British Journal of Clinical Pharmacology (Br J Clin Pharmacol )

Publisher: British Pharmacological Society, Blackwell Publishing

Description

The Journal of The British Pharmacological Society. Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology contains papers and reports on all aspects of drug action in humans: invited review articles, original papers, short communications and correspondence. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. Proceedings of the meetings of the Clinical Section of the British Pharmacological Society are published in abstract form and supplements containing information on new methods, new drugs and new approaches to treatment are supplied free of charge.

  • Impact factor
    3.58
  • 5-year impact
    3.56
  • Cited half-life
    8.70
  • Immediacy index
    1.15
  • Eigenfactor
    0.02
  • Article influence
    0.99
  • Website
    British Journal of Clinical Pharmacology website
  • Other titles
    British journal of clinical pharmacology (Online), BJCP
  • ISSN
    1365-2125
  • OCLC
    45425630
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Blackwell Publishing

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • Some journals impose embargoes typically of 6 or 12 months, occasionally of 24 months
    • no listing of affected journals available as yet
  • Conditions
    • See Wiley-Blackwell entry for articles after February 2007
    • Publisher version cannot be used
    • On author or institutional or subject-based server
    • Server must be non-commercial
    • Publisher copyright and source must be acknowledged with set statement ("The definitive version is available at www.blackwell-synergy.com ")
    • Articles in some journals can be made Open Access on payment of additional charge
    • 'Blackwell Publishing' is an imprint of 'Wiley-Blackwell'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Structured SummaryAimsIn order to exert its pharmacodynamic effect, the diabetes drug metformin needs to be taken up into hepatocytes by the organic cation transporter (OCT) system. A recent in vitro study found that proton pump inhibitors (PPIs) inhibit OCT1, OCT2, and OCT3, suggesting that PPIs might reduce metformin's effectiveness. This pharmacoepidemiologic study looked for for evidence of a clinical effect of such an interaction.Methods Observational cohort study examining changes in glycosylated hemoglobin (HbA1c) with exposure to metformin and to PPIs as single agents and in combination. The aim was to assess evidence of a deleterious drug-drug interaction.ResultsPPIs did not reduce the effectiveness of metformin, and indeed were associated with a minimally better glycemic response by -0.06 HbA1c percentage points (95% confidence interval, -0.10 to -0.01) in metformin initiators.Conclusions Despite a mechanistic basis for a potential drug-drug interaction, we found no evidence of a deleterious interaction between PPIs and metformin.
    British Journal of Clinical Pharmacology 09/2014;
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    ABSTRACT: Objective We aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam.Methods In an open, one-sequence, cross-over study, sixteen healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and at regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics.ResultsDose-normalised AUC and Cmax were 37.1 h*ng/ml [95%-CI: 35.5–40.6] and 39.1 ng/ml [30.4–50.2] for the microdose and 39.0 h*ng/ml [36.1–42.1] and 37.1 ng/ml [26.9–51.3] for the milligram dose. Clmet was 253 ml/min [201–318] vs. 278 ml/min [248–311] for i.v. doses and 1880 ml/min [1590-2230] vs. 2050 ml/min [1720 – 2450] for oral doses. Oral bioavailability of a midazolam microdose was 23.4% [20.0–27.3] vs. 20.9% [17.1–25.5] after the regular dose. Hepatic and gut extraction ratios for microgram doses were 0.44 [0.39–0.49] and 0.53 [0.45–0.63] and compared well with those for milligram doses (0.43 [0.37–0.49] and 0.61 [0.53–0.70]).Conclusion The pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to safely assess systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity.
    British Journal of Clinical Pharmacology 09/2014;
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    ABSTRACT: Background The incidence of adverse drug events (ADEs) in surgical and non-surgical patients may differ. This IPDMA identifies patient characteristics and types of medication most associated with patients experiencing ADEs and suggests target areas for reducing harm and implement focused interventions.Methods Authors of eligible studies on preventable ADEs (pADEs) were approached for collaboration. For assessment of differences among (non-)surgical patients and identification of associated factors descriptive statistics, Pearson Chi-Square, Poisson and logistic regression analyses were performed. For identification of high risk drugs (HRDs), a model was developed based on frequency, severity and preventability of medication related to ADEs.ResultsIncluded were 5,367 patients from four studies. Patients aged ≥ 77 years experienced more ADEs and pADEs compared to patients aged ≤ 52 years (odds ratios (OR) 2.12 (95%CI 1.70-2.65) and 2.55 (95%CI 1.70-3.84) respectively, both p<0.05). Polypharmacy on admission also increased the risk of ADEs (OR 1.21 (95%CI 1.03-1.44), p<0.05) and pADEs (OR 1.85 (95%CI 1.34-2.56), p < 0.05). pADEs were associated with more severe harm than non-preventable ADEs (54% versus 32%, p < 0.05). The top five HRDs were: antibiotics, sedatives, anticoagulants, diuretics and antihypertensives. Events associated with HRDs included diarrhoea or constipation, abnormal liver function test and central nervous system events. Most pADEs resulted from prescribing errors (90%).Conclusion Elderly patients with polypharmacy on admission and receiving antibiotics, sedatives, anticoagulants, diuretics or antihypertensives were more prone to experiencing ADEs. Efficiency in prevention of ADEs may be improved by targeted vigilance systems for alertness of physicians and pharmacists.
    British Journal of Clinical Pharmacology 09/2014;
  • British Journal of Clinical Pharmacology 09/2014;
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    ABSTRACT: Idiosyncratic drug reactions (IDRs) represent a major health problem, as they are unpredictable, often severe and can be life threatening. The low incidence of IDRs makes their detection during drug development stages very difficult causing many post marketing drug withdrawals and black box warnings. The fact that IDRs are always not predictable based on the drug's known pharmacology and have no clear dose-effect relationship with the culprit drug renders diagnosis of IDRs very challenging, if not impossible without the aid of a reliable diagnostic test. Drug provocation test (DPT) is considered the gold standard for diagnosis of IDRs but it is not always safe to perform on patients. In vitro tests have the advantage of bearing no potential ham to patients; however, available in vitro tests are not commonly used clinically because of lack of validation and their complex and expensive procedures. This review discusses the current role of in vitro diagnostic testing for diagnosis of IDRs and gives a brief account of their technical and mechanistic aspects. Advantages, disadvantages and major challenges that prevent these tests from becoming mainstream diagnostic tools are also discussed here.
    British Journal of Clinical Pharmacology 09/2014;
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    ABSTRACT: Structured summaryAimsHyponatraemia is one of the major adverse effects of thiazide diuretics and the leading cause of drug-induced hyponatraemia requiring hospital admission. We sought to review and analyse all published cases of this important condition.Methods Ovid Medline, Embase, Web of Science and PubMed electronic databases were searched to identify all relevant articles published before October 2013. A proportions meta-analysis was undertaken.Results102 articles were identified of which 49 were single patient case reports. Meta-analysis showed that mean age was 75 (95% CI 73–77) years, 79% were women (95% CI 74–82) and mean body mass index was 25 (95% CI 20–30) kg/m2. Presentation with thiazide-induced hyponatraemia occurred a mean of 19 (95% CI 8-30) days after starting treatment, with mean trough serum sodium concentration of 116 (95% CI 113 to 120) mM and serum potassium of 3.3 (95% CI 3.0 to 3.5) mM. Mean urinary sodium concentration was 64 mM (95% CI 47 to 81); the most frequently reported thiazides were hydrochlorothiazide, indapamide and bendroflumethiazide.Conclusions Patients with thiazide-induced hyponatraemia were characterised by advanced age, female gender, inappropriate saliuresis and mild hypokalaemia. Low BMI was not found to be a significant risk factor, despite previous suggestions. The time from thiazide initiation to presentation with hyponatraemia suggests that the recommended practice of performing a single investigation of serum biochemistry 7–14 days after thiazide initiation may be insufficient or suboptimal. Further larger and more systematic studies of thiazide-induced hyponatraemia are required.
    British Journal of Clinical Pharmacology 08/2014;
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    ABSTRACT: Structured summaryBackground Acute lymphoblastic leukemia (ALL) is the most common of all pediatric cancers. Aside from predisposing to ALL, polymorphisms could also be associated with poor outcome. Indeed, genetic variations involved in drug metabolism could, at least partially, be responsible for heterogeneous responses to standardized leukemia treatments, hence requiring more personalized therapy.Aims(a) to determine the prevalence of seven common genetic polymorphisms including those that affect the folate and/or thiopurine metabolic pathways, i.e., cyclin D1 (CCND1-G870A), ɣ-glutamyl hydrolase (GGH-C452T), methylenetetrahydrofolate reductase (MTHFR-C677T and MTHFR-A1298C), thymidylate synthase promoter (TYMS-TSER), thiopurine methyltransferase (TPMT*3A and TPMT*3C) and inosine triphosphate pyrophosphatase (ITPA-C94A), in Caucasian (N=94, age< 20) and Vietnamese (N=141, age< 16) childhood ALL; (b) to assess the impact of a multilocus genetic risk score (MGRS) on relapse-free survival (RFS) using a cox proportional-hazards regression model.ResultsThe prevalence of MTHFR-677TT genotype was significantly higher in Caucasian (p = 0.008), in contrast to the prevalence of TYMS-TSER*3R/3R and ITPA-94AA/AC genotypes which were significantly higher in Vietnamese (p < 0.001 and p = 0.02, respectively). Compared to children with a low MGRS (≤3), those with a high MGRS (≥4) were 2.06 (95% CI = 1.01 – 4.22; p = 0.04) times more likely to relapse. Adding MGRS into a multivariate Cox regression model with race/ethnicity and four clinical variables improved the predictive accuracy of the model (AUC from 0.682 to 0.709 at 24 months).Conclusion Including MGRS into a clinical model improved the predictive accuracy of short and medium-term prognosis, hence confirming the association between well determined pharmacogenotypes and outcome of pediatric ALL. Whether variants on other genes associated with folate metabolism can substantially improve the predictive value of current MGRS is not known but deserves further evaluation.
    British Journal of Clinical Pharmacology 08/2014;
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    ABSTRACT: Short summaryElectronic cigarettes are increasingly popular for smokers as an aid in the cessation of smoking. They are considered a less harmful alternative for traditional cigarettes. However, the liquid fillings of the electronic cigarettes (‘e-liquid’) contain high concentrations of nicotine which may cause potentially lethal poisoning when ingested.We present a case of nicotine poisoning in a 27 year-old male who attempted suicide by ingestion of a large amount of e-liquid. Given the increasing popularity of electronic cigarettes the frequency of nicotine intoxications is likely to rise in the next years. Physicians working in the Emergency Department and general practice should become familiar with this intoxication.
    British Journal of Clinical Pharmacology 08/2014;
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    ABSTRACT: summaryAimsWe aimed to compare the performances of contemporary cystatin C (Cys)-based GFR equations, and the creatinine-only Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for predicting gentamicin clearance.Methods The bias and imprecision of the CKD-EPI, CKD-EPI_Cys, and creatinine-cystatin C CKD-EPI (CKD-EPI_CrCys) equations for predicting gentamicin clearances, were assessed in 260 patients treated with gentamicin during 2012-2013. The creatinine-cystatin C Berlin Initiative Study equation (BIS_CrCys) was examined in the ≥ 70 y subgroup. The reference gentamicin clearance was calculated using post-dose plasma concentrations.ResultsThe CKD-EPI_CrCys equation had the highest percentage of estimates within 30% of the reference gentamicin clearance (70%, P = 0.003) and lowest root mean square error (95% CI) of 29 (26-32) ml min−1 of the three equations for the entire cohort. There was no significant improvement in the performances of the equations with the exclusion of 41 patients with abnormal thyroid function tests or steroid co-prescription at the time of the index gentamicin dose. Of the remaining 219 patients, adjustment for individual BSA improved the performances of all GFR equations (P ≤ 0.003) in those with body mass indices (BMI) < 18.5 or ≥ 30 kg m-2, but not those with BMI 18.5-29.9 kg m-2. There was no advantage of the BIS_CrCys over the CKD-EPI_CrCys equation in the ≥ 70 y subgroup.Conclusions The CKD-EPI_CrCys equation provided the best estimate of gentamicin clearance. If used for guiding gentamicin dosing, the results from GFR equations should be adjusted for individual BSA at the extremes of body size.
    British Journal of Clinical Pharmacology 08/2014;
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    ABSTRACT: AimsSignificant differences between dogs and humans have been observed in the concentration-QTc effect relationship of compounds with known pro-arrhythmic properties. These findings suggest that interspecies differences must be considered when evaluating drug effects. The aim of this study was to evaluate the performance of model-based approach to assess the risk of QT(c) prolongation for three investigational compounds (NCE01, NCE02 and NCE03).Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and healthy subjects were included in this analysis. Pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. An integrated PKPD model was then used to describe QT prolongation. A threshold of > 10 ms was used to characterise the probability of QTc prolongation.ResultsThe PKPD relationships of all three compounds were successfully described in both species. A strong effect was observed after administration of NCE01 to dogs and humans, with a slope of 0.0061 and 0.0662 ms/nM, respectively and maximum probability of QT(c) prolongation >10ms at Cmax. For NCE02 and NCE03, QT(c)-shortening and borderline QT effects were observed both in dogs and humans, as described by negative or very shallow slopes (NCE02: -0.00098 and -0.01 ms/nM; NCE03: 0.00064 and -0.0002 ms/nM).Conclusions Whilst NEC01 shows clear pro-arrhythmic effects, the liability for QT/QTc prolongation for NCE02 and NCE03 can be deemed low at the expected therapeutic exposure. Moreover, our results show the advantages of an integrated PKPD approach as the basis for translating pro-arrhythmic effects from dogs to humans.
    British Journal of Clinical Pharmacology 08/2014;
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    ABSTRACT: AimsTo investigate the pharmacokinetics (PK) of sertraline in overdose and the effect of single dose activated charcoal (SDAC).Methods Patients presenting to a toxicology unit with sertraline overdoses had demographic and clinical information recorded, and serial serum collected for measurement of sertraline concentrations. Monolix® version 4.2 was used to develop a population PK model of sertraline overdose and the effect of SDAC. Uncertainty in dose time was accounted for by shifting dose time using lag time with between subject variability (BSV). BSV on relative fraction absorbed was used to model uncertainty in dose.ResultsThere were 77 timed sertraline concentrations measured in 28 patients with sertraline overdoses with a median dose of 1550mg (250–5000 mg). SDAC was given to seven patients between 1.5 and 4h post-overdose. A one compartment model with lag time of one hour, and first order input and elimination adequately described the data. Including BSV on both lag time and relative fraction absorbed improved the model. The population PK parameter estimates for absorption rate constant, volume of distribution and clearance were 0.895h-1, 5340L and 130L/h respectively. The calculated half-life of sertraline following overdose was 28hours (IQR:19.4 –30.6h). When given up to 4h post-overdose, SDAC significantly increased the clearance of sertraline by a factor of 1.9, decreased the area under the curve and decreased the maximum plasma concentration (Cmax).Conclusions Sertraline had linear kinetics in overdose with parameter values similar to therapeutic use. SDAC is effective in increasing clearance when given 1.5 to 4h post-overdose.
    British Journal of Clinical Pharmacology 08/2014;
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    ABSTRACT: Current guidelines limit regular use of inhaled corticosteroids (ICS) to a specific subgroup of patients with chronic obstructive pulmonary disease (COPD) in whom the forced expiratory volume in 1 s is <60% of predicted and who have frequent exacerbations. In these patients, there is evidence that ICS reduce the frequency of exacerbations and improve lung function and quality of life. However, a review of the literature suggests that the evidence available may be interpreted to favour or contradict these observations. It becomes apparent that COPD is a heterogeneous condition. Clinicians therefore need to be aware of the heterogeneity as well as having an understanding of how ICS may be used in the context of the specific subgroups of patients with COPD. This review argues for and against the use of ICS in COPD by providing an in-depth analysis of the currently available evidence.
    British Journal of Clinical Pharmacology 08/2014; 78(2):282-300.
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    ABSTRACT: AimEpilepsy is a complex disease necessitating continuous development of new therapeutic strategies to encounter drug-resistant cases. Among new adjuvant antiepileptic drugs, rufinamide is structurally distinct from other antiepileptic drugs. It is used to treat partial-onset seizures and seizures associated with Lennox-Gastaut syndrome (LGS) in adult and children. To date, there has been no attempt to systematically evaluate risks of rufinamide adverse events.Methods We performed a quantitative risk analysis of central nervous system (CNS) adverse events of rufinamide from all randomized, double blind, add-on, placebo-controlled trials. The meta-analysis was undertaken with fixed effects models.ResultsOf the 886 publications reviewed, 99 papers were retrieved and five articles met inclusion criteria. 1252 patients were included. Our study showed that exposure to rufinamide is associated with a significant increase in risk of somnolence [relative ratio (RR) 1.87; 95% confidence interval (CI) 1.33 to 2.62; P=0.0003] dizziness (RR 2.66; 95% CI 2.00 to 3.55; P=0.00001), fatigue (RR 2.14; 95% CI 1.57 to 2.91; P=0.01), and headache (RR 1.28; 95% CI 1.02 to 1.59, P= 0.03). In addition, exposure to rufinamide was associated with higher treatment discontinuation rates as compared to placebo (RR 2.65; 95% CI 1.74 to 4.03; P=0.00001).Conclusions The risk of CNS adverse events appears to be increased in patients exposed to rufinamide as well as the treatment discontinuation rates. However, although statistical associations were significant, additional long-term safety studies are required to confirm the clinical significance of these findings, as most reports described only mild and moderate adverse events.
    British Journal of Clinical Pharmacology 08/2014;
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    ABSTRACT: AimIntrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intrauterine and perinatal complications. High levels of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial etiopathogenesis of ICP. The aim of this study was to further investigate the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio.Methods Using HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by RT-QPCR and immunofluorescence.ResultsIn ICP, markedly increased levels of bile acids (tauroconjugates >glycoconjugates >>unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced levels in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS levels. ABCG2 mRNA abundance was increased in placentas from ICP patients vs controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2.ConclusionsUDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on levels of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high levels of bile acids and PMS during ICP.
    British Journal of Clinical Pharmacology 08/2014;
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    ABSTRACT: AimsErythromycin is a macrolide antibiotic, which is frequently used as a topical formulation for the treatment of acne. It is also known as an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A4. In this study the systemic availability of topical erythromycin and hence the influence on the activity of CYP3A is evaluated in comparison to orally administered erythromycin.Methods Sixteen healthy volunteers received consecutively topical (2 x 800 mg) and oral erythromycin (two dose groups 250 and 1000 mg with n=8) to assess erythromycin pharmacokinetics. A microdose midazolam (3μg orally) was used to determine the effect on CYP3A activity.ResultsAfter topical administration, erythromycin was detected in the plasma of every participant without causing a statistically significant alteration of CYP3A activity. After oral administration dose normalised erythromycin exposure (AUC∞) was 1335 h*ng/mL after 250 mg and was 3-fold higher for the 1000 mg dose (4051 h*ng/mL; p<0.01) suggesting non-linear pharmacokinetics of erythromycin. Both oral doses inhibited CYP3A activity, midazolam clearance was decreased to 61 % (250 mg) and 21 % (1000 mg). The relationship between erythromycin exposure and CYP3A activity (Hill equation) revealed a 50% reduction of CYP3A activity by an erythromycin AUC∞ of 2106 h*ng/mL.Conclusion Topical erythromycin did not cause clinically relevant CYP3A alterations although low systemic availability of erythromycin was observed. This supports the assumption that treatment with topical erythromycin is not critical in terms of CYP3A inhibition. Furthermore, substantial non-linearity of erythromycin pharmacokinetics after 2 different oral doses was observed possibly due to autoinhibition.
    British Journal of Clinical Pharmacology 08/2014;
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    ABSTRACT: In the EMA, the involvement of patients has been increasingly recognized as valuable and necessary. Specifically in scientific committees, patients through patient representatives are actively involved in deliberations and decision-making processes. These scientific committees are meant to ensure that licensed medicines have a positive benefit-risk ratio in favor of the patients and users. To investigate what the contributions are of patient representatives in benefit-risk assessment, we interviewed 15 scientific committee members, 10 of whom are/were EU-state regulatory representatives and 5 are/were patient representatives. We asked the participants questions related to the benefit-risk assessment tasks of their committees, the connection between patient representatives and the patient perspective, and the contribution of patient representatives in the various benefit-risk assessments tasks. We found that the contribution of patient representatives benefit/risk assessment may be a variable of the benefits and the risks involved in the drug such that the necessity of their contribution is strongly felt when both benefits and risks are high, when benefits are almost equal or are equal to risks, and when both benefits and risks are low. In terms of the various benefit-risk tasks, patient representatives contribute to benefit-risk analysis by providing criteria that help-define the benefit-risk picture; in benefit/risk evaluation, patient representatives aid in providing a specific basis for the values and weights given to specific benefits and risks; and in decision-making, they provide what may be crucial patient perspective in terms of the acceptability of risks. Hence, patient representatives provide a specific expertise in these scientific committees.
    British Journal of Clinical Pharmacology 07/2014;
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    ABSTRACT: AimsThe main goal of the study was to describe the pharmacokinetics of maternal zidovudine (ZDV) administrations during pregnancy and labor and to evaluate its impact on fetal concentrations and exposures.MethodsA total of 195 HIV-infected pregnant and non-pregnant women aged 16-59 years were included, 273 maternal and 79 cord blood ZDV concentrations were collected. A population pharmacokinetic model was developed to describe ZDV concentrations as a function of time in the mother and the fetus. Fetal exposures resulting from maternal oral administration and infusion were estimated and compared to therapeutic exposures (3-5 mg.h/L) and to exposure providing higher risk of toxicity(> 8.4 mg.h/L). Different protocols for ZDV administration during labor were simulated.ResultsThe median fetal exposure and the percentage of children with values above 8.4 mg.h/L were 3.20 mg.h/L and 0 % after maternal oral administration respectively, and 9.71 mg.h/L and 51 % after maternal infusion during labor. Two options were considered to reduce fetal exposure during labor: (i) maternal infusion rates could be 1 mg/h/kg during 1 hour followed by 0.5 mg/h/kg, (ii) mother could only take oral ZDV every 5 hours from start of labor until delivery with her neonate having their first ZDV dose as soon as possible after birth.Conclusions Zidovudine exposures are very important during labor and during the first days of neonate's life. Maternal ZDV dose should be reduced in addition to the neonate doses reduction already proposed.
    British Journal of Clinical Pharmacology 07/2014;
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    ABSTRACT: AimFurther to its pivotal role in hemostasis, FXa promotes effects on the vascular wall. The purpose of the study was to evaluate if FXa modifies the expression level of energy metabolism and oxidative stress-related proteins in femoral arteries obtained from type-2 diabetic patients with end-stage vasculopathy.Methods Femoral arteries were obtained from 12 type-2 diabetic patients underwent to leg amputation. Segments from the femoral arteries were in vitro incubated alone and in the presence of 25 nmol/L FXa and 25 nmol/L FXa+ 50 nmol/L Rivaroxaban.ResultsIn the femoral arteries, FXa increased triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase isotype 1 expression but decreased pyruvate dehydrogenase expression. These facts were accompanied by an increased content of acetyl-CoA. Aconitase activity was reduced in FXa-incubated femoral arteries as compared with control. Moreover, FXa increased the protein expression level of oxidative stress-related proteins that was accompanied by an increased malonyldialdehyde arterial content. The FXa inhibitor, Rivaroxaban, failed to prevent the reduced expression of pyruvate dehydrogenase induced by FXa but reduced acetyl-CoA content and reverted the decreased aconitase activity observed with FXa alone. Rivaroxaban + FXa but not FXa alone increased the expression level of carnitine palmitoyltransferase I and II, two mitochondrial long-chain fatty acid transporters. Rivaroxaban also prevented the increased expression of oxidative stress-related proteins induced by FXa alone.Conclusions In isolated femoral arteries from type-2 diabetic patients with end-stage vasculopathy, FXa promoted disruption of the aerobic mitochondrial metabolism. Rivaroxaban prevented such effects and even seem to favour long-chain fatty acid transport into mitochondria.
    British Journal of Clinical Pharmacology 07/2014;
  • British Journal of Clinical Pharmacology 07/2014; 78(1).
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    ABSTRACT: Vitamin D is a particularly important sterol hormone and its effects beyond bone are increasingly recognised. Over the last decade clinical interest has grown in vitamin D, with increased recognition of deficiency and hence increased prescribing of vitamin D products. However, the increased prescription of vitamin D has generally been met with unlicensed vitamin D products which potentially expose the patient to clinical risk. This review discusses the issues relating to the clinical use of unlicensed vitamin D products, safety concerns that may arise from this, as well as discussing the medico-legal responsibilities of the prescriber and dispenser.
    British Journal of Clinical Pharmacology 07/2014;

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