bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses
Authors: Rogers  , Friedhoff
Published: March 2003

Aim The aim of this study was to characterize the pharmacokinetic and pharmacodynamic profile of donepezil HCl, a chemically distinct and specific acetylcholinesterase (AChE) inhibitor for the treatment of Alzheimer’s disease, following administration of single oral doses.

Methods This was a double‐blind, randomized, single‐dose, placebo‐controlled, sequential‐group, ascending‐dose study in healthy male volunteers (n=48). Six dose levels were investigated, ranging from 0.3 to 6.0 mg. Donepezil concentrations in plasma were determined by HPLC with UV detection. Pharmacodynamic activity was determined by the radioenzymatic measurement of erythrocyte membrane acetylcholinesterase (rbc‐AChE) inhibition.

Results The pharmacokinetic disposition of donepezil was observed to be both linear and dose proportional following single‐dose administration. The mean peak plasma concentration (Cmax ) of donepezil was observed at 4.1±1.5 h. The mean terminal disposition half‐life was 81.5±22.0 h. The post‐absorption phase of the plasma concentration–time curves for the 4.0 mg and 6.0 mg doses appeared to be biphasic, but the rate of donepezil clearance was independent of dose. Plasma concentrations for the 0.3, 0.6 and 0.9 mg dose groups were generally below the level of HPLC detection (2.0 ng ml−1 ), preventing accurate characterization of these doses. A direct correlation was observed between plasma donepezil concentrations and extent of AChE inhibition. For the 4.0 and 6.0 mg donepezil dose groups, maximal AChE inhibition (Emax ) ranged from 33% to 35% and there was significant correlation between AChE inhibition and donepezil plasma concentration (P<0.005).

Conclusions The pharmacokinetics of donepezil were found to be linear and dose proportional following the administration of single doses to healthy volunteers. A direct correlation was also observed between plasma donepezil concentrations and AChE inhibition. The extended half‐life of donepezil makes it suitable for once‐daily dosing.
The effect of multiple doses of donepezil HCl on the pharmacokinetic and pharmacodynamic profile of warfarin
Authors: Tiseo  , Foley  , Friedhoff
Published: March 2003

Aim The aim of the study was to examine the pharmacokinetic and pharmacodynamic profiles of single doses of warfarin (25 mg) following administration alone, and in combination with multiple doses of donepezil HCl (10 mg day−1 ) in healthy volunteers.

Methods This was an open‐label, two‐period crossover study in 12 healthy male volunteers, aged 18–55 years, who were randomized to one of the following treatment groups: (A) donepezil administered for 19 consecutive days with a single dose of warfarin administered on day 14. On day 20, there was a 21‐day washout period after which a single dose of warfarin was again administered, and (B) an initial 13‐day period with no medication, then a single dose of warfarin administered alone on day 14, followed by a 14‐day washout period. Donepezil was then administered for 19 days (to day 47), with an additional single dose of warfarin administered on day 41. Serial blood samples were collected over 144 h following both warfarin administrations in each treatment group. Pharmacokinetic parameters were assessed for both (R )‐ and (S )‐warfarin concentrations in plasma, and pharmacodynamic analyses utilizing prothrombin time were undertaken. Warfarin concentrations in plasma were determined by HPLC with fluorescence detection. The pharmacokinetic parameters Cmax, AUC(0–∞), CL T/F, Vλz/F and t½ of both (R )‐ and (S )‐warfarin, maximum prothrombin time (Rmax ) and the area under the prothrombin–time curve (AUCPT ), were compared in the presence and absence of donepezil by analysis of variance (ANOVA ).

Results No statistically significant differences in (R )‐ or (S )‐warfarin pharmacokinetics were observed when warfarin administered alone was compared to warfarin administered concurrently with donepezil. Warfarin pharmacodynamic parameters, Rmax and AUCPT, were also unchanged by concomitant administration of donepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed.

Conclusions Concurrent administration of donepezil HCl does not alter the pharmacokinetic or pharmacodynamic profile of single doses of warfarin in healthy volunteers. These findings suggest that donepezil may be safely co‐administered with warfarin without the need for dose modification.
Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin
Authors: Sükrü Aynacioglu  , Brockmöller Jürgen , Bauer Steffen , Sachse Christoph , Güzelbey Pinar , Öngen Zuhal , Nacak Muradiye , Roots Ivar
Published: March 2003

Aims The genetically polymorphic cytochrome P450 enzyme CYP2C9 metabolizes many important drugs. We studied the frequency of the amino acid variants cysteine144 (CYP2C9*2 ) and leucine359 (CYP2C9*3 ) in a Turkish population and the correlation between genotype and phenotype using phenytoin as probe drug.

Methods CYP2C9 alleles *2 and *3 were measured in 499 unrelated Turkish subjects by PCR and restriction fragment length pattern analysis. Phenotyping was performed in a subgroup of 101 volunteers with a single oral dose of 300 mg phenytoin and concentration analysis in serum drawn 12 h after dosage.

Results CYP2C9 allele frequencies in 499 unrelated Turkish subjects were 0.794 for CYP2C9*1, 0.106 for CYP2C9*2 and 0.100 for CYP2C9*3. Mean phenytoin serum concentrations at 12 h after dosage were 4.16 mg l−1 (95% CI 3.86–4.46) in carriers of the genotype CYP2C9*1/1, 5.52 mg l−1 (4.66–6.39) in CYP2C9*1/2, and 5.65 mg l−1 (4.86–6.43) in CYP2C9*1/3. These differences were significant and accounted for 31% of total variability in phenytoin trough levels. Mean 12 h concentration ratios of 5‐(para‐hydroxyphenyl)‐5‐phenylhydantoin/phenytoin (p‐HPPH/P) were 0.43 (0.39–0.47) for CYP2C9*1/1 compared with 0.26 (0.21–0.31) for CYP2C9*1/2, 0.14 (0.13–0.14) for CYP2C9*2/2, 0.21 (0.18–0.24) for CYP2C9*1/3, and 0.02 for CYP2C9*3/3; all mutant genotypes were significantly different compared with CYP2C9*1/1.

Conclusions Frequency of the two CYP2C9 variants in Turkish subjects was in a similar range as in other Caucasian populations. A significant proportion of the interindividual variability in phenytoin trough levels is explained by the genotypes. The 12 h serum concentrations after a single phenytoin dose may be used for routine phenotyping of CYP2C9 mediated metabolic clearance and the p‐HPPH/P ratios may be even more sensitive indicators of CYP2C9 activity.
Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin‐angiotensin system
Authors: Buchwalder‐Csajka  , Buclin  , Brunner  , Biollaz
Published: March 2003

Aims The performance of the experimental paradigm of angiotensin challenges with continuous non‐invasive blood pressure measurement was evaluated. Angiotensin dose–response relationships were characterized, along with the influence of clinical covariates. The stability of angiotensin‐induced peaks and the variability of the angiotensin doses were assessed. Finally, the predictive value of studies based on angiotensin challenges to determine drug doses effective in therapeutics was evaluated.

Methods The data were gathered from 13 clinical studies on nine angiotensin II receptor antagonists, one ACE inhibitor and one dual ACE‐NEP inhibitor, using Finapres® for measuring the response to exogenous angiotensin challenges. Modelling of angiotensin dose–response curves and determination of the inter and intrasubject variability were performed by nonlinear regression (NONMEM). The different sources of variations in angiotensin I and II doses and angiotensin‐induced peaks were evaluated by analyses of variance. The dose of ACE inhibitors and angiotensin II receptor antagonists inhibiting blood pressure increase by at least 75%, as measured by this method, was chosen for comparison with the labelled starting dose.

Results Angiotensin challenges exhibited a clear dose–response relationship which can be characterized both by an Emax or a log linear model. The log linear model gave an average systolic/diastolic response of 24±6/20±5 mmHg for a unit dose of 1 μg of angiotensin II equivalents, and an increase of 6/6 mmHg for each doubling of the dose. The angiotensin ED50 calculated values were 0.67 μg for systolic and 0.84 μg for diastolic blood pressure. The angiotensin doses for eliciting a given response and the angiotensin induced peaks were fairly constant between period and subject, but vary significantly between studies. Based on an inhibition of blood pressure by 75%, the agreement was good between the doses of ACE inhibitors and angiotensin receptor antagonists predicted from studies using the methodology of angiotensin challenges and the doses shown to be clinically efficacious, in spite of high intersubject and intrasubject variabilities.

Conclusions This experimental method represents a valid surrogate for the therapeutic target and a useful tool for the pharmacokinetic and pharmacodynamic profiling of drugs acting on the renin‐angiotensin system.
Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity
Authors: Brynne  , Forslund  , Hallén  , Gustafsson  , Bertilsson
Published: March 2003

Aims To investigate the pharmacokinetics and safety of tolterodine and tolterodine metabolites after single‐and multiple‐dose administration in the absence and presence of ketoconazole, an inhibitor of cytochrome P450 (CYP) 3A4, in healthy volunteers with deficient CYP2D6 activity, i.e. poor metabolisers of debrisoquine.

Methods Eight healthy volunteers received single oral doses (2 mg) of tolterodine l‐tartrate. Following a wash‐out period of about 3 months, six of the subjects participated in a multiple‐dose (1 mg twice daily) phase of the study. Ketoconazole 200 mg was given once daily for 4–4.5 days during both the single and multiple dose tolterodine administration phases. Blood samples were drawn and the pharmacokinetics of tolterodine and its metabolites were determined.

Results A decrease (P<0.01) in apparent oral clearance of tolterodine, from 10– 12 l h−1 to 4.3–4.7 l h−1, was obtained during concomitant administration of ketoconazole, yielding at least a two‐fold increase in the area under the serum concentration‐time curve after single as well as after multiple doses following single dose administration of tolterodine. The mean (±s.d.) terminal half‐life increased by 50% from 9.7±2.7 h to 15±5.4 h in the presence of ketoconazole.

Conclusions CYP3A4 is the major enzyme involved in the elimination of tolterodine in individuals with deficient CYP2D6 activity (poor metabolisers), since oral clearance of tolterodine decreased by 60% during ketoconazole coadministration. This inhibition resulted in 2.1‐fold increase in AUC.
Possible enhancement of the first‐pass metabolism of phenacetin by ingestion of grape juice in Chinese subjects
Authors: Xiao Dong  , Zhi Ping  , Zhong Xiao  , Chong Shu  , Fattore  , Gatti  , D’Urso  , Perucca
Published: March 2003

Aims This serendipitous study revealed an unexpected effect of Jufeng grape juice on the CYP1A2‐mediated metabolism of phenacetin. Investigation of the inhibition of CYP1A2 by grapefruit juice was involved but a translation error led to the grape juice substitution.

Methods Twelve healthy subjects took a single oral dose of phenacetin (900 mg) on two randomized occasions together with 200 ml water or grape juice. Plasma phenacetin and paracetamol concentrations were assessed by h.p.l.c.

Results Ingestion of grape juice was associated with reduced plasma phenacetin concentrations, while paracetamol levels were unaffected. Paracetamol to phenacetin AUC ratios increased from 13.9±3.1 to 24.3±3.8 after ingestion of grape juice.

Conclusions These findings suggest enhanced first‐pass metabolism of phenacetin, due to CYP1A2 activation by grape juice or to desaturation of CYP1A2 isoenzymes secondary to a slower rate of phenacetin absorption.
Effects of bupivacaine on human erythrocytes submitted to stress and evidence for an interaction between bupivacaine and flumazenil
Authors: Lenfant François , Lahet Jean Jacques , Volot François , Schafer Isabelle , Freysz Marc , Rochette Luc
Published: March 2003

Aims To examine the effects of bupivacaine on erythrocytes submitted to an oxidative stress (AAPH) and to provide evidence for an in vitro interaction between bupivacaine and flumazenil.

Methods Human erythrocytes were studied with or without AAPH in the presence of different concentrations of bupivacaine (0.15, 0.3, 0.9 and 1.8 mmol l−1 ), or flumazenil (0.16 mmol l−1 ) and with the association of flumazenil and two doses of bupivacaine (0.15 and 0.3 mmol l−1 ). Potassium efflux was measured by flame photometry at
t0, and every 30 min for 2 h.

Results In the absence of AAPH, extracellular potassium remained unchanged. Oxidative stress induced a significant increase in extracellular potassium, which was not modified by incubation with flumazenil. Bupivacaine significantly lowered the increase in extracellular potassium in a dose‐related fashion. The association with flumazenil blunted the effects of bupivacaine.

Discussion In this model, bupivacaine proved effective in protecting erythrocytes against oxidative stress. Flumazenil interacted with bupivacaine and blunted its protective effects.
Glucuronidation and sulphation of paracetamol in HIV‐positive patients and patients with AIDS
Authors: O’Neil  , Pezzullo  , Di Girolamo  , Tsoukas  , Wainer
Published: March 2003

Aims To gauge the effect of disease state and disease progression on the glucuronidation and sulphation of paracetamol (APAP) among HIV‐positive patients and patients with AIDS.

Methods The extent of APAP glucuronidation and APAP sulphation was assessed using a spot urine sample collected 4 h after the oral administration of 500 mg of APAP to 108 patients with AIDS or HIV infection. The molar concentrations of APAP and its glucuronide and sulphate metabolites were determined using a validated h.p.l.c. method and glucuronidation and sulphation indices were constructed using APAP metabolite/APAP molar concentration ratios.

Results No effect of disease state, AIDS vs asymptomatic HIV positive vs control, on APAP glucuronidation or sulphation was observed. The patient population was studied over time and disease progression also did not significantly alter the calculated glucuronidation and sulphation indices. The effect of the concomitant administration of other therapeutic agents was assessed and in the cross sectional portion of the study dapsone appeared to significantly decrease APAP sulphation as did lamivudine. In the longitudinal portion of the study the latter effect was not observed but zidovudine was seen to increase APAP glucuronidation. The data also indicates that APAP glucuronidation may be reduced in patients who are >10% below their ideal body weight.
Lack of interaction between thioctic acid, glibenclamide and acarbose
Authors: Gleiter  , Schreeb  , Freudenthaler  , Thomas  , Elze  , Fieger‐Büschges  , Potthast  , Schneider  , Schug  , Blume  , Hermann
Published: March 2003

Aims Thioctic acid (TA), glibenclamide and acarbose are widely used to either alone or concomitantly treat patients suffering from noninsulin‐dependent diabetes (NIDDM). This study systematically investigated drug–drug interactions between TA and glibenclamide and TA and acarbose.

Methods Fourteen male and 10 female healthy volunteers participated a randomized, open three period cross over trial (treatments A–C) followed by a fourth period (treatment D). A baseline profile for plasma insulin and glucose concentrations, variables which served as pharmacodynamic measures, was assessed before entering the trial. Treatments were A=600 mg TA orally, B=3.5 mg glibenclamide orally, C=600 mg TA+3.5 mg glibenclamide, D=600 mg TA+50 mg acarbose. Time courses of R(+)‐TA and S(−)‐TA as well as glibenclamide concentrations were measured with specific analytical methods.

Results There was no clinically relevant change of TA enantiomer pharmacokinetics by glibenclamide or acarbose. Also, glibenclamide pharmacokinetics were not altered by TA to a clinically meaningful extent. Plasma insulin and glucose concentrations did not indicate an interaction between TA and glibenclamide or TA and acarbose. Glibenclamide had the expected effect on insulin and glucose levels independent of comedication. There were only minor and short lasting adverse events with the majority being (expected) hypoglycaemic symptoms occurring during the treatments with glibenclamide.

Conclusions Coadministration of single doses of TA and glibenclamide or TA and acarbose does not appear to cause drug–drug interactions.
Pharmacokinetics of tolbutamide in ethnic Chinese
Authors: Gross Annette S. , Bridge Simone , Shenfield Gillian M.
Published: March 2003

Aims Ethnic differences in drug disposition have been described for many drugs. Despite the widespread use of tolbutamide in Asian populations, the pharmacokinetics of tolbutamide, a CYP2C9 substrate, have not been described in ethnic Chinese.

Methods The pharmacokinetics of tolbutamide (500 mg orally) were studied in 10 young, healthy volunteers (seven male/three female; age 21–29 years), each of whom had four ethnic Chinese grandparents. Plasma concentrations of tolbutamide were measured for 32 h post‐dose by high performance liquid chromatography. The concentrations of hydroxytolbutamide and carboxytolbutamide were also measured in urine for 32 h post‐dose. Noncompartmental pharmacokinetic parameters were calculated using standard equations and compared with those previously reported in Caucasian subjects using the Mann‐Whitney U test.

Results Pharmacokinetic parameters in Chinese (mean±s.d.) including Cmax (63±11 μg ml−1 ), tmax (median 3.3 h; range 1.6–6.0 h), V /F (9.1±1.7 l) and t1/2, (9.1 h; harmonic mean) were similar to the values in Caucasians. CL/F (637±88 ml h−1 ) was higher in Chinese than Caucasians. The urinary recoveries of hydroxytolbutamide (13±1% of dose) and carboxytolbutamide (68±5% of dose) and the partial apparent metabolic clearance (0.15±0.02 ml min−1 kg−1 ) in Chinese were comparable with Caucasians.

Conclusions The pharmacokinetics of tolbutamide have been described in ethnic Chinese and the disposition is similar to that reported in Caucasians. This study suggests that there is no substantial ethnic difference in the tolbutamide hydroxylase activity of CYP2C9.
Therapeutic drug monitoring of antimetabolic cytotoxic drugs
Authors: Lennard
Published: March 2003

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration‐effect relationship for a single drug may not be the same as that when the drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead of, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life‐threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs.
Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations
Authors: Von Moltke Lisa L. , Greenblatt David J. , Granda Brian W. , Duan Su Xiang , Grassi Jeffrey M. , Venkatakrishnan Karthik , Harmatz Jerold S. , Shader Richard I.
Published: March 2003

Aims To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings.

Methods Kinetic properties of zolpidem biotransformation to its three hydroxylated metabolites were studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes.

Results The metabolic product termed M‐3 accounted for more than 80% of net intrinsic clearance by liver microsomes in vitro. Microsomes containing human cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA‐transfected human lymphoblastoid cells mediated zolpidem metabolism in vitro. The kinetic profile for zolpidem metabolite formation by each individual cytochrome was combined with estimated relative abundances based on immunological quantification, yielding projected contributions to net intrinsic clearance of: 61% for 3 A4, 22% for 2C9, 14% for 1A2, and less than 3% for 2D6 and 2C19. These values were consistent with inhibitory effects of ketoconazole and sulfaphenazole on zolpidem biotransformation by liver microsomes. Ketoconazole had a 50% inhibitory concentration (IC50 ) of 0.61 μm vs formation of the M‐3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by ≈40%, somewhat less than anticipated based on the IC50 value and total plasma ketoconazole levels, but much more than predicted based on unbound plasma ketoconazole levels.

Conclusions The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition.
Withdrawal of peripheral vasodilators in primary care
Authors: Stewart Derek , Krska Janet , Kendle Keith , Wintour David , McGregor Campbell
Published: March 2003

Aims
 To investigate the use of peripheral vasodilators in selected practices in primary care and to observe the effect of withdrawing therapy in a sample of patients.

Methods
 Patients receiving repeat prescriptions for peripheral vasodilators, identified from two practices in Grampian, were interviewed prior to and following withdrawal of therapy.

Results
 Of the 35 patients, review of the continued need for therapy was documented in the medical notes of only one patient. Treatment was successfully withdrawn from 17 patients, generating considerable savings.

Conclusions
 Review of peripheral vasodilators merits further attention in larger numbers of patients.
The pharmacokinetics of lamivudine in healthy Chinese subjects
Authors: Jiang J. , Hu P. , Xie H. , Chen H. , Fan F. , Harker A. , Johnson M. A.
Published: March 2003

Aims
 The purpose of this study was to investigate the pharmacokinetics of daily oral doses of lamivudine administered to healthy Chinese subjects for 1 week.

Methods
 Twenty‐four subjects were enrolled, 12 males and 12 females, all between the ages of 18 and 40 years. After an overnight fast, all subjects received a single oral dose of 100 mg lamivudine. Blood was obtained before lamivudine administration and at regular intervals to 24 h post dose. Subsequent doses were given once daily for a total of 7 days. On the last day another full pharmacokinetic profile was obtained to 24 h postdose. Timed urine collections were performed for all subjects on day 1 only. Pharmacokinetic parameters were calculated by using standard non compartmental techniques.

Results
 Lamivudine was well absorbed in all subjects (tmax 1 h). On day 1 and day 7 the overall geometric mean Cmax was 1304 and 1385 ng ml−1, and AUC(0,24h) was 4357 and 4353 ng ml−1 h, respectively. On average 78% of the lamivudine dose was recovered in urine as parent compound. Pharmacokinetic parameters were very similar between male and female subjects, between day 1 and day 7 and in comparison with data obtained in many other pharmacokinetic studies.

Conclusions
 This study demonstrated that the pharmacokinetics of lamivudine are essentially identical between Chinese and Caucasian subjects, and between males and females. It confirms 100 mg lamivudine is an appropriate dose for use in Chinese patients, providing adequate exposure for optimal antiviral effect.
Inhibition of vasoconstriction by the thromboxane A2 antagonist GR32191B in the human radial artery
Authors: He Guo‐Wei , Yang Cheng‐Qin
Published: March 2003

Aims
 The newly revived coronary bypass graft, the radial artery (RA), is more spastic than the internal mammary artery. Thromboxane A2 is a potent vasoconstrictor for arterial grafts. This study was therefore designed to determine whether the specific thromboxane A2 (TP) receptor antagonist, GR32191B, is effective in inhibition of prostanoid or nonprostanoid receptors in the RA.

Methods
 The effect of GR32191B was studied in human RA segments, taken from coronary bypass patients, in organ chambers. Two effects of GR32191B were tested: (1) the relaxation induced by GR32191B in the RA precontracted with the TP receptor agonists U46619 and PGF2α or nonprostanoid vasoconstrictors (noradrenaline [NA], angiotensin II [AII], and K+ ) and (2) the inhibitory effect of GR32191B on TP receptor agonists and nonprostanoid vasoconstrictors.

Results
 In U46619 (10 nm, n=7) and PGF2α (1 μm, n=7) precontracted RA, GR32191B induced 100% relaxation (10–100 μm ) but not after precontraction with nonprostanoid stimuli (5.8% for K+, 25 mm, n=6, 24.4% for NA, 3 μm, n=8, and 53.2% for AII, 3 nm, n=5) (P<0.001). Treatment with GR32191B (30 nm ) significantly depressed the contraction with U46619 (from 160.1±11.0% to 116.8±13.1%, P<0.05) or PGF2α (from 91.3±12.3% to 42.2±9.2%, P<0.01). The contraction was further abolished by 3 μm GR32191B. However, GR32191B at 3 μm did not significantly inhibit the contraction induced by either NA, AII, or K+.

Conclusions
 GR32191B is a highly potent and specific TP receptor antagonist for the human RA. It may be particularly useful in inhibiting TXA2‐mediated vasoconstriction and therefore in reducing the complications related to vasospasm in this graft.
Pharmacodynamics of milnacipran in young and elderly volunteers
Authors: Hindmarch I. , Rigney U. , Stanley N. , Briley M.
Published: March 2003

Aims To investigate the pharmacodynamics of milnacipran in healthy young and elderly volunteers.

Methods Randomized double‐blind crossover designs were employed and a standardized psychometric battery was administered pre and post dose for both studies. In the first study 10 healthy young volunteers received milnacipran 12.5 mg, 25 mg, 50 mg, 100 mg as a single dose or matched placebo. The test battery was administered at baseline and at 1, 2, 4 and 6 h post dose. The second study compared the effects of milnacipran 75 mg (50 mg+25 mg) per day, amitriptyline 50 mg (25 mg+25 mg) per day and placebo for 3 days’ dosing in healthy volunteers aged over 65 years. The test battery was administered at baseline and at 2, 10 and 24 h post dose. The psychometric battery included critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT) and tests of short‐term memory (STM), subjective sedation (LARS) and subjective sleep (LSEQ).

Results Milnacipran produced no significant dose related effects in the young volunteers. For the elderly, milnacipran significantly (P<0.05) raised CFF scores compared with placebo but had no significant effects on any of the other measures used. Amitriptyline, in contrast, significantly (P<0.05) lowered CFF threshold, lengthened CRT and increased error on the CTT. On the subjective variables, LARS and LSEQ, amitriptyline increased ratings both of sedation and of difficulty in waking from sleep.

Conclusions The results showed that milnacipran at single doses of up to 100 mg in healthy young volunteers is free from disruptive effects on cognitive function and psychomotor performance. In addition, milnacipran 75 mg (50+25 mg) appears to be free of negative effects on cognitive function in elderly volunteers, where it seemingly improves performance on CFF. In contrast, the tricyclic antidepressant amitriptyline, used here as a positive internal control, significantly impaired performance in the elderly on the majority of psychometric measures used in this study. This finding not only validated the sensitivity of this current test battery but also indicates the potential behavioural toxicity of amitriptyline in clinical use in the elderly.
Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions
Authors: Prakash C. , Kamel A. , Cui D. , Whalen R. D. , Miceli J. J. , Tweedie D.
Published: March 2003

Aims  To identify the cytochrome P450 (CYP) isoform(s) responsible for the formation of the primary metabolite of ziprasidone (ziprasidone sulphoxide), to determine the kinetics of its formation and to predict possible drug interactions by investigating CYP isoform inhibition in an in vitro study.

Methods  In vitro metabolism of [14C]‐ziprasidone was studied using human liver microsomes. The metabolites were identified using mass spectrometry. The kinetics of metabolite formation were determined using [14C]‐ziprasidone (10–200 μm) over 5 min, and Km and Vmax were estimated from Lineweaver‐Burk plots. IC50 values for the inhibition of specific probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, by ziprasidone, risperidone and 9‐hydroxyrisperidone were also determined using human liver microsomes from three subjects. Mean Ki values were calculated.

Results  Three CYP‐mediated metabolites – ziprasidone sulphoxide, ziprasidone sulphone and oxindole acetic acid – were identified. The apparent Km and Vmax values for the formation of the major metabolite, ziprasidone sulphoxide (measured as the sum of sulphoxide and sulphone) were 235 μm and 1.14 nmol mg− 1 protein min− 1, respectively. Isoform‐selective inhibitors and recombinant enzymes indicated that CYP3A4 is responsible for the formation of ziprasidone metabolites. Ziprasidone was not a substrate for the other isoforms studied. Similar in vitro inhibition of CYP2D6 (Ki 6.9–16 μm) and CYP3A4 (Ki 64–80 μm) was obtained with ziprasidone, risperidone and 9‐hydroxyrisperidone. The in vivo free drug concentrations associated with clinically effective doses of ziprasidone are at least 1500‐fold lower than the mean Ki for either CYP2D6 inhibition or CYP3A4 inhibition.

Conclusions  Ziprasidone is predominantly metabolized by CYP3A4 in human liver microsomes and is not expected to mediate drug interactions with coadministered CYP substrates, at clinically effective doses.
Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive metabolizers
Authors: Wilner K. D. , Demattos S. B. , Anziano R. J. , Apseloff G. ,   &, Gerber N.
Published: March 2003

Aims  To determine whether ziprasidone alters the metabolizing activity of the 2D6 isoenzyme of cytochrome P450 (CYP2D6).

Methods  Twenty‐four healthy young subjects aged 18–45 years were screened for CYP2D6 metabolizing activity and shown to be extensive metabolizers of dextromethorphan. These subjects were then randomized to receive a single dose of ziprasidone 80 mg, paroxetine 20 mg or placebo, 2 h before receiving a dose of dextromethorphan. Urine samples for the determination of dextromethorphan concentrations were collected over the 8 h period following dextromethorphan dosing, and used for the determination of dextromethorphan/dextrorphan ratios. Blood samples were collected immediately before and up to 10 h after the administration of ziprasidone or paroxetine, and used to derive pharmacokinetic parameters of ziprasidone and paroxetine.

Results  There were no statistically significant changes in the urinary dextromethorphan/dextrorphan ratio in the ziprasidone group or the placebo group. By contrast, there was a 10‐fold increase in the urinary dextromethorphan/dextrorphan ratio in the paroxetine group and this differed significantly from those in the ziprasidone and placebo groups (P= 0.0001).

Conclusions  The findings of this study suggest that ziprasidone does not inhibit the clearance of drugs metabolized by CYP2D6.
Dose loading with delayed‐release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters
Authors: Hussain F. N. , Ajjan R. A. , Riley S. A.
Published: March 2003

Aims  Tissue concentrations of 5‐aminosalicylic acid (5ASA) and its metabolites may influence the clinical course of inflammatory bowel disease. Since the factors that determine tissue drug concentrations are unknown we have studied the relationships between the oral dose of delayed‐release mesalazine, rectal tissue drug concentrations and standard pharmacokinetic parameters.

Methods  Twelve healthy volunteers were studied following 7 days treatment with 1.2, 2.4 and 4.8 g of delayed‐release mesalazine daily. 5‐aminosalicylic acid and N‐acetyl 5‐aminosalicylic acid concentrations were measured in serum, urine, stool and rectal tissue biopsies.

Results  Serum concentrations and 24 h urinary excretion of 5ASA and N‐acetyl 5ASA increased as the oral dose of mesalazine was increased from 1.2 g through 2.4 g to 4.8 g daily (serum area under curve (AUC):5ASA = 3.9, 15.4 and 46.8 µg ml−1 h, P < 0.0001; N‐acetyl 5ASA = 17.2, 30.9 and 57.8 µg ml−1 h, P < 0.0001: urinary excretion: 5ASA = 1.8, 85.5 and 445 mg, P < 0.0001; N‐acetyl 5ASA = 250, 524 and 1468 mg, P < 0.0001, respectively). Faecal 5ASA excretion increased as the oral dose increased from 1.2 g to 2.4 g but did not increase further with 4.8 g daily dosing whereas faecal N‐acetyl 5ASA excretion was similar at all three doses. Rectal tissue concentrations of 5ASA increased markedly, and N‐acetyl 5ASA increased modestly, as the dose of oral mesalazine increased from 1.2 g to 2.4 g daily but neither increased further with 4.8 g daily dosing.

Conclusions  The relationship between the ingested dose of delayed‐release mesalazine and rectal tissue drug concentrations is complex. Factors other than dose are likely to be important determinants of rectal tissue drug concentrations.
Dutch Hospital Drug Formularies: pharmacotherapeutic variation and conservatism, but concurrence with national pharmacotherapeutic guidelines
Authors: Fijn R. , Engels S. A. G. , Brouwers, J. R. B. J. , Knaap R. J. , De Jong L. T. W. , Van den Berg ‐
Published: March 2003

Aims 
This research examines current hospital drug formularies (HDFs) of all Dutch general hospitals. It assesses the extent to which they recommend the same drugs, the breadth of their coverage in terms of therapeutic areas, drug groups incorporated and individuals drugs included, and their extent of conservatism by considering the year of introduction of the drugs included within groups. Furthermore, it considers the extent to which their recommendations concur and comply with those of national pharmacotherapeutic guidelines and the WHO Essential Drugs List (EDL).

Methods 
Seventy‐eight (81%) out of all 96 current Dutch HDFs were received of which 62 were suitable for study. Differences between HDFs and eventual associations with hospital characteristics were researched by statistical testing and case‐control studies. To evaluate HDFs’ concurrence with national guidelines and compliance with the WHO EDL, nine drug groups were studied in detail: benzodiazepines, calcium channel blockers, β‐adrenoceptor blocking agents, ACE‐inhibitors, angiotensin‐II inhibitors, NSAIDs, H2‐receptor antagonists, 5HT3‐antagonists, and H+‐pump inhibitors. Concurrence and compliance with national guidelines and the WHO EDL was defined as inclusion of recommended drugs. Non‐concurrence was defined as inclusion of nonrecommended drugs.

Results 
The total number of indications addressed and drug groups incorporated within HDFs varied from 28 to 72 (median 56) and from 30 to 123 (median 97), respectively. The total number of individual drug entities (pharmacological substances) included ranged from 239 to 658 (median 430) and the total number of drug products, including all different dosage forms, from 412 to 1121 (median 655). Within drug groups, drug entities first marketed were most frequently included. Teaching hospitals were most likely to include recently marketed drugs. Depending on the drug group, HDFs’ concurrence and compliance with national guidelines and the WHO EDL ranged from 35% to 100%.

Conclusions 
Findings indicate that Dutch HDFs are rather uniform in the indications addressed and the drug groups incorporated. However, the number of individual drug entities and drug products included within groups varies considerably. Furthermore, Dutch HDFs are considered rather conservative, as older drugs are favoured over more recent drugs. Generally, with some drug exceptions, Dutch HDFs concur and comply with recommendations in national pharmacotherapeutic guidelines and with the WHO EDL over 90%.
Antidepressants in the elderly: challenges for study design and their interpretation
Authors: Parikh C.
Published: March 2003

Drug treatment of depressive illness in the elderly differs from that in younger patients and there is no clear consensus as to first line treatment in the former. Nor is it possible to extrapolate directly from studies in younger patients to the elderly with these agents. Whilst there are over two dozen antidepressants currently marketed in the U.K., most studies have been on younger adults and have excluded very old and frail patients. Design short‐comings of the few trials conducted in elderly patients do not allow accurate interpretation of differences in efficacy or safety between drugs.

This paper identifies key deficiencies in the evidence currently available in support of both older and newer antidepressant agents and makes the proposal that specific studies are required in the elderly to determine the efficacy and safety of antidepressants in the treatment of depressive illness. It outlines a Phase II and III clinical trial programme which could be used to provide adequate evidence of efficacy and safety of new agents and which conforms to current European guidelines. Dose finding studies, short‐term efficacy, prevention of relapse (continuation therapy) and prevention of recurrence (maintenance therapy) studies are discussed as are key issues to be addressed in the trial protocol.
A double‐blind, placebo‐controlled study to assess tolerability, pharmacokinetics and preliminary pharmacodynamics of single escalating doses of Z13752A, a novel dual inhibitor of the metalloproteases ACE and NEP, in healthy volunteers
Authors: Bani, M. , Colantoni A. , Guillaume M. , Macchi F. , Moroni G. , Persiani S.
Published: March 2003

Aims
The objective of this study was to evaluate the tolerability of a novel dual ACE‐NEP inhibitor, Z13752A, after the oral administration of rising single doses in healthy volunteers. This study was also a preliminarily investigation of Z13752A pharmacodynamics (PD) and pharmacokinetics (PK).

Methods
In this randomized, placebo‐controlled, sequential study, two alternating panels of eight healthy male volunteers each (six subjects receiving the active treatment + two subjects receiving placebo) were treated with increasing oral doses of Z13752A: 10, 50, 200, and 600 mg were given to panel I and 20, 100, 400 and 800 mg were given to panel II. The study was double‐blind relative to placebo or active treatment, and was open with respect to the dose levels. The same volunteer received placebo only once.

Results
Single oral doses of Z13752A, as high as 800 mg, were well tolerated. Only six mild‐to‐moderate adverse events mainly headache, were reported and appeared to be of little clinical relevance. After administration of 200, 400, 600 and 800 mg of Z13752A, a nonsignificant fall in diastolic blood pressure was detected, in both the standing and supine position. After single oral doses of Z13752A, ACE inhibition appeared to be significant at all the doses tested, linearly correlated with the dose and was almost complete at doses ≥ 100–200 mg. NEP inhibition was indicated by elevation of ANP and cGMP plasma concentrations in almost all subjects. In the 200–800 mg dose range, Z13752A produced a 50–100% increase of plasma cGMP levels and a 50–80% elevation in urinary cGMP concentrations. Detectable plasma levels of Z13752A were found in all the treated subjects. Z13752A was well and rapidly absorbed, with peak concentrations reached approximately 2.5 h after administration. The mean apparent elimination half‐life from plasma was approximately 12 h. The pharmacokinetics of Z13752A after single oral doses were characterized by low intersubject variability and appeared to be dose‐independent.

Conclusions
Z13752A showed a good single dose tolerability profile at doses up to 800 mg. The pharmacokinetic data indicate that Z13752A administered orally is rapidly absorbed and available to the systemic circulation in humans. The relatively slow clearance indicates that a once‐a‐day dose regimen could be considered for Z13752A.
Attitudes and knowledge of hospital pharmacists to adverse drug reaction reporting
Authors: Green Christopher F. , Mottram David R. , Rowe Philip H. , Pirmohamed Munir
Published: March 2003

Aims  To investigate the attitudes of UK hospital pharmacists towards, and their understanding, of adverse drug reaction (ADR) reporting.

Methods  A postal questionnaire survey of 600 randomly selected hospital pharmacists was conducted.

Results  The response rate was 53.7% (n = 322). A total of 217 Yellow Cards had been submitted to the CSM/MCA by 78 (25.6%) of those responding. Half of those responding felt that ADR reporting should be compulsory and over three‐quarters felt it was a professional obligation. However, almost half were unclear as to what should be reported, while the time available in clinical practice and time taken to complete forms were deemed to be major deterrents to reporting. Pharmacists were not dissuaded from reporting by the need to consult a medical colleague or by the absence of a fee. Education and training had a significant influence on pharmacists' participation in the Yellow Card Scheme.

Conclusions  Pharmacists have a reasonable knowledge and are supportive of the Yellow Card spontaneous ADR reporting scheme. However, education and training will be important in maintaining and increasing ADR reports from pharmacists.
Effect of dexmedetomidine, an α2‐adrenoceptor agonist, on human pupillary reflexes during general anaesthesia
Authors: Larson Merlin D. , Talke Pekka O.
Published: March 2003

Aims  To test the hypothesis that the α2‐adrenergic agonist, dexmedetomidine, dilates the pupil and does not alter the pupillary light reflex of anaesthetized patients.

Methods  Eight volunteers were administered general anaesthesia with propofol, nitrous oxide and alfentanil. One hour and 25 min after induction of anaesthesia, a 45 min infusion of dexmedetomidine was begun, targeting a plasma concentration of 0.6 ng ml−1. Pupil size, pupillary light reflex amplitude, light reflex recovery time, and reflex dilation were measured before and during dexmedetomidine infusion.

Results  Dexmedetomidine produced no change in pupil size and light reflex recovery time, increased the light reflex from 0.30 ± 0.14 to 0.37 ± 0.12 mm and significantly reduced pupillary reflex dilation by 72 ± 62%.

Conclusions  These pupillary effects of dexmedetomidine in humans are difficult to reconcile with the findings obtained in cats and rats that have demonstrated a direct inhibitory effect of α2‐adrenergic agonists on the pupilloconstrictor nucleus. The increase in the magnitude of the light reflex in response to dexmedetomidine does not necessarily involve an anxiolytic mechanism.
A placebo‐controlled study examining the effect of allopurinol on heart rate variability and dysrhythmia counts in chronic heart failure
Authors: Shehab Abdullah M. A. , Butler Robert , MacFadyen Robert J. , Struthers Allan D.
Published: March 2003

Aims  Allopurinol improves endothelial function in chronic heart failure by reducing oxidative stress. We wished to explore if such an effect would attenuate autonomic dysfunction in CHF in line with many other effective therapies in CHF.

Methods  We performed a prospective, randomized, double‐blind cross‐over study in 16 patients with NYHA Class II‐IV chronic heart failure (mean age 67 ± 10 years, 13 male, comparing allopurinol (2 months) at a daily dose of 300 mg (if creatinine < 150 µmol l−1) or 100 mg (if creatinine > 150 µmol l−1) with matched placebo. Mean heart rate and dysrhythmia counts were recorded from 24 h Holter tapes at monthly intervals for 6 months. We assessed autonomic function using standard time domain heart rate variability parameters (HRV): SDNN, SDANN, SDNN index, rMSSD and TI.

Results  Allopurinol had no significant effect on heart rate variability compared with placebo; the results are expressed as a difference in means ± s.d. with 95% confidence interval (CI) between allopurinol and placebo: SDNN mean=6.5 ± 4.8 ms, P = 0.18 and 95% CI (−3.7, 17); TI mean=−2.1 ± 1.4, P = 0.16 and 95% CI (−5.2, 0.8); SDANN mean=−2.8 ± 7 ms, P = 0.68 and 95% CI (−18, 12); SDNNi mean=2 ± 6.6, P = 0.7 and 95% CI (−12, 16); RMSSD mean=−0.9 ± 2, P = 0.68 and 95% CI (−5.6, 3.7). For mean heart rate the corresponding results were 0.9 ± 1.4, P = 0.5 and 95% CI (−2, 3.8). Log 24 h ventricular ectopic counts (VEC) were 0.032 ± 0.37, P = 0.7 and 95% CI (−0.1, 0.2). Patient compliance with study medication was good since allopurinol showed its expected effect of reducing plasma uric acid (P < 0.001).

Conclusions  Allopurinol at doses, which are known to reduce oxidative stress appear to have no significant effect on resting autonomic tone, as indicated by time domain heart rate variability or on dysrhythmia count in stable heart failure patients.
The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine
Authors: Yasuda Sally Usdin , Zannikos Peter , Young Andrea E. , Fried Karen M. , Wainer Irving W. , Woosley Raymond L.
Published: March 2003

Aims  To examine the stereoselective disposition of chlorpheniramine and to evaluate the role of CYP2D6 in chlorpheniramine pharmacokinetics in humans.

Methods  Eight healthy volunteers (six extensive metabolizers with respect to CYP2D6 and two poor metabolizers) received a single 8 mg oral dose of rac‐chlorpheniramine either given alone or following administration of quinidine 50 mg every 6 h for 2 days prior to the study day and every 6 h thereafter until the end of the study. Plasma concentrations of (S)‐(+)‐ and (R)‐(−)‐enantiomers of chlorpheniramine were determined using liquid chromatography/mass spectrometry.

Results  In extensive metabolizers, mean Cmax was greater (12.55±1.51 ng ml−1vs 5.38±0.44 ng ml−1) and CLoral was lower (0.49±0.08 l h−1 kg−1vs 1.07±0.15 l h−1 kg−1) for (S)‐(+)‐ than for (R)‐(−)‐chlorpheniramine (P<0.005). For (S)‐(+)‐chlorpheniramine, administration of quinidine, an inhibitor of CYP2D6, resulted in an increase in Cmax to 13.94±1.51 (P<0.01), a reduction in CLoral to 0.22±0.03 l h−1 kg−1 (P<0.01), and a prolongation of elimination half‐life from 18.0±2.0 h to 29.3±2.0 h (P<0.001). Administration of quinidine decreased CLoral for (R)‐(−)‐chlorpheniramine to 0.60±0.10 l h−1 kg−1 (P<0.005). In CYP2D6 poor metabolizers, systemic exposure was greater after chlorpheniramine alone than in extensive metabolizers, and administration of quinidine resulted in a slight increase in CLoral.

Conclusions  Stereoselective elimination of chlorpheniramine occurs in humans, with the most pharmacologically active (S)‐(+)‐enantiomer cleared more slowly than the (R)‐(−)‐enantiomer. CYP2D6 plays a role in the metabolism of chlorpheniramine in humans.