bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and tolerability of oral rizatriptan in healthy male and female volunteers
Authors: Lee  , Conroy  , Stepanavage  , Mendel  , Somers  , McLoughlin  , Olah  , De Smet  , Keymeulen  , Rogers  
Published: March 2003

Aims The pharmacokinetics and dose proportionality of rizatriptan single oral doses from 2.5 to 15 mg administered as solutions to healthy volunteers were studied.Methods In a randomized, crossover study with four periods, twenty‐four healthy volunteers (12 males and 12 females) took single oral doses of 2.5, 5, 10, and 15 mg rizatriptan in Periods 1–4. In a fifth period, subjects received 4 mg intravenous (i.v.) rizatriptan as a reference. Plasma and urine rizatriptan concentrations were determined at several timepoints/intervals for 12 and 24 h, respectively.Results The arithmetic mean AUC values following single oral doses of 2.5, 5, 10, and 15‐mg rizatriptan were 16, 33, 72, and 127 ng ml−1 h, respectively, in males; and 19, 42, 97, and 161 ng ml−1 h, respectively, in females. The overall bioavailability (F ) of rizatriptan was ∼40% in males. Following the 4 mg reference i.v. dose, the apparent plasma clearance (CL) and renal clearance (CLr ) were 1042 and 225 ml min−1, respectively, in males; and 821 and 174 ml min−1, respectively, in females.Conclusions The disposition kinetics of oral rizatriptan were linear for doses of 2.5–10 mg in males, and for doses of 2.5–5 mg in females. However, the degree of nonlinearity for higher doses was minor for both genders. The plasma concentrations of rizatriptan were slightly greater in women compared to men but the difference was not considered to be clinically meaningful. Also, the clearance of rizatriptan appeared to be mainly nonrenal.
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%.