bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral Contraception Does Not Alter Single Dose Saquinavir Pharmacokinetics in Women
Authors: Fröhlich Margit , Burhenne Jürgen , Martin‐Facklam Meret , Weiss Johanna , Von Wolff Michael , Strowitzki Thomas , Walter‐Sack Ingeborg , MD Walter E. Haefeli 
Published: December 2004

AimsWomen experience more adverse drug reactions (ADR) to antiretroviral therapy than men. This may be attributed to higher plasma concentrations of protease inhibitors due to pharmacokinetic interactions with hormonal preparations. Thus, in the present study we aimed to investigate the influence of oral contraceptives (OC) on the pharmacokinetics of the protease inhibitor saquinavir.MethodsSaquinavir was administered in a hard gelatin capsule formulation (Invirase®) to rule out confounding by pharmaceutical aids of the more frequently used soft gelatin capsule. After an overnight fast, eight healthy female participants ingested a single oral dose of 600 mg saquinavir immediately before and after the 19th dose of a combined, low dose OC (0.03 mg ethinylestradiol, 0.075 mg gestodene) in a prospective, fixed sequence study design. The first saquinavir application was scheduled on day 1, 2, or 3 of the individual menstrual cycle. Plasma concentrations of saquinavir and relative concentrations of its M2&M3‐hydroxy metabolites were determined by LC/MS/MS for 48 h.ResultsIntake of OC resulted in a significant decrease in morning serum concentrations (before intake of OC, compared to day 19 of OC therapy) of 17β‐estradiol by −23.4 pg ml−1 (57%, 95%CI: −76% to −37.4%); progesterone by −0.25 ng ml−1 (33%, 95%CI: −45.3% to −21.5%); follicle‐stimulating hormone by −4.06 U l−1 (82%, 95%CI: −96.5% to −67.7%); and luteinizing hormone by −3.49 U l−1 (74%, 95%CI: −93 to −54.6%). Conversely, sexual hormone binding globulin serum concentrations increased by 83.6 nmol l−1 (205%, 95%CI: 32.2% to 377%). Pharmacokinetic parameters of saquinavir (AUC, Cmax, tmax, t1/2, CLR) were not affected by OC, nor was the relative metabolic ratio of saquinavir/M2&M3‐hydroxy saquinavir. Furthermore, there was no association of serum hormone concentrations or MDR1‐polymorphisms (C3435T and G2677T) with pharmacokinetic parameters of saquinavir.ConclusionsThere was no effect of OC on saquinavir pharmacokinetics. Thus, pharmacokinetic interactions of synthetic sexual steroids with saquinavir are not likely to account for the increased ADR to antiretroviral therapy seen in women.
Acute otitis media in children: a retrospective analysis of physician prescribing patterns
Authors: Quach Caroline , Collet Jean‐Paul , LeLorier Jacques 
Published: December 2004

BackgroundAcute otitis media (AOM) is one of the most common infectious diseases of childhood and the most frequent indication for antibiotic use in children.AimTo better understand the prescribing patterns and appropriateness of AOM therapy.MethodsWe investigated a historical cohort of children aged ≤ 6 years who had a first AOM episode between June 1999 and June 2002, using the Régie de l’assurance maladie du Quebec (RAMQ) administrative databases. Conformity of prescription was based on the consensus guidelines on AOM treatment from the Drug‐resistant Streptococcus pneumoniae Therapeutic Working Group. These recommendations suggested amoxicillin as the first‐line drug, and amoxicillin‐clavulanic acid or cefuroxime for children who had received antibiotics in the previous month. Data were analysed using descriptive statistics, χ2 test and logistic regression.ResultsDuring the study period, 60 513 children ≤ 6 years of age experienced their first AOM episode with a mean age of 2.6 years. They were seen by 4708 physicians [87% general practitioners (GPs), 9% paediatricians, and 3% ENT specialists]. Amoxicillin was the antibiotic that was prescribed the most (43%), followed by cefprozil and azithromycin. Overall, 42% of physicians adhered to antibiotic guideline recommendations. Compared with GPs, paediatricians were almost as likely to prescribe in conformity with the consensus guidelines, whereas ENT specialists were 50% less likely to prescribe an antibiotic recommended by the guidelines.ConclusionContinuing medical education is necessary to ensure appropriate adherence to antibiotic guidelines.
Potential for drug interactions involving cytochromes P450 2D6 and 3A4 on general adult psychiatric and functional elderly psychiatric wards
Authors: Davies S. J. C. , Eayrs S. , Pratt P. , Lennard M. S. 
Published: December 2004

AimsTo assess the potential for interactions involving cytochromes P450 2D6 (CYP2D6) and 3A4 (CYP3A4) between drugs prescribed in a city in‐patient psychiatric service.MethodsPrescription information was obtained from all 236 patients in general adult wards and all 87 patients in functional elderly wards under a city psychiatric service. The frequencies with which combinations of drugs expected to interact via CYP2D6 or CYP3A4 were documented and compared between these two settings.ResultsAll 2089 drug prescriptions, of which 1237 (59%) were administered, were analyzed. One hundred and seventy‐two patients (73%) on adult wards and 59 (68%) on functional elderly wards were prescribed at least one drug metabolized by and/or inhibiting CYP2D6, the difference being nonsignificant (95% confidence interval on the difference −6.3%, 16.4%). Anticipated interactions from 62/82 CYP2D6‐related combinations prescribed on adult wards (27/100 patients) and 19/30 prescribed to elderly patients (22/100 patients) were judged to be clinically important or potentially clinically important. The proportion of patients on functional elderly wards prescribed at least one drug interacting with CYP3A4 (87%) was significantly greater than that for patients on adult wards (57%, P < 0.001). The frequency of interactions involving CYP3A4 was significantly greater on functional elderly than adult wards (43/100 vs 22/100 patients, P < 0.025, 95% confidence interval on the difference 4, 38/100).ConclusionsOur findings confirm extensive polypharmacy on general adult psychiatric and functional elderly psychiatric wards. A substantial proportion of patients were receiving combinations of drugs that interact with CYP2D6 and/or CYP3A4, many of which are known to produce clinically important interactions. Doctors practising in old age psychiatry should be aware that patients on functional elderly wards are at increased risk of clinically important CYP3A4 interactions. Psychiatrists should consider the pharmacokinetic implications of drugs prescribed for use ‘as needed’, because of the potential for unpredictable interactions.
Database analyses for the prediction of in vivo drug–drug interactions from in vitro data
Authors: Ito Kiyomi , Brown Hayley S. , Houston J. Brian 
Published: December 2004

AimsIn theory, the magnitude of an in vivo drug–drug interaction arising from the inhibition of metabolic clearance can be predicted using the ratio of inhibitor concentration ([I]) to inhibition constant (Ki). The aim of this study was to construct a database for the prediction of drug–drug interactions from in vitro data and to evaluate the use of the various estimates for the inhibitor concentrations in the term [I]/Ki.MethodsOne hundred and ninety‐three in vivo drug–drug interaction studies involving inhibition of CYP3A4, CYP2D6 or CYP2C9 were collated from the literature together with in vitro Ki values and pharmacokinetic parameters for inhibitors, to allow calculation of average/maximum systemic plasma concentration during the dosing interval and maximum hepatic input plasma concentration (both total and unbound concentration). The observed increase in AUC (decreased clearance) was plotted against the estimated [I]/Ki ratio for qualitative zoning of the predictions.ResultsThe incidence of false negative predictions (AUC ratio > 2, [I]/Ki < 1) was largest using the average unbound plasma concentration and smallest using the hepatic input total plasma concentration of inhibitor for each of the CYP enzymes. Excluding mechanism‐based inhibition, the use of total hepatic input concentration resulted in essentially no false negative predictions, though several false positive predictions (AUC ratio < 2, [I]/Ki > 1) were found. The incidence of true positive predictions (AUC ratio > 2, [I]/Ki > 1) was also highest using the total hepatic input concentration.ConclusionsThe use of the total hepatic input concentration of inhibitor together with in vitro Ki values was the most successful method for the categorization of putative CYP inhibitors and for identifying negative drug–drug interactions. However this approach should be considered as an initial discriminating screen, as it is empirical and requires subsequent mechanistic studies to provide a comprehensive evaluation of a positive result.
Pharmacokinetics of levosimendan and its circulating metabolites in patients with heart failure after an extended continuous infusion of levosimendan
Authors: Antila Saila , Kivikko Matti , Lehtonen Lasse , Eha Jaan , Heikkilä Aira , Pohjanjousi Pasi , Pentikäinen Pertti J. 
Published: December 2004

AimsThe purpose of the study was to characterize the pharmacokinetics of levosimendan and its metabolites OR‐1855 and OR‐1896 in patients with congestive heart failure.MethodsLevosimendan was administered as a continuous intravenous infusion for 7 days. Twelve subjects received the drug at an infusion rate of 0.05 µg kg−1 min−1 and 12 at a rate 0.1 µg kg−1 min−1.ResultsSteady state concentrations of levosimendan were achieved within 4 h. Peak concentrations of the metabolites occurred after termination of the infusion. The mean (± SD) half‐life of the active metabolite OR‐1896 was 81 ± 37 h after the lower dose and 81 ± 28 h after the higher dose (P = 0.992, 95% confidence interval on the difference −27.5, 27.7).ConclusionsThe metabolites of levosimendan, OR‐1855 and OR‐1896, were formed and eliminated slowly, their peak concentrations occurring after termination of the 7‐day infusion of the drug.
Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems
Authors: Sinzinger H. , O'Grady J. 
Published: December 2004

AimsMuscular problems are the major group of side‐effects during statin treatment. They are known to occur much more frequently during and after exercise.Methods and resultsFor the last 8 years we have monitored 22 professional athletes in whom, because of familial hypercholesterolaemia, treatment with different statins was attempted. Only six out of the 22 finally tolerated at least one member of this family of drugs. In three of these six the first statin prescribed allowed training performance without any limitation. Changing the drug demonstrated that only two tolerated all the four or five statins examined (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin). Cerivastatin was not among the statins prescribed.ConclusionsThese findings indicate that in top sports performers only about 20% tolerate statin treatment without side‐effects. Clinical decision making as to lipid lowering therapy thus becomes a critical issue in this small subgroup of patients.
Recent advances in drug action and therapeutics: Relevance of novel concepts in G‐protein‐coupled receptor and signal transduction pharmacology
Authors: Brink C. B. , Harvey B. H. , Bodenstein J. , Venter D. P. , Oliver D. W. 
Published: December 2004

Problem statementDuring especially the past two decades many discoveries in biological sciences, and in particular at the molecular and genetic level, have greatly impacted on our knowledge and understanding of drug action and have helped to develop new drugs and therapeutic strategies. Furthermore, many exciting new drugs acting via novel pharmacological mechanisms are expected to be in clinical use in the not too distant future.Scope and contents of reviewIn this educational review, these concepts are explained and their relevance illustrated by examples of drugs used commonly in the clinical setting, with special reference to the pharmacology of G‐protein‐coupled receptors. The review also addresses the basic theoretical concepts of full and partial agonism, neutral antagonism, inverse agonism and protean and ligand‐selective agonism, and the relevance of these concepts in current rational drug therapy. Moreover, the mechanisms whereby receptor signalling (and eventually response to drugs) is fine‐tuned, such as receptor promiscuity, agonist‐directed trafficking of receptor signalling, receptor trafficking, receptor ‘cross‐talk’ and regulators of G‐protein signalling (RGSs) are discussed, from theory to proposed therapeutic implications.ConclusionsIt is concluded that the understanding of molecular receptor and signal transduction pharmacology enables clinicians to improve their effective implementation of current and future pharmacotherapy, ultimately enhancing the quality of life of their patients.
Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes
Authors: Yasui‐Furukori Norio , Takahata Takenori , Nakagami Taku , Yoshiya Gen , Inoue Yoshimasa , Kaneko Sunao , Tateishi Tomonori 
Published: December 2004

AimsOmeprazole is mainly metabolized by the polymorphic cytochrome P450 (CYP) 2C19. The inhibitory effect of fluvoxamine, an inhibitor of CYP2C19 as well as CYP1A2, on the metabolism of omeprazole was compared between different genotypes for CYP2C19.MethodsEighteen volunteers, of whom six were homozygous extensive metabolizers (EMs), six were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, participated in the study. A randomized double‐blind, placebo‐controlled crossover study was performed. All subjects received two six‐day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 40 mg dose of omeprazole on day six in both cases. Plasma concentrations of omeprazole and its metabolites, 5‐hydroxyomeprazole, omeprazole sulphone, and fluvoxamine were monitored up to 8 h after the dosing.ResultsDuring placebo administration, geometric means of peak concentration (Cmax), under the plasma concentration‐time curve from 0 to 8 h (AUC(0,8 h)) and elimination half‐life (t1/2) of omeprazole were 900 ng ml−1, 1481 ng ml−1 h, and 0.6 h in homozygous EMs, 1648 ng ml−1, 4225 ng ml−1 h, and 1.1 h in heterozygous EMs, and 2991 ng ml−1, 11537 ng ml−1 h, and 2.8 h in PMs, respectively. Fluvoxamine treatment increased Cmax of omeprazole by 3.7‐fold (95%CI, 2.4, 5.0‐fold, P < 0.01) and 2.0‐fold (1.4, 2.6‐fold, P < 0.01), AUC(0,8 h) by 6.0‐fold (3.3, 8.7‐fold, P < 0.001) and 2.4‐fold (1.7, 3.2‐fold, P < 0.01), AUC(0,∞) by 6.2‐fold (3.0, 9.3‐fold, P < 0.01) and 2.5‐fold (1.6, 3.4‐fold, P < 0.001) and prolonged t½ by 2.6‐fold (1.9, 3.4‐fold, P < 0.001) and 1.4‐fold (1.02, 1.7‐fold, P < 0.05), respectively. However, no pharmacokinetic parameters were changed in PMs. The AUC(0,8 h) ratios of 5‐hydroxyomeprazole to omeprazole were decreased with fluvoxamine in homozygous EMs (P < 0.05) and heterozygous EMs (P < 0.01).ConclusionsEven a low dose of fluvoxamine increased omeprazole exposure in EMs, but did not increase omeprazole exposure in PMs after a single oral dose of omeprazole. These findings confirm a potent inhibitory effect of fluvoxamine on CYP2C19 activity. The bioavailability of omeprazole might, to some extent, be increased through inhibition of P‐glycoprotein during fluvoxamine treatment.
Effect of St John's wort on the activities of CYP1A2, CYP3A4, CYP2D6, N‐acetyltransferase 2, and xanthine oxidase in healthy males and females
Authors: Wenk Markus , Todesco Liliane , Krähenbühl Stephan 
Published: December 2004

AimsTo investigate the influence of St. John's wort (SJW) on CYP3A4, CYP1A2, CYP2D6, N‐acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activities in healthy males and females.MethodsEight males and eight females were treated with SJW extract (3 × 300 mg day−1) for 14 days. Assessment of CYP1A2, NAT2, XO, CYP2D6, and CYP3A4 activities was performed before and at the end of the study period, using caffeine, dextromethorphan, and endogenous cortisol as probes. The corresponding metabolic ratios measured were 17MX/137MX in saliva and (AFMU+1MX+1MU)/17MU in urine for CYP1A2, AFMU/1MX for NAT2, 1MU/1MX for XO, DOR/DMO for CYP2D6, 3MM/DMO and 6OHC/C for CYP3A4, all determined in urine.ResultsThe ratios of the treatment to baseline values for CYP3A4 using cortisol as the probe were 1.5 [95% confidence interval (CI) 1.3, 1.9] for males, and 1.9 (1.1, 3.0) for females. The corresponding ratios using dextromethorphan as the probe for CYP2D6 were 0.9 (95% CI 0.5, 2.1) for males and 1.9 (1.3, 3.2) for females. For CYP1A2, a significant increase in the metabolic ratios was found only for females (ratio of values 1.2; 95% CI 1.1, 1.4). No influence of SJW on CYP2D6, NAT2, and XO activities was observed.ConclusionsAn induction of CYP3A4 by SJW was confirmed. CYP1A2 appears to be induced by SJW only in females. The activities of CYP2D6, NAT2, and XO were not affected by SJW.
The effect of quinidine, used as a probe for the involvement of P‐glycoprotein, on the intestinal absorption and pharmacodynamics of methadone
Authors: Kharasch Evan D. , Hoffer Christine , Whittington Dale 
Published: December 2004

AimsThere is considerable unexplained interindividual variability in the methadone dose‐effect relationship. The efflux pump P‐glycoprotein (P‐gp) regulates brain access and intestinal absorption of many drugs. Evidence suggests that methadone is a P‐gp substrate in vitro, and P‐gp affects methadone analgesia in animals. However the role of P‐gp in human methadone disposition and pharmacodynamics is unknown. This investigation tested the hypothesis that the intestinal absorption and pharmacodynamics of oral and intravenous methadone are greater after inhibition of intestinal and brain P‐gp, using the P‐gp inhibitor quinidine as an in vivo probe.MethodsTwo randomized, double‐blind, placebo‐controlled, balanced crossover studies were conducted in healthy subjects. Pupil diameters and/or plasma concentrations of methadone and the primary metabolite EDDP were measured after 10 mg intravenous or oral methadone HCl, dosed 1 h after oral quinidine (600 mg) or placebo.ResultsQuinidine did not alter the effects of intravenous methadone. Miosis tmax (0.3 ± 0.3 vs 0.3 ± 0.2 h (−0.17, 0.22)), peak (5.3 ± 0.8 vs 5.1 ± 1.0 mm (0.39, 0.84)) and AUC vs time (25.0 ± 5.7 vs 26.8 ± 7.1 mm h (−6.1, 2.5)) were unchanged (placebo vs quinidine (95% confidence interval on the difference)). Quinidine increased (P < 0.05) plasma methadone concentrations during the absorptive phase, decreased tmax (2.4 ± 0.7 vs 1.6 ± 0.9 h (0.33, 1.2)), and increased peak miosis (3.2 ± 1.5 vs 4.3 ± 1.6 mm (−1.96, −0.19)) after oral methadone. The Cmax (55.6 ± 10.3 vs 59.4 ± 14.1 ng ml−1 (−8.5, 0.65)) and AUC of methadone (298 ± 46 vs 316 ± 74 ng ml−1 h (−54, 18)) were unchanged, as were the EDDP : methadone AUC ratios. Quinidine had no effect on the rate constant for transfer of methadone between plasma and effect compartment (ke0) (2.6 ± 2.6 vs 2.5 ± 1.4 h−1 (−3.5, 4.2)).ConclusionsQuinidine increased the plasma concentrations of oral methadone in the absorptive phase and the miosis caused by methadone, suggesting that intestinal P‐gp affects oral methadone absorption and hence its clinical effects. Quinidine had no effect on methadone pharmacodynamics after intravenous administration, suggesting that if quinidine is an effective inhibitor of brain P‐gp, then P‐gp does not appear to be a determinant of the access of methadone to the brain.
Comparison of once‐daily nifedipine controlled‐release with twice‐daily nifedipine retard in the treatment of essential hypertension
Authors: Minami Junichi , Numabe Atsushi , Andoh Norikazu , Kobayashi Naohiko , Horinaka Shigeo , Ishimitsu Toshihiko , Matsuoka Hiroaki 
Published: December 2004

AimsNifedipine is a short‐acting calcium antagonist formulated into several different oral preparations, each of which may have different effects on haemodynamics and autonomic nervous function. We compared the effects of nifedipine controlled‐release (CR) and nifedipine retard on 24‐h blood pressure, heart rate, rate–pressure product, and power spectral measures of heart rate variability in patients with essential hypertension.MethodsAfter 4 weeks of a drug‐free period, 25 patients were randomized to receive either once‐daily treatment with nifedipine CR (20–40 mg daily; 12 patients) or twice‐daily treatment with nifedipine retard (20–40 mg daily; 13 patients) for 12 weeks. The ambulatory blood pressure, heart rate, and ECG R–R intervals were measured during a 24‐h period using a portable recorder (TM‐2425) at the end of the drug‐free and the treatment periods. A power‐spectral analysis of R–R intervals was performed to obtain the low‐frequency (LF) and high‐frequency (HF) components.ResultsNifedipine CR and nifedipine retard reduced 24‐h blood pressure significantly by 15.9 ± 3.2 (SE)/8.7 ± 1.4 mmHg and by 10.9 ± 2.8/9.4 ± 1.7 mmHg, respectively, after the 12‐week treatment. Nifedipine CR did not change the 24‐h heart rate sig‐nificantly, while nifedipine retard increased it significantly by 3.9 ± 2.1 beats min−1. Nifedipine CR produced a significant reduction in rate–pressure product throughout a 24‐h period, while nifedipine retard did not change the rate–pressure product significantly. In addition, nifedipine retard significantly decreased the 24‐h and daytime average values of the LF and HF components, while nifedipine CR affected the nighttime LF component alone and did not change the HF component throughout a 24‐h period.ConclusionsThese results demonstrate that both nifedipine CR and nifedipine retard are effective as antihypertensive agents, but nifedipine CR has less influence on the autonomic nervous system and heart rate than nifedipine retard.
Meta‐analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes
Authors: Cheung Bernard M. Y. , Lauder Ian J. , Lau Chu‐Pak , Kumana Cyrus R. 
Published: December 2004

AimsSince 2002, there have been five major outcome trials of statins reporting findings from more than 47 000 subjects. As individual trial results differed, we performed a meta‐analysis to ascertain the effectiveness and safety of statins overall and in subgroups. The aim of the study was to estimate the effect of statins on major coronary events and strokes, all‐cause mortality and noncardiovascular mortality, and in different subgroups.MethodsPubMed was searched for trials published in English. Randomized placebo‐controlled statin trials with an average follow up of at least 3 years and at least 100 major coronary events were included. For each trial, the statin used, number and type of subjects, proportion of women, mean age and follow up, baseline and change in lipid profile, cardiovascular and non‐cardiovascular outcomes were recorded.ResultsTen trials involving 79 494 subjects were included in the meta‐analysis. Due to heterogeneity, ALLHAT‐LLT was excluded from some analyses. Statin therapy reduced major coronary events by 27% (95%CI 23, 30%), stroke by 18% (95%CI 10, 25%) and all‐cause mortality by 15% (95%CI 8, 21%). There was a 4% (95%CI −10, 3%) nonsignificant reduction in noncardiovascular mortality. The reduction in major coronary events is independent of gender and presence of hypertension or diabetes. The risk reduction was greater in smokers (P < 0.05). Coronary events were reduced by 23% (95%CI 18, 29%) in pravastatin trials and 29% (95%CI 25, 33%) in five trials using other statins. Pravastatin reduced strokes by 12% (95%CI 1, 21%) whilst other statins reduced strokes by 24% (95%CI 16, 32%) (P = 0.04).ConclusionsStatins reduce coronary events, strokes and all‐cause mortality without increasing noncoronary mortality. The benefits accrue in men and women, hypertensives and normotensives, diabetics and nondiabetics, and particularly in smokers. Pravastatin appears to have less impact on strokes.