bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of the vasorelaxant effect of nitroprusside and nitroglycerin in the human radial artery in vitro
Authors: He Guo‐Wei , Yang Cheng‐Qin
Published: March 2003

Aims In recent years the radial artery (RA) has been re‐introduced for coronary artery bypass grafting (CABG). However, the potential for vasospasm remains a clinical problem when this vessel is employed and effective vasodilator agents are required to combat vasospastic events. This in vitro study was designed to compare the vasodilator effects of sodium nitroprusside (SNP) and nitroglycerin (NTG) in the human RA.

Methods Human RA segments (n=70) were taken from vessels employed for grafting in patients undergoing CABG. Concentration‐relaxation curves for SNP and NTG were established in RA which had been precontracted with various vasoconstrictors (potassium chloride [K+], the thromboxane A2 mimetic agent U46619 or endothelin‐1 [ET‐1]).

Results Both SNP and NTG caused complete relaxation and EC50s were similar except that NTG was 6.2‐fold more potent than SNP in U46619‐induced contraction (−7.50±0.16 vs−6.71±0.38 log m, P=0.04). After treatment with verapamil and NTG solution during harvesting, the RA segments responded with reduced maximal relaxation to NTG (84.9±3.9%, compared with 98.8±0.8% in the control, P=0.004). The vessel became less sensitive to NTG (E
C50: −6.29±0.4 vs−7.50±0.16 log m, P=0.01). In investigations carried out with SNP, tolerance was only seen in the magnitude of the relaxation (87.4±4.7%vs 99.2±0.6% in the control, P=0.03).

Conclusions Both NTG and SNP are potent vasodilators in the RA. NTG may have more potent effects in certain situations (constriction related to thromboxane A2). However, tolerance to NTG may develop. A cross tolerance to SNP may exist but the effect is weak so that SNP may be preferable to NTG as a vasodilator in the RA postoperatively. Other vasodilators may be the drugs of choice under such circumstances.
Photoinduced covalent binding of frusemide and frusemide glucuronide to human serum albumin
Authors: Mizuma§ Takashi , McDonagh Antony F. , Lin Emil T. , Benet Leslie Z.
Published: March 2003

Aims To study reaction of photoactivated frusemide (F) and F glucuronide (Fgnd metabolite) with human serum albumin in order to find a clue to clarify a mechanism of phototoxic blisters from high frusemide dosage.

Methods F was exposed to light in the presence of human serum albumin (HSA). HSA treated with this method (TR‐HSA) was characterized by fluorescence spectroscopic experiment, alkali treatment and reversible binding experiment.

Results Less 4‐hydroxyl‐N‐furfuryl‐5‐sulphamoylanthranilic acid (4HFSA, a photodegradation product of F) was formed in the presence of HSA than in the absence of HSA. A new fluorescence spectrum excited at 320 nm was observed for TR‐HSA. Alkali treatment of TR‐HSA released 4HFSA. Quenching of the fluorescence due to the lone tryptophan near the warfarin‐binding site of HSA was observed in TR‐HSA. The reversible binding of F or naproxen to the warfarin‐binding site of TR‐HSA was less than to that of native HSA. These results indicate the photoactivated F was covalently bound to the warfarin‐binding site of HSA. The covalent binding of Fgnd, which is also reversibly bound to the wafarin‐binding site of HSA, was also induced by exposure to sunlight. Fgnd was more photoactive than F, indicating that F could be activated by glucuronidation to become a more photoactive compound.

Conclusions The reactivity of photoactivated F and Fgnd to HSA and/or to other endogenous compounds may cause the phototoxic blisters that result at high F dosage.
Pharmacokinetic and pharmacodynamic characterization of OROS® and immediate‐release amitriptyline
Authors: Gupta Suneel K. , Shah Jaymin C. , Hwang Stephen S.
Published: March 2003

Aims To characterize the pharmacokinetics of amitriptyline and its metabolite nortriptyline following OROS® and IR treatments, and to correlate them with anticholinergic side‐effects.

Methods The pharmacokinetics and safety of amitriptyline following administration of an osmotic controlled release tablet (OROS® and an immediate release (IR) tablet were evaluated in 14 healthy subjects. In this randomized, open label, three‐way crossover feasibility study, the subjects received a single 75 mg OROS® tablet, three 25 mg IR tablets administered every 8 h, or 3×25 mg IR tablets administered at nighttime. In each treatment arm serial blood samples were collected for a period of 84 h after dosing. The plasma samples were analysed by gas chromatography for amitriptyline and its metabolite nortriptyline. Anticholinergic effects such as saliva output, visual acuity, and subject‐rated drowsiness and dry mouth were measured on a continuous scale during each treatment period.

Results Following dosing with OROS® (amitriptyline hydrochloride), the mean maximal plasma amitriptyline concentration Cmax (15.3 ng ml−1 ) was lower and the mean tmax (25.7 h) was longer than that associated with the equivalent IR dose administered at nighttime (26.8 ng ml−1 and 6.3 h, respectively). The bioavailability of amitriptyline following OROS® dosing was 95% relative to IR every 8 h dosing, and 89% relative to IR nighttime dosing. The metabolite‐to‐drug ratios after the three treatment periods were similar, suggesting no change in metabolism between treatments. The relationships between plasma amitriptyline concentration and anticholinergic effects (e.g. reduced saliva weight, dry mouth, and drowsiness) were similar with all three treatments. Of the anticholinergic effects, only decreased saliva weight and dry mouth correlated well with plasma amitriptyline concentrations; drowsiness did not. There was no apparent correlation between anticholinergic effects and the plasma nortriptyline concentration.

Conclusions The bioavailability of OROS® (amitriptyline hydrochloride) was similar to that of the IR treatments and the pharmacokinetics of amitriptyline after OROS® dosing may decrease the incidence of anticholinergic effects compared with that seen with nighttime dosing of the IR formulation. Therefore, this controlled‐release formulation of amitriptyline may be appropriate for single daily administration.
Cohort study on calcium channel blockers, other cardiovascular agents, and the prevalence of depression
Authors: Dunn Nicholas R. , Freemantle Shayne N. , Mann Ronald D.
Published: March 2003

Aims
 Some reports have suggested that calcium channel blockers may be associated with an increased incidence of depression or suicide. There is a paucity of evidence from large scale studies. The aim of this study was to assess rates of depression with calcium channel antagonists using data from prescription event monitoring studies.

Methods
 Observational studies on large cohorts of patients using lisinopril, enalapril (ACE inhibitors), nicardipine (type 2 calcium channel blocker) and diltiazem (type 3 calcium channel blocker) were conducted, using prescription‐event monitoring. Rates of depression in the different drugs and rate ratios (95% CI) were computed.

Results
 The crude overall rates of depression during treatment were 1.89, 1.92 and 1.62 per 1000 patient months for the ACE inhibitors, diltiazem and nicardipine, respectively. Using the ACE inhibitors as the reference group, the rate ratios for depression were 1.07 (0.82–1.40) and 0.86 (0.69–1.08) for diltiazem and nicardipine, respectively.

Conclusions
 This study does not support the hypothesis that calcium channel blockers are associated with depression, when considering patients treated in general practice in the UK.
Patterns of neuroleptic drug prescription: a national cross‐sectional survey of a random sample of French psychiatrists
Authors: Fourrier Annie , Gasquet Isabelle , Allicar Marie Pierre , Bouhassira Myriam , Lépine Jean Pierre , Bégaud Bernard
Published: March 2003

Aims To describe the psychiatric indications of neuroleptics (especially the relative share of schizophrenic and other psychotic disorders) and the usage patterns of these drugs (dose, duration, coprescriptions).

Methods A one‐day national cross‐sectional survey in a random sample of 723 French psychiatrists was carried out in 1996. Each psychiatrist was asked to complete a standardized questionnaire for the first three patients seen the day of the survey to whom at least one neuroleptic was prescribed (initiated or renewed).

Results One thousand seven hundred and fifty‐four questionnaires were returned. Three quarters of the patients (74%) were psychotic (664 with schizophrenia, and 636 other psychosis), 19.3% were depressive and 6.7% had other psychiatric disorders. Phenothiazines were the most often prescribed (40.8%), followed by butyrophenones (22.5%), benzamides (15.8%), other neuroleptics (14.8%) and thioxanthenes (6.1%). Among schizophrenic subjects, an average number of 1.54 (95% CI: 1.50–1.60) neuroleptics were prescribed per patient, compared with 1.4 (95% CI: 1.32–1.41) and 1.2 (95% CI: 1.14–1.23) in other psychotic and depressive subjects, respectively. Regardless of the indication, non‐neuroleptic psychotropic drugs were coprescribed in 75.4%, mainly benzodiazepines (75.7%). Adjuvant drugs used in prevention or treatment of side‐effects were coprescribed in 46.7%, mostly anticholinergic antiparkinsonians (86.1%).

Conclusions Neuroleptics are mainly prescribed for psychotic disorders and especially schizophrenia. However, current recommendations are not always followed.
The effect of NAT2 genotype and gender on the metabolism of caffeine in nonsmoking subjects
Authors: Welfare Mark R , Bassendine Margaret F , Daly Ann K
Published: March 2003

Aims
 To establish whether gender or N‐acetyltransferase 2 (NAT2) genotype influence the urinary 17 U+17X/137X ratio after dosing with caffeine.

Methods
 Ninety‐two nonsmoking individuals underwent caffeine phenotyping. NAT2 genotype was determined by the polymerase chain reaction followed by a restriction digest (PCR‐RFLP).

Results
 The median ratio for urinary 17 U+17X/137X was 6.7 (range 1.45–18.65). 55% of subjects were slow acetylators. Gender did not affect the metabolic ratio or NAT2 genotype. Mean 17 U+17X/137X ratio differed between fast (6.75) and slow (8.69) acetylators (95% CI for the difference, 0.32–3.56).

Conclusions
 The findings are further evidence that the 17 U+17X/137X urinary ratio is not a robust measure of CYP1A2 activity. A possible mechanism by which the ratio might be influenced by NAT2 genotype is suggested.
Stereoselective glucuronidation of formoterol by human liver microsomes
Authors: Zhang Mei , Fawcett J. Paul , Kennedy Julia M. , Shaw John P.
Published: March 2003

Aims Formoterol is a β2‐adrenoceptor agonist marketed as a racemic mixture of the active (R; R)‐ and inactive (S; S)‐enantiomers (rac‐formoterol). The drug produces prolonged bronchodilation by inhalation but there is significant interpatient variability in duration of effect. Previous work has shown that in humans formoterol is metabolized by conjugation with glucuronic acid but little is known about the stereoselectivity of this reaction. The aim of the present study was to investigate the glucuronidation of formoterol enantiomers in vitro by human liver microsomes.

Methods The kinetics of formation of formoterol glucuronides during incubation of racemate and of single formoterol enantiomers with human liver microsomes (n=9) was characterized by chiral h.p.l.c. assay.

Results The kinetics of glucuronidation of the two formoterol enantiomers obeyed the Michaelis‐Menten equation. Glucuronidation of formoterol was stereoselective and occurred more than two times faster for (S; S)‐formoterol than for (R; R)‐formoterol. In incubations with single formoterol enantiomers, the median (n=9) Km values for (R; R)‐glucuronide and (S; S)‐glucuronide were 827.6 and 840.4 μm, respectively, and the median V max values were 2625 and 4304 pmol min−1 mg−1, respectively. Corresponding values determined in incubations with rac‐formoterol were 357.2 and 312.1 μm and 1435 and 2086 pmol min−1 mg−1 for (R; R)‐ and (S; S)‐glucuronide, respectively. Interindividual variation was large with the ratio of V max/Km (S; S/R; R) ranging from 0.57 to 6.90 for incubations with rac‐formoterol.

Conclusions Our study demonstrates that glucuronidation of formoterol by human liver microsomes is stereoselective and subject to high interindividual variability. These findings suggest that clearance of formoterol in humans is subject to variable stereoselectivity which could explain the variation in duration of bronchodilation produced by inhaled formoterol in patients with asthma.
Gastric decontamination performed 5 min after the ingestion of temazepam, verapamil and moclobemide: charcoal is superior to lavage
Authors: Lapatto‐reiniluoto O. , Kivistö K. T. , Neuvonen P. J.
Published: March 2003

Aims
 The aim was to study the efficacy of gastric lavage and activated charcoal in preventing the absorption of temazepam, verapamil and moclobemide when gastric decontamination was performed immediately after ingestion of the drugs.

Methods
 Nine healthy volunteers took part in a randomized cross‐over study with three phases. The subjects were administered single oral doses of 10 mg temazepam, 80 mg verapamil and 150 mg moclobemide. Five minutes later, they were assigned to one of the following treatments: 200 ml water (control), 25 g activated charcoal as a suspension in 200 ml water or gastric lavage. Plasma concentrations and the cumulative excretion into urine of the three drugs were determined up to 24 h.

Results
 The mean AUC(0,24 h) of temazepam, verapamil and moclobemide was reduced by 95.2% (P < 0.01), 92.8% (P < 0.01) and 99.7% (P < 0.01), respectively, by activated charcoal compared with control. Gastric lavage did not reduce significantly the AUC(0,24 h) of these drugs. The 24 h cumulative excretion of temazepam, verapamil and moclobemide into urine was reduced significantly (P < 0.05) by charcoal but not by gastric lavage. Charcoal reduced the AUC(0,24 h), Cmax and urinary excretion of all three drugs significantly more than lavage.

Conclusions
 Activated charcoal is very effective and gastric lavage can be rather ineffective in preventing the absorption of temazepam, verapamil and moclobemide when the treatment is given very rapidly after ingestion of the drugs, before tablet disintegration has occurred.
Drug utilization evaluation of nonprescription H2‐receptor antagonists and alginate‐containing preparations for dyspepsia
Authors: Krska, Janet , John, David Neale , Hansford Denise , Kennedy Emily J.
Published: March 2003

Aims  To evaluate the use, efficacy and adverse effects of nonprescription H2‐receptor antagonists and alginate‐containing preparations obtained from community pharmacies.

Methods  Questionnaires were distributed to customers from 39 pharmacies in Scotland and Wales.

Results  Of 767 customers recruited, 608 (79.3%) returned an initial questionnaire and 472 (61.5%) customers a second questionnaire. The vast majority of respondents (424, 69.7%) had suffered their symptoms on three or more occasions and 369 (60.7%) had previously tried medicines to relieve their symptoms. Referrals to a doctor were less frequent than recommended in guidelines and few of those who were referred actually saw a doctor. Over a quarter of those returning the second questionnaire claimed to be taking more than one product simultaneously for symptom control. Eight customers who were taking prescribed ulcer‐healing drugs obtained H2‐receptor antagonists. The majority of respondents (355/472, 75.2%) obtained some or complete symptom relief using the product obtained and 369/472 (78.2%) were completely satisfied with their product. H2‐receptor antagonists were more likely to produce complete relief of symptoms than alginate‐containing preparations (P < 0.05). Only 14 respondents (3.0%) reported side‐effects from the product used which were mostly gastro‐intestinal.

Conclusions  The study demonstrated that drug utilization studies are feasible to carry out in a community pharmacy setting. While the results support published evidence of the efficacy and minimal toxicity of these products, they also highlight the possibility of H2‐receptor antagonists being used outwith their licenced indications.
Sensitivity of repeated interdigital web pinching to detect antinociceptive effects of ibuprofen
Authors: Growcott J. W. , Stone A. , Beise, R. , Stammer, H. , Tetzloff W. , DeMey C.
Published: March 2003

Aims
 The aim of the current study was to assess the viability of the interdigital web pinch model as a test for analgesic activity in volunteer‐based early phase drug development.

Methods
 Pain thresholds and sensitization to a series of four sessions of interdigital web pinching (12 Newtons force) were measured in 26 male volunteers before and 1 and 3 h after oral dosing with ibuprofen (800 mg) or placebo to ibuprofen. Within each time point, the pain thresholds were measured by calculating the average visual analogue scores (VAS) for the first session of pinching (VAS‐1). Sensitization to pinching was assessed by calculating the average changes in these scores for the three subsequent sessions of pinching (VAS‐2). Moreover, the difference between the VAS score after the first session of pinching and that obtained at the end of the fourth session of pinching was calculated as a secondary endpoint (VAS‐3).

Results
 Treatment with ibuprofen had no significant effect on VAS‐1 at either 1 or 3 h after dosing. However, the mean values of VAS‐2 and VAS‐3, were significantly reduced (P < 0.05) following treatment with ibuprofen.

Conclusions
 This model has been able to detect an antinociceptive effect with ibuprofen. However, large numbers of subjects were required in order to demonstrate this effect and this feature would restrict the model’s utility in early phase clinical trials where small numbers of subjects are normally employed.
Graft material and results of platelet inhibitor trials in peripheral arterial reconstructions: reappraisal of results from a meta‐analysis
Authors: Watson Hugh R. , Skene Allan M. , Belcher Glyn
Published: March 2003

Aims  To investigate the characteristics of published trials in order to establish the origin of the differing results obtained in trials of platelet inhibitors after peripheral bypass procedures.

Methods  Analysis of the information from 11 randomised, controlled trials of platelet inhibitors after peripheral bypass procedures published up until 1999 and involving 2302 patients undergoing peripheral bypass operations, 1250 of whom were treated with platelet inhibitors.

Results  There is a significant treatment benefit of platelet inhibitors on meta‐analysis of the trials, but a significant heterogeneity amongst the individual trial results. The proportion of patients in a trial with prosthetic grafts was a significant factor in explaining the heterogeneity. Proportion of prosthetic grafts was associated with sample size and with the proportion of grafts above the knee, but these were not found to make an independent contribution to the heterogeneity observed. The platelet inhibitor regimen used, the severity of ischaemic symptoms and the proportion of smokers included were also not found to be important.

Conclusions  The improvement of graft patency by aspirin and related platelet inhibitors in clinical trials in peripheral bypass procedures can be attributed to an effect on patients with prosthetic grafts. There is little evidence that these agents prevent occlusion of vein grafts. The conclusion of an earlier meta‐analysis that antiplatelet agents should be used for all bypasses is not supported.
Comparison of the effects of clonidine and yohimbine on pupillary diameter at different illumination levels
Authors: Phillips M. A. , Szabadi E. , Bradshaw C. M.
Published: March 2003

Aims
To evaluate the pupillary effects of single doses of the α2‐adrenoceptor agonist clonidine and the α2‐adrenoceptor antagonist yohimbine under several illumination conditions.

Methods
Sixteen healthy male volunteers received clonidine 0.2 mg, yohimbine 22 mg, clonidine 0.2 mg + yohimbine 22 mg in a double‐blind placebo‐controlled, cross‐over study. 2 h post drug ingestion pupil diameter was recorded in darkness, and at luminance levels of 6 Cd m−2, 91 Cd m−2 and 360 Cd m−2. The effects of the active treatments on pupil diameter were also expressed as the differences from the placebo condition (‘placebo‐corrected’ data; mean [95% CI]).

Results
Clonidine had little effect on pupil diameter in darkness; however, it caused a significant, light‐dependent, miosis when the eye was illuminated. On the other hand yohimbine increased pupil size; this increase was significant at 91 and 360 Cd m−2. There were no significant differences between the effects of the combined treatment (clonidine 0.2 mg + yohimbine 22 mg) and the effect of placebo.

Conclusions
The pupillary effects of clonidine and yohimbine are likely to reflect the interaction of these drugs with inhibitory α2‐adrenoceptors located on central noradrenergic neurones, which in turn would lead to a decrease and an increase, respectively, in sympathetic outflow to the iris. The light dependence of the pupillary effects of these drugs, however, suggests that the parasympathetic light reflex pathway is also involved, which is known to be under inhibitory control from the central noradrenergic neurones. Modulation of parasympathetic outflow seems to play an important role since both drugs had relatively little effect on pupil diameter in darkness when sympathetic activity predominates.
Plasma erythropoietin concentrations in patients receiving intensive platinum or nonplatinum chemotherapy
Authors: Canaparo R. , Casale F. , Muntoni E. , Zara G. P. , Pepa C. Della , Berno E. , Pons N. , Fornari G. , Eandi M.
Published: March 2003

Aims
Platinum chemotherapy has been shown to have potent antineoplastic activity against various tumours, especially testicular, bladder, ovarian, head and neck cancers. This activity is accompanied by side‐effects of nephrotoxicity and cumulative myelosuppression, the latter frequently presenting as severe anaemia. Cisplatin and carboplatin nephrotoxicity might lower erythropoietin (Epo) secretion and, by this mechanism, contribute to the anaemia that follows therapy with this chemotherapeutic agent. The aim of the present work is to study the plasma immunoerythropoietin and haemoglobin levels of cancer patients treated with platinum or 5‐fluorouracil‐based chemotherapy.

Methods
Plasma was obtained from 25 patients who were about to receive chemotherapy for advanced malignancy: 15 treated with cisplatin or carboplatin and 10 with nonplatinum drugs. Blood was collected on the first day (before drug administration) and around day 15 of every chemotherapy course. Complete blood count, creatinine and immunoreactive Epo levels were also measured in 22 healthy volunteers.

Results
An increase in Epo levels occurred following every course of 5‐FU or platinum based chemotherapy in patients with steady concentrations of creatinine and decreased levels of haemoglobin (Hb). In particular, we observed an increase after about 15 days of the chemotherapy treatment and the Epo levels declined toward normal just before the following course. This phenomenon was evident in every course.

Conclusions
Our results suggest that chemotherapy administration, using the current standards of hydration and forced diuresis, slightly lowered Hb levels but did not depress Epo production, both in 5‐FU and in platinum treated subjects.
Citalopram and demethylcitalopram in human milk; distribution, excretion and effects in breast fed infants
Authors: Rampono Jonathan , Kristensen Judith H. , Hackett L. Peter , Paech Michael , Kohan Rolland , Ilett Kenneth F.
Published: March 2003

Aims To characterize milk/plasma (M/P) ratio and infant dose, for citalopram and demethylcitalopram, in breast‐feeding women taking citalopram for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants.

Methods Seven women (mean age 30.6 years) taking citalopram (median dose 0.36 mg kg−1 day−1) and their infants (mean age 4.1 months) were studied. Citalopram and demethylcitalopram in plasma and milk were measured by high‐performance liquid chromatography over a 24 h dose interval. Infant exposure was estimated (two separate methods) as the product of milk production rate and drug concentration in milk, normalized to body weight and expressed as a percentage of the weight‐adjusted maternal dose.

Results Mean M/PAUC values of 1.8 (range 1.2–3) and 1.8 (range 1.0–2.5) were calculated for citalopram and demethylcitalopram, respectively. The mean maximum concentrations of citalopram and demethylcitalopram in milk were 154 (95% CI, 102–207) µg l−1 and 50 (23–77) µg l−1. Depending on the method of calculation, mean infant exposure was 3.2 or 3.7% for citalopram and 1.2 or 1.4% for demethylcitalopram. Citalopram (2.0, 2.3 and 2.3 µg l−1) was detected in three of the seven infants. Demethylcitalopram (2.2 and 2.2 µg l−1) was detected in plasma from two of the same infants. No adverse effects were seen in the infants, all were within appropriate percentile limits for weight and all had normal Denver developmental quotients.

Conclusions The mean combined dose of citalopram and demethylcitalopram (4.4–5.1% as citalopram equivalents) transmitted to infants via breast milk is below the 10% notional level of concern. Plasma concentrations of these drugs in the infants were very low or absent and there were no adverse effects. These data support the safety of the use of citalopram in breast feeding women. Nevertheless, each decision to breast feed should always be made as an individual risk:benefit analysis.
Assessment of forearm vasodilator responses to acetylcholine and albuterol by strain gauge plethysmography: reproducibility and influence of strain gauge placement
Authors: Walker H. A. , Jackson G. , Ritter J. M. , Chowienczyk P. J.
Published: March 2003

Aims  To determine the within‐subject reproducibility of the forearm blood flow response to acetylcholine and the β2‐adrenoceptor agonist albuterol as measured by strain gauge plethysmography. To examine the influence of strain gauge placement on these responses.

Methods  Vasodilator response to brachial artery infusion of drugs was assessed by strain gauge plethysmography in six healthy men on each of three occasions separated by 1 week. Strain gauges were placed on both arms at the point of maximum diameter. On the infused arm two further gauges were positioned approximately 4 cm proximal and distal to the middle gauge.

Results  Within‐subject coefficients of variation (WCV) of absolute blood flow responses for each dose of acetylcholine (7.5, 15, 30 µg min−1) ranged from 24% to 27%, as compared with WCV values of 41% to 62% for the percentage changes in blood flow ratio (infused : noninfused arm). For albuterol (0.3, 1, 3 µg min−1) the corresponding WCV values were 16% to 19% and 30% to 55% for absolute blood flow and percentage change in blood flow ratio, respectively. WCV for the area under dose‐response curve (AUC) for absolute blood flow was 18% and 13% for acetylcholine and albuterol, respectively. Vasodilator responses were similar whether recorded proximal to or at the point of maximal forearm circumference. Distal strain gauge misplacement underestimated responses and the difference was greater for acetylcholine than for albuterol.

Conclusions  In healthy men, the WCV for responses expressed as absolute blood flow, to acetylcholine and albuterol ranges from 16% to 27%.
Involvement of human liver cytochrome P4502B6in the metabolism of propofol
Authors: Oda Yutaka , Hamaoka Naoya , Hiroi Toyoko , Imaoka Susumu , Hase Ichiro , Tanaka Kazuo , Funae Yoshihiko , Ishizaki Takashi , Asada Akira
Published: March 2003

Aims  To determine the cytochrome P450 (CYP) isoforms involved in the oxidation of propofol by human liver microsomes.

Methods  The rate constant calculated from the disappearance of propofol in an incubation mixture with human liver microsomes and recombinant human CYP isoforms was used as a measure of the rate of metabolism of propofol. The correlation of these rate constants with rates of metabolism of CYP isoform‐selective substrates by liver microsomes, the effect of CYP isoform‐selective chemical inhibitors and monoclonal antibodies on propofol metabolism by liver microsomes, and its metabolism by recombinant human CYP isoforms were examined.

Results  The mean rate constant of propofol metabolism by liver microsomes obtained from six individuals was 4.2 (95% confidence intervals 2.7, 5.7) nmol min−1 mg−1 protein. The rate constants of propofol by microsomes were significantly correlated with S‐mephenytoin N‐demethylation, a marker of CYP2B6 (r =0.93, P < 0.0001), but not with the metabolic activities of other CYP isoform‐selective substrates. Of the chemical inhibitors of CYP isoforms tested, orphenadrine, a CYP2B6 inhibitor, reduced the rate constant of propofol by liver microsomes by 38% (P < 0.05), while other CYP isoform‐selective inhibitors had no effects. Of the recombinant CYP isoforms screened, CYP2B6 produced the highest rate constant for propofol metabolism (197 nmol min−1 nmol P450−1). An antibody against CYP2B6 inhibited the disappearance of propofol in liver microsomes by 74%. Antibodies raised against other CYP isoforms had no effect on the metabolism of propofol.

Conclusions  CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes.
Effect of MAO‐A inhibition on the pharmacokinetics of almotriptan, an antimigraine agent in humans
Authors: Fleishaker Joseph C. , Ryan Kristi K. , Jansat Josep M. , Carel Barabara J. , Bell David J. A. , Burke Moira T. , Azie Nkechi E.
Published: March 2003

Aims  To assess the effect of a reversible MAO‐A inhibitor, moclobemide, on the single‐dose pharmacokinetics of almotriptan and assess the clinical consequences of any interaction.

Methods
 Twelve healthy volunteers received the following treatments in a randomized, open‐label, two‐way crossover design (with a 1 week washout between treatments): (A) one 150 mg moclobemide tablet every 12 h for 8 days and one 12.5 mg almotriptan tablet on the morning of day 8; and (B) one 12.5 mg almotriptan tablet on day 8. Plasma almotriptan was quantified by h.p.l.c.‐MS‐MS, while urinary concentrations were measured by h.p.l.c.‐u.v. Vital signs, ECGs, and adverse events were evaluated after almotriptan administration. Treatment effects on pharmacokinetics and vital signs were assessed by analysis of variance.

Results
 Mean almotriptan AUC was higher (483 ± 99.9 vs 352 ± 75.4 ng ml−1 h, P = 0.0001) and oral clearance was lower (26.6 ± 4.00 vs 36.6 ± 5.89 l h−1, P = 0.0001) when almotriptan was administered with moclobemide. Mean half‐life was longer (4.22 ± 0.78 vs 3.41 ± 0.45 h, P = 0.0002) after coadministration with moclobemide. Renal clearance of almotriptan was unaffected by moclobemide. No serious adverse events occurred and no clinically significant vital sign changes were observed.

Conclusions
 Moclobemide increased plasma concentrations of almotriptan on average by 37%, but the combined administration of these two compounds was well tolerated. The degree of interaction was much less than that seen previously for sumatriptan or zolmitriptan given with moclobemide.
Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes
Authors: Yeo Karen Rowland , Yeo Wilfred W.
Published: March 2003

Aims  To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil.

Methods  Simvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1–250 µm). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate.

Results  When verapamil was coincubated with simvastatin, IC50 values ranged from 23 to 26 µm for all major metabolites. The IC50 values ranged from 4.8 to 5.6 µm on preincubation of verapamil for 30 min in the presence of an NADPH‐generating system. Corresponding IC50 values for diltiazem ranged from110–127 µm and from 21–27 µm, respectively. Verapamil and diltiazem inhibited testosterone 6β‐hydroxylation in a time‐ and concentration‐dependent manner, key features of mechanism‐based inactivation. Values for the inactivation parameters kinact and KI were 0.15 ± 0.04 min−1 (mean ± s.d.) and 2.9 ± 0.6 µm, respectively, for verapamil and 0.07 ± 0.01 min−1 and 3.3 ± 1.5 µm, respectively, for diltiazem.

Conclusions  The IC50 values for coincubation of verapamil and diltiazem were 46‐ and 220‐fold higher, respectively, than those reported previously for mibefradil, and 16‐ and 71‐fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism‐based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.
Serum cystatin C is not a better marker of creatinine or digoxin clearance than serum creatinine
Authors: O'Riordan S. , Ouldred E. , Brice S. , Jackson S. H. D. , Swift C. G.
Published: March 2003

Aims  To assess whether cystatin C, a new serum marker of renal function, is a better index of creatinine or digoxin clearance than serum creatinine in older people.

Methods  Twenty‐two volunteers over the age of 65 years (mean 73±5) were recruited from a healthy elderly volunteer database. None of the volunteers was taking digoxin or other medication known to interfere with digoxin kinetics or assay. Digoxin was infused at a dose of 7–10 µg kg−1 and blood samples were taken over the following 48 h and assayed for serum digoxin. Serum cystatin C, creatinine and creatinine clearance were measured and a calculated creatinine clearance was estimated using the Cockcroft Gault formula. Digoxin clearance was calculated using a pharmacokinetic software package. All values were log transformed to normalize their distribution.

Results  Of the 22 volunteers enrolled into the study, 18 completed the study. Serum cystatin C ranged between 0.72 and 1.89 mg l−1 and serum creatinine ranged from 69.6 to 153.9 µmol l−1. Measured creatinine clearance ranged from 38 to 123 ml min−1 and calculated creatinine clearance from 29.5 to 88.0 ml min−1. Digoxin clearance ranged from 51.0 to 103.5 ml min−1. Cystatin C correlated extremely well with creatinine (r=0.93, P<0.001, 95% CI 0.82, 0.97) and with creatinine clearance (r=0.67, P=0.002, 95% CI 0.3, 0.87). Neither serum cystatin C nor serum creatinine correlated with digoxin clearance (r=0.25, P=0.31, 95% CI −0.25, 0.64 and r=0.44, P=0.068, 95% CI −0.03, 0.75, respectively). Measured creatinine clearance, however, did correlate well with digoxin clearance (r=0.55, P=0.018, 95% CI 0.11, 0.81).

Conclusions  Serum cystatin C and serum creatinine show very similar correlations with creatinine and digoxin clearances. Serum cystatin C does not offer any advantages in this respect. It remains to be seen whether cystatin C offers any advantage over creatinine in elderly people in other respects.
Lead poisoning: case studies
Authors: Gordon J. N. , Taylor A. , Bennett P. N.
Published: March 2003

Early clinical features of lead toxicity are non‐specific and an occupational history is particularly valuable.

Lead in the body comprises 2% in the blood (t1/2 35 days) and 95% in bone and dentine (t1/2 20–30 years). Blood lead may remain elevated for years after cessation from long exposure, due to redistribution from bone.

Blood lead concentration is the most widely used marker for inorganic lead exposure. Zinc protoporphyrin (ZPP) concentration in blood usefully reflects lead exposure over the prior 3 months.

Symptomatic patients with blood lead concentration >2.4 µmol l−1 (50 µg dl−1) or in any event >3.8 µmol l−1 (80 µg dl−1) should receive sodium calciumedetate i.v., followed by succimer by mouth for 19 days.

Asymptomatic patients with blood lead concentration >2.4 µmol l−1 (50 µg dl−1) may be treated with succimer alone.

Sodium calciumedetate should be given with dimercaprol to treat lead encephalopathy.
Clinical Pharmacology: Principles and practice of drug therapy in medical education
Authors: Whiting Brian , Holford Nicholas H. G. , Begg Evan J.
Published: March 2003

Educational reform has taken place in many Medical Schools. A traditional passive approach has been replaced by a more active, student‐centred approach, founded on Problem‐Based Learning. This has not been without risk because many well‐structured courses have been abandoned, and this is of particular significance to the principles and practice of drug therapy.

Here we outline an approach which could be incorporated into a medical curriculum and suggest some guidelines and a list of questions that should be asked in clinical situations involving drug therapy.
Effects of oral monosodium (l)‐glutamate on insulin secretion and glucose tolerance in healthy volunteers
Authors: Chevassus Hugues , Renard Eric , Bertrand Gyslaine , Mourand Isabelle , Puech Raymond , Molinier Nathalie , Bockaert Joël , Petit Pierre , Bringer Jacques
Published: March 2003

Aims  To investigate the effects of glutamate on insulin secretion and glucose tolerance in humans.

Methods  Monosodium (l)‐glutamate (10 g) was given orally in a double‐blind placebo‐controlled cross‐over study to 18 healthy volunteers, aged 19–28 years, with an oral (75 g) glucose load.

Results  The 75 min insulin response (AUC(0,75 min)), up to tmax of glutamate kinetics, was significantly correlated with the AUC(0,75 min) of glutamate concentrations (r=0.485, P=0.049). Glucose tolerance was not affected.

Conclusions  Oral (l)‐glutamate enhances glucose‐induced insulin secretion in healthy volunteers in a concentration‐dependent manner.
ACE inhibitors
Authors: Kelland N. F. , Webb D. J.
Published: March 2003

Edited by P. D’Orlèans‐Juste & G. E. Plante  Published by Birkhauser [Milestones in drug therapy series]  187 pages, price @116, ISBN 3‐7643‐5982‐X
Pharmacokinetics and safety of JTE‐522, a novel selective cyclooxygenase‐2 inhibitor, in healthy male volunteers
Authors: Ikeda Yasuhiko , Umemura Kazuo , Kondo Kazunao , Nakashima Mitsuyoshi , Kobayashi Takuo , Takahashi Mitsuru
Published: March 2003

Aims  The pharmacokinetics and safety profile of JTE‐522, 4‐(4‐cyclohexyl‐2 methyloxazol‐5‐yl)‐2‐fluorobenzensulphonamide, a novel selective cyclooxygenase‐2 inhibitor were investigated in healthy male volunteers.

Methods  Initially, as a pilot study, five groups of two subjects were given oral doses of 3–100 mg of JTE‐522. After safety assessment, subjects were given 150 and 200 mg of JTE‐522. The effect of food‐intake on the pharmacokinetics of JTE‐522 at a dose of 150 mg was examined. In the multiple‐dose study, subjects were given 150 mg of JTE‐522 once a day for 7 days. Concentrations of unchanged JTE‐522 in plasma, blood and urine were determined by high performance liquid chromatography (h.p.l.c.). Concentrations of metabolites were estimated with h.p.l.c. chromatograms and calibration curves for quantification of unchanged JTE‐522.

Results  In the course of this study, no serious abnormality attributable to the test drug was observed, suggesting that JTE‐522 was well tolerated in healthy subjects. In a single‐dose study, the concentrations of JTE‐522 in blood were much higher than the corresponding concentrations in plasma. JTE‐522 was readily distributed to blood cells and percentage distribution into blood cells was more than 99.0%. However, the values of Cmax in blood at doses of 100, 150, 200 mg JTE‐522 were 15241, 20445 ± 3918 (16333–24556), 20965 ± 3260 (17544–24386) ng ml−1, respectively. These findings suggest that JTE‐522 has a high affinity for blood cells and the distribution into blood cells is limited at the higher doses of over 100 mg. In a multiple dose study, pharmacokinetic parameters including t1/2 and AUC after the fourth administration were comparable with that of the seventh administration. Thus, these findings suggest the absence of accumulation on the multiple‐dosing of JTE‐522.

Conclusions  These results indicate that JTE‐522 has an acceptable pharmacokinetic profile for clinical use without any serious adverse events as we verified in healthy young male volunteers.
MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males
Authors: Gerloff Thomas , Schaefer Melanie , Johne Andreas , Oselin Kersti , Meisel Christian , Cascorbi Ingolf , Roots Ivar
Published: March 2003

Aims  A noncoding single nucleotide polymorphism (SNP) in exon 26 3435C > T of the highly polymorphic MDR1 gene has been demonstrated to alter digoxin absorption after induction of the MDR1 gene product P‐glycoprotein by rifampicin or after multiple oral dosing. The aim of the study was to investigate the effects of the major known MDR1 SNPs on the absorption of digoxin after a single oral dose in a large sample without drug pretreatment.

Methods  Fifty healthy white male subjects between the age of 18 and 40 years were enrolled. Following an overnight fast, all subjects received a single oral dose of 1 mg digoxin. Venous blood samples were taken at intervals up to 4 h post dose to obtain a pharmacokinetic profile.

Results  AUC(0,4 h), Cmax and tmax, used as indices of digoxin absorption, were not significantly different in any of the genotype groups tested. In particular, there was no significant difference between homozygous carriers of the C and T allele in exon 26 3435 (AUC(0,4 h) 9.24 and 9.38 µg l−1 h, Cmax 4.73 and 3.81 µg l−1, tmax 0,83 and 01.14 h).

Conclusions  This lack of effect of the major MDR1 SNPs on digoxin absorption might be explained by saturation of the maximum transport capacity of intestinal Pgp at the dose used.
A systematic review of systematic reviews of homeopathy
Authors: Ernst E.
Published: March 2003

Homeopathy remains one of the most controversial subjects in therapeutics. This article is an attempt to clarify its effectiveness based on recent systematic reviews. Electronic databases were searched for systematic reviews/meta‐analysis on the subject. Seventeen articles fulfilled the inclusion/exclusion criteria. Six of them related to re‐analyses of one landmark meta‐analysis. Collectively they implied that the overall positive result of this meta‐analysis is not supported by a critical analysis of the data. Eleven independent systematic reviews were located. Collectively they failed to provide strong evidence in favour of homeopathy. In particular, there was no condition which responds convincingly better to homeopathic treatment than to placebo or other control interventions. Similarly, there was no homeopathic remedy that was demonstrated to yield clinical effects that are convincingly different from placebo. It is concluded that the best clinical evidence for homeopathy available to date does not warrant positive recommendations for its use in clinical practice.
Bioanalysis of the novel peptide anticancer drug kahalalide F in human plasma by h.p.l.c. under basic conditions coupled with positive turbo‐ionspray tandem mass spectrometry
Authors: Stokvis E. , Rosing H. , López‐Lázaro L. , Jimeno J. M. , Supko J. G. , Schellens J. H. M. , Beijnen J. H.
Published: March 2003

Kahalalide F (KF) is a cyclic depsipeptide derived from the marine mollusc Elysia rufescens. Anti‐cancer activity of KF was observed both in vitro and in vivo especially against prostate cancer cell lines [1]. In order to support the Phase I study a method was developed and validated for the quantitative determination of KF in human plasma using high performance liquid chromatography (h.p.l.c.) coupled with positive turbo‐ionspray tandem mass spectrometry ((h.p.l.c.)‐TISP‐MS/MS). Miniaturized LC combined with mass spectrometric detection was essential to obtain the required selectivity and sensitivity. The use of trifluoroacetic acid, conventionally used in the mobile phase in the LC analysis of peptides, was omitted due to its signal suppressing effects on electrospray ionization. An alternative approach was followed employing a basic mobile phase using a stationary phase that is stable under basic conditions. KF remained positively charged under these conditions while the mobile phase background remained low.

The method involves a solid phase extraction (SPE) on C18 columns as sample pre‐treatment followed by LC‐MS/MS analysis. The LC separation was performed on a Zorbax Extend C18 column (150×2.1 mm i.d., particle size 5 µm) with acetonitrile‐10 mm ammonium acetate in water (85 : 15, v/v) as the mobile phase, pumped at a flow‐rate of 0.20 ml min−1. A butyric acid analogue of KF was used as the internal standard.

A lower limit of quantitation (LLQ) of 1 ng ml−1 was obtained using a 500 µl sample volume with a linear dynamic range up to 1000 ng ml−1. Accuracies were within 15.1% for the LLQ and within 9.0% for other quality control samples. Precisions did not exceed 9.9%. The drug was found to be stable in the biomatrix for at least 9 months at −20° C and for at least 24 h at ambient temperatures. The results demonstrate that an accurate, selective and sensitive bioanalytical method has been developed for KF analysis in human plasma. The method was successfully applied in a Phase I clinical study of KF. At the starting dose of 20 µg m−2 a Cmax of 1.75 ng ml−1 was obtained.
Good clinical practice: a nuisance, a help or a necessity for clinical pharmacology?
Authors: Sweatman John
Published: March 2003

This article reviews the impact of good clinical practice (GCP) on clinical pharmacology with particular reference to the new European Union Clinical Trial Directive. The Directive will be applied to both commercial and noncommercial studies on medicinal products for human use. The Directive requires that GCP should be used in all clinical trials except noninterventional studies. GCP is likely to follow the International Conference on Harmonization GCP guidelines in many aspects. GCP will enforce tighter guidelines on ethical aspects of a clinical study. Higher standards will be required in terms of comprehensive documentation for the clinical protocol, record keeping, training, and facilities including computers. Quality assurance and inspections will ensure that these standards are achieved. The additional requirements of GCP are discussed and any advantage to the study subject. The impact of the new Directive within the Research Governance Framework of the UK Department of Health is reviewed.