bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of intramuscular artemether in patients with severe falciparum malaria with or without acute renal failure
Authors: Karbwang J. , Na‐Bangchang K. , Tin T. , Sukontason K. , Rimchala W. , Harinasuta T.
Published: March 2003

Aims
 The pharmacokinetics of intramuscular artemether and its major plasma metabolite–dihydroartemisinin, were investigated in patients with severe manifestations of falciparum malaria.

Methods
 Six severe falciparum malaria patients with acute renal failure (ARF) and 11 without ARF were recruited into the study. They were treated with intramuscular artemether at a loading dose of 160 mg, followed by daily doses of 80 mg for another 6 days (total dose 640 mg).

Results
 Patients with and without ARF showed a good initial response to treatment; the parasite and fever clearance times were 66(30–164) and 76(36–140) h [median(range)], respectively. None had reappearance of parasitaemia in their peripheral blood smear within 7 days of initiation of treatment. In comatose patients, the time to recovery of consciousness was 51.6(22–144) h. Artemether was detected in plasma as early as 1 h after a 160 mg dose, and declined to undetectable levels within 24 h in most cases. Patients with ARF had significantly higher Cmax [2.38(1.89–3.95) vs 1.56(1.05–3.38) ng ml−1 mg−1 dose], AUC [35.4(22–52.9) vs 25.2(13.4–52.9) ng ml−1 h mg−1 dose], and lower Vz/F [5.45(3.2–6.9) vs 8.6(4.2–12.3) l kg−1] and CL/F [7.4(5.4–13.8) vs 19.1(8.5–25.1) ml min−1 kg−1] when compared with those without ARF. In addition, t1/2,z was significantly longer in ARF patients [7.0(5.5–10.0) vs 5.7(4.2–6.6) h]. The pharmacokinetics of dihydroartemisinin in the two groups of patients were comparable.

Conclusions
 ARF significantly modified the pharmacokinetics of intramuscular artemether. The changes could be attributed to either improved absorption/ bioavailability, a reduction of systemic clearance, or a change in plasma protein binding of the drug.
A new regimen for starting warfarin therapy in out‐patients
Authors: Oates A. , Jackson P. R. , Austin C. A. , Channer K. S.
Published: March 2003

Aims
 Oral anticoagulation is increasingly used in elderly patients with atrial fibrillation to prevent embolic phenomena. The use of anticoagulants in this population is prophylactic rather than therapeutic and so there is no urgency to establish anticoagulation within the desired therapeutic range. The aim of the study was to develop an out‐patient regimen for initiation of oral anticoagulation with warfarin which requires only weekly monitoring of the International Normalized Ratio (INR).

Methods
 The study was undertaken in two phases. In the first phase, factors which predict the final maintenance dosage of warfarin were defined and used to build a decision tree and dosage algorithm. In the second study the algorithm was tested. Patients were given 2 mg warfarin daily for 2 weeks and the INR at this time was used to predict the maintenance dose. Patients then attended for weekly measurements of the INR until steady state had been reached. Dosage adjustments were not made unless the INR was >4.0 or <1.5 for 2 consecutive weeks. The accuracy of the prediction was measured by calculating the mean INR of weeks 6–8 and the number of patients in the target range 2.0–3.0 was determined.

Results
 One hundred and seven consecutive out‐patients (mean age 70 years range 64–86) completed the first study. The age, sex, height, weight, alcohol intake, number of cigarettes smoked, concomitant medication, clinical evidence of right heart failure, liver failure, abnormalities in liver enzyme estimations, baseline INR and INR after 2 weeks of 2 mg warfarin daily were used in a polytomous logistic regression analysis with stepwise inclusion of factors to determine which factors influenced the eventual maintenance dosage of warfarin. The INR after 2 weeks of 2 mg warfarin therapy predicted 70% of the variability of the maintenance dose. Of other factors only the sex of the patient had a large enough effect to be included in the prediction algorithm. One hundred and six patients (mean age 71 years range 50–85 years) completed the second study. Only one patient needed a dose adjustment in the first 2 weeks of warfarin 2 mg daily (INR 4.4). Overall, 60% patients were in the narrow target range (INR 2.0–3.0) at steady state. In five patients the INR was >4.0 at any visit after the second week and needed dosage adjustment. In four patients the INR was <1.5 at steady state.

Conclusions
 We have developed a method of predicting the maintenance dose of warfarin in an elderly population based on the INR after 2 weeks of warfarin 2 mg daily, and the sex of the patient. This is a safe and convenient way of initiating warfarin therapy as an out‐patient which requires only weekly INR checks.
Determination of inulin clearance by bolus intravenous injection in healthy subjects and ascitic patients: equivalence of systemic and renal clearances as glomerular filtration markers
Authors: Orlando  , Floreani  , Padrini  , Palatini
Published: March 2003

Aims Determination of systemic inulin clearance by the standard technique of constant intravenous infusion has long been accepted as a reliable method for measuring glomerular filtration rate (GFR) without urine collection, except in oedematous patients. However, recent studies using standard clearance techniques have claimed that systemic inulin clearance is significantly greater than renal clearance and therefore overestimates GFR. The main purpose of this investigation was to re‐evaluate the relationship between systemic and renal inulin clearance using a different technical approach. A reassessment was also made of inulin disposition kinetics.

Methods Systemic and renal inulin clearances were simultaneously evaluated, in healthy subjects and patients with oedema and ascites, by analysis of the total area under the plasma concentration‐time curve (AUC) following bolus intravenous injection. Renal clearance was calculated as the ratio of the total amount recovered in the urine to the AUC, and systemic clearance as dose/AUC.

Results Inulin disposition kinetics were best described by a tri‐exponential model. In healthy subjects the volume of the central compartment (mean (s.d.) value 3.86 (1.00) 70 kg−1 ) was slightly greater than the plasma volume; steady‐state volume of distribution was 11.00 (1.21) l 70 kg−1, in accordance with the tenet that the inulin space is somewhat smaller than the extracellular fluid volume. The values of systemic and renal inulin clearances were very similar (96.1 (10.0) and 94.6 (12.5) ml min−1 70 kg−1, respectively, in healthy subjects; 104.6 (16.3) and 102.6 (18.5) ml min−1 in ascitic patients). They were also highly correlated to each other in both healthy subjects (r=0.96, P<0.001) and patients with ascites (r=0.98, P<0.001).

Conclusions The method described here constitutes a simpler and more precise technique for measuring renal inulin clearance than the standard method, which is based on constant infusion and timed collections of urine samples, since it avoids errors connected with short successive urine collections. By the present method we demonstrated that renal and systemic inulin clearances are virtually identical in both healthy subjects and patients with expanded extracellular fluid volume. Determination of systemic inulin clearance by the presently described technique is therefore a method of general validity for measuring GFR without urine collection.
Concurrent administration of donepezil HCl and digoxin: assessment of pharmacokinetic changes
Authors: Tiseo  , Perdomo  , Friedhoff
Published: March 2003

Aim The aim of this study was to examine the pharmacokinetics of donepezil HCl and digoxin separately, and in combination, following administration of single oral doses. Changes in cardiac conduction parameters following drug administration were also assessed.

Methods This was an open‐label, randomized, three‐period crossover study in healthy male volunteers (n=12). During each treatment period, subjects received a single dose of either donepezil HCl (5 mg), digoxin (0.25 mg), or a combination of both drugs. Each treatment period was followed by a 2‐week, drug‐free washout period.

Results All 12 volunteers completed the study without incident. No statistically significant differences in donepezil pharmacokinetics (Cmax, tmax, AUC(0–120), AUC(0–∞) or t½ ) were observed when donepezil administered alone was compared with donepezil administered in combination with digoxin. Similarly, no statistically significant differences in digoxin pharmacokinetics were observed when digoxin was administered alone or in combination with donepezil. No clinically relevant changes in cardiac conduction (lead II ECG) were observed in any subject during any treatment period.

Conclusions Co‐administration of single doses of donepezil HCl (5 mg) and digoxin (0.25 mg) produced no changes in the pharmacokinetic profile of either drug. In addition, co‐administration produced no changes in cardiac conduction parameters during the 24 h of telemetry monitoring following drug administration.
Drug and Therapeutics (D & T) committees in Dutch hospitals: a nation‐wide survey of structure, activities, and drug selection procedures
Authors: Fijn  , Brouwers  , Knaap  , De Jong‐Van den Berg
Published: March 2003

Aims To determine structure, activities and drug selection processes used by Dutch hospital drug and therapeutics (D & T) committees.

Methods A pretested structured survey questionnaire based on the Australian process and impact indicators, previous research, and consultation of professionals was developed. Subsequently, D & T committees that met predefined selection criteria were asked to participate.

Results The overall response rate was 70% (38/54). D & T committees varied considerably in size and representation of clinical expertise. Although responsibilities were theoretically alike, actual responsibilities were frequently passed on to other authorities, such as pharmacy staff. Few committees used detailed guidelines or decision supportive matrices to establish transparency in drug selection. With respect to drug selection, the value scores on the information resources used, the factors involved, and the selection criteria used varied. Hospital pharmacists were likely to be most involved and to have the greatest impact. A consensus was most difficult to achieve for drugs used in cardiology, oncology, and psychiatry. Interference of industrial marketing strategies on drug selection was recognized and identified.

Conclusions Our results indicate that Dutch hospital D & T committees differ with respect to their clinical expertise and their activities, a situation comparable with that observed in other countries. Furthermore, the lack of transparency in drug selection was considerable. These findings clarify the differences previously found between Dutch hospital drug formularies.
The treatment of eczema with Chinese herbs: a systematic review of randomized clinical trials
Authors: Armstrong  , Ernst
Published: March 2003

Aims Chinese herbal treatments are being promoted as a treatment for eczema. The aim of this study was to systematically review the evidence for or against this notion.

Methods Extensive literature searches were carried out to identify all randomised clinical trials on the subject. Data were extracted from these in a predefined standardized fashion.

Results Only two randomized clinical trials were located. Both imply that a complex mixture of Chinese herbs is more effective than placebo in treating eczema. Yet several caveats exist, most importantly the lack of independent replication. Adverse effects have also been reported.

Conclusions At present it is unclear whether Chinese herbal treatments of eczema do more good than harm.
Pharmacokinetics and bioavailability of oral 5′‐deoxy‐5‐fluorouridine in cancer patients
Authors: Van Der Heyden  , Highley  , De Bruijn  , Tjaden  , Reeuwijk  , Van Slooten  , Van Oosterom  , Maes
Published: March 2003

Aims Oral administration of 5‐fluorouracil (FUra), an important cytotoxic agent, is limited by a wide variation in bioavailability. 5′‐deoxy‐5‐fluorouridine (dFUrd), a masked form of FUra, has shown promise clinically when given intravenously or orally as a solution or tablet. This study investigates the efficacy of an oral capsule formulation of dFUrd in generating continuous systemic levels of this compound in cancer patients.

Methods Six patients with advanced intestinal or ovarian malignancies were given three cycles of dFUrd, days 1–5, at intervals of 4 weeks. The doses of dFUrd were 600 mg m−2 three times daily, 800 mg m−2 three times daily, and 1000 mg m−2 three times daily, on cycles one, two and three, respectively (total dose 36 g m−2 ). The initial dose in each cycle was given as a slow intravenous injection over 10 min, and the remainder orally. Plasma and urine levels of dFUrd and two of its metabolites, FUra and 5,6‐dihydro‐5‐fluorouracil (FUraH2 ), were monitored in six patients at each dose level.

Results All six patients completed the study, receiving three different doses over a 3 month period, following which one had achieved a partial response, one had stable disease, and four had developed progressive disease. Side‐effects were negligible, and only two instances of transient diarrhoea WHO grade 1 were seen. Total body clearance (CLtot) of intravenous dFUrd decreased with increasing dose; 2.7, 2.0 and 1.3 l min−1 m−2, following doses of 600, 800 and 1000 mg m−2, respectively. The mean elimination half‐life of intravenous dFUrd increased with the dose from 15 to 22 min. Oral dFUrd was rapidly absorbed with a lag time of less than 20 min. The mean elimination half‐life (t1/2, z ) of oral dFUrd was 32–45 min in the dose range 600–1000 mg m−2. The AUC of FUra and FUraH2 increased overproportionally with increasing intravenous doses of dFUrd. The mean systemic bioavailability of oral dFUrd was 34–47%.

Conclusions dFUrd, which selectively releases the antimetabolite FUra in tumour cells, can be given orally at doses of 600–1000 mg m−2 three times daily for 5 days. The systemic levels achieved are equivalent to those seen following continuous infusions of dFUrd or FUra. Toxicity is tolerable, and further clinical investigation of oral dFUrd is warranted.
The rational use of β‐adrenoceptor blockers in the treatment of heart failure. The changing face of an old therapy
Authors: Squire Iain B. , Barnett David B.
Published: March 2003

Heart failure is one of the commonest debilitating conditions of industrialized society, with mortality and morbidity comparable with that of the common neoplastic diseases. The role of antagonists of the adrenergic β‐receptor (β‐blockers) in heart failure has been the subject of debate for many years. Data from studies of the therapeutic use of β‐blockers in patients following acute myocardial infarction suggest that in this circumstance these agents confer at least as much benefit to patients with heart failure as they do to those without. Similarly retrospective analysis of a number of the studies of angiotensin converting enzyme (ACE) inhibitors in heart failure suggest a greater effect of the combination of β‐blocker with ACE inhibitor compared with ACE inhibitor alone.

The results of recent prospective, placebo‐controlled studies of the addition of β‐blocker to standard therapy in patients with chronic heart failure have confirmed a significant beneficial effect. β‐blocker therapy in these studies was well tolerated and in addition to improved mortality, β‐blocker therapy is associated with improved morbidity in terms of progressive heart failure and numbers of hospitalizations.

Initiation of β‐blocker therapy in heart failure may be associated with deterioration of cardiac function in the short term. Treatment should be started at a low dose of β‐blocker with slow up‐titration in a number of steps over several weeks. In spite of the established benefits of ACE inhibition in patients with heart failure, this treatment is under‐utilized. Part of this shortfall is due to physicians’ perceptions regarding potential unwanted effects of ACE inhibition. Perceptions regarding unwanted effects of β‐adrenoceptor blocker therapy are likely to be at least as great. While β‐blockade represents a welcome addition to the therapeutic armoury of physicians caring for patients with heart failure, initiation and stabilization of β‐adrenoceptor blocker therapy should be undertaken under specialist supervision.
Formation of omeprazole sulphone but not 5‐hydroxyomeprazole is inhibited by grapefruit juice
Authors: Tassaneeyakul Wichittra , Tassaneeyakul Wongwiwat , Vannaprasaht Suda , Yamazoe Yasushi
Published: March 2003

Aims To determine the effect of grapefruit juice on omeprazole metabolism in vivo.

Methods This was a randomized crossover study with a 2 week washout period. Omeprazole (20 mg) was taken orally by 13 healthy volunteers after an overnight fast with either grapefruit juice or water. Serial blood samples were obtained over 12 h and standardized meals were served 3 and 10 h after the administration of omeprazole. Plasma concentrations of omeprazole and its major metabolites, 5‐hydroxyomeprazole and omeprazole sulphone, were determined by high performance liquid chromatography (h.p.l.c.).

Results Mean area under the plasma concentration vs time curve (AUC) between 0 and 12 h for omeprazole sulphone was approximately 20% lower (P<0.01) in the group receiving grapefruit juice. There was no significant difference in the mean AUC of 5‐hydroxyomeprazole or omeprazole. The AUC ratio of omeprazole sulphone to omeprazole, an index of CYP3A4 activity, was decreased by 33% (P<0.001) after administration of grapefruit juice whereas the AUC ratio of 5‐hydroxyomeprazole to omeprazole, an index of CYP2C19 activity, did not differ between the two phases of the study. Although the time to peak concentration (tmax ) and terminal half‐life (t1/2,z) of omeprazole and its two main metabolites were not altered, the peak concentration (Cmax ) of omeprazole sulphone was significantly reduced after administration of grapefruit juice.

Conclusion Administration of grapefruit juice decreased the formation of omeprazole sulphone but not 5‐hydroxyomeprazole. These results indicate that activities of CYP3A4, but not of CYP2C19, are inhibited by the simultaneous administration of grapefruit juice.
Sleeping with the enemy? A randomized controlled trial of a collaborative health authority/industry intervention to influence prescribing practice
Authors: Freemantle Nick , Johnson Richard , Dennis Jane , Kennedy Andrew , Marchment Mike
Published: March 2003

Aims To evaluate the effectiveness of a health authority/pharmaceutical company collaborative intervention to influence the choice of proton pump inhibitors

Methods Randomized controlled trial, with general practices forming the unit of allocation and analysis.

Results Constructive working relationships were achieved with five of six pharmaceutical companies involved. One hundred and two out of 140 practitioners in intervention group practices received at least one visit from an industry representative. There were no reports of representatives operating outside their agreed remit. Prescribing in both the intervention and control group moved towards that recommended by the guidelines but there was no difference between the groups in either the proportion of prescriptions in line with the guidelines or the overall cost.

Conclusions Health authorities can achieve professional working relationships with the pharmaceutical industry although no changes in practice attributable to the intervention are achieved. Further work is required to develop effective means to influence prescribing in line with independent guidelines especially in the context of the development of Primary Care Groups.
The risk of acute pancreatitis associated with acid‐suppressing drugs
Authors: Eland I. A. , Alvarez C. Huerta , Stricker B. H. CH. , Rodrı´guez L. A. Garcı´a
Published: March 2003

Aims
 To assess the risk of acute pancreatitis associated with use of acid‐suppressing drugs.

Methods
 We conducted a retrospective cohort study with a nested case‐control design within the General Practice Research Database (GPRD) in the United Kingdom. The cohort included 180 178 persons aged 20–74 years, who had received at least one prescription of cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, or omeprazole from January 1992 to September 1997 and who did not have major risk factors for pancreatic diseases. Patients with a computerized medical history compatible with idiopathic acute pancreatitis were validated through review of medical records. For the nested case‐control analysis 1000 controls were randomly selected from the study population.

Results
 We identified 88 potential cases of idiopathic acute pancreatitis. Medical records were available for 86. After review of these records 36 cases of acute pancreatitis were confirmed. Seven cases occurred during nonuse, corresponding to a background incidence rate (IR) of 4.4/100 000 person‐years (PY). Six cases occurred during current use of ranitidine (IR 10.5/100 000 PY), five patients were current users of cimetidine (IR 13.9/100 000 PY), and three were current users of omeprazole (IR 7.8/100 000 PY). There were no cases among current users of famotidine, lansoprazole, or nizatidine. Relative risk (RR) compared with nonuse and corrected for age, gender, calendar year and use of medication known to be associated with acute pancreatitis was 1.3 (95% CI: 0.4,4.1) for ranitidine, 2.1 (95% CI: 0.6,7.2) for cimetidine, and 1.1 (95% CI: 0.3,4.6) for omeprazole.

Conclusions
 The results of this study do not support an association between acute pancreatitis and the use of acid‐suppressing drugs, although a substantial increase in risk cannot be excluded with confidence.
Pharmacokinetics of epimeric budesonide and fluticasone propionate after repeat dose inhalation – intersubject variability in systemic absorption from the lung
Authors: Minto Charles , Li Benny , Tattam Bruce , Brown Ken , Seale J. Paul , Donnelly Richard
Published: March 2003

Aims
Pharmacokinetic variability is likely to be a significant factor contributing to the interindividual differences in dose requirements, anti‐inflammatory response and side‐effects with inhaled corticosteroids (ICS), but there is limited information about the disposition of ICS during regular dosing with a pressurized metered dose inhaler (pMDI). This study uses a mixed effects modelling approach to quantify and compare the interindividual variability in pharmacokinetics of epimeric budesonide (BUD) and fluticasone propionate (FP) after repeat‐dose inhalation.

Methods
This pharmacokinetic substudy was part of a previously published open‐label, randomised, placebo‐controlled, 7‐period crossover study to evaluate the short‐term effects on plasma cortisol levels of inhaled BUD (400, 800, 1600 µg twice daily) and FP (375, 750, 1000 µg twice daily) via pMDI in a group of healthy male volunteers. On the fifth day of each high‐dose treatment period (BUD 1600 µg twice daily and FP 1000 µg twice daily), venous blood samples were collected in nine subjects prior to the last dose and at 15 min, 30 min, 1, 2, 4, 6 and 8 h postdose for measurement of plasma drug concentrations to determine the pharmacokinetics of epimeric BUD and FP following inhalation. Non‐compartmental analysis and a mixed effects model were used to characterize the disposition profiles.

Results
Both drugs had a rapid absorption half‐life (BUD 10 min vs FP 11.3 min), but quite different elimination half‐lives (BUD 2.4 h vs FP 7.8 h). Although there were intraindividual differences in the handling of the 22R‐and 22S‐epimers of BUD, there were no consistent pharmacokinetic differences between the two enantiomers in the group as a whole. Consistent with previous reports of FP’s higher volume of distribution (V) and lower systemic bioavailability (F), the V/F ratio was lower for BUD than FP (498 l vs 8100 l). The parameter with the greatest interindividual variability for both BUD and FP was the rate of systemic absorption from the lung.

Conclusions
This is the first report describing the pharmacokinetics of epimeric BUD and FP after repeat dose inhalation via pMDI. Three observations may be of clinical relevance: (1) there is considerable intersubject variability in the rate of absorption of both drugs from the lung; (2) in some individuals there was a long t½,z for BUD, resulting in higher and more sustained plasma drug levels in the 4–12 h postdose period than would be predicted from single‐dose pharmacokinetic data; and (3) there is evidence of diurnal variation in FP pharmacokinetics, with higher‐than‐expected plasma drug concentrations in the morning compared with the evening.
Steady‐state pharmacokinetics of lithium in healthy volunteers receiving concomitant meloxicam
Authors: Türck D. , Heinzel G. , Luik G.
Published: March 2003

Aims
This open, controlled study investigated the effect of concomitant 15 mg oral meloxicam on the pharmacokinetics of lithium in healthy male volunteers.

Methods
On days 1–14 lithium was coadministered with meloxicam to 16 volunteers; on days 10–14 lithium was administered in individualized dosage regimes to achieve stable lithium plasma concentrations in the lower therapeutic range of 0.3–0.7 mmol l−1. A 12 h steady‐state concentration profile for lithium was obtained at day 14, after which meloxicam was withdrawn. The lithium dose remained unchanged from day 15 to day 22, at which time a second lithium concentration profile was determined.

Results
Lithium and meloxicam were well tolerated throughout the study and all 16 volunteers completed the study. Lithium predose concentrations (Cpre,ss) and area under the curve (AUCss) values both increased by 21% (paired t‐test P = 0.0002; 90% confidence intervals for test/reference ratios: 113–130% and 115–128%, respectively) when lithium was coadministered with meloxicam compared with values obtained for lithium alone. The geometric mean lithium Cpre,ss was 0.65 mmol l−1 when coadministered with meloxicam and 0.54 mmol l−1 for lithium alone. Lithium Cmax,ss values were increased by 16% by coadministration of meloxicam, from 0.97 mmol l−1 to 1.12 mmol l−1. The total plasma clearance of lithium was lower with concomitant meloxicam administration (82.5% of value for lithium alone).

Conclusions
Meloxicam (15 mg) moderately increased the plasma concentration of lithium in healthy volunteers, but by a magnitude thought to be of low clinical relevance. Nevertheless, lithium plasma concentrations should be closely monitored in patients receiving concomitant meloxicam and lithium therapy.
The effects of lamotrigine on the pharmacokinetics of lithium
Authors: Chen Chao , Veronese Laurence , Yin Yin
Published: March 2003

Aims
The treatment of bipolar disorder often includes use of multiple drug therapies. Lithium is one of the most commonly used treatments, but has a narrow therapeutic window. Lamotrigine, an established antiepileptic drug, is emerging as a potentially important new therapy in the treatment of bipolar disorder. The objective of this two‐treatment crossover study was to determine whether lamotrigine affects lithium pharmacokinetics.

Methods
Twenty healthy adult men completed the study. Subjects took 2 g lithium gluconate anhydrous every 12 h in the morning and evening for 5 days and in the morning of day 6, with or without 100 mg lamotrigine once daily in the morning for 6 days. Blood and urine samples were collected on day 6 of both treatments to characterize the pharmacokinetics of lithium using noncompartmental methods.

Results
The geometric least‐square mean ratio for renal clearance of lithium between the combination treatment and lithium alone treatment was 0.93 (95% confidence interval 0.85–1.02). Both treatments were well tolerated.

Conclusions
Lamotrigine does not cause significant change in the pharmacokinetics of lithium.
Nebivolol decreases systemic oxidative stress in healthy volunteers
Authors: Troost R. , Schwedhelm E. , Rojczyk S. , Tsikas D. , Frölich J. C.
Published: March 2003

Aims
Nebivolol is a selective, vasodilatory β1‐adrenergic receptor antagonist which has been suggested to possess additional antioxidative properties. The aim of the present study was to assess the actions of nebivolol in antihypertensive doses on systemic oxidative stress in healthy volunteers, reflected by 24 h urinary excretion of 8‐iso‐PGF2α.

Methods
In a double‐blind, cross‐over study, 12 healthy volunteers received 5 mg nebivolol once daily or placebo for a total of 7 days, separated by a wash out period of 2 weeks. After each treatment period 24 h urinary excretion of 8‐iso‐PGF2α was determined by gas chromatography‐tandem mass spectrometry.

Results
After the 7 day treatment period nebivolol decreased significantly urinary excretion of 8‐iso‐PGF2α by 24% from 55.3 ± 5.1 pmol mmol−1 creatinine during the placebo period to 42.3 ± 4.7 pmol mmol−1 creatinine (mean ± s.e. mean, P = 0.01), a mean decrease of 13 pmol mmol−1 creatinine (95% CI: −22.8; −3.1).

Conclusions
Our data show for the first time that nebivolol decreases systemic oxidative stress in young healthy volunteers.
Effect of rifampicin on the pharmacokinetics and pharmacodynamics of glimepiride
Authors: Niemi Mikko , Kivistö Kari T. , Backman Janne T. , Neuvonen Pertti J.
Published: March 2003

Aims  To study the effects of rifampicin on the pharmacokinetics and pharmaco‐dynamics of glimepiride, a new sulphonylurea antidiabetic drug.

Methods  In this randomised, two‐phase cross‐over study, 10 healthy volunteers were treated for 5 days with 600 mg rifampicin or placebo once daily. On day 6, a single oral dose of 1 mg glimepiride was administered. Plasma glimepiride and blood glucose concentrations were measured up to 12 h.

Results  Rifampicin decreased the mean area under the plasma concentration‐time curve of glimepiride by 34% (P < 0.001) and the mean elimination half‐life by 25% (P < 0.05). No significant differences in the blood glucose response to glimepiride were observed between the placebo and rifampicin phases. However, symptomatic hypoglycaemia occurred only during the placebo phase.

Conclusions  The effects of rifampicin on the pharmacokinetics of glimepiride suggest that rifampicin induced the CYP2C9‐mediated metabolism of glimepiride and thereby slightly increased its systemic clearance. Because the interaction was modest and did not significantly alter the glucose‐lowering effect of glimepiride in healthy volunteers, it is probably of limited clinical significance. However, in some patients the hypoglycaemic effect of glimepiride may be reduced during concomitant treatment with rifampicin.
Identification of the human cytochrome P450 isoforms mediating in vitro N‐dealkylation of perphenazine
Authors: Olesen Ole V. , Linnet Kristian
Published: March 2003

Aims
To identify the human cytochrome P450 (CYP) isoforms mediating the N‐dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions of the CYP isoforms involved.

Methods
cDNA‐expressed CYP isoforms were used to identify the isoforms that are able to mediate the N‐dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N‐dealkylation reaction.

Results
CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N‐dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N‐dealkylation. Apparent Km values of CYP1A2 and CYP2D6 were in the range 1–2 µm, and Km values of CYP2C19 and CYP3A4 were 14 µm and 7.9 µm, respectively. Ketoconazole inhibition of N‐dealkylation mediated by a mixed HLM indicated that CYP3A4 accounted for about 40% of perphenazine N‐dealkylation at therapeutically relevant concentrations.The contribution of the CYP isoforms 1A2, 2C19 and 2D6 amounted to 20–25% each as measured by the percentage inhibition obtained by addition of furafylline, fluvoxamine or quinidine, respectively. HLM‐mediated N‐dealkylation of perphenazine accounted for 57% of the total amount of substrate consumed during incubation.

Conclusions
The present in vitro study suggests that CYP isoforms 1A2, 3A4, 2C19 and 2CD6 are primarily involved in the N‐dealkylation of perphenazine. The relatively modest role of CYP2D6 is at variance with in vivo studies, which indicate a greater contribution of this isoform. Alternative metabolic pathways, corresponding to 43% of the HLM‐mediated metabolism of the drug, may depend more strongly on CYP2D6.
Evaluation of a pharmacokinetic interaction between remacemide hydrochloride and phenobarbitone in healthy males
Authors: Hooper W. D. , Eadie M. J. , Blakey G. E. , Lockton J. A. , Manun'Ebo M.
Published: March 2003

Aims  To determine whether there is a pharmacokinetic interaction between the antiepileptic drugs remacemide and phenobarbitone.

Methods  In a group of 12 healthy adult male volunteers, the single dose and steady‐state kinetics of remacemide were each determined twice, once in the absence and once in the presence of phenobarbitone. The effect of 7 days remacemide intake on initial steady‐state plasma phenobarbitone concentrations was also investigated.

Results  Apparent remacemide clearance (CL/F) and elimination half‐life values were unchanged after 7 days intake of the drug in the absence of phenobarbitone (1.25 ± 0.32 vs 1.18 ± 0.22 l kg−1 h−1 and 3.29 ± 0.68 vs 3.62 ± 0.85 h, respectively). Concomitant administration of remacemide with phenobarbitone resulted in an increase in the estimated CL/F of remacemide (1.25 ± 0.32 vs 2.09 ±0.53 l kg−1 h−1), and a decreased remacemide half‐life (3.29 ± 0.68 vs 2.69 ± 0.33 h). The elimination of the desglycinyl metabolite of remacemide also appeared to be increased after the phenobarbitone intake (half‐life 14.72 ± 2.82 vs 9.61 ± 5.51 h, AUC 1532 ± 258 vs 533 ± 281 ng ml−1 h). Mean plasma phenobarbitone concentrations rose after 7 days of continuing remacemide intake (12.67 ± 1.31 vs 13.86 ± 1.81 μg ml−1).

Conclusions  Phenobarbitone induced the metabolism of remacemide and that of its desglycinyl metabolite. Remacemide did not induce its own metabolism, but had a modest inhibitory effect on the clearance of phenobarbitone.
Co‐prescribing of SSRIs and TCAs in Australia: how often does it occur and who is doing it?
Authors: McManus Peter , Mant Andrea , Mitchell Philip , Birkett Don , Dudley John
Published: March 2003

Aims  To determine the frequency with which the selective serotonin re‐uptake inhibitor (SSRI) antidepressants are used as add‐on therapy to the tricyclic antidepressants (TCA) rather than as replacement therapy.

Methods  The data analysed were profiles of prescription records by date of supply to the patient. From within the national administrative dispensing claims database, the subset eligible for social security entitlements was identified as individuals by means of their coded permanent identification numbers (PINs). Following the initial supply of an SSRI in January 1996, the subsequent 6 months dispensing of SSRI and TCA antidepressants to these individuals was examined. The main outcome measure was the proportion of individuals to whom SSRIs and TCAs were dispensed concurrently, as an indirect measure of coprescription. In instances where a patient was receiving prescriptions for SSRIs and TCAs that had been written by the one doctor only, the major specialty of the doctor was investigated.

Results  55 271 PINs were dispensed 63 865 SSRI prescriptions in January 1996 which represented over half (52%) of the total community SSRI prescriptions dispensed in that month. The number of these patients meeting the criteria for coprescription of SSRIs and TCAs over the next 6 months was 2773 (5%). The coprescribing instances were highest in Queensland and the prescribers most frequently involved had psychiatry major specialty codes.

Conclusions  Among SSRI users there is a cohort of patients who, within the same time frame, are receiving supplies of a TCA, the nonselective drug that the SSRIs were designed to replace. This is indirect evidence of probable coprescription. Such combination use is of uncertain clinical and cost effectiveness, and carries additional risks. The SSRIs were included on the subsidy list in Australia on the basis of reasonable cost effectiveness as monotherapy compared with the TCAs. Our data imply that for some patients, antidepressant prescribing is inconsistent with the basis on which government subsidy was approved.
Lack of effect of ondansetron on the pharmacokinetics and analgesic effects of morphine and metabolites after single‐dose morphine administration in healthy volunteers
Authors: Crews, Kristine Radomski , Murthy, Bindu P. , Hussey Elizabeth K. , Passannante Anthony N. , Palmer Jonathan L. , Maixner William , Brouwer Kim L. R.
Published: March 2003

Aims  The purpose of this investigation was to study the influence of ondansetron on the single‐dose pharmacokinetics and the analgesic effects elicited by morphine and the 3‐ and 6‐glucuronide metabolites of morphine in healthy volunteers.

Methods
This was a randomized, double‐blind, placebo‐controlled, two‐way crossover study in which six male and six female subjects were administered a single 10 mg intravenous dose of morphine sulphate, followed 30 min later by a single 16 mg intravenous dose of ondansetron hydrochloride or placebo. Serum and urine concentrations of morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) samples were quantified over 48 h using high performance liquid chromatography with detection by mass spectrometry. Analgesia was assessed in the volunteers with a contact thermode device to provide a thermal pain stimulus. Four analgesic response variables were measured including thermal pain threshold, thermal pain tolerance, temporal summation of pain and mood state.

Results
The two treatments appeared to be equivalent based on the 90% confidence intervals (0.6, 1.67) of the least squares means ratio. All least squares means ratio confidence intervals for each parameter, for each analyte fell within the specified range, demonstrating a lack of an interaction.

Conclusions
The results of this study suggest that administration of ondansetron (16 mg i.v.) does not alter the pharmacokinetics of morphine and its 3‐ or 6‐glucuronide metabolites to a clinically significant extent, nor does it affect the overall analgesic response to morphine as measured by the contact thermode system.
Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind‐up of the second pain response in healthy male volunteers
Authors: Hughes A. M. , Rhodes J. , Fisher G. , Sellers M. , Growcott J. W.
Published: March 2003

Aims  The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind‐up of second pain response in healthy male volunteers.

Methods  The trial was a randomized, double‐blind, placebo‐controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg−1 dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg−1 ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind‐up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDICTM thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen.

Results  Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind‐up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (−5.52, 4.24) and 11.75 vs 15.25 (−11.89, 4.90) for left‐ and right‐hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind‐up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left‐ and right‐hand, respectively.

Conclusions  Wind‐up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind‐up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.
An indirect response model of homocysteine suppression by betaine: optimising the dosage regimen of betaine in homocystinuria
Authors: Matthews Angela , Johnson Trevor N. , Rostami‐Hodjegan Amin , Chakrapani Anupam , Wraith J. Edward , Moat Stuart J. , Bonham James R. , Tucker Geoffrey T.
Published: March 2003

Aims  To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of betaine in the treatment of classical homocystinuria due to cystathionine β‐synthase (CβS) deficiency with a view to optimizing the dosage regimen.

Methods  Betaine was given as a single oral dose of 100 mg kg−1 to six patients (age range 6–17 years) who normally received betaine but whose treatment had been suspended for 1 week prior to the study. Plasma betaine and total homocysteine concentrations were measured by high performance liquid chromatography (h.p.l.c.) at frequent intervals over 24 h. The best‐fit PK model was determined using the PK‐PD program Win‐Nonlin and the concentration‐time‐effect data analysed by an indirect PD model. Using the PK and PD parameters, simulations were carried out with the aim of optimizing betaine dosage.

Results  Betaine PK was described by both mono‐ and bi‐exponential disposition functions with first order absorption and a lag time. The correlation coefficient between betaine oral clearance and body weight was 0.6. Mean betaine clearance was higher in males than in females (P=0.03). PK‐PD simulation indicated minimal benefit from exceeding a twice‐daily dosing schedule and a 150 mg kg−1 day−1 dosage for betaine.

Conclusions  PK‐PD modelling allows recommendations for optimal dosage of betaine in the treatment of homocystinuria, that have the potential for improved patient compliance and both therapeutic and pharmacoeconomic benefit.
Determination of the relative bioavailability of salbutamol to the lungs and systemic circulation following nebulization
Authors: Silkstone V. L. , Corlett S. A. , Chrystyn H.
Published: March 2003

Aims  Clinical studies comparing nebulized drug delivery systems could be flawed because of the high doses used. We have compared lung and total systemic delivery of salbutamol from a nebuliser with that from a metered dose inhaler by measuring urinary recovery of drug and its sulphate metabolite.

Methods  Twelve healthy volunteers provided urine samples at 0, 0.5, 1, 2, 4, 8, 12 and 24 h after the start of dosing. Formulations and doses were 5×100 µg oral solution (ORAL), 5×100 µg from a metered dose inhaler (MDI), 2.5 mg using a nebuliser (NEB) and NEB with 25 g oral charcoal (NEBC). Each study phase was separated by 7 days and the order of dosing was randomized.

Results  Mean (s.d.) 30 min urinary salbutamol excretion after ORAL, MDI, NEB and NEBC was 0.4 (0.7), 12.1 (3.7), 15.0 (3.9) and 18.2 (5.7) µg, respectively (all P<0.001 compared with ORAL). When normalized for the dose available for inhalation from MDI, NEB and NEBC, the mean (s.d.) 30 min urinary excretion of salbutamol was 2.4 (0.7), 2.9 (0.6) and 2.7 (0.6)%, respectively, with a mean ratio (90% confidence interval) between NEB and NEBC, of 95.3 (91.1, 99.5)%. The mean (s.d.) excretion of salbutamol plus its metabolite over 24 h post ORAL, MDI, NEB and NEBC dosing was 297.9 (38.3), 290.3 (41.4), 266.5 (44.6) and 151.7 (40.9) µg, respectively. The mean ratio (90% confidence interval) between MDI and ORAL, and NEB and ORAL were 97.5 (94.1, 101.0) and 90.7 (81.2, 100.2)%, respectively. The NEBC data indicate that 6.07 (1.04)% of the nominal nebulized dose was delivered to the lungs.

Conclusions  The 30 min urinary recovery of salbutamol, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the lung deposition of nebulized systems. Similarly, the urinary 24 h recovery of salbutamol plus its metabolite, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the delivery of nebulized drug to the systemic circulation.
Stereoselective urinary excretion of formoterol and its glucuronide conjugate in human
Authors: Zhang Mei , Fawcett J. Paul , Shaw John P.
Published: March 2003

Aims
Formoterol is an inhaled β2‐adrenoceptor agonist used as a racemic mixture of the active (R; R)‐ and inactive (S; S)‐enantiomers (rac‐formoterol). Glucuronidation is an important route of metabolism in humans which occurs faster for (S; S)‐formoterol in human liver microsomes. The aim of this study was to investigate the stereoselectivity of urinary excretion of formoterol and its glucuronide conjugate after oral dosing with rac‐formoterol.

Methods
Seven nonsmoking volunteers (six males, one female) were included in the study. After an overnight fast, a single 60 µg oral dose of rac‐formoterol fumarate dihydrate was ingested. Urine samples were collected at 1 h intervals for the first 4 h, and at 6, 8, 12 and 24 h after dosing. Formoterol enantiomers were analysed by chiral h.p.l.c. assay and formoterol glucuronides were determined as formoterol enantiomers after enzymatic cleavage with β‐glucuronidase.

Results
The female subject displayed a different pattern of metabolism and statistical analysis was therefore limited to data for the six males. The median (range) of the total urinary excretion of formoterol was 37.8% (20.9–51.2%) of the dose. The medians (ranges) of the amounts of (R; R)‐ and (S; S)‐formoterol and of (R; R)‐ and (S; S)‐formoterol glucuronide excreted were 2.1 (1.0–2.9), 3.5 (2.6–3.8), 21.0 (13.1–31.0) and 10.3 (4.2–14.6)%, respectively, of the dose. Unchanged (S; S)‐formoterol excretion was significantly greater than that of unchanged (R; R)‐formoterol and (R; R)‐formoterol glucuronide excretion was significantly greater than that of (S; S)‐formoterol glucuronide. The total RR‐formoterol (unchanged drug plus glucuronide) excreted was significantly greater than the total (S; S)‐formoterol.

Conclusions
Our study demonstrates that the urinary excretion of formoterol in male humans after oral administration of rac‐formoterol is stereoselective with preferential excretion of the active (R; R)‐formoterol as unchanged drug and glucuronide. The different pattern of metabolism in the female subject provides impetus for further studies of the effect of gender on the stereoselective metabolism and pharmacokinetics of formoterol.