bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical pharmacologists and drug regulation—future perspective in Japan
Authors: HIROKAWA K. 
Published: October 2003

1The Japanese pharmaceutical administration system, and recommendations for the improvement of clinical trial methodology following the implementation of GCP guidelines in Japan are described with special reference to three recent developments in Japanese drug regulation. 2The implementation of GCP guidelines has not been fully satisfactory and clinical trials in Japan still run into problems. The Ministry of Health and Welfare has recently established a Committee on Safety of Medicines after serious trouble with a new drug was experienced. The Committee released an interim report on the reform of clinical trials supervision and the system for examination of New Drug Applications. 3ICH‐GCP guidelines will be implemented in Japan in the next few years. The principal differences between Japanese GCP and ICH‐GCP guidelines, and their effects on clinical trials in Japan with reference to the acceptability of ICH‐GCP, are discussed. 4The final proposals on the National Health Insurance drug pricing method and the appropriate use of drugs by the Central Social Insurance Medical Council are anticipated to have a significant impact on the drug market. The changes in pricing system, especially premiums for innovative drugs, and the implications for the drug market are considered. 5In these changed circumstances, the importance of the role of clinical pharmacologists in the framework of the new drug regulations in Japan is reviewed.
The regulation of pulmonary vascular tone
Authors: WILKINS MARTIN R. , LAN ZHAO  , AL‐TUBULY RIDA 
Published: October 2003

1The ability to manipulate pharmacologically pulmonary vascular tone independent of effects on systemic blood vessels is a desirable objective. Elucidation of the biochemical mechanisms underlying hypoxia‐induced pulmonary vasoconstriction (HPV) may permit preferential targeting of the pulmonary circulation. 2Here we review our studies of the role of locally synthesized candidate vasoactive factors in HPV. In addition, we present data demonstrating an attenuated pressor response to hypoxia in the pulmonary circulation of Fischer 344 rats compared with the Wistar‐Kyoto (WKY) rat strain. 3We propose that a systematic genome‐wide search using the HPV phenotype and a panel of highly informative microsatellite markers will elucidate the genetic loci underlying the difference in susceptibility to HPV in these two rat strains and provide a valuable and novel insight into the factors that determine the HPV response.
Pharmacokinetics of bismuth and ranitidine following multiple doses of ranitidine bismuth citrate
Authors: KOCH K. M. , KERR B. M. , GOODING A. E. , DAVIS I. M. 
Published: October 2003

1The pharmacokinetics of bismuth and ranitidine derived from oral doses of ranitidine bismuth citrate 800 mg given twice daily for 28 days were examined in this double‐blind, placebo‐controlled, parallel‐group study in 27 healthy subjects.2Bismuth accumulation in plasma reflected its multicompartmental disposition, achieving the majority of predicted steady state within 14–28 days. Bismuth absorption from ranitidine bismuth citrate is limited (<0.5% of the dose), and bismuth elimination is predominantly renal secretion. Peak plasma concentrations did not exceed 19 ng ml−1, remaining well below those associated with bismuth toxicity. Bismuth was measurable at low concentrations in plasma and urine for up to 5 months after the last dose. Plasma bismuth concentration‐time data and urinary excretion data were best described by separate multicompartmental models, with terminal half‐lives averaging 21 days and 45 days, respectively.3The pharmacokinetics of ranitidine derived from ranitidine bismuth citrate were similar to those of ranitidine administered alone. Ranitidine did not appreciably accumulate in plasma.4Ranitidine bismuth citrate was well‐tolerated during 28 days of repeated dosing.
Effects of age on cardiovascular responses to adrenaline in man
Authors: White M. , Leenen F. H. H. 
Published: October 2003

Aims Whereas the effects of ageing on β‐receptor mediated responses have been extensively studied in vitro and in vivo using the β‐adrenoceptor agonist isoprenaline, little is known regarding ageing induced changes in responses to endogenous catecholamines. In the present study, we assessed age‐related changes in cardiac responses to the endogenous β‐adrenoceptor agonist adrenaline and the influence of age‐related changes in arterial baroreflex function on these responses.
Methods Adrenaline alone was infused in 14 young subjects, age 30±2 years (eight males, six females), and 18 older subjects (six males, 12 females), age 60±2 years, and together with ganglionic blockade (trimetaphan) in seven young and 11 older subjects. Adrenaline was infused at 3–4 incremental rates, each rate for 8 min. Cardiac function was assessed by echocardiography.
Results Adrenaline alone, at infusion rates 20–160 ng kg−1 min−1 caused similar increases in heart rate in the two groups. In contrast, adrenaline caused larger increases in stroke volume, ejection fraction, cardiac index and systolic blood pressure and larger decreases in end‐systolic wall stress and diastolic blood pressure in the young compared with older subjects. Older females exhibited the smallest increases in stroke volume index and ejection fraction. With concomitant ganglionic blockade, all above cardiovascular responses to adrenaline were similar in the young and older group. Plasma adrenaline increased similarly in the two groups.
Conclusions We conclude that ganglionic blockade does not unmask an age‐related decrease in cardiovascular responses to adrenaline (in contrast to isoprenaline). A concomitant ageing induced decrease in neuronal uptake (which applies to adrenaline, but not isoprenaline) may explain such a differential effect..
Intra‐arterial substance P mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability
Authors: Newby David E. , Sciberras David G. , Mendel Carl M. , Gertz Barry J. , Boon Nicholas A. , Webb David J. 
Published: October 2003

Aims The current studies were designed to characterize the pharmacology, reproducibility and tolerability of the vasodilator response to intra‐arterial substance P infusion in the forearm of healthy man. Methods On different occasions, eight healthy male volunteers received brachial artery infusions of substance P at doubling doses ranging from 0.5 to 128 pmol min−1. Blood flow was measured in both arms using venous occlusion plethysmography. Results Substance P induced dose‐dependent vasodilatation in the human forearm which had a log‐linear relationship to dose. At doses of 1–8 pmol min−1, mean responses were highly reproducible both within and between days. There were no differences between responses to discontinuous doses and continuous doses of substance P. Substance P was generally well tolerated at doses of ≤64 pmol min−1 with no significant alteration in arterial blood pressure or heart rate. Skin oedema in the infused forearm and systemic vasodilatation, manifested by facial flushing and non‐infused forearm vasodilatation, occurred at doses of ≥16 pmol min−1. Conclusions Forearm vasodilatation to substance P represents a reproducible and useful model in the assessment of peripheral endothelial cell NK1 receptor function.
Hospitalization for serious blood and skin disorders followinguse of co‐trimoxazole
Authors: Myers Marian Wald , Jick Hershel 
Published: October 2003

Aims The objective of this study was to quantify the risk of serious blood and skin disorders associated with co‐trimoxazole.
Methods We conducted a population‐based cohort study of serious blood and skin disorders requiring hospitalization among otherwise healthy users of co‐trimoxazole at Group Health Cooperative and Puget Sound (GHC).
Results During the years 1987 to 1993 we found six cases of co‐trimoxazole‐associated blood disorders and three cases of co‐trimoxazole‐associated skin disorders yielding risks of 5.6/100 000 (95% CI 2.6–12.2) and 2.8/100 000 (95% CI 0.9–8.2) respectively. In all cases found there was prompt recovery after discontinuation of co‐trimoxazole. We found no cases of toxic epidermal necrolysis.
Conclusions We conclude that the risk of blood and skin disorders associated with the use of co‐trimoxazole leading to hospitalization is low.
Hospitalization for serious blood and skin disorders following co‐trimoxazole
Authors: Wald Myers Marian , Jick Hershel 
Published: October 2003

Aims To quantify the risk of serious blood and skin disorders requiring hospitalization among otherwise healthy users of co‐trimoxazoleMethods We conducted a population‐based cohort study at Group Health Cooperative of Puget Sound (GHC).Results During the years 1987 to 1993 we found six cases of co‐trimoxazole‐associated blood disorders and three cases of co‐trimoxazole‐associated skin disorders yielding risks of 5.6/100,000 (95% CI 2.6–12.2) and 2.8/100,000 (95% CI 0.9–8.2) respectively. In all cases found there was prompt recovery after discontinuation of co‐trimoxazole. We found no cases of toxic epidermal necrolysis.Conclusions We conclude that the risk of blood and skin disorders associated with the use of co‐trimoxazole leading to hospitalization is low.
Association between CYP2C19 genotype and proguanil oxidative polymorphism
Authors: Coller J. K. , Somogyi A. A. , Bochner F. 
Published: October 2003

Aims To examine the relationship between proguanil metabolism and the number of mutations in CYP2C19 by comparing the CYP2C19 genotype and proguanil phenotype of 10 subjects.Methods Partial clearance and urinary metabolic ratio data were obtained from a previous study of 10 subjects [
5]. Analysis of CYP2C19 genotypes was performed using PCR amplification followed by restriction endonuclease digestion of genomic DNA from a blood sample.Results The intrinsic partial clearance of PG to CG ranged from 0.41–10.1l h−1, and was related to the number of functional CYP2C19 alleles present. Genotypic PMs had metabolic ratios >13, while genotypic heterozygote EMs had metabolic ratios <9.Conclusions Proguanil may be a suitable phenotyping probe for the CYP2C19 genetic polymorphism, however the exact antimode of the urinary metabolic ratio chosen to separate poor and extensive metabolisers needs further investigation.
No effect of short‐term omeprazole intake on acenocoumarol pharmacokinetics and pharmacodynamics
Authors: De Hoon J. N. J. M. , Thijssen H. H. W. , Beysens A. J. M. M. , Van Bortel L. M. A. B. 
Published: October 2003

Aims To investigate the effect of omeprazole on the pharmacokinetics of R‐ and S‐acenocoumarol and on their combined anticoagulant activity. Methods Eight healthy male subjects completed a double‐blind, randomized, placebo‐controlled, two‐way cross‐over study. Subjects were given either omeprazole 40 mg or placebo once daily for 3 days. On day 2 of each study period, a single 10 mg oral dose of racemic acenocoumarol was administered and venous blood samples were collected for pharmacokinetic and pharmacodynamic assessments. A wash‐out period of 2 weeks separated the two study periods. Results The pharmacokinetics of R‐ and S‐acenocoumarol (AUC 3016±221 and 233±14 ng ml−1 h, respectively) did not change after omeprazole (AUC 2929±256 and 220±18 ng ml−1 h, respectively). Anticoagulant activity (INRmax 1.7±0.1) was unaffected by co‐administration of omeprazole (INRmax 1.7±0.1). Conclusions The short‐term intake of omeprazole does not affect acenocoumarol pharmacokinetics or pharmacodynamics. These data differ from the results of previous studies on the effect of omeprazole on warfarin, suggesting a different in vivo interaction profile of omeprazole on acenocoumarol than on warfarin. Drug interaction studies with oral anticoagulants should not be restricted to the use of warfarin.
Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p‐hydroxylation
Authors: Schmider Jürgen , Greenblatt David J. , Von Moltke Lisa L. , Karsov Dmitry , Shader Richard I. 
Published: October 2003

Aims Inhibition of cytochrome P450 (CYP) activity by selective serotonin reuptake inhibitors (SSRIs) has frequently been reported with regard to pathways mediated by CYP2D6, CYP3A4/5, and CYP1A2. Little data exist on the capability of SSRIs to inhibit CYP2C9. Methods We investigated the effect of SSRIs on p‐hydroxylation of phenytoin (PPH), an established index reaction reflecting CYP2C9 activity, in an in vitro assay using liver tissue from six different human donors. Results In control incubations (without inhibitor), 5‐( p‐hydroxy‐phenyl)‐5phenylhydantoin (HPPH) formation rates were: Vmax 0.023 nmol min−1 mg−1; Km 14.3 &mgr;m. Average inhibition constants (Ki ) differed significantly among the SSRIs, with fluvoxamine having the lowest Ki (6 &mgr;m ) followed by R‐fluoxetine (13 &mgr;m ), norfluoxetine (17 &mgr;m ), RS‐fluoxetine (19 &mgr;m ), sertraline (33 &mgr;m ), paroxetine (35 &mgr;m ), S‐fluoxetine (62 &mgr;m ), and desmethylsertraline (66 &mgr;m ). Thus, assuming comparable molar concentrations at the site of inhibition, fluvoxamine can be expected to have the highest probability of interfering with the metabolism of CYP2C9 substrates. S‐fluoxetine is on average a 5 fold weaker CYP2C9 inhibitor than either R‐fluoxetine or the racemic mixture. Conclusions These findings are consistent with published case reports describing SSRI‐related increments in plasma phenytoin levels. Because phenytoin has a narrow therapeutic index, plasma levels should be closely monitored when SSRIs are coadministered.
Consulting the oracle: a Delphi Study to determine the content of a postgraduate distance learning course in therapeutics
Authors: Boath E. , Mucklow J. , Black P. 
Published: October 2003

Aims To determine the content of a distance learning course in therapeutics for general practitioners (GPs).Methods This paper reports the results of a three‐round Delphi study. The respondent group comprised 21 GPs who were expert in their field. In the first round, the experts were interviewed to determine the knowledge, skills, competencies and attitudes required by GPs to prescribe effectively; the justification for, and scope of a distance learning course; and the preferred learning methods, format and methods of assessment. The first round generated 251 statements, which were collapsed into 108 statements covering thirteen domains. In the second and third rounds, a questionnaire was posted to the GPs. 95% responded to the second round questionnaire and agreed upon 86 statements, which were then collated into four domains. In the third round, 19 GPs rated each of the 86 statements on a five point scale. Consensus was reached for 99% of statements: 40 on the aims, design, format, organization and assessment of the course; and 45 on the knowledge and skills to be acquired by GPs who complete the course.Results The results revealed a consensus in favour of:• modules at regular intervals• some flexibility in meeting deadlines• interaction among students for mutual support• easy access to course tutors• some face‐to‐face contact to complement distance learning material• clear guidance on effective and safe prescribing• emphasis on importance of ‘people skills’Conclusions The Delphi process can be used to determine the competencies required for continuing medical education in therapeutics.
Endotoxin depresses hepatic cytochrome P450‐mediated drug metabolism in women
Authors: Shedlofsky S. I. , Israel B. C. , Tosheva R. , Blouin R. A. 
Published: October 2003

Aims In men, the inflammatory response to intravenous endotoxin depresses apparent oral clearances of antipyrine, hexobarbitone, and theophylline. The aim of this study was to investigate whether there might be gender differences in the regulation of hepatic cytochromes P450.Methods Experiments were carried out in seven healthy women volunteers (ages 19–51, median 22 years). Each woman received a cocktail of the three drugs on two occassions, once after a saline injection and again after endotoxin.Results Endotoxin injections, but not saline, caused the expected physiologic responses of inflammation including fever and increases in circulating tumor necrosis factor‐α, interleukin‐6, and C‐reactive protein. When compared with the saline control studies, endotoxin significantly decreased clearances of all probes: antipyrine, 31% (95%CI 21%–41%); hexobarbitone, 20% (95%CI 10–31%); and theophylline, 20% (95%CI 10%–30%). The decreases were comparable with those found in the men previously studied (35%, 27%, and 22%, respectively).Conclusions These data show that endotoxin‐induced inflammation decreases hepatic cytochrome P450‐mediated metabolism of selected probe drugs in women as it does in men.
An investigation of hospital generated pharmaceutical care when patients are discharged home from hospital
Authors: Smith L. , McGowan L. , Moss‐Barclay C. , Wheater J. , Knass D. , Chrystyn H. 
Published: October 2003

Aims To investigate how seamless pharmaceutical care could be delivered.Methods Elderly patients discharged from hospital, to their own home, were randomized into control and study groups. Control and study group patients received the normal discharge information. The study group were also counselled about their medicines and informed about their pharmaceutical care plan. Copies of the plan were given to the study patients. All patients received a domiciliary visit between 7 and 10 days after discharge. Their current medication was compared with that on discharge and contact was made with the General Practitioner as appropriate.Results Twenty‐eight study and 25 control patients with a mean (s.d.) age of 77.5 (7.3) and 77.6 (6.1) years completed the study. A pharmaceutical domiciliary visit was necessary for 21 (75%) and 24 (96%) of the study and control patients respectively. Compliance was better (P<0.01) in the study group. Unintentional changes to the medication of 31 (14 study and 17 control) patients were found during the visit and after contact with the prescriber all but one prescription was restored to that on discharge.Conclusions At present it is difficult to ensure seamless pharmaceutical care. A pharmaceutical domiciliary visit may be useful to ensure seamless therapeutic care and thus avoid unnecessary healthcare events and costs after a patient is discharged home.
Do trandolapril and indomethacin influence renal function and renal functional reserve in hypertensive patients?
Authors: Pritchard G. , Lyons D. , Webster J. , Petrie J. C. , MacDonald T. M. 
Published: October 2003

Aims To assess the effect of trandolapril (2 mg once daily) and indomethacin (25 mg three times daily), alone and in combination, on renal function and renal functional reserve in hypertensive patients (DBP 95–115 mmHg) requiring regular non‐steroidal anti‐inflammatory drugs (NSAIDs).Methods Randomized, double‐blind, placebo‐controlled, four way crossover design. After 3 weeks treatment renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured using the p‐aminohippurate (PAH) and inulin methods. Renal functional reserve was estimated by measuring RPF and GFR at the end of an intravenous infusion of dopamine 2 μg kg−1 and 10% amino acid solution.Results There was no significant difference in RPF between treatments: −22.79 ml min−1 (95% CI −54.82, 9.24) for placebo and trandolapril, −10.37 ml min−1 (95% CI −30.7, 9.96) for placebo and indomethacin, −14.78 ml min−1 (95% CI −50.33, 20.77) for placebo and trandolapril with indomethacin. There was no significant difference in functional reserve RPF between treatments: −34.96 ml min−1 (95% CI −119.8, 49.88) for placebo and trandolapril, 29.78 ml min−1, −15.18, 74.74) for placebo and indomethacin, and −25.84 ml min−1 (95% CI −87.62, 35.94) for placebo and trandolapril with indomethacin. There was no significant difference in GFR between treatments: −1.01 ml min−1 (95% CI −7.45, 5.42) for placebo and trandolapril, −7.88 ml min−1 (95% CI −15.08, −0.68) for placebo and indomethacin, and −0.36 ml min−1 (95% CI −7.58, 6.86) for placebo and trandolapril with indomethacin. There was no significant difference in functional reserve GFR between treatments: 5.13 ml min−1 (95% CI −4.97, 15.23) for placebo and trandolapril, 6.31 ml min−1 (95% CI −1.88, 14.5) for placebo and indomethacin, 7.21 ml min−1 (95% CI 1.26, 13.16) for placebo and trandolapril with indomethacin.Conclusion In hypertensives chronic treatment with NSAIDs or ACEI alone or in combination did not change RPF or GFR and did not change renal functional reserve capacity of RPF or GFR.
Pharmacokinetics of the S(+) and R(−) enantiomers of vigabatrin during chronic dosing in a patient with renal failure
Authors: Jacqz‐Aigrain Evelyne , Guillonneau Marianne , Rey Elisabeth , Macher Marie‐Alice , Montes Christine , Chiron Catherine , Loirat Chantal 
Published: October 2003

Aims To study the pharmacokinetics of vigabatrin in a patient affected with tuberous sclerosis who developed major agitation and aggression, while receiving vigabatrin orally (1.5 g every 12 h) and in whom impaired renal function was diagnosed.Methods The patient received vigabatrin (0.5 g day−1 ). A pharmacokinetic study of the S(+) and R(−) enantiomers of vigabatrin was performed before and during dialysis. Plasma concentrations were measured at 0, 1, 2, 3, 4, 6, 12, 18 and 24 h by a specific GCMS assay.Results Before dialysis, the maximum and minimun plasma concentrations of vigabatrin at steady‐state were lower for the S(+) than for the R(−) enantiomer, while the apparent oral clearance was higher for the S(+) than for the R(−) enantiomer (2.97 vs 0.48 l h−1 ). In addition, the haemodialysis clearance was similar for the two enantiomers (4.96 vs 5.15 l h−1 ).Conclusions Vigabatrin is an irreversible inhibitor of GABA‐transaminase, effective in the treatment of drug‐resistant epilepsy and reported to be eliminated unchanged by renal excretion. Although vigabatrin is known to have stereoselective kinetics, the difference in plasma dry concentrations and pharmacokinetics of the S(+) and R(−) enantiomers that we observed during long term administration at high doses in a patient with impaired renal function, has not been reported before. The question remains of the potential toxicity of the high levels of the R(−) enantiomer.
Single and multiple dose pharmacokinetics of felbamate in the elderly
Authors: Richens A. , Banfield C. R. , Salfi M. , Nomeir A. , Lin C. C. , Jensen P. , Affrime M. B. , Glue P. 
Published: October 2003

Aims The objective of this study was to compare the pharmacokinetics, safety and tolerability of the antiepileptic drug felbamate in young and elderly healthy vounteers.Methods The single and multiple dose pharmacokinetics of felbamate were examined in an open‐label two‐dose level parallel group study in 24 elderly (66 to 78‐year‐old) and 11 young (18 to 45‐year‐old) healthy volunteer subjects. Pharmacokinetics were determined from blood samples obtained over 120 h after administration of single 600 mg or 1200 mg doses, and after multiple doses of 600 mg or 1200 mg administered every 12 h. Safety and tolerability were assessed through laboratory tests, ECGs, vital signs and reported adverse events.Results Single dose felbamate pharmacokinetic parameters differed between young and elderly subjects; compared with young subjects, elderly subjects had lower mean clearance (31.2 vs 25.1 ml min−1; 90% CI −11.4 to −0.9; P=0.02) and a trend towards a greater half‐life (18.6 vs 21.0 h; 90% CI −0.6 to 5.4; P=0.11). Mean AUC and Cmax values were also higher in elderly subjects. No gender differences were noted for weight‐adjusted pharmacokinetic variables. Felbamate was less well tolerated in elderly subjects compared with young subjects, as shown by higher rates of adverse event reporting and dropouts at the higher dose level. This may be due to age‐related pharmacokinetic differences, to the rapid dose titration schedule used in this study, and/or to altered sensitivity to felbamate’s pharmacodynamic effects.Conclusions These findings imply that elderly subjects require lower initial dosing and slower dose titration of felbamate than non‐elderly subjects.