bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.
Analgesic efficacy of sustained release paracetamol in patients with osteoarthritis of the knee
Authors: Bacon T. H. , Hole J. G. , North M. , Burnett I. 
Published: March 2003

Aims  Paracetamol is widely recommended as the initial treatment for pain associated with osteoarthritis (OA). A sustained release (SR) paracetamol formulation (Panadol Extend™) was compared with standard immediate release (IR) paracetamol (Panadol™) in patients with knee pain secondary to OA. The primary parameter for assessment of efficacy was patient‐assessed global pain relief as determined on day 8 of the treatment period.Methods  A double‐blind, double‐dummy, randomized study was conducted. Patients (n=403) were treated for 7 days with paracetamol 4 g day−1 (SR paracetamol, two 665 mg tablets taken three times daily; IR paracetamol, two 500 mg tablets taken four times daily). Patients completed daily pain measurements and assessed global pain relief at the end of the study. Therapeutic noninferiority was defined on the basis of achieving statistical noninferiority for global pain relief.Results  Analysis of the primary parameter for the intention to treat population showed that the difference in proportion of patients (SR−IR paracetamol) achieving a successful response on day 8 was −0.7%; 90% CI (−8.82%, 7.45%), P=0.890. For the per protocol population the difference in proportion was −3.0%; 90% CI (−11.61%, 5.66%), P=0.571. As the lower bound of the 90% CI for the treatment difference in each case was greater than the prespecified value (−15%), SR paracetamol was considered to be statistically noninferior to IR paracetamol in terms of pain relief. The treatments were not significantly different for any of the secondary parameters in either populations.Conclusions  SR paracetamol taken three times daily was statistically and therapeutically noninferior to IR paracetamol taken four times daily in patients with knee pain due to OA. SR paracetamol may be more convenient for patients with chronic pain and has the potential to enhance compliance and therefore pain relief.
Pharmacokinetics of tibolone in early and late postmenopausal women
Authors: Timmer C. J. , Verheul H. A. M. , Doorstam D. P. 
Published: March 2003

Aims  Tibolone is a tissue‐specific compound with favourable effects on bone, vagina, climacteric symptoms, mood and sexual well being in postmenopausal women, without stimulating the endometrium or breast. Since tibolone is used for the treatment of both young and elderly postmenopausal women, its pharmacokinetics were studied to investigate potential differences with age. In addition, the bioequivalence of the 1.25 and 2.5 mg tablets was evaluated.Methods  Single doses of 1.25 or 2.5 mg of tibolone were given in a double‐blind, randomized, two‐way cross‐over study to women aged between 45 and 55 years or between 65 and 75 years of age.Results  Age did not have a significant effect on Cmax, tmax, and t½ of tibolone and its metabolites and on the body weight standardized oral clearance (CL/F kg−1) of the 3α‐ and 3β‐hydroxy tibolones. In early postmenopausal women, significantly lower values were found for the AUC(0,16 h), and AUC(0,∞) of 3α‐hydroxy tibolone 24.6±6.6 vs 29.2±4.9 and 27.1±6.9 vs 32.3±6.5 ng ml−1 h for the 1.25 mg tablet, respectively, and 45.4±13.9 vs 55.7±14.1 and 49.6±14.6 vs 62.6±17.3 ng ml−1 h for the 2.5 mg tablet, respectively. When these values were adjusted for the significantly higher body weight of the early postmenopausal women, the differences disappeared. No significant differences between early and late postmenopausal women were found for the AUC(0,8 h), and AUC(0,∞) of 3β‐hydroxy tibolone. The rate of absorption of tibolone and the rates of absorption or formation of the 3α‐ and 3β‐hydroxy tibolones were significantly higher after the 1.25 mg dose than after the 2.5 mg tablet, resulting in increases of 32%, 27% and 17% for the dose normalized‐Cmax of tibolone and the 3α‐ and 3β‐hydroxy tibolones, respectively. tmax for tibolone and its metabolites was 12–27% less after 1.25 mg compared to 2.5 mg, which was statistically significant. The two formulations were bioequivalent with respect to the dose‐normalized AUC(0,∞) and the AUC(0,tfix) values for the 3α‐hydroxy tibolone (ratio point estimate [90%, confidence limits]: 1.08 [1.04, 1.14] and 1.08 [1.03, 1.13], respectively) and for the 3β‐hydroxy tibolone (1.07 [1.01, 1.14] and 1.04 [0.96, 1.12], respectively). Both formulations were also bioequivalent with respect to CL/F kg−1 and t½.Conclusions  The pharmacokinetics of tibolone are similar in early (age 45–55 years) and late (65–75 years) postmenopausal women. The 2.5 and 1.25 mg tablets are bioequivalent with respect to the extent of absorption. The rate of absorption or formation of the metabolites of tibolone were not bioequivalent, but these differences are considered to have no clinical relevance in view of the chronic administration of tibolone.