bluuebunny/crossref_metadata_2025 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

Aims

Women 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.

Methods

Saquinavir 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.

Results

Intake 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.

Conclusions

There 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

Background

Acute otitis media (AOM) is one of the most common infectious diseases of childhood and the most frequent indication for antibiotic use in children.

Aim

To better understand the prescribing patterns and appropriateness of AOM therapy.

Methods

We 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.

Results

During 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.

Conclusion

Continuing 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

Aims

To assess the potential for interactions involving cytochromes P450 2D6 (CYP2D6) and 3A4 (CYP3A4) between drugs prescribed in a city in‐patient psychiatric service.

Methods

Prescription 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.

Results

All 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).

Conclusions

Our 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

Aims

In 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.

Methods

One 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.

Results

The 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.

Conclusions

The 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

Aims

The 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.

Methods

Levosimendan 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.

Results

Steady 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).

Conclusions

The 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

Aims

Muscular 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 results

For 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.

Conclusions

These 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 statement

During 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 review

In 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.

Conclusions

It 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

Aims

Omeprazole 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.

Methods

Eighteen 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.

Results

During 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).

Conclusions

Even 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

Aims

To 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.

Methods

Eight 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.

Results

The 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.

Conclusions

An 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

Aims

There 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.

Methods

Two 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.

Results

Quinidine 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)).

Conclusions

Quinidine 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

Aims

Nifedipine 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.

Methods

After 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.

Results

Nifedipine 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.

Conclusions

These 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

Aims

Since 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.

Methods

PubMed 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.

Results

Ten 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).

Conclusions

Statins 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.
Effects of various factors on steady‐state plasma concentrations of risperidone and 9‐hydroxyrisperidone: lack of impact of MDR‐1 genotypes
Authors: Yasui‐Furukori Norio , Mihara Kazuo , Takahata Takenori , Suzuki Akihito , Nakagami Taku , De Vries Ronald , Tateishi Tomonori , Kondo Tsuyoshi , Kaneko Sunao
Published: December 2004

Aims

An in vitro study has suggested that risperidone is a substrate of P‐glycoprotein, which is coded by MDR‐1 gene. Thus, we studied the effects of major polymorphisms of the MDR‐1 gene on plasma drug concentrations.

Methods

Subjects were 85 schizophrenic patients receiving 3 mg twice daily of risperidone. Sample collections were conducted 12 h after the bedtime dosing. Plasma concentrations of risperidone and 9‐hydroxyrisperidone were quantified using LC/MS/MS. MDR‐1 genotypes (C3435T and G2677T/A) and CYP2D6 genotypes were identified using PCR‐RFLP methods.

Results

There was no difference in geometric mean (95% CI) of steady‐state plasma concentration of risperidone between C3435T genotypes [C/C, C/T, T/T; 2.06 (1.63, 6.47), 2.96 (3.10, 7.91), 2.28 (1.81, 8.04) ng ml−1, P = 0.759] or G2677T/A genotypes [G/G, G/T or A, T or A/T or A; 1.62 (0.08, 6.07), 2.64 (3.25, 7.10), 2.71 (2.77, 8.72) ng ml−1, P = 0.625] or 9‐hydroxyrisperidone between C3435T genotypes [38.3 (33.7, 50.1), 34.9 (32.9, 42.0), 35.7 (31.7, 42.3) ng ml−1, P = 0.715] or G2677T/A genotypes [40.6 (33.0, 51.8), 35.0 (33.3, 42.4), 36.1 (32.8, 47.2) ng ml−1, P = 0.601]. Multiple regression analyses including CYP2D6 genotypes, sex, and age revealed that steady‐state plasma concentration of risperidone correlated with the number of mutated alleles for CYP2D6 (standardized partial correlation coefficients (beta) = 0.540, P < 0.001) and those of 9‐hydroxyrisperidone (standardized beta = 0.244, P = 0.038) and active moiety (standardized beta = 0.257, P = 0.027) correlated with age.

Conclusions

These findings suggest that the MDR‐1 variants are not associated with steady‐state plasma concentration of risperidone or 9‐hydroxyrisperidone, but CYP2D6 genotypes and age are determinants of these concentrations.
Modelling the cardiovascular effects of ephedrine
Authors: Persky Adam M. , Berry N. Seth , Pollack Gary M. , Brouwer Kim L. R.
Published: December 2004

Aims  Recent reports have called into question the safety of ephedra supplements especially with regards to their cardiovascular effects. The purpose of this analysis was to characterize, via pharmacokinetic/pharmacodynamic modelling, the cardiovascular effects of ephedrine, the main active ingredient of ephedra, in apparently healthy, overweight volunteers.

Methods  In a randomized, double‐blind, crossover, placebo‐controlled study, eight subjects received either placebo, 0.25, 0.5 or 1.0 mg kg−1 ephedrine sulphate by mouth with a 7‐day washout between treatments. Plasma ephedrine concentrations, heart rate and blood pressure were determined for 8 h postdose.

Results  The pharmacokinetics of ephedrine were best described by a one‐compartment model with first‐order absorption and elimination. The percentage change in heart rate was described by a linear model with a resulting slope of 0.14%·l µg−1 (CV = 59%). The percentage change in systolic blood pressure demonstrated clockwise hysteresis, and a sigmoidal tolerance model was used to describe the data. The mean maximum predicted effect (Emax) was 53.7% (CV = 41%) with an EC50 of 107 µg·l−1 (CV = 65%) and an inhibitory maximum (Imax) of 39.8% (CV = 60%). Tolerance developed with a mean half‐life of 15 min (range 6–140 min).

Conclusions  This is the first study to apply a comprehensive pharmacokinetic/pharmacodynamic model to the cardiovascular effects of orally administered ephedrine. Although systolic blood pressure increases quickly after administration, the increase is nearly abolished by compensatory mechanisms.
Population pharmacokinetic modelling of Emfilermin (recombinant human leukaemia inhibitory factor, r‐hLIF) in healthy postmenopausal women and in infertile patients undergoing in vitro fertilization and embryo transfer
Authors: Goggin Timothy , Nguyen Quyen T. X. , Munafo Alain
Published: December 2004

Aims  The aim of this analysis was to develop a population pharmacokinetic model for Emfilermin (recombinant human leukaemia inhibitory factor, r‐hLIF) following subcutaneous administration to healthy postmenopausal women and to infertile patients undergoing in vitro fertilization and embryo transfer (IVF‐ET).

Methods  Data from three studies, a single and a repeat dose Phase I study in postmenopausal women as well as a proof of concept study in patients undergoing in vitro fertilization and embryo transfer were combined and analyzed. The structural pharmacokinetic model was developed using the rich data from the Phase I studies and the full pharmacostatistical model was then derived using all the data.

Results  The pharmacokinetics of r‐hLIF after repeated subcutaneous administration were described by a one‐compartment disposition model with a zero order input. The duration of the absorption phase was short (0.8 h) and invariant. The apparent clearance in postmenopausal women was 57 l h−1 (CV = 17%). In in vitro fertilization and embryo transfer patients, the apparent clearance was decreased by 35% compared with postmenopausal women. The apparent volume of distribution was 235 l (interindividual CV = 28%) and exhibited an interoccasion variability of 23%. It increased (for weight above 62 kg) or decreased (for weight below 62 kg) by 29% for every 10 kg body weight. The median posthoc estimates of apparent clearance and volume of distribution and their variability were consistent with the population estimates. In postmenopausal women, the results were consistent with those obtained by noncompartmental analysis. The residual variability on r‐hLIF serum concentrations was 20%.

Conclusions  The pharmacokinetics of r‐hLIF after repeated SC administration were described by a one compartment disposition model, with zero order input, in postmenopausal women and those undergoing IVF or intracytoplasmic sperm injection and embryo transfer. Absorption of r‐hLIF was rapid as was its subsequent clearance. The apparent volume of distribution of r‐hLIF was moderate to high, depended on body weight and showed interoccasion variability.
Single‐dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects
Authors: Kovarik John M. , Schmouder Robert , Barilla Denise , Wang Yibin , Kraus Gerolf
Published: December 2004

Aims

FTY720 is a sphingosine‐1‐phosphate receptor agonist that redirects lymphocytes from the circulation to lymph nodes without impairing lymphocyte function. It is being developed as an immunomodulator for the prevention of acute rejection after organ transplantation. This study was performed to provide guidance on administration with respect to meals and to measure pharmacologic responses in healthy subjects.

Methods

In this randomized, two‐period, crossover study, 14 healthy subjects received placebo on day −1 of each period with baseline circadian measurements of lymphocyte count and heart rate. Subjects subsequently received a single 1 mg oral dose of FTY720 on day 1 under fasting conditions and after a high fat meal. Blood FTY720 concentrations, lymphocyte count, and supine heart rate were assessed over an 8 day period after each FTY720 dose. The effect of food on FTY720 pharmacokinetics was assessed by standard bioequivalence testing.

Results

Both the peak concentration (0.65 ± 0.17 vs 0.64 ± 0.18 ng ml−1) and total exposure (AUC 149 ± 65 vs 139 ± 43 ng ml−1 h) did not differ significantly between fasting and fed states, respectively. The corresponding fed/fasting ratios and 90% confidence intervals were 1.00 (0.86, 1.17) for Cmax and 0.98 (0.86, 1.11) for AUC. Under both treatment conditions peripheral blood lymphocyte count decreased from baseline by 38 ± 9% over the first 2 days postdose and then increased towards predose values over the subsequent week. Whereas a circadian rhythm in supine heart rate was preserved in the presence of FTY720, the heart rate vs time curve was shifted downwards by 10% over the first day postdose and then recovered to prestudy values by days 3–5 postdose. These changes were asymptomatic.

Conclusions

Single 1 mg doses of FTY720 were well tolerated in healthy subjects and elicited a moderate decrease in peripheral blood lymphocyte count and a transient decrease in heart rate consistent with its pharmacological mode of action. FTY720 may be administered without regard to the timing of meals or their fat content.
Tissue pharmacokinetics of levofloxacin in human soft tissue infections
Authors: Bellmann Romuald , Kuchling Gerald , Dehghanyar Pejman , Zeitlinger Markus , Minar Erich , Mayer Bernhard X. , Müller Markus , Joukhadar Christian
Published: December 2004

Aims

The present study addressed the ability of levofloxacin to penetrate into subcutaneous adipose tissues in patients with soft tissue infection.

Methods

Tissue concentrations of levofloxacin in inflamed and healthy subcutaneous adipose tissue were measured in six patients by microdialysis after administration of a single intravenous dose of 500 mg. Levofloxacin was assayed by high‐performance liquid chromatography.

Results

The mean concentrationvstime profile of free levofloxacin in plasma was identical to that in inflamed and healthy tissues. The ratios of the mean area under the free levofloxacin concentrationvstime curve from 0 to 10 h (AUC(0,10 h)) in tissue to that in plasma were 1.2 ± 1.0 for inflamed and 1.1 ± 0.6 for healthy subcutaneous adipose tissue (mean ± SD). The mean difference in the ratio of the AUCtissue : AUCplasmafor inflamed and healthy tissue was 0.09 (95% confidence interval −0.58, 0.759,P > 0.05). Interindividual variability in tissue penetration was high, as indicated by a coefficient of variation of approximately 82% for AUCtissue : AUCplasmaratios.

Conclusions

The penetration of levofloxacin into tissue appears to be unaffected by local inflammation. Our plasma and tissue data suggest that an intravenous dose of 500 mg levofloxacin provides effective antibacterial concentrations at the target site. However, in treatment resistant patients, tissue concentrations may be sub‐therapeutic.
Drug metabolism and ageing
Authors: Kinirons M. T. , O'Mahony M. S.
Published: December 2004

Important changes in drug metabolism occur with ageing. Age‐associated reductions in function of some but not all cytochrome P450 enzymes (CYPs) have been described. Induction and inhibition of CYPs needs to be revisited in light of recent advances. The function and pharmacology of transporters have not yet been examined for an age‐related effect. Finally, the concept of frailty is being underpinned by studies documenting a decline in drug metabolism and changes in disposition in frail older people compared with either healthy elderly or the young.
Cardiac monitoring of patients receiving arsenic trioxide therapy
Authors: Unnikrishnan Dilip , Dutcher Janice P. , Garl Susan , Varshneya Nikita , Lucariello Richard , Wiernik Peter H.
Published: December 2004

Arsenic trioxide (ATO) is approved for the treatment of acute promyelocytic leukaemia and is under investigation for other malignancies. We report the cardiac findings in 18 patients with haematologic malignancies treated with ATO and assess the role of cardiac factors in fluid retention syndrome observed during ATO therapy. Based on initial observations in 10 patients treated with ATO, cardiac functions in the subsequent eight patients were evaluated prospectively. Evaluation included pre‐ and during‐treatment electrocardiograms, Holter monitoring, echocardiograms, multigated acquisition scan and cardiac stress tests if indicated. All eight patients developed fluid retention during ATO, evidenced by pulmonary congestion, oedema and pleural/pericardial effusions. No cardiac factors were identified that contributed to fluid retention. Six patients had prolonged corrected QT (QTc) compared with baseline, three developed ventricular tachycardia. Sinus tachycardia, ventricular premature contractions, and non‐sustained ventricular/supraventricular tachycardia were seen during ATO treatment. Fluid retention and cardiac events did not correlate with the dose or total amount of ATO or prior anthracycline therapy. In summary, fluid overload during ATO therapy does not appear to be cardiac in origin but appears to be drug‐related, and may reflect cytokine‐induced capillary leak. QTc prolongation, transient arrhythmias and clinically significant arrhythmias were seen with therapeutic doses of ATO.
Production of interferon‐γ by lymphocytes from paroxysmal nocturnal haemoglobinuria patients: relationship with clinical status
Authors: Coluzzi Serelina , Biffoni Mauro , Pasqualetti Daniela , Perrone Maria Paola , Vaglio Stefania , Rahimi Hassan , Arista Maria Cristina , Laurenti Luca , Cerretti Raffaella , Girelli Gabriella
Published: December 2004

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of phosphatidylinositol glycan class A (PIG‐A) defective haematopoietic cells, probably due to the immune‐mediated alterations of the bone marrow environment selecting PIG‐A− stem cells. The present study investigated the presence of alterations of the immune system in a population of 11 PNH patients. The production of interferon‐γ (IFN‐γ) and interleukin‐2 (IL‐2), evaluated by intracellular cytokine analysis, and the frequencies of class I and II human leucocyte antigen (HLA) alleles were studied in comparison with healthy human subjects. Similar percentages of lymphocytes produced cytokines in PNH patients and controls after costimulation‐independent activation; however, a negative correlation was found between the percentage of IFN‐γ producing cells and white cell or platelets counts. PNH patients showed an higher percentage, compared with controls, of IFN‐γ producing cells after costimulation‐dependent activation. The frequency of HLA‐A31 was higher in patients than in controls (27·2% vs. 4%), similarly to that of HLA‐B7 (27·2% vs. 6%). With regard to class II alleles, 18% of PNH patients expressed DQB1*04 compared with none of 50 control cases. This study supports the hypothesis that immune alteration are present in PNH and that the immunogenetic background could influence the development of the disease.
Effectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy‐proven primary refractory Hodgkin's disease
Authors: Moskowitz Craig H. , Kewalramani Tarun , Nimer Stephen D. , Gonzalez Maria , Zelenetz Andrew D. , Yahalom Joachim
Published: December 2004

Prospective randomized studies have determined that high dose therapy and autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed Hodgkin's disease (HD); however, the role of this approach in patients with primary refractory disease has been controversial. This report is an integrated analysis of 75 consecutive patients with biopsy‐confirmed primary refractory HD, who were treated with high dose chemoradiotherapy (HDT) and ASCT at the Memorial Sloan Kettering Cancer Center. The patients underwent conventional dose cytoreductive chemotherapy followed by HDT and ASCT. At a median follow‐up of 10 years for surviving patients, the event‐free survival (EFS), progression‐free survival (PFS) and overall survival (OS) rates were 45%, 49% and 48% respectively. Only chemosensitivity to standard‐dose second‐line chemotherapy (SDSC) predicted for a better survival, thus responding patients had an EFS, PFS and OS of 60%, 62% and 66%, respectively,versus19%, 23% and 17% for patients who had a poor response to SDSC (P < 0·001). While patients with chemosensitive disease have an excellent outcome with HDT and ASCT, novel approaches are needed to cure HD patients who fail front‐line and second‐line chemotherapy.
Intracellular signalling molecules as immunohistochemical markers of normal and neoplastic human leucocytes in routine biopsy samples
Authors: Pozzobon Michela , Marafioti Teresa , Hansmann Martin‐Leo , Natkunam Yasodha , Mason David Y.
Published: December 2004

We have investigated whether intracellular signal transduction molecules can be used as immunohistological markers of normal and neoplastic human leucocytes in routine tissue sections. We obtained selective labelling of white cells for eight such molecules (the ‘linker’ molecules SLP‐76 and BLNK, the Src family kinases Lyn, Fyn, Syk and Hck, and the phospholipases PLC‐γ1 and PLC‐γ2). Antibodies to SLP‐76 and PLC‐γ1 selectively labelled T cells, and antibodies to BLNK, Lyn, Fyn, Syk and PLC‐γ2 labelled B cells (although Fyn immunostaining was restricted to mantle zone B cells). Antibodies to the Syk and Hck kinases labelled probable thymocyte precursors at the periphery of the thymic cortex. In addition to lymphoid cells, several other leucocyte types were immunostained (e.g. SLP‐76, Lyn, Syk and Hck were found in megakaryocytes, myeloid cells and/or macrophages, and PLC‐γ2 was detected in arterial endothelium). SLP‐76 and PLC‐γ1 were found in most T‐cell lymphomas studied, and some B‐cell lymphomas were also positive for PLC‐γ1 (e.g. diffuse large cell and Burkitt's lymphoma). The five B cell‐associated markers were found in most B‐cell non‐Hodgkin's lymphomas, although some diffuse large B‐cell lymphomas were negative (e.g. for Lyn) and anti‐Fyn tended not to stain small B‐cell neoplasms. The observation that a range of leucocyte signalling molecules can be detected in routine biopsies offers new possibilities for studying normal and neoplastic human white cells in diagnostic tissue samples.
Intravenous (IV) anti‐D and IV immunoglobulin achieve acute platelet increases by different mechanisms: modulation of cytokine and platelet responses to IV anti‐D by FcγRIIa and FcγRIIIa polymorphisms
Authors: Cooper Nichola , Heddle Nancy M. , de Haas Masja , Reid Marion E. , Lesser Martin L. , Fleit Howard B. , Woloski B. M. R. , Bussel James B.
Published: December 2004

Intravenous (IV) anti‐D and IV immunoglobulin (IVIG) slow the Fcγ receptor (FcγR)‐mediated destruction of antibody‐coated platelets in patients with immune thrombocytopenic purpura (ITP). This pilot study explored the mechanism of these immunoglobulin preparations by measuring interleukin‐10 (IL‐10), monocyte chemoattractant protein‐1 (MCP‐1), IL‐6 and tumour necrosis factor α (TNFα), before and after infusion and by assessing the effect of FcγRIIa and FcγRIIIa polymorphisms on both cytokine and haematologic responses to anti‐D. Following IVIG, only IL‐10 was increased at 2 h and MCP‐1 on day 7 (P < 0·05). In contrast, 2 h after anti‐D infusion, plasma levels of all four cytokines were increased (P < 0·01); five of six patients with the highest MCP‐1, IL‐6 and TNFα levels had chills. Higher IL‐10 levels correlated with platelet increases at 24 h and haemoglobin decreases at day 7 (P < 0·025). Patients with the FcγRIIa‐131HH genotype had significantly higher MCP‐1, IL‐6 and TNFα levels. Patients with the FcγRIIIa‐158VF genotype had higher platelet increments at day 7 (P < 0·05). Soluble CD16 (sCD16) was increased 2 h after IV anti‐D; day 7 levels correlated with day 7 haemoglobin decreases (P < 0·01). In conclusion, the relationship of FcγRIIa and FcγRIIIa polymorphisms with both cytokine levels and platelet increments implicated these receptors in responses to anti‐D and supported different mechanisms of FcγR interaction to those seen with IVIG.
Granulocyte‐macrophage colony‐stimulating factor to increase efficacy of mitoxantrone, etoposide and cytarabine in previously untreated elderly patients with acute myeloid leukaemia: a Swedish multicentre randomized trial
Authors: Löfgren C. , Paul C. , Åström M. , Hast R. , Hedenius M. , Lerner R. , Liliemark J. , Nilsson I. , Rödjer S. , Simonsson B. , Stockelberg D. , Tidefelt U. , Björkholm M.
Published: December 2004

A total of 110 patients, aged 64 years or over, with de novo acute myeloid leukaemia (AML) and white blood cell counts <50 × 109/l were treated with 3 d of cytarabine 1 g/m2 twice daily, mitoxantrone 12 mg/m2 and etoposide 200 mg/m2, randomized with or without the addition of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) 200 μg/m2. The primary aim was to evaluate the effect of GM‐CSF on the remission rate. Secondary aims included comparison of duration of remission, survival and infectious complications and the impact of maintenance therapy with thioguanine. Complete remission (CR) was achieved by 64% of patients without GM‐CSF, and by 65% of patients who received GM‐CSF, the median remission duration was 13 vs. 6 months, the median overall survival (OS) was 14 vs. 9 months, the mean time to neutrophil recovery was 25 vs. 17 d (P = 0·03) and the number of positive blood cultures was 46 vs. 39 (P = 0·05) respectively. The impact of thioguanine remains unanswered since only 30 patients remained in CR after consolidation therapy. We conclude that induction therapy is feasible with acceptable toxicity in elderly patients with AML, albeit with a high relapse rate and short OS. GM‐CSF prior to, and in combination with, induction treatment reduced the time to neutrophil recovery and the number of neutropenic septicaemia cases but did not improve the OS of AML in the elderly.
Increased soluble guanylate cyclase activity in the red blood cells of sickle cell patients
Authors: Conran Nicola , Oresco‐Santos Camila , Acosta Heloisa C. , Fattori André , Saad Sara T. O. , Costa Fernando F.
Published: December 2004

Activation of soluble guanylate cyclase (sGC) has been reported to up‐regulate γ‐globin gene transcription in erythroid cell lines and primary erythroblasts. sGC is activated by nitric oxide (NO), subsequently catalysing the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP), which mediates various physiological responses. To study the importance of this mechanism in the erythroid cells of sickle cell patients, cGMP levels were measured in the red blood cells (RBC) of normal individuals, steady‐state sickle cell patients (SS) and SS patients on hydroxyurea (HU) therapy (SS + HU). cGMP levels were found to be significantly higher in RBC of SS patients (SS RBC) than in RBC of normal individuals, and were further increased in RBC of SS + HU patients. cGMP levels correlated with fetal haemoglobin (HbF) levels in SS/SS + HU patients, but not with reticulocyte count. Furthermore, NO‐stimulated sGC activity, following incubation of cells with a NO donor, was significantly greater in SS RBC than in normal RBC. These results demonstrate, for the first time, an increased metabolism of NO mediated by sGC in the SS RBC, which is further increased by hydroxyurea. Augmentation of cGMP levels by NO in erythroid cells may constitute a mechanism for induction of HbF and other erythrocyte functions and represent a possible therapeutic target for treatment of sickle cell disease.