker of CYP3A activity.

Methods  A single oral dose (0.2 mg kg−1) of rac‐methadone was administered to eight healthy female volunteers. Frequent blood samples and all urine over seven time periods was collected for 96 h following dosing. The UCR and the concentration of the major CYP3A metabolite of methadone, EDDP, were measured in urine. Methadone enantiomer concentrations were determined in plasma and urine. All quantifications were performed by validated high performance liquid chromatography assays.

Results  In all volunteers a significant decline of the UCR from immediately predose values was observed at the 4–8 and 8–12 h collection periods (P < 0.05, 95% CI for the differences: 0.4,16 and 0.6,16, respectively) with a return to immediately predose values after 2–3 days, suggesting methadone was an inhibitor of CYP3A. The UCR was found to be significantly correlated with the amount of EDDP excreted in the urine and with the area under the plasma concentration vs time profile for total (R + S) methadone, supporting in vitro data that CYP3A is primarily responsible for EDDP formation and has a significant influence on methadone disposition.

Conclusions  Methadone appears to be a CYP3A inhibitor in vivo following a single oral dose and measurements of the urinary cortisol ratio appear to be a useful index to follow this inhibition.
Interim analyses and sequential designs in phase III studies
Authors: Todd Susan , Whitehead Anne , Stallard Nigel , Whitehead John
Published: March 2003

Recruitment of patients to a clinical trial usually occurs over a period of time, resulting in the steady accumulation of data throughout the trial's duration. Yet, according to traditional statistical methods, the sample size of the trial should be determined in advance, and data collected on all subjects before analysis proceeds. For ethical and economic reasons, the technique of sequential testing has been developed to enable the examination of data at a series of interim analyses. The aim is to stop recruitment to the study as soon as there is sufficient evidence to reach a firm conclusion. In this paper we present the advantages and disadvantages of conducting interim analyses in phase III clinical trials, together with the key steps to enable the successful implementation of sequential methods in this setting. Examples are given of completed trials, which have been carried out sequentially, and references to relevant literature and software are provided.
Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers
Authors: Khaliq Yasmin , Gallicano Keith , Tisdale Christine , Carignan Germain , Cooper Curtis , McCarthy Anne
Published: March 2003

Aims  To evaluate the pharmacokinetic interaction between ritonavir and mefloquine.

Methods  Healthy volunteers participated in two separate, nonfasted, three‐treatment, three‐period, longitudinal pharmacokinetic studies. Study 1 (12 completed): ritonavir 200 mg twice daily for 7 days, 7 day washout, mefloquine 250 mg once daily for 3 days then once weekly for 4 weeks, ritonavir restarted for 7 days simultaneously with the last mefloquine dose. Study 2 (11 completed): ritonavir 200 mg single dose, mefloquine 250 mg once daily for 3 days then once weekly for 2 weeks, ritonavir single dose repeated 2 days after the last mefloquine dose. Erythromycin breath test (ERMBT) was administered with and without drug treatments in study 2.

Results  Study 1: Ritonavir caused less than 7% changes with high precision (90% CIs: −12% to 11%) in overall plasma exposure (AUC(0,168 h)) and peak concentration (Cmax) of mefloquine, its two enantiomers, and carboxylic acid metabolite, and in the metabolite/mefloquine and enantiomeric AUC ratios. Mefloquine significantly decreased steady‐state ritonavir plasma AUC(0,12 h) by 31%, Cmax by 36%, and predose levels by 43%, and did not affect ritonavir binding to plasma proteins. Study 2: Mefloquine did not alter single‐dose ritonavir pharmacokinetics. Less than 8% changes in AUC and Cmax were observed with high variability (90%CIs: −26% to 45%). Mefloquine had no effect on the ERMBT whereas ritonavir decreased activity by 98%.

Conclusions  Ritonavir minimally affected mefloquine pharmacokinetics despite strong inhibition of CYP3A4 activity from a single 200 mg dose. Mefloquine had variable effects on ritonavir pharmacokinetics that were not explained by hepatic CYP3A4 activity or ritonavir protein binding.
The effect of rizatriptan, ergotamine, and their combination on human peripheral arteries: a double‐blind, placebo‐controlled, crossover study in normal subjects
Authors: Tfelt‐Hansen Peer , Seidelin Kaj , Stepanavage Michael , Lines Christopher
Published: March 2003

Aims  To compare the peripheral vasoconstrictor effects of ergotamine, rizatriptan, and their combination, in normal subjects.

Methods  This was a double‐blind, four‐way, crossover study. Sixteen young male volunteers, selected as responders to the vasoconstrictor effect of 0.5 mg ergotamine i.v., were administered 10 mg oral rizatriptan, 0.25 mg i.v. ergotamine, 10 mg oral rizatriptan+0.25 mg i.v. ergotamine, and placebo. The vasoconstrictor effect on peripheral arteries was measured with strain gauge plethysmography up to 8 h after dosing. The 8 h assessment period was divided into two 4 h intervals to assess the immediate (0–4 h) vs sustained effect (4–8 h) of treatment.

Results  For the 0–4 h interval, the decreases in peripheral systolic blood pressure gradients were: placebo (−1 mmHg [95% CI: −3, 1])<rizatriptan (−5 mmHg [95% CI: −7, −3])<ergotamine (−15 mmHg [95% CI: −16, −13])=rizatriptan+ergotamine (−15 mmHg [95% CI: −17, −13]). For the 4–8 h interval, the decreases were: placebo (−5 mmHg [95% CI: −8, −3])=rizatriptan (−8 mmHg [95% CI: −11, −5])<ergotamine (−26 mmHg [95% CI: −29, −24])=rizatriptan+ergotamine (−28 mmHg [95% CI: −31, −26]).

Conclusions  In normal subjects, rizatriptan 10 mg orally had only a small transient vasoconstrictor effect on peripheral arteries compared with the sustained and more pronounced effect of 0.25 mg i.v. ergotamine. Furthermore, rizatriptan exerted no additional effect on ergotamine‐induced constriction of peripheral arteries when the two drugs were given in combination.
Association between antidepressant drug use and hyponatraemia: a case‐control study
Authors: Movig Kris L. L. , Leufkens Hubert G. M. , Lenderink Albert W. , Van Den Akker Veronique G. A. , Hodiamont Paul P. G. , Goldschmidt Henk M. J. , Egberts Antoine C. G.
Published: March 2003

Aims  To estimate the risk of, and risk factors for, hyponatraemia associated with the use of selective serotonin reuptake inhibitors (SSRIs) compared with the use of other antidepressant drugs.

Methods  A case‐control study of psychiatric in‐ and out‐patients on antidepressant drugs performed in the mid‐southern part of The Netherlands over a 2 year period. Cases (n=29) were all using antidepressant drugs with a serum sodium concentration of ≤130 mmol l−1 while controls (n=78) were patients on antidepressants with a normal sodium concentration (136–144 mmol l−1). Information on blood sodium concentrations was obtained from clinical chemistry data while information on drug use was obtained from community and hospital pharmacy databases. Medical records were used to ascertain possible risk and confounding factors. Unconditional multivariate logistic regression was used to estimate odds ratios for hyponatraemia in patients on SSRIs compared with patients on other antidepressant drugs.

Results  SSRIs were associated with an increased risk of hyponatraemia (OR 3.3; 95% CI 1.3, 8.6) compared with other classes of antidepressant drugs. Stratified and interaction analyses revealed that elderly patients using diuretics concomitantly with SSRIs were at the highest risk of experiencing hyponatraemia (OR 13.5; 95% CI 1.8, 101).

Conclusions  SSRIs are more frequently associated with hyponatraemia than other classes of antidepressant drugs. This adverse drug reaction was more common in older patients (≥65 years) and in those using diuretics.
The bioavailability and pharmacokinetics of subcutaneous, nebulized and oral morphine‐6‐glucuronide
Authors: Penson Richard T. , Joel Simon P. , Roberts Michael , Gloyne Anna , Beckwith Stephen , Slevin Maurice L.
Published: March 2003

Aims  Morphine‐6‐glucuronide (M6G), one of the active metabolites of morphine, has attracted considerable interest as a potent opioid analgesic with an apparently superior therapeutic index. To date studies have used the intravenous route, which is generally unacceptable in the treatment of cancer related pain. The aim of this study was to define the pharmacokinetics, toxicity and cardio‐respiratory effects of three alternative routes of administration of M6G.

Methods  Ten healthy volunteers participated in an open randomized study. Subjects received M6G 2 mg as an intravenous bolus, 20 mg orally, 2 mg subcutaneously and 4 mg by the nebulized route. Pulse, blood pressure, respiratory rate and peak flow rate were monitored and subjective toxicity recorded on rating and visual analogue scales.

Results  After i.v. M6G the mean (±s.d.) AUC(0,∞) standardized to a dose of 1 mg was 223±57 nmol l−1 h, mean elimination half‐life was 1.7±0.7 h and the mean clearance was 157±46 ml min−1. These parameters were virtually identical after subcutaneous administration which had a bioavailability (F(0,∞)) of 102±35% (90% CI 82, 117%) and tmax of 0.5±0.2 h. The mean bioavailability of nebulized M6G was 6±2% (90% CI 4, 7%) with a tmax of 1.2±0.8 h. Following oral M6G two plasma M6G peaks were seen in 7 of the 10 subjects, the first with a tmax of 3.1 (±0.9) h. The second peak had a tmax of 13.4 (±5.0) h, started approximately 4 h after dosing, and was associated with the detection of plasma M3G and morphine, suggesting that M6G was significantly hydrolysed in the gut to morphine, which was then glucuronidated following absorption. Although the overall mean bioavailability was 11±3% (90% CI 9, 12%), confining the analysis to data from the first peak suggested a bioavailability of directly absorbed M6G of only 4±4%. Apart from a characteristic dysphoria following intravenous and subcutaneous M6G, there was no significant toxicity.

Conclusions  With the minimal toxicity reported in this and previous studies, subcutaneous infusion of M6G may potentially provide clinically useful analgesia for advanced cancer pain. Nebulized M6G is not significantly absorbed via the lungs, and if opiates are shown to have a local effect in the lung, reducing the sensation of breathlessness, then nebulized administration is likely to minimize systemic effects. Oral M6G has poor bioavailability, but is significantly hydrolysed in the gut to morphine, which is subsequently glucuronidated following absorption. This circuitous route accounts for the majority of systemically available M6G after oral administration.
High persistence of statin use in a Danish population: Compliance study 1993–1998
Authors: Larsen John , Andersen Morten , Kragstrup Jakob , Gram Lars F.
Published: March 2003

Aims  Several studies have found that compliance with lipid‐lowering drug (LLD) treatment is low. However, the results of these studies were based on crude measures of compliance. The aim of this study was to describe compliance with statin treatment by analysing prescription patterns on an individual level in a population‐based prescription database over a 6 year period.

Methods  For incident statin users, all prescriptions for statins and drugs indicating cardiovascular disease or diabetes were retrieved from the OPED prescription database covering a population of about 470 000 inhabitants. Treatment was considered discontinued if the interval between two prescriptions exceeded number of tablets prescribed, plus 30 days. Compliance was assessed in terms of persistence and continuity. Persistence was defined as the period from the first prescription date to the date of discontinuation. Continuity was defined as the number of days with treatment (=number of tablets) divided by the total number of days in the period of persistence.

Results  11% of the study cohort only received a single statin prescription. Survival analyses revealed a median persistence of 41 months. Less than 15% of the patients had more than 20% days without therapy within the period of persistence. Patients under 45 years without drug indicators of cardiovascular disease or diabetes presented the lowest compliance.

Conclusions  The study showed good compliance with statin treatment in terms of persistence and continuity. A high percentage of the youngest patients, however, seemed to discontinue treatment before obtaining the full benefit in terms of decreased risk of coronary heart morbidity and mortality.
Dose‐dependent increase of saquinavir bioavailability by the pharmaceutic aid cremophor EL
Authors: Martin‐Facklam Meret , Burhenne Jürgen , Ding Reinhard , Fricker Ruth , Mikus Gerd , Walter‐Sack Ingeborg , Haefeli Walter E.
Published: March 2003

Aims  Bioavailability of orally administered drugs depends on several factors including active excretion, e.g. by P‐glycoprotein (PGP), and presystemic metabolism, e.g. by cytochrome P450 3A (CYP3A), in both gastrointestinal tract and liver. Many drugs including saquinavir are substrates of both PGP and CYP3A. It was the aim of this study to test whether the extremely low bioavailability of saquinavir can be increased dose‐dependently in vivo by cremophor EL, an ‘inactive’ pharmaceutic aid known to inhibit PGP in vitro.

Methods  In a randomized, placebo‐controlled, double‐blind, four phase cross‐over design single doses of oral saquinavir (Invirase®, 600 mg, without food) were administered with increasing single doses of oral cremophor EL (up to 5000 mg) to eight healthy, male individuals. Saquinavir plasma concentrations were determined by LC/MS/MS up to 48 h after intake. Main outcome measures were area under the plasma concentration time curve (AUC), peak concentration (Cmax), time to reach Cmax (tmax) and terminal elimination half‐life (t½).

Results  Cremophor EL dose‐dependently increased Cmax, AUC(0,4 h), and AUC(0,∞) of saquinavir. As compared with placebo, the increment observed after 5000 mg cremophor EL was 13‐fold for both Cmax and AUC(0,4 h) and 5‐fold for AUC(0,∞). The terminal half‐life and the time to reach Cmax (tmax) were unchanged.

Conclusions  Cremophor EL increased the systemic availability of saquinavir without affecting its elimination suggesting that cremophor EL is not devoid of pharmacological action and acts as a modulator of the absorption process, probably by inhibiting intestinal PGP.