bluuebunny/crossref_metadata_2025 huggingface dataset:
Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end‐stage renal disease: evidence for a ‘futile cycle’ of elimination
Authors: Grubb  , Rudy  , Brater  , Hall
Published: March 2003

Aims To assess if futile cycling of ketoprofen occurs in patients with decreased renal function.

Methods Ketoprofen was administered to six haemodialysis‐dependent patients with end‐stage renal disease as single (50 mg) or multiple doses (50 mg three times daily, for 7 days). Plasma and dialysate concentrations of the unconjugated and glucuronidated R‐ and S‐enantiomers of ketoprofen were determined using h.p.l.c. following the single and multiple dosing.

Results The oral clearance was decreased and terminal elimination half‐lives of R‐ and S‐ketoprofen and the corresponding acyl glucuronides were increased in functionally anephric patients compared with healthy subjects. In contrast with the R‐isomers, S‐ketoprofen and S‐ketoprofen glucuronide exhibited an unexpected accumulation (2.7–3.8 fold) after repeated dosing achieving S:R ratios of 3.3±1.7 and 11.2±5.3, respectively. The plasma dialysis clearances for R‐ and S‐ketoprofen glucuronides were 49.4±19.8 and 39.0±15.9 ml min−1, respectively, and 10.8±17.6 and 13.3±23.5 ml min−1 for unconjugated R‐ and S‐ketoprofen.

Conclusions The selective accumulation of S‐ketoprofen and its acyl glucuronide are consistent with amplification of chiral inversion subsequent to futile cycling between R‐ketoprofen and R‐ketoprofen glucuronide. Severe renal insufficiency, and possibly more modest decrements, results in a disproportionate increase in systemic exposure to the S‐enantiomer which inhibits both pathologic and homeostatic prostaglandin synthesis.
Lymphocyte‐sensitivity to glucocorticoid correlates with the sensitivity to cyclosporin A and tacrolimus in chronic renal failure patients
Authors: Horigome  , Hirano  , Oka  , Takeuchi  , Sakurai  , Kozaki  , Matsuno  , Nagao  , Kozaki
Published: March 2003

Aims Association between lymphocyte‐sensitivity to immunosuppressants in transplant recipients in vitro and clinical outcomes has been demonstrated. In general, renal transplant recipients are treated with a combination of immunosuppressants such as either glucocorticoid/cyclosporin A (CsA) or glucocorticoid/tacrolimus (FK506) but the pharmacological complementarity of these drugs is still controversial. We examined relationships between the lymphocyte‐sensitivities to these immunosuppressants.

Methods We examined lymphocyte‐sensitivities to prednisolone (PSL), CsA, and FK506 in vitro in a total of 190 chronic renal failure (CRF) patients and 140 healthy subjects. The lymphocyte‐sensitivity was evaluated from the IC50 value against mitogen‐stimulated lymphocyte‐blastogenesis in vitro.

Results Statistically significant correlations of the IC50 values in CRF patients between the following pairs of drugs were observed: PSL and CsA (P<0.0001; n=129, r=0.419), PSL and FK506 (P<0.001; n=54, r=0.441), and CsA and FK506 (P<0.0001; n=45, r=0.608).Similar correlations were also observed in lymphocytes from healthy subjects. The population of CRF patients who exhibited high IC50 values (low sensitivities) to PSL and FK506 was significantly larger than that of healthy subjects (P<0.05).

Conclusions Patients who showed low lymphocyte‐sensitivity to either of the drugs also may exhibit low sensitivity to the others, and thus they may have a high risk of unsatisfactory outcome under combination therapy after renal transplantation. To overcome this risk, the selection of immunosuppressants is recommended to be restricted according to individual lymphocyte‐sensitivities to these drugs in vitro, or alternatively, by addition of other drugs with different mechanisms for immunosuppression.
Persistence of anti‐hypertensive effect after missed dose of perindopril
Authors: Tan  , Leenen
Published: March 2003

Aims To assess the persistence of the antihypertensive effect of the ACE‐inhibitor perindopril after one missed dose.

Methods After a placebo run‐in period, 10 hypertensive patients were started on perindopril 4 mg once daily in the morning, increased to 8 mg once daily after 4 weeks if office diastolic BP >85 mmHg. 24 h BP monitoring was performed at the end of the placebo run‐in period and during active treatment in week 9 and 10 on either active treatment or a placebo‐day using a double‐blind, randomized, cross‐over design.

Results Office BP decreased from 155±3/100±2 mmHg at the end of placebo to 139±3/89±2 mmHg (P<0.05 vs placebo) after 8 weeks of active treatment. After 2 months of active treatment, 24 h ABP showed significant decreases in day BP by −11±1/−7±1 mmHg and in night BP by −11±2/−7±1 mmHg while on active treatment. During the placebo‐day, daytime BP showed decreases by −10±1/−5±1 and night BP by −8±2/−6±1 mmHg (NS vs active treatment day).

Conclusions Perindopril 4–8 mg day−1 causes a persistent decrease in BP during the 24 h dosing interval, which is mostly maintained over the 24–48 h after dosing.
Pharmacokinetics of rifabutin in HIV‐infected patients with or without wasting syndrome
Authors: Gatti  , Di Biagio  , De Pascalis  , Guerra  , Bassetti  , Bassetti
Published: March 2003

Aims The purpose of the study was to compare the pharmacokinetic parameters of rifabutin obtained in a group of patients without wasting syndrome (NWS) with those obtained in a group with wasting syndrome (WS).

Methods A single dose of 300 mg rifabutin was administered in the fasting state to the patients in both study groups and blood samples were scheduled to be collected at the following times: 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72 and 96 h following administration. Data were analysed using noncompartmental methods. The pharmacokinetic parameters of rifabutin in patients with and without wasting syndrome were compared using the Mann–Whitney U‐test.

ResultsCmax was 0.34±0.14 mg l−1 in NWS patients and 0.55±0.16 mg l−1 (P=0.01) in patients with WS. tmax was 4.2±1.5 and 3.3±2.3 h (P=0.17) in NWS and WS patients, respectively. The AUCs were similar in the two study groups. V/F was 2905±1646 l in NWS patients and 1701±492 l (P=0.07) for the WS group. These differences are less pronounced following normalization of V/F to patients body weight (43.7±20.1 vs 35.4±10.3 l kg−1 ). t1/2,λz tended to be shorter in patients with WS (31.4±12.9 vs 46.0±23.5 h, P=0.12).

Conclusions Our study suggests that the pharmacokinetics of rifabutin in patients with wasting syndrome are not altered to a degree that is clinically important.
The therapeutic monitoring of antimicrobial agents
Authors: Begg Evan J. , Barclay Murray L. , Kirkpatrick Carl J. M.
Published: March 2003

Aims To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents.

Methods Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring were reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualisation of therapy, sampling times, methods of analysis, interpretative problems and cost‐effectiveness of monitoring.

Results There is a strong historical case for monitoring aminoglycosides. The recent move to once‐daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances.

Conclusions The approach to monitoring aminoglycosides needs to be redefined in the light of once‐daily dosing. It is premature to suggest that less stringent monitoring is necessary as toxicity remains a problem with these drugs. The ideal method of monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is monitored occasionally to ensure efficacy while flucytosine is monitored occasionally to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.
The effects of vapreotide, a somatostatin analogue, on gastric acidity, gallbladder emptying and hormone release after 1 week of continuous subcutaneous infusion in normal subjects
Authors: Ritz Marc Alain , Drewe Jürgen , Ziel Annette , Hildebrand Pius , Schneider Pierre , Lahlou Najiba , Beglinger Christoph
Published: March 2003

Aims Somatostatin analogues (e.g. vapreotide) are used for treatment of acromegaly, endocrine tumours and variceal bleeding. The pharmacodynamic effects of vapreotide have, however, not been documented in the gastrointestinal tract. The aim of this study was to investigate the effects of continuous vapreotide administration on gastric acidity, gallbladder contraction and hormone release.

Methods Ten healthy males participated in this randomised, placebo‐controlled, double‐blind, crossover trial. A constant vapreotide (or placebo) infusion (1.5 mg day−1 s.c.) was given for 7 days with a portable pump. Intragastric pH was monitored on days 2 and 7. Gallbladder volume was sonographically assessed and the maximal ejection fraction was calculated. In addition basal and postprandial plasma levels of gastrin and cholecystokinin (CCK) were measured.

Results After an initial increase in the median 24 h intragastric pH to a value of 2.6 on day 2, vapreotide’s effect on pH decreased: (day 7: median pH=1.9; respective placebo values were 1.7 and 1.5). On the same days with vapreotide treatment, gallbladder contraction and plasma levels of CCK were reduced; maximal ejection fractions after meal stimulation were 18% and 20% (respective placebo values were 57% and 62%). Plasma gastrin levels were not changed with vapreotide treatment.

Conclusions The short lasting effect of vapreotide on intragastric acidity suggests a down‐regulation of somatostatin receptors during treatment. The lack of effect on gastrin indicates that the effects on gastric pH are not mediated by gastrin. Constant vapreotide infusion (but not placebo) reduced gallbladder contraction suggesting a long‐lasting effect on biliary function.
Estimation of the initial distribution volume of glucose by an incremental plasma glucose level at 3 min after i.v. glucose in humans
Authors: Hirota Kazuyoshi , Ishihara Hironori , Tsubo Toshihito , Matsuki Akitomo
Published: March 2003

Aims The initial distribution volume of glucose (IDVG) could be a clinically useful indicator of the central extracellular fluid (ECF) space volume, namely the interstitial fluid volume status of highly perfused organs. In this study, we determined the formula of IDVG using incremental plasma glucose levels after i.v. glucose.

Methods One hundred and fifty patients admitted to the general intensive care unit of the University of Hirosaki hospital were entered into this prospective study which was conducted in two stages. In the first stage 300 data points from 100 patients were used to measure the IDVG (3 determinations for each patients). This utilized a one compartment model to describe the incremental plasma glucose decay curve following an intravenous bolus injection of glucose which, in turn, was used to derive the parameters of an equation for IDVG prediction following a single plasma sample. The second stage was a validation of the equation using a separate data set (150 points) from a further 50 patients.

Results A one phase exponential decay model was well‐fitted for the IDVG‐postadministration glucose level curve, and indicated that the incremental glucose level at 3 min after i.v. glucose was best‐correlated to the IDVG compared with those at 1, 2, 4, 5 and 7 min postadministration. The formula of the IDVG was obtained from the curve: IDVG=24.44×e−0.0298×ΔGL+2.70, where ΔGL=incremental glucose level at 3 min after i.v. glucose. Another 150 samples showed that the measured‐IDVG from a one compartment model and predicted‐IDVG from the formula were 7.24±1.63 and 7.27±1.52 l, respectively, and that there was a significant correlation between the two IDVGs (r=0.966, P<0.0001).

Conclusions Using an incremental glucose level at 3 min after i.v. glucose, we have established the reliable formula for determination of the IDVG which could be a clinically useful indicator of the central ECF volume.
Retrospective analysis of the frequency and recognition of adverse drug reactions by means of automatically recorded laboratory signals
Authors: Tegeder  , Levy  , Muth‐Selbach  , Oelkers  , Neumann  , Dormann  , Azaz‐Livshits  , Criegee‐Rieck  , Schneider  , Hahn  , Brune  , Geisslinger
Published: March 2003

Aims To estimate the frequency of adverse drug reactions (ADRs) identified through the use of automatic signals generated from laboratory data (ALS) in hospitalised patients. To determine the frequency of spontaneous recognition of these ADRs by the attending physicians and to assess the potential value of ALS for detection of ADRs.

Methods Laboratory results of patients hospitalised in a nine bed medical ward were automatically recorded over a period of 17 months. Values exceeding defined boundaries were used as ALS. Charts of every third patient were analysed retrospectively with regard to adverse drug related reactions and causality was evaluated as well as whether the ADR had been recognised during the period of hospitalisation.

Results The charts and ALS of 98 patients were analysed. In 18 cases a drug‐related adverse reaction was probable. Awareness to the reaction by the treating physicians was evident in 6 out of these 18 ADRs. Approximately 80% of the ADRs were considered predictable. Three ADRs were regarded as serious.

Conclusions Adverse drug reactions are common and often preventable. Only one third of ADRs which could have been detected through ALS were recognised by the attending physicians. An increased doctor’s awareness of the frequency of drug related abnormal laboratory results by means of ALS is likely to increase the recognition rate of ADRs and might help to prevent them.
Morphine and morphine‐6‐glucuronide in the plasma and cerebrospinal fluid of children
Authors: Hain Richard D. W. , Hardcastle  , Pinkerton  , Aherne
Published: March 2003

Aims To measure morphine and morphine‐6‐glucuronide in the plasma and cerebrospinal fluid of children following a single intravenous dose of morphine.

Methods Twenty‐nine paired samples of cerebrospinal fluid and plasma were collected from children with leukaemia undergoing therapeutic lumbar puncture. An intravenous dose of morphine was administered at selected intervals before the procedure. Concentrations of morphine and morphine‐6‐glucuronide (M6G) were measured in each sample. Morphine was measured using a specific radioimmunoassay (r.i.a.) and M6G was measured using a novel enzyme‐linked immunosorbent assay (ELISA).

Results The ELISA for measuring M6G was highly sensitive. The intra‐and interassay variations were less than 15%. Using a two‐compartment model for plasma morphine, the area under the curve to infinity (AUC, 7143 ng ml−1 min), volume of distribution (3.6 l kg−1 ) and elimination half‐life (88 min) were comparable with those reported in adults. Clearance (35 ml min−1 ) was higher than that in adults. Morphine‐6‐glucuronide was readily synthesized by the children in this study. The elimination half‐life (321 min) and AUC (35507 ng ml−1 min) of plasma M6G were much greater than those of morphine.

Conclusions Extensive metabolism of morphine to M6G in children with cancer has been demonstrated. These data provide further evidence to support the importance of M6G accumulation after multiple doses. There was no evidence that morphine passed more easily into the CSF of children than adults.
Risk of malformations and other outcomes in children exposed to fluconazole in utero
Authors: Sørensen Henrik Toft , Nielsen Gunnar Lauge , Olesen Charlotte , Larsen Helle , Steffensen Flemming Hald , Schønheyder Henrik C. , Olsen Jørn , Czeizel Andrew E.
Published: March 2003

Aim
 Fluconazole is an active drug systematically used in the oral treatment of vaginal candidiasis and other fungal diseases. We examined the risk of malformations and other birth outcomes following pregnancy related exposures.

Method
 From 1 January 1991 to 31 December 1996 we identified 165 women who had taken fluconazole just before or during pregnancy in the Pregnancy Outcome Section of the North Jutland Pharmacoepidemiological Prescription Database, Denmark, which is linked to the Danish Medical Birth Registry. We compared their birth outcomes (malformation, low birth weight and preterm delivery) with the outcomes among 13 327 women who did not receive any prescriptions during their pregnancies.

Results
 The prevalence of malformation was 3.3% (four cases) among the 121 women, who had used fluconazole in the first trimester, and 5.2% (697 cases) in offspring to controls (odds ratio: 0.65, 95% confidence limits: 0.24–1.77). Furthermore, we did not find any significantly elevated risk of preterm delivery (odds ratio: 1.17, 95% confidence limits: 0.63–2.17) and low birth weight (odds ratio: 1.19, 95% confidence limits: 0.37–3.79).

Conclusion
 The study showed no increased risk of congenital malformations, low birth weight or preterm birth in offspring to women who had used single dose fluconazole before conception or during pregnancy.
The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)‐verapamil in humans
Authors: Sandström Rikard , Knutson Tina W. , Knutson Lars , Jansson Britt , Lennernäs Hans
Published: March 2003

Aims
 The purpose of this human intestinal perfusion study was to investigate the effect of ketoconazole on the jejunal permeability and first‐pass metabolism of (R)‐ and (S)‐verapamil in humans.

Methods
 A regional single‐pass perfusion of the jejunum was performed using a Loc‐I‐Gut® perfusion tube in six healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The inlet concentration of (R/S)‐verapamil was 120 mg l−1 in both periods, and ketoconazole was added at 40 mg l−1 in period 2. (R/S)‐verapamil was also administered as a short intravenous infusion of 5 mg, over a period of 10 min. The appearance ratios of the CYP3A formed metabolites (R)‐ and (S)‐norverapamil were also estimated in the outlet jejunal perfusate.

Results
 The effective jejunal permeability (Peff) of both (R)‐ and (S)‐verapamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P‐glycoprotein mediated efflux. However, the appearance ratio of both (R)‐ and (S)‐norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of absorption into plasma of (R)‐ and (S)‐verapamil increased despite the low dose of ketoconazole added, indicating an inhibition of the gut wall metabolism of (R/S)‐verapamil by ketoconazole.

Conclusions
 Ketoconazole did not affect the jejunal Peff of (R/S)‐verapamil, but it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of verapamil. This might be due to ketoconazole being less potent as an inhibitor of P‐glycoprotein than of CYP3A4 in vivo in humans.
Modification of general practitioner prescribing of antibiotics by use of a therapeutics adviser (academic detailer)
Authors: Ilett Kenneth F. , Johnson Sarah , Greenhill Graham , Mullen Lenette , Brockis Jennifer , Golledge Clayton L. , Reid Donald B.
Published: March 2003

Aims This was a pilot study of the use of a clinical pharmacist as a therapeutics adviser (academic detailer) to modify antibiotic prescribing by general practitioners.

Methods Following a visit by the adviser (March‐May), 112 general practitioners were recruited and randomised to control or active groups. A panel of experts prepared a best practice chart of recommended drugs for upper and lower respiratory tract infections, otitis media and urinary tract infections. The adviser made a 10–15 min visit to each prescriber in the active group (June–July), gave them the chart and discussed its recommendations briefly. Doctors in the control group were not visited nor given the chart. Prescription numbers for all prescribers were obtained from the Commonwealth Health Insurance Commission for the pre(March‐May) and postdetailing (August–September) periods using a three month lag time for data collection. Data for total numbers of prescriptions and for selected individual antibiotics used in these two periods were analysed using nonparametric statistics.

Results Prescribing patterns were similar for the control and active groups in the predetailing period. For both groups, there were significant (P<0.03) increases (45% for control and 40% for active) in total number of antibiotic prescriptions in the post compared with the predetailing period. This trend was anticipated on the basis of the winter seasonal increase in respiratory infections. In line with the chart recommendations for first‐line treatment, doctors in the active group prescribed significantly more amoxycillin (P<0.02) and doxycycline (P<0.001) in the post vs predetailing periods. By contrast, doctors in the control group prescribed significantly more cefaclor (P<0.03) and roxithromycin (P<0.03), drugs that were not recommended. The total cost of antibiotics prescribed by doctors in the control group increased by 48% ($37 150) from the preto postdetailing periods. In the same time period, the costs for the active group increased by only 35% ($21 020).

Conclusions We conclude that the academic detailing process was successful in modifying prescribing patterns and that it also decreased prescription numbers and costs. Application of the scheme on a nationwide basis could not only improve prescriber choice of the most appropriate antibiotic but also result in a significant saving of health care dollars.
Inhibitory effects of amiodarone and its N‐deethylated metabolite on human cytochrome P450 activities: Prediction of in vivo drug interactions
Authors: Ohyama K. , Nakajima M. , Suzuki M. , Shimada N. , Yamazaki H. , Yokoi T.
Published: March 2003

Aims
 To predict the drug interactions of amiodarone and other drugs, the inhibitory effects and inactivation potential for human cytochrome P450 (CYP) enzymes by amiodarone and its N‐dealkylated metabolite, desethylamiodarone were examined.

Methods
 The inhibition or inactivation potency of amiodarone and desethylamiodarone for human CYP activities were investigated using microsomes from B‐lymphoblastoid cell lines expressing CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The in vivo drug interactions of amiodarone and desethylamiodarone were predicted in vitro using the 1+Iu/Ki values.

Results
 Amiodarone weakly inhibited CYP2C9, CYP2D6, and CYP3A4‐mediated activities with Ki values of 45.1–271.6 μm. Desethylamiodarone competitively inhibited the catalytic activities of CYP2D6 (Ki=4.5 μm ) and noncompetitively inhibited CYP2A6 (Ki=13.5 μm ), CYP2B6 (Ki=5.4 μm ), and CYP3A4 (Ki=12.1 μm ). The catalytic activities of CYP1A1 (Ki=1.5 μm, α=5.7), CYP1A2 (Ki=18.8 μm, α=2.6), CYP2C9 (Ki=2.3 μm, α=5.9), and CYP2C19 (Ki=15.7 μm, α=4.5) were inhibited by desethylamiodarone with mixed type. The 1+Iu/Ki values of desethylamiodarone were higher than those of amiodarone. Amiodarone inactivated CYP3A4, while desethylamiodarone inactivated CYP1A1, CYP1A2, CYP2B6, and CYP2D6.

Conclusions
 The interactions between amiodarone and other drugs might occur via the inhibition of CYP activities by its N‐dealkylated metabolite, desethylamiodarone, rather than by amiodarone itself. In addition, the inactivation of CYPs by desethylamiodarone as well as by amiodarone would also contribute to the drug interactions.
Comparison of the neurokinin‐1 antagonist GR205171, alone and in combination with the 5‐HT3 antagonist ondansetron, hyoscine and placebo in the prevention of motion‐induced nausea in man
Authors: Reid K. , Palmer J. L. , Wright R. J. , Clemes S. A. , Troakes C. , Somal H. S. , House F. , Stott J. R. R.
Published: March 2003

Aims
In man a neurokinin‐1 (NK1) receptor antagonist has previously been shown to be ineffective in the prevention of motion‐induced nausea. The antiemetic efficacy of NK1 receptor antagonists against chemotherapy‐induced emesis is, however, enhanced when combined with a 5‐HT3 receptor antagonist. Hence the efficacy of the NK1 antagonist GR205171 in combination with the 5‐HT3 antagonist ondansetron (Zofran™) was assessed in motion‐induced nausea.

Methods
GR205171 25 mg i.v., with and without concomitant administration of ondansetron 8 mg i.v., and hyoscine hydrobromide 0.6 mg orally (positive control) were compared with placebo in a model of motion‐induced nausea. The study was performed to a four‐period, randomized, balanced, double‐blind, crossover design in 16 healthy subjects. The end‐point was the exposure to the motion stimulus required to produce moderate nausea in the subjects.

Results
The motion stimulus required to produce moderate nausea was significantly greater for the positive control than placebo (P < 0.001). There was no significant difference between either GR205171 or GR205171 plus ondansetron and placebo (P = 0.648 and 0.342, respectively).

Conclusions
The enhancement of NK1 receptor antagonist antiemetic activity through combination with a 5‐HT3 receptor antagonist is not replicated in motion‐induced nausea.
Effect of P‐glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine
Authors: Drewe Jürgen , Ball Howard A. , Beglinger Christoph , Peng Bin , Kemmler Andreas , Schächinger Hartmut , Haefeli Walter E.
Published: March 2003

Aims
To investigate the effect of acute P‐glycoprotein inhibition by the multidrug‐resistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G).

Methods
In a double‐blind, three‐way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO2, blood pressure) of morphine were compared with and without acute inhibition ofP‐glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18 healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With the expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h.

Results
The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically significant increase in the AUC and Cmax of M3G (11.8 and 8.3%, respectively). The t½ and tmax were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not significantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (Emax 48 ms, compared with the predose absolute reaction time of 644 ms), which was not detected by the alertness‐drowsiness score, indicating only slight sedation. There was a significant decrease in systolic blood pressure (Emin−9 mmHg), and a trend for a fall in diastolic blood pressure (Emin−14.5 mmHg) and respiratory rate (Emin−1.8 breath·min−1). For all these parameters, the effects of PSC/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a significant increase in PCO2 (Emax 0.69 kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination.

Conclusions
Acute inhibition of P‐glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety‐related pharmacodynamic profile of morphine in a clinically significant manner.
Steady‐state pharmacokinetics of (R)‐ and (S)‐methadone in methadone maintenance patients
Authors: Foster David J. R. , Somogyi Andrew A. , Dyer Kyle R. , White Jason M. , Bochner Felix
Published: March 2003

Aims  To investigate the steady‐state pharmacokinetics of (R)‐ and (S)‐methadone in a methadone maintenance population.

Methods  Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma α1‐acid glycoprotein concentrations were quantified by radial immunoassay.

Results  (R)‐methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)‐methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)‐methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)‐methadone, while

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

, steady‐state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)‐methadone and (S)‐EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%.

Conclusions  Steady‐state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose‐plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic‐pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.
Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis
Authors: Mayo Patrick R. , Skeith Kenneth , Russell Anthony S. , Jamali Fakhreddin
Published: March 2003

Aims  Inflammation reduces hepatic clearance of many drugs with unknown therapeutic consequences. This study was carried out to examine the effect of rheumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of verapamil.

Methods  Eight RA patients were age‐ and sex‐matched with eight healthy volunteers. The disease severity was assessed, and ECG, blood pressure and verapamil enantiomers concentrations were measured for 12 h post 80 mg oral verapamil. Serum interleukin‐6 (IL‐6) and nitrite (NO2–) were measured in predose samples.

Results  IL‐6 and NO2– concentrations were significantly increased in parallel with disease severity. Oral clearance of both S‐ and R‐verapamil was significantly decreased by RA. While the unbound fraction of S‐ and R‐verapamil decreased by 5 and 7‐fold, respectively, the unbound AUC remained unchanged for the more potent enantiomer, S‐verapamil. AUC of norverapamil enantiomers was increased 2–3‐fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR‐interval was significantly reduced by one fold and the effect on the heart rate and blood pressure did not increase.

Conclusions  RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic blood flow. A significant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro‐inflammatory cytokines and/or NO.
Patterns of prescription and drug use in ophthalmology in a tertiary hospital in Delhi
Authors: Biswas Nihar R. , Jindal Sanjay , Siddiquei M. Mairaj , Maini Rajiv
Published: March 2003

Aims  The present study was carried out to describe the patterns of prescription and drug use in Ophthalmology in out‐patients at Dr Rajendra Prasad (R.P.) Centre for Ophthalmic Sciences of All India Institute of Medical Sciences (A.I.I.M.S.), New Delhi.

Methods  Prescriptions of 1017 out‐patients were audited through a specially designed form and analysed for the following: average number of drugs per prescription, duration of treatment (recorded or not), dosage forms prescribed, frequency of administration (recorded or not), number of encounters with antibiotics and percentage of drugs prescribed by generic name.

Results  Prescription analysis showed that the average number of drugs per prescription was 3.03. Duration of treatment was recorded for only 26.4% of the drugs prescribed. The maximum number of drugs prescribed were in the form of eye drops (76%), followed by tablets (10.9%), ointments (6.4%), syrups (1%), capsules (0.7%), lotions (0.3%) and injections (0.1%). No dosage form was recorded for 4.6% of the drugs prescribed. The frequency of administration was recorded for only 77.9% of the drugs prescribed. The number of antibiotics prescribed was 1059 which constitutes 34.2% of the total number of drugs prescribed. The percentage of drugs prescribed by generic name was only 35%.

Conclusions  The results obtained in this study indicated an awareness of polypharmacy but a high incidence of common prescription writing errors such as not recording the duration of therapy, frequency of administration and dosage form. Moreover prescribing by generic name was also low.
A dose–response study of adrenaline combined with lignocaine 2%: effect on acute postoperative pain after oral soft tissue surgery
Authors: Jorkjend L. , Skoglund L. A.
Published: March 2003

Aims  The combination of lignocaine and adrenaline may cause more postoperative pain than other types of local anaesthetic agents with comparable clinical efficacy. This study investigates the dose‐response effect of adrenaline added to lignocaine on postoperative pain, when used as local anaesthetic for oral soft tissue surgery.

Methods  A controlled, randomized, double‐blind, parallel group study included 195 patients (108 females/87 males) with mean age 49 years (range 26–75 years). The patients were allocated to one of three treatment groups receiving lignocaine 2% (n = 66), lignocaine 2% with adrenaline 1 : 160 000 (n = 63) or lignocaine 2% with adrenaline 1 : 80 000 (n = 66).

Results  Lignocaine 2% with adrenaline 1 : 80 000 gave significantly more pain intensity than lignocaine 2% or lignocaine 2% with adrenaline 1 : 160 000. The postoperative pain intensity courses after lignocaine 2% and lignocaine 2% with adrenaline 1 : 160 000 showed a similar pattern except for the time period just after completion of surgery when lignocaine 2% with adrenaline 1 : 80 000 caused less pain.

Conclusions  High adrenaline concentrations (1 : 80 000) combined with lignocaine local anaesthetic solution offers no advantage with respect to pain alleviation during the immediate postoperative pain period. High exogenous adrenaline concentrations may play a significant role in enhancing acute postoperative intensity.
Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects
Authors: Lebrun‐Vignes B. , Archer V. Corbrion , Diquet B. , Levron J. C. , Chosidow O. , Puech A. J. , Warot D.
Published: March 2003

Aims  Itraconazole is a potent inhibitor of CYP3A4 activity and is often used in combination with corticosteroids. Since the latter are partly metabolized by CYP3A4, we studied the interaction between itraconazole, prednisone and methylprednisolone in healthy male subjects.

Methods  The effects of 4 days administration of oral itraconazole (400 mg on the first day then 200 mg day−1 for 3 days) on the pharmacokinetics of prednisolone after a single oral dose of prednisone (60 mg) and the pharmacokinetics of methylprednisolone after single oral dose of methylprednisolone (48 mg) were studied in 14 healthy male subjects in a two‐period cross‐over trial. Plasma cortisol concentrations were determined as a pharmacodynamic index.

Results  Itraconazole increased the mean area under the methylprednisolone concentration‐time curve from 2773 ng ml−1 h to 7011 ng ml−1 h (P < 0.001) and the elimination half‐life from 3.2 h to 5.5 h (P < 0.001). The pharmacokinetics of prednisolone were unchanged. Cortisol concentrations at 24 h were lower after administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 ng ml−1vs 109 ng ml−1, P < 0.001).

Conclusions  Itraconazole increased methylprednisolone concentrations markedly with enhanced suppression of endogenous cortisol secretion, but had no effect on prednisolone pharmacokinetics. The pharmacokinetic interaction between methylprednisolone and itraconazole is probably related to inhibition of hepatic CYP3A4 activity by itraconazole.
Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N‐acetyltransferase in healthy human subjects
Authors: Frye Reginald F. , Branch Robert A.
Published: March 2003

Aims  Short‐term disulfiram administration has been shown to selectively inhibit CYP2E1 activity but the effects of chronic disulfiram administration on the activities of drug metabolizing enzymes is unclear. The purpose of this study was to evaluate the effects of disulfiram given for 11 days on selected drug metabolizing enzyme activities.

Methods  Seven healthy volunteers were given disulfiram 250 mg daily for 11 days. Activities of the drug metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, CYP2E1 and N‐acetyltransferase were determined using the probe drugs caffeine, mephenytoin, debrisoquine, chlorzoxazone, and dapsone, respectively. Chlorzoxazone was administered before disulfiram administration and after the second and eleventh doses of disulfiram, while the other probe drugs were given before disulfiram administration and after the eleventh disulfiram dose.

Results  Disulfiram administration markedly inhibited chlorzoxazone 6‐hydroxylation by more than 95%, but did not affect metabolism of debrisoquine or mephenytoin. Caffeine N3‐demethylation was decreased by 34% (P < 0.05). Monoacetyldapsone concentrations were markedly elevated by disulfiram administration resulting in a nearly 16‐fold increase in the dapsone acetylation index, calculated as the plasma concentration ratio of monoacetyldapsone to dapsone. CYP‐mediated dapsone N‐hydroxylation was not significantly altered.

Conclusions  These data suggest that disulfiram‐mediated inhibition is predominantly selective for CYP2E1. The magnitude of CYP2E1 inhibition was similar after both acute and chronic disulfiram administration. The effects on caffeine N3‐demethylation (CYP1A2) and dapsone metabolism suggest that chronic disulfiram administration may affect multiple drug metabolizing enzymes, which could potentially complicate the use of chronically administered disulfiram as a diagnostic inhibitor of CYP2E1.
Web based information on clinical toxicology for the United Kingdom: uptake and utilization of TOXBASE in 2000
Authors: Bateman D. Nicholas , Good Alison M. , Kelly Catherine A. , Laing William J.
Published: March 2003

Aims  To examine the use and uptake of TOXBASE, an Internet database for point of care provision of poisons information in the United Kingdom during its first calendar year of web‐based access.

Methods  Interrogation of the database software to examine: use by different types of user and geographical origin; profile of ingredient and product access; time of access to the system; profile of access to other parts of the database.

Results  Registered users of the system increased in the first full year of operation (1224 new users) and usage of the system increased to 111 410 sessions with 190 223 product monograph accesses in 2000. Major users were hospitals, in particular accident and emergency departments. NHS Direct, a public access information service staffed by nurses, also made increasing use of the system. Usage per head of population was highest in Northern Ireland and Scotland, and least in southern England. Ingredients accessed most frequently were similar in all four countries of the UK. Times of use of the system reflect clinical activity, with hospitals making many accesses during night‐time hours. The most popular parts of the database other than poisons information were those dealing with childhood poisoning, information on decontamination procedures, teratology information and slang terms for drugs of abuse.

Conclusions  This Internet system has been widely used in its first full year of operation. The provision of clinically relevant, up to date, information at the point of delivery of patient care is now possible using this approach. It has wide implications for the provision of other types of therapeutic information in clinical areas. Web‐based technology represents an opportunity for clinical pharmacologists to provide therapeutic information for clinical colleagues at the bedside.
Surrogacy in antiviral drug development
Authors: Shaunak Sunil , Davies Donald S.
Published: March 2003

The coming of age of molecular biology has resulted in an explosion in our understanding of the pathogenesis of virus related diseases. New pathogens have been identified and characterized as being responsible for old diseases. Empirical clinical evaluation of morbidity and mortality as outcome measures after a therapeutic intervention have started to give way to the use of an increasing number of surrogate markers. Using a combination of these markers, it is now possible to measure and monitor the pathogen as well as the host's response. Nowhere is this better exemplified in virology than in the field of AIDS. We have utilized the advances in pathogenesis and new antiretroviral drug development to:

• develop a new class of drugs which block the entry of HIV‐1 into cells.

• develop a new approach for effectively delivering these drugs to those tissues in which most viral replication takes place.

Over the last 10 years, our work has progressed from concept to clinical trial. Our laboratory based evaluation of the new molecules developed as well as our clinical evaluation of their safety and efficacy have had to respond and adapt to the rapid changes taking place in AIDS research. This paper discusses the problems encountered and the lessons learnt.
Early clinical experience with the novel proteasome inhibitor PS–519
Authors: Shah I. M. , Lees K. R. , Pien C. P. , Elliott P. J.
Published: March 2003

Aims
The main objective of this study was to investigate the safety, tolerability and pharmacodynamics of the novel proteasome inhibitor PS−519 in young male volunteers. Many pro‐inflammatory mediators such as cytokines and cell adhesion molecules that are responsible for the development of the cerebral infarct are under the control of the transcription factor Nuclear Factor kappa‐B (NF‐κB). The activity of NF‐κB is itself tightly regulated through the multicatalytic enzyme known as the proteasome. PS‐519 is a novel and highly selective small molecule that inhibits the proteasome.   An   ex   vivo  assay   of   20S   proteasome   activity   allows   monitoring   of the drug effect in blood. PS‐519 is protective in multiple animal models of cerebral ischaemia over a range of doses that achieve 20S inhibition of 40%−80%.

Methods
PS‐519 has been administered to healthy male volunteers as single and repeated doses up to 1.6 mg m−2. It was given as an intravenous bolus over 20–30 s in a double blind, randomized, placebo‐controlled phase I study, examining vital signs, safety, tolerability and blood 20S proteasome inhibition.

Results
Thirty‐nine subjects received single doses of 0.012 mg m−2−1.6 mg m−2 and 28 subjects received doses of 0.5 mg m−2−1.6 mg m−2 on three consecutive days. The drug was well tolerated. There was no clear treatment‐emergent symptom or abnormality of laboratory tests. Proteasome inhibition in blood samples as measured by 20S assay achieved the intended maximum target level of 70–80% with 1.6 mg m−2, and was reproducible with repeated dosing.

Conclusions
This study has demonstrated that proteasome inhibition is well tolerated by healthy subjects at levels that are maximally neuroprotective in experimental conditions. Further clinical evaluation appears justified.
Absolute bioavailability of midazolam after subcutaneous administration to healthy volunteers
Authors: Pecking M. , Montestruc F. , Marquet P. , Wodey E. , Homery M.‐C. , Dostert P.
Published: March 2003

Aims
Midazolam is given intravenously for induction of anaesthesia and conscious sedation and by subcutaneous infusion in patients in palliative care units. The objective of the present study was to determine the absolute bioavailability of subcutaneous midazolam and its pharmacokinetics in young, healthy, male volunteers. 

Methods
Eighteen volunteers were given single doses of 0.1 mg kg−1 midazolam i.v. and s.c. after a wash‐out period of 7–15 days in an open‐label, randomized, cross‐over study. Blood samples were collected up to 12 h post‐infusion. Plasma concentrations of midazolam and of its two metabolites, 1′‐OHM and 4‐OHM, were assessed using an h.p.l.c.‐MS method (LOQ 0.5 ng ml−1 for each analyte). Vital signs, cardiac parameters and oximetry were monitored. Local tolerance was determined and adverse events were also monitored.

Results
After   s.c.   infusion  tmax   and  Cmax   were   0.51 ± 0.18 h   and 127.8 ± 29.3 ng ml−1 (mean ± s.d.), respectively. No statistically significant difference was detected in AUC(0,∞) after i.v. and s.c. administration. The mean (± s.d.) absolute bioavailability of subcutaneous midazolam was 0.96 (± 0.14) (CI 0.84, 1.03).   Mean   (± s.d.)  t1/2   was   similar   after   s.c.   (3.2   (± 1.0)   h)   and   i.v.   infusion   (2.9   (± 0.7)   h),   although   a   statistically   significant   difference   was   reached   (P < 0.05). Mean CL and V of i.v. midazolam were 4.4 ± 1.0 ml min−1 kg−1 and 1.1 ± 0.2 l kg−1 (mean ± s.d.), respectively. Plasma concentrations of 1’‐OHM were higher than those of 4‐OHM. Few mild and transient adverse events were noted and there were no clinically significant effects on EEG, blood pressure and laboratory parameters.

Conclusions
This study has shown that subcutaneous midazolam has excellent bioavailability and that administration of midazolam by this route could be preferable when the intravenous route is inappropriate.