Explore and compare junior doctors’ perceptions of their self-efficacy in prescribing, their prescribing errors and the possible causes of those errors.
A cross-sectional questionnaire study was distributed to foundation doctors throughout Scotland, based on Bandura's Social Cognitive Theory and Human Error Theory (HET).
548 questionnaires were completed (35.0% of the national cohort). F1s estimated a higher daytime error rate (median 6.7 (IQR 2-12.4)) than F2s (4.0 IQR (0-10) (p=0.002)), calculated based on the total number of medicines prescribed. The majority of self-reported errors (250; 49.2%) resulted from unintentional actions. Interruptions and pressure from other staff were commonly cited causes of errors. F1s were more likely to report insufficient prescribing skills as a potential cause of error than F2s (p= 0.002). The prescribers did not believe that the outcomes of their errors were serious. F2s reported higher self-efficacy scores than F1s in most aspects of prescribing (p<0.001).
Foundation doctors were aware of their prescribing errors, yet were confident in their prescribing skills and apparently complacent about the potential consequences of prescribing errors. Error causation is multi-factorial often due to environmental factors, but with lack of knowledge also contributing. Thereforeinterventions are needed at all levels, including environmental changes, improving knowledge, providing feedback and changing attitudes towards the role of prescribing as a major influence on patient outcome.
he assessment of QTc interval prolongation relies on the evidence of drug effects in healthy subjects. This study demonstrates the relevance of pharmacokinetic-pharmacodynamic (PKPD) relationships to characterise drug-induced QTc-interval prolongation and explore the discrepancies between clinical trials and real-life conditions.
d,l-sotalol data from healthy subjects and from the Rotterdam Study cohort were used to assess treatment response in a phase I setting and in real life situation, respectively. Using modelling and simulation, drug effects at therapeutic doses were predicted in both populations.
Inclusion criteria were shown to restrict the representativeness of the trial population, as compared to real-life conditions. A significant part of the typical patient population was excluded from trials based on weight and baseline QT-interval measurements. Relative risk was significantly different between sotalol users with and without heart failure, hypertension, diabetes, and myocardial infarction. Although drug effects do cause an increase in relative risk of QT interval prolongation, the presence of diabetes represented an increase in relative risk from 4.0 (2.7 - 5.8) to 6.5 (1.6 - 27.1), whilst for myocardial infarction it increased from 3.4 (2.3 - 5.13) to 15.5 (4.9 - 49.3) (p<0.01).
Our findings show that drug effects on QTc-interval do not explain the observed QTc values in the population. The prevalence of high QTc values in the real-life population can be assigned to co-morbidities and concomitant medications. These findings substantiate the need to account for these factors when evaluating cardiovascular risk of medicinal products.
In most therapeutic areas, multiple drug options are increasingly becoming available, but there is often a lack of evidence from head-to-head clinical trials that allow for direct comparison of the efficacy and/or safety one drug versus another. This review provides an introduction to, and overview of, common methods used for comparing drugs in the absence of head-to-head clinical trial evidence. Naïve direct comparisons are in most instances inappropriate and should only be used for exploratory purposes and when no other options are possible. Adjusted indirect comparisons are currently the most commonly accepted method, and use links through one or more common comparators.Mixed treatment comparisons use Bayesian statistical models to incorporate all available data for a drug, even data that are not relevant to the comparator drug. MTCs reduce uncertainty but have not yet been widely accepted by researchers, nor drug regulatory and reimbursement authorities. All indirect analyses are based on the same underlying assumption as meta-analyses; namely that the study populations in the trials being compared are similar.
To investigate the overall incidence and risk of hypertension in cancer patients who receive axitinib and compare the differences in incidences between axitinib and other four approved vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKIs).
Several databases were searched, including Pubmed, Embase and Cochrane databases. Eligible studies were phase II and III prospective clinical trials of patients with cancer assigned axitinib at a starting dose of 5mg orally twice daily with data on hypertension available. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.
A total of 1908 patients from 10 clinical trials were included. The overall incidences of all-grade and high-grade hypertension in cancer patients were 40.1% (95% CI: 30.9-50.2%) and 13.1% (95%CI: 6.7-24%). The use of axitinib was associated with significantly increased risk of all-grade (RR 3.00, 95%CI: 1.29-6.97, p=0.011) and high-grade hypertension (RR1.71, 95%CI: 1.21-2.43, p=0.003). And the risk of axitinib associated all-grade and high-grade hypertension in renal cell carcinoma (RCC) is significantly higher than those in non-RCC. Additionally, the risk of hypertension with axitinib was substantially higher than other approved VEGFR-TKIs, while the risk of all-grade hypertension with axitinib was similar to pazopanib (RR 1.05; 95%CI: 0.95-1.17, p=0.34).
While sharing similar spectrum of target receptors with other VEGFR-TKIs, axitinib is associated with an unexpectedly high risk of developing hypertension. Close monitoring and appropriate management for hypertension are recommended during the treatment.
Prescribing errors are common and inadequate preparation of prescribers appears to contribute. A junior doctor-led prescribing tutorial programme has been developed for Edinburgh final year medical students to increase exposure to common prescribing tasks. The aim of this study was to assess the impact of these tutorials on students and tutors.
196 tutorials were delivered to 183 students during 2010-2011. Each student completed a questionnaire after tutorial attendance which explored their previous prescribing experiences and the perceived benefits of tutorial attendance. Tutors completed a questionnaire which evaluated their teaching experiences and the impact on their prescribing practice. Student tutorial attendance was compared with end-of-year examination performance using linear regression analysis.
The students reported increased confidence in their prescribing knowledge and skills after attending tutorials. Students who attended more tutorials also tended to perform better in end-of-year examinations (Drug Prescribing: r=0.16, P=0.015; Fluid Prescribing: r=0.18, P=0.007). Tutors considered that participation enhanced their own prescribing knowledge and skills. Although they were occasionally unable to address student uncertainties, 80% of tutors reported frequently correcting misconceptions and deficits in student knowledge. 95% of students expressed a preference for prescribing training delivered by junior doctors over more senior doctors.
A ‘near-peer’ junior doctor-led approach to delivering prescribing training to medical students was highly valued by both students and tutors. Although junior doctors have relatively less clinical experience of prescribing, we believe that this can be addressed by training and academic supervision and is outweighed by the benefits of these tutorials.
There are now more than ten experimental vaccine formulations which induce T and B cell immunity towards the internally situated virus proteins matrix (M1 and M2e) and nucleoprotein (NP), and towards stem and stalk regions of the HA which have a shared antigenic structure amongst many of the 17 influenza A virus sub types. Such “universal vaccines” could be used, at least in theory, as a prophylactic stockpile vaccine for newly emerged epidemic and novel pandemic influenza A viruses or as a supplement to conventional HA/NA vaccines. My own laboratory has approached the problem from the clinical viewpoint by identifying CD4+ cells which are present in influenza infected volunteers who resist influenza infection. We have established precisely which peptides in M and NP proteins react with these immune CD4 cells. These experimental vaccines induce immunity in animal models but with a single exception no data has been published on protection against influenza virus infection in humans. The efficacy of the latter vaccine is based on vaccinia virus (MVA) as a carrier and was analysed in a quarantine unit. Given the absence of induced HI antibody in the new universal vaccines a possible licensing strategy is a virus challenge model in quarantine whereby healthy volunteers can be immunised with the new vaccine and thereafter deliberately infected and clinical signs recorded alongside quantities of virus excreted and compared to unvaccinated controls.
Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for eribulin associated neutropenia.
A combined dataset of 12 phase I, II and III studies for eribulin mesilate was analyzed. The population PK of eribulin was described using a previously developed model. The relationship between eribulin PK and neutropenia was described using a semi-physiological life-span model for hematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework.
Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated at 4.03·109 neutrophils/L (relative standard error (RSE) 1.2%), with inter-individual variability (IIV, 37.3CV%). The mean transition time (MTT) was estimated at 109 h (RSE 1.8 %, IIV 13.9CV%), the feedback constant (γ) was estimated at 0.216 (RSE 1.4%, IIV 12.2CV%), and the SLOPE was estimated at 0.0451 μg/L (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and G-CSF were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on MTT.
The developed model can be applied to quantitatively investigate optimal treatment strategies across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of inter-individual variability in the neutropenia time-course.
Early prediction of (non-)response to infliximab therapy can improve therapeutic benefit by avoiding unnecessary periods of high disease activity during ineffective therapy. This prospective cohort study therefore aims to study the predictive value of (1) disease activity alone and (2) infliximab serum trough levels in addition to disease activity six weeks after start of treatment for achieving low disease activity after 6 months.
Disease activity and infliximab serum trough levels were assessed in all RA patients at 2, 6 and 26 weeks after initiation of infliximab therapy. ROC curves and Youden indices were used to calculate specificity for prediction of good response after 6 months while aiming for maximum sensitivity.
57 consecutive RA patients starting with infliximab therapy were included. After 6 months, 15 (26%, CI 15-38%) patients reached good EULAR response. A disease activity score < 4.2 at 6 weeks after initiation of therapy was a moderate predictor for reaching EULAR-response after 6 months (sensitivity: 100%, specificity: 49%). Infliximab serum trough levels (>2.5 mg/L) as predictor complimentary to disease activity (< 4.2) slightly increased the specificity from 49% to 54% without changing the sensitivity (100%). As 39% of the patients did not fulfill at least one of these criteria at week 6, these patients could be switched to another therapy already after 6 weeks.
The combination of disease activity and infliximab serum trough levels could be a fair predictor to early identify (after 6 weeks) patients who have insufficient response after 6 months of therapy.
Cannabinoid receptor type 1 (CB1) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, peripherally selective CB1 antagonist TM38837 was studied in humans.
This was a double-blind, randomized, placebo-controlled, cross-over study. In occasion 1-4, 24 healthy subjects received 5x4mg THC with TM38837 100 mg, 500 mg, or placebo, or placebos only. During occasion 5, subjects received placebo TM38837+THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic effects (PD) were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK-PD modelling.
TM38837 plasma concentration profile was relatively flat compared to rimonabant. TM38837 showed an estimated terminal half-life of 771 hours. THC induced effects on VAS feeling high, body sway, and heart rate were partly antagonized by rimonabant 60 mg [-26.70% (95%CI -40.9-/-12.6%); -7.10%, (95%CI -18.1-5.3%); -7.30%, (95%CI -11.5%-/-3.0%) respectively] and TM38837 500 mg [-22.10% (95%CI -34.9-/-9.4%); -12.20% (95%CI -21.6%-/-1.7%); -8.90% (95%CI -12.8%-/-5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects, and limited heart rate effects.
Rimonabant showed larger effects than TM38837, however, heart rate effects were similar. TM38837 100 mg had no impact on CNS-effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.
A growing body of evidence suggests that bisphosphonates may have chemopreventive potential against colorectal cancer. Our aim was to examine this association through a meta-analysis of observational studies.
A comprehensive search for relevant articles published up to October 2012 was performed, reviews of each study were conducted and data were abstracted. Prior to meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects and the fixed-effects models. Subgroup and sensitivity analyses were also performed.
Eight large population-based epidemiological studies (one case-control, two nested case-control analyses within a cohort, and five cohort studies), involving more than 630,000 participants, contributed to the analysis. We found no evidence of publication bias. However, significant heterogeneity was detected among the cohort studies. The analysis revealed a significant protective association between bisphosphonate use and colorectal cancer risk (fixed RR=0.85, 95% CI: 0.80–0.90; random RR=0.85, 95% CI: 0.75–0.96). When the analysis was stratified into subgroups according to study design, the association was inverse in both case-control and cohort studies, but only in the former it was statistically significant. The sensitivity analysis confirmed the stability of our results. Furthermore, we found evidence for a dose effect; “Long-term” bisphosphonate use was associated with a 27% decrease in the risk of developing colorectal cancer as compared with non-use (RR=0.73, 95% CI: 0.57–0.93).
Our findings support a protective effect of bisphosphonates against colorectal cancer. However, further evidence is warranted.
The United States (US) is considered the center of prescription drug abuse. Since drug abuse is a worldwide phenomenon, it would be valuable to determine if the trend of increasing prescription opioid misuse and abuse seen in the US is developing in the United Kingdom (UK). To compare trends in deaths associated with prescription opioid drugs, mortality data was obtained online for England, Wales, and Scotland from the Office for National Statistics and the General Register Office and for the US from The National Vital Statistics System (NVSS). Mortality trends in the US show a relentless increase of deaths from unintentional drug poisoning with opioid analgesics in the last decade. In 2010, the number of deaths related to opioid analgesics was over 16,500, more than double the number of 2002 and more than twice the number of deaths from heroin and cocaine deaths combined [1]. Although the number of deaths related to drug poisoning reviewed from England and Wales is not as high as the US, the overall trends are remarkably similar (Figure 1). The prominent role of methadone in UK opioid deaths also is striking. In Scotland, methadone-related deaths increased from 71 in 2001 to 275 in 2011 [2] and they currently represent over half of all reported opioid deaths. However, this should be viewed in the context of a considerable increase in the availability of opioid substitution treatment in the UK [3]. In the US, most cases relate to opioid analgesics, and the number of oxycodone deaths slightly exceeds the number of methadone deaths. Tramadol presents interesting data in the UK: in 1996, England and Wales reported one death with the drug mentioned, but by 2011 there were 154 deaths [4]. In Scotland, tramadol-related deaths increased from 8 in 2001 to 34 deaths in 2011 [2]. The increase in tramadol-related deaths may reflect a rise in tramadol prescriptions, therefore availability, but also points to the need to monitor closely any increase in deaths caused by opioid analgesics as it may signal an emerging problem in the UK similar to the issue that is now well-established in the US.
]]>To ascertain the effects of the Medicines and Healthcare products Regulatory Agency's (MHRA) safety update in June 2010 on the volume of prescribing of quinine and on indices of quinine toxicity.
We analysed quarterly primary care total and quinine prescribing data for England and quinine prescribing volume for individual Primary Care Trusts (PCTs) in the North East of England from 2007/8 to 2011/12 obtained from the ePACT.net database. We also analysed quinine toxicity enquiries to the National Poisons Information Service (NPIS) via Toxbase® and by telephone between 2004/5 and 2011/12. Joinpoint regression and Pearson's correlation tests were used to ascertain changes in trends in prescribing and indices of toxicity, and associations between prescribing and indices of toxicity respectively.
Total prescribing continued to increase, but annual growth in quinine prescribing in England declined from 6.0% to -0.6% following the MHRA update (difference -0.04 [95% CI -0.07 to -0.01] quinine prescriptions/ 100 patients /quarter, p=0.0111). Much larger reductions were observed in PCTs which introduced comprehensive prescribing reviews. The previously increasing trend in Toxbase® quinine searches was reversed (difference -19.76 [95% CI -39.28 to -9.20] user sessions /quarter, p=0.0575). NPIS telephone enquiries for quinine have declined with stabilisation of the proportion of moderate to severe cases of quinine poisoning since the update.
The MHRA advice was followed by limited reductions in the growth in quinine prescribing and in indicators of quinine overdose and toxicity. Quinine prescribing, however, remains common and further efforts are needed to reduce availability and use.
To examine the impact of fee-for-service pharmacist-led medication review on patient outcomes and quantify this according to the type of review undertaken e.g. adherence support and clinical medication review.
Relevant published studies were identified from Medline, Embase and International Pharmaceutical Abstract databases (from inception to February 2011). Study inclusion criteria were: fee-for-service medication review, presence of a control group and pre-specified patient outcomes. Outcomes were grouped into primary (changes in biomarkers, hospitalisation, and mortality) and secondary outcomes (medication adherence, economic implications and quality of life). Meta-analyses for primary outcomes were conducted using random effects models, and secondary outcomes were summarized using descriptive statistics.
Of the 135 relevant articles located, 21 studies met the inclusion criteria for primary outcomes, and 32 for secondary outcomes. Significant results favouring pharmacists’ intervention were found for blood pressure (OR 3.50, 95%CI 1.58 to 7.75, p=0.002) and low density lipoprotein (OR 2.35, 95%CI 1.17 to 4.72, p=0.02). Outcomes on hospitalisation (OR 0.69, 95%CI 0.39 to 1.21, p=0.19) and mortality (OR 1.50, 95%CI 0.65 to 3.46, p=0.34) indicated no differences between the groups. On subgroup analysis, clinical medication review (OR 0.46, 95%CI 0.26 to 0.83, p=0.01) but not adherence support review (OR 0.88, 95%CI 0.59 to 1.32, p=0.54) reduced hospitalisation. The majority of the studies (57.9%) showed improvement in medication adherence.
Fee-for-service pharmacist-led medication reviews showed positive benefits on patient outcomes. Interventions that include a clinical review had a significant impact on patient outcomes by attainment of target clinical biomarkers and reduced hospitalisation.
Many anticancer agents damage DNA and activate cell cycle checkpoints that permit time for the cells to repair their DNA and recover. These checkpoints have undergone intense investigation as potential therapeutic targets, and Chk1 inhibitors have emerged as promising novel therapeutic agents. Chk1 was initially recognized as a regulator of the G2/M checkpoint, but has since been demonstrated to have additional roles in replication fork stability, replication origin firing and homologous recombination. Inhibition of these pathways can dramatically sensitize cells to some antimetabolites. Current clinical trials with Chk1 inhibitors are primarily focusing on their combination with gemcitabine. Here, we discuss the mechanisms of, and emerging uses for Chk1 inhibitors as single agents and in combination with antimetabolites. We also discuss the pharmacodynamic issues that need to be addressed in attaining maximum efficacy in vivo. Following administration of gemcitabine to mice and humans, tumor cells accumulate in S phase for at least 24 h before recovering. In addition, stalled replication forks evolve over time to become more Chk1 dependent. We emphasize the need to assess cell cycle perturbation and Chk1 dependence of tumors in patients administered gemcitabine. These assessments will define the optimum dose and schedule for administration of these drug combinations.
To summarize the scientific evidence about the risks of using methylphenidate for ADHD in pregnancy and lactation, to present a case in which interruption of treatment after delivery and during breastfeeding was harmful and to discuss the implications of treating or not ADHD in pregnancy and lactation.
For the systematic review, databases searched included : Pubmed, Psychinfo, Web of Science, Embase, Biosis and Medline. Results- Three articles were found with a total sample of 41 children exposed to methylphenidate in pregnancy. Malformations reported included: congenital heart defects (n=2), finger abnormalities (syndactyly, adactyly and polydactyly n=2) and limb malformations (n=1). Other problems included premature birth, asphyxia and growth retardation. One case report (n=1) and one case series (n=3) were identified regarding exposure to methylphenidate through breast feeding. In all cases, children developed normally and no adverse effects were reported. In our case report we describe an infant exposed to methylphenidate during pregnancy and breast feeding, which developed normally having no detectable congenital abnormalities.
The number and size of the studies found were small. Identified cases were not representative of the general adult ADHD population having methylphenidate as monotherapy during pregnancy as all the articles reported combinations of methylphenidate with either known teratogenic drugs or drugs of abuse.
There is a paucity of data regarding the use of methylphenidate in pregnancy, and further studies are required. Although the default medical position is to interrupt any non-essential pharmacological treatment during pregnancy and lactation, in ADHD this may present a significant risk. Doctors need to evaluate each case carefully before interrupting treatment.
To assess centrally mediated analgesic mechanisms in clinical trials with pain patients, objective standardized methods such as electroencephalography (EEG) has many advantages. The aim of this review is to provide the reader with an overview of present findings in analgesics assessed with spontaneous EEG and evoked brain potentials (EPs) in humans. Furthermore, EEG methodologies will be discussed with respect to translation from animals to humans and future perspectives in predicting analgesic efficacy.
We searched PubMed with MeSH terms “analgesics”, “electroencephalography” and “evoked potentials” for relevant articles. Combined with a search in their reference lists 15 articles on spontaneous EEG and 55 papers on EPs were identified.
Overall, opioids produced increased activity in the delta band in the spontaneous EEG, but increases in higher frequency bands were also seen. The EP amplitudes decreased in the majority of studies. Anticonvulsants used as analgesics showed inconsistent results. The N-Methyl-D-aspartate receptor antagonist ketamine showed an increase in the theta band in spontaneous EEG and decreases in EP amplitudes. Tricyclic antidepressants increased the activity in the delta, theta and beta bands in the spontaneous EEG while EPs were inconsistently affected. Weak analgesics were mainly investigated with EPs and a decrease in amplitudes was generally observed.
This review reveals that both spontaneous EEG and EPs are widely used as biomarkers for analgesic drug effects. Methodological differences are common and a more uniform approach will further enhance the value of such biomarkers for drug development and prediction of treatment response in individual patients.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and results from mutations in PKD1 or PKD2. Cyst initiation and expansion arise from a combination of abnormal cell proliferation, fluid secretion, extracellular matrix defects and results in kidney enlargement and interstitial fibrosis. Since its first descriptions over 200 years ago, ADPKD has been considered an untreatable condition and its management limited to blood pressure reduction and symptomatic treatment of disease complications. Results of the recently reported TEMPO 3/4 trial thus represent a paradigm shift in demonstrating for the first time that cystic disease and loss of renal function can be slowed in humans. In this paper, we review the major therapeutic strategies currently being explored in ADPKD including a range of novel approaches in preclinical models. It is anticipated that the clinical management of ADPKD will undergo a revolution in the next decade with the translation of new treatments into routine clinical use.
Vitamin D preparations are widely available as food supplements in most countries without the need of any medical prescription. We describe 3 cases of severe Vitamin D-intoxication, reported in the Italian National Institute of Health reporting system for natural health products. The cases reported share important similarities with other cases reported in literature, showing that vitamin D intoxication due to the use of food supplements is not a rare phenomenon. A major problem is that vitamin D preparations do not undergo specific quality control for good manufacturing practice due to the fact that they are labeled as “food supplements”. The 3 cases reported, with capsules containing vitamin D doses 880 times higher than those declared could be considered the demonstration of the absence of appropriate quality control in product preparation. The present cases of vitamin D intoxication emphasize the need of marketing preparations produced under precise rules to define the amount of potentially toxic ingredients.
To characterise the PK of rhC1INH in healthy volunteers and HAE patients.
C1INH plasma levels following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme.
A one-compartment model with Michaelis-Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 (95% CI: 0.839 – 0.968) and 0.176 (95% CI: 0.154 – 0.200) U/mL in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 (95% CI: 2.68 – 3.03) L. The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 (95% CI: 1.41 – 1.88) U/mL/h and 1.60 (95% CI: 1.14 – 2.24) U/mL, respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Body weight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U/mL) for at least 94% of all patients.
The PPK model for C1INH supports a dosing scheme on a 50 U/kg basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration.
To characterize pharmacokinetic (PK) parameters of MK-0916 and its safety and tolerability in lean, healthy males following single and multiple oral doses; to assess (by stable-isotope labeling) in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916.
Data are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first, subjects received single oral doses of 0.4–100 mg MK-0916 (n=16). In the second, subjects received 0.2–225 mg MK-0916 followed by daily doses of 0.2–100 mg for 13 days beginning on Day 2 or Day 15 (n=80). Plasma and urine drug concentrations were measured for PK analysis. For pharmacodynamic analysis, concentrations of plasma [13C4]cortisol were measured by high-pressure liquid chromatography/tandem mass spectrometry following a single oral dose of 5 mg [13C4]cortisone.
Doses ≥3 mg were rapidly absorbed (Tmax 1.1–1.8 h). Exposure (measured as AUC0–168h) increased approximately in proportion to dose. Values for Cmax and C24h increased in excess of dose-proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nM and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11β-HSD1 inhibition was well-represented by a simple Emax model with an IC50 = 70.4 nM. Exposure to MK-0916 was generally well tolerated.
These findings indicate that 11β-HSD1 is effectively inhibited in human subjects by doses of MK-0916 that are well-tolerated.
This study investigated the tolerability, safety, pharmacokinetics, and pharmacodynamics of ponesimod, a novel oral selective sphingosine-1-phosphate (S1P1) receptor modulator in development for the treatment of auto-immune diseases.
This was a double-blind, placebo-controlled, ascending, single-dose study. Healthy male subjects received doses of 1 to 75 mg or placebo control.
Ponesimod was well tolerated. Starting with a dose of 8 mg, transient asymptomatic reductions in heart rate were observed. Ponesimod pharmacokinetics were dose proportional. The median time to maximum concentration (tmax) ranged from 2.0 to 4.0 h and ponesimod was eliminated with a mean half-life (t1/2) varying between 21.7 and 33.4 h. Food had a minimal effect on ponesimod pharmacokinetics. Doses of ≥ 8 mg reduced dose-dependently total lymphocyte count. Lymphocyte counts returned to normal ranges within 96 h. A pharmacokinetic/pharmacodynamic model was developed that adequately described the observed effects of ponesimod on total lymphocyte counts.
Single doses of ponesimod up to and including 75 mg were well tolerated. The results of this ascending single-dose study indicate an immunomodulator potential for ponesimod and a pharmacokinetic/pharmacodynamic profile consistent with once-a-day dosing.
Iontophoresis is a method of non-invasive transdermal drug delivery based on the transfer of charged molecules using a low-intensity electric current. Both local and systemic administration is possible, however the skin pharmacokinetics of iontophoretically-delivered drugs is complex and difficult to anticipate. The unquestionable theoretical advantages of the technique make it attractive in several potential applications. After a brief review of the factors influencing iontophoresis, we detail the current applications of iontophoresis in therapeutics and the main potential applications under investigation, including systemic and topical drugs and focusing on the treatment of scleroderma-related ulcerations. Finally, we address the issue of safety, which could be a limitation to the routine clinical use of iontophoresis.
The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol.
Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50-600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLCR) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT).
Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: UT = (1-D/(ID50+D))*(UP-UR)+UR, fitted the data well (R2=0.74, P< 0.0001). The parameters and their best-fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID50 = 226 mg; 95% CI: 167–303 mg), apparent resistant plasma urate (UR = 0.20 mmol/L; 0.14 – 0.25 mmol/L). Incorporation of CLCR did not significantly improve the fit (P=0.09).
A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by the creatinine clearance.
Muscle injuries and extensive exercise are associated with cyclooxygenase dependent formation of inflammatory prostaglandins. Since the effect of topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) on local cyclooxygenase is unknown, the present exploratory, open label, non-randomized study set out to measure exercise induced release of prostaglandins before and after epicutaneous administration of diclofenac.
Microdialysis was used to determine the local interstitial concentration of PGE2 and 8-iso-PGF2α as well as diclofenac concentrations in the vastus lateralis under rest, dynamic exercise and during recovery in twelve healthy subjects at baseline and after a treatment phase applying a total of 7 plasters medicated with 180 mg of diclofenac epolamine over 4 days.
Globally, at baseline PGE2 concentrations were 1169±780pg/mL at rest and 1287±459pg/mL during dynamic exercise and increased to 2005±1126pg/mL during recovery. After treatment average PGE2 levels were 997±588pg/mL at rest and 1339±892pg/mL during exercise. In contrast to the baseline phase no increase in PGE2 levels was recorded during the recovery period after treatment (PGE2 1134±874pg/mL). 8-iso-PGF2α was neither affected by exercise nor by treatment with diclofenac. Local and systemic levels of diclofenac were highly variable but comparable to previous clinical pharmacokinetic studies.
We can hypothesize an effect of topical diclofenac epolamine plaster on limiting the increase of local levels of the pro-inflammatory prostaglandin PGE2 induced in muscle of healthy human subjects following a standardised physical exercise. No effect of diclofenac treatment on 8-iso-PGF2α levels was observed, mainly since isoprostane is produced by a free radical-catalysed lipid peroxidation mechanism independent of cyclooxygenases.
Acetlycholine is involved in the control of airway smooth muscle constriction and in recruitment of inflammatory cells via neuronal and paracrine effects on muscarinic type 3 receptors. Long acting muscarinic antagonists (LAMA) are well established in guidelines for COPD but are not currently licensed for use in asthma. There are emerging data from key clinical trials to show that LAMA may confer bronchodilator effects and improved control when used in addition to inhaled corticosteroid (ICS) alone or in conjunction with long acting beta-agonists (LABA). Further studies in persistent asthmatic patients are required to evaluate ICS sparing effects of LAMA looking particularly at airway hyper-responsiveness and surrogate inflammatory markers, in addition to evaluation of possible synergy between LAMA and LABA when given together. Future possible development of combination inhalers comprising ICS/LAMA or ICS/LAMA/LABA will require long term studies looking at asthma control and exacerbations in both adult and pediatric patients.
The current investigation aims to provide new insights into fetal exposure to tacrolimus in utero by evaluating maternal and umbilical cord blood (venous and arterial), plasma and unbound concentrations at delivery. This study also presents a case report of tacrolimus excretion via breast milk.
Maternal and umbilical cord (venous and arterial) samples were obtained at delivery from eight solid organ allograft recipients to measure tacrolimus and metabolite bound and unbound concentrations in blood and plasma. Tacrolimus pharmacokinetics in breast milk were assessed in one subject.
Mean (± SD) tacrolimus concentrations at the time of delivery in umbilical cord venous blood (6.6 ± 1.8 ng/mL) were 71 ± 18% (range 45–99%) of maternal concentrations (9.0 ± 3.4 ng/mL). The mean umbilical cord venous plasma (0.09 ± 0.04 ng/mL) and unbound drug concentrations (0.003 ± 0.001 ng/mL) were approximately one fifth of the respective maternal concentrations. Arterial umbilical cord blood concentrations of tacrolimus were 100 ± 12% of umbilical venous concentrations. In addition, infant exposure to tacrolimus through the breast milk was less than 0.3% of the mother's weight-adjusted dose.
Differences between maternal and umbilical cord tacrolimus concentrations may be explained in part by placental P-gp function, greater red blood cell partitioning and higher hematocrit levels in venous cord blood. The neonatal drug exposure to tacrolimus via breast milk is very low and likely does not represent a health risk to the breastfeeding infant.
Ciclosporin A (CsA) dosing in immunosuppression after paediatric kidney transplantation remains challenging, and appropriate target CsA exposures (AUC) are controversial. This study aimed to develop a time-to-first-acute rejection (AR) model and to explore predictive factors for therapy outcome.
Patient records at the Children's Hospital in Helsinki, Finland, were analysed. A parametric survival model in NONMEM was used to describe the time to first AR. The influences of AUC and other covariates were explored using stepwise covariate modelling (SCM), bootstrap-SCM and cross-validated SCM. The clinical relevance of the effects was assessed with the time at which 90 % of the patients were AR-free (T90).
Data from 87 patients (0.7-19.8 years, 54 experiencing an AR), was analysed. The baseline hazard was described with a function changing in steps over time. No statistically significant covariate effects were identified, a finding substantiated by all methods used. Thus, within the observed AUC range (90 % interval 1.13-8.40 h*mg/l), a rise in AUC was not found to increase protection from AR. Dialysis time, sex and baseline weight were potential covariates, but the predicted clinical relevance of their effects was low. For the strongest covariate, dialysis time, median T90 was 5.8 (90 % confidence interval 5.1-6.8) days for long (90thpercentile) and 7.4 (6.4-11.7) days for short (10thpercentile) times.
A survival model with discrete time-varying hazards described the data. Within the observed range, AUC was not identified as a covariate. This feedback on clinical practice may help avoiding unnecessarily high CsA dosing in children.
To compare results from analysis of averaged and single-sweep EPs by visual inspection and spectral analysis in order to identify an objective measure for the analgesic effect of buprenorphine and fentanyl.
Twenty-two healthy males were included in a randomized study to assess the changes in EPs after 110 sweeps of painful electrical stimulation to the median nerve following treatment with buprenorphine, fentanyl or placebo patches. Bone pressure, cutaneous heat and electrical pain ratings were assessed. EPs and pain assessments were obtained before drug administration, 24, 48, 72, and 144 hours after beginning of treatment. Features from EPs were extracted by three different approaches: 1) Visual inspection of amplitude and latency of the main peaks in the average EPs; 2) Spectral distribution of the average EPs; and 3) spectral distribution of the EPs from single-sweeps.
Visual inspection revealed no difference between active treatments and placebo (all P>0.05). Spectral distribution of the averaged potentials showed a decrease in the beta(12-32Hz) band for fentanyl (P=0.036), which however did not correlate to pain ratings. Spectral distribution in the single-sweep EPs revealed significant increases in the theta, alpha and beta bands for buprenorphine (all P<0.05) as well as theta band increase for fentanyl (P=0.05). For buprenorphine, beta band activity correlated to bone pressure and cutaneous heat pain (both P=0.04; r=0.90).
In conclusion single-sweep spectral band analysis increases the information on the brains response to opioids and may be used to identify the response to analgesics.
A competency model for planning and monitoring Clinical Pharmacology staff development is presented. The method provides a means to objectively define, and monitor development of key skills and knowledge areas required to fulfill the role of Clinical Pharmacologist as practiced at Roche. Skills critical to the future needs of the department can be highlighted as priority development areas and effectively communicated to staff and senior management. Individual as well as overall departmental staff development progress can be monitored. The method is easily modified to suit other disciplines or institutional definitions of the role of CP.
]]>While the worldwide prevalence of cocaine use remains significant, medications, or small molecule approaches, to treat drug addictions have met with limited success. Anti-addiction vaccines, on the other hand, have demonstrated great potential for treating drug abuse using a distinctly different mechanism of eliciting an antibody response that blocks the pharmacological effects of drugs. We provide a review of vaccine-based approaches to treating stimulant addictions; specifically methamphetamine and cocaine addictions.
This selective review article focuses on the one cocaine vaccine that has been into clinical trials and presents new data related to pre-clinical development of a methamphetamine (MA) vaccine. We also review the mechanism of action for vaccine induced antibodies to abused drugs, which involves kinetic slowing of brain entry as well as simple blocking properties.
We present pre-clinical innovations for methamphetamine (MA) vaccines including hapten design, linkage to carrier proteins and new adjuvants beyond alum. We provide some new information on hapten structures and linkers and variations in protein carriers. We consider a carrier – outer membrance polysaccharide coat protein (OMPC) – that provides some self-adjuvant through lipopolysaccharide components and provide new results with a monophosopholipid adjuvant for the more standard carrier proteins with cocaine and MA. The review then covers the clinical trials with the cocaine vaccine TA-CD
The clinical prospects for advances in this field over the next few years include a multi-site cocaine vaccine clinical trial to be reported in 2013 and phase 1 clinical trials of a MA vaccine in 2014.
Glycopyrronium bromide (NVA237) is a once-daily long-acting muscarinic antagonist recently approved for the treatment of chronic obstructive pulmonary disease (COPD). In this study we used population pharmacokinetic (PK) modeling to provide insights into the impact of the lung PK of glycopyrronium on its systemic PK profile and in turn understand the impact of lung bioavailability and residence time on the choice of dosing regimen.
We developed and validated a population PK model to characterize the lung absorption of glycopyrronium using plasma PK data derived from studies in which this drug was administered by different routes to healthy volunteers. The model was also used to carry out simulations of once-daily and twice-daily regimens and characterize amounts of glycopyrronium in systemic compartments and lungs.
The model-derived PK parameters were comparable to those obtained with non-compartmental analysis, confirming the usefulness of our model. The model suggested that the lung absorption of glycopyrronium was dominated by slow-phase absorption with a half-life of about 3.5 days, which accounted for 79% of drug absorbed through the lungs into the bloodstream, from where glycopyrronium was quickly eliminated. Simulations of once-daily and twice-daily administration generated similar PK profiles in the lung compartments.
Phosphate handling in the body is complex and involves hormones produced by the bone, the parathyroid gland and the kidneys. Phosphate is mostly found in hydroxyapatite, however recent evidence suggests that phosphate is also a signaling molecule associated with bone formation. Phosphate balance requires careful regulation of gut and kidney phosphate transporters, SLC34 transporter family, but phosphate signaling in osteoblasts and vascular smooth muscle cells is likely mediated by SLC20 transporter family (PiT1 and PiT2). If not properly regulated, phosphate imblanace could lead to mineral disorders as well as vascular calcification. In chronic kidney disease-mineral bone disorder, hyperphosphatemia has been consistently associated with extra-osseous calcification and cardiovascular disease. This review focuses on the physiological mechanisms involved in phosphate balance and cell signaling (i.e. osteoblasts and vascular smooth muscle cells) as well as pathological consequences of hyperphosphatemia. Finally, conventional as well as new and experimental therapeutics in the treatment of hyperphosphatemia are explored.
Strategies for assisting smoking cessation include behavioural counselling to enhance motivation and to support attempts to quit and pharmacological intervention to reduce nicotine reinforcement and withdrawal from nicotine. Three drugs are currently used as first-line pharmacotherapy for smoking cessation: nicotine replacement therapy, bupropion, and varenicline. Compared to placebo, the drug effect varies from 2.27 (95% CI 2.02-2.55) for varenicline, to 1.69 (95% CI 1.53-1.85) for bupropion, and to 1.60 (95% CI 1.53-1.68) for any form of nicotine replacement therapy. Despite some controversy regarding the safety of bupropion and varenicline, regulatory agencies consider these drugs as having a favourable benefit/risk profile. However, given the high rate of psychiatric comorbidity in dependent smokers, practitioners should closely monitor patients for neuropsychiatric symptoms. Second-line pharmacotherapies include nortriptyline and clonidine. This review also offers an overview of pipeline developments and issues related to smoking cessation in special populations: persons with psychiatric comorbidity and pregnant and adolescent smokers.
Apixaban is an oral, direct, factor-Xa inhibitor approved for thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery. This open-label, parallel-group study investigated effect of extremes of body weight on apixaban pharmacokinetics, pharmacodynamics, safety and tolerability.
Fifty-four healthy subjects were enrolled (18 each into low (≤ 50 kg), reference (65–85 kg) and high (≥ 120 kg) body weight groups. Following administration of a single oral dose of 10 mg apixaban, plasma and urine samples were collected for determination of apixaban pharmacokinetics and anti-factor Xa activity. Adverse events, vital signs and laboratory assessments were monitored.
Compared with the reference body weight group, low body weight had approximately 27% and 20% higher apixaban maximum observed plasma concentration (Cmax) and area under the concentration–time curve extrapolated to infinity (AUC(0,∞)), respectively; and high body weight had approximately 31% and 23% lower apixaban Cmax and AUC(0,∞), respectively. Apixaban renal clearance was similar across weight groups. Plasma anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Apixaban was well tolerated in this study.
The modest change in apixaban exposure is unlikely to require dose adjustment for apixaban based on body weight alone; however, caution is warranted in the presence of additional factors (such as severe renal impairment) that could increase apixaban exposure.
On 3 September 2012, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) notified healthcare professionals of immediate changes to the intravenous acetylcysteine license terms, altering the treatment pathway for paracetamol poisoning. We sought to evaluate awareness of this amongst healthcare professionals.
We surveyed doctors, nurses and pharmacists in the 1-12 week period following the implementation date.
44 individuals completed the survey in paper form (response rate 86%) and 220 in electronic form (response rate unknown). The resulting sample of 264 individuals was drawn from 41 institutions, and included 143 doctors, 58 pharmacists, and 50 nurses. 157 (59%) were aware of the changes, and 133 (50%) had adopted them in practice. Awareness differed between healthcare professions (P=0.001) and specialties (P=0.002). For respondents aware of the changes, the main sources of information were alerts issued internally (reported by 57%); from the MHRA (25%); and other professional bodies (24%). The proportion of individuals that reported receiving practical implementation instructions (e.g. a protocol) was higher among respondents who had changed their practice than for those who had not (86% versus 25%, respectively; P<0.001).
Less than two-thirds of healthcare professionals in specialties managing patients with paracetamol poisoning were aware of important changes to its treatment pathway in the 12 weeks after they took effect, and only half had adopted them in practice. Alternative communication strategies should be explored to improve dissemination of similar information from the MHRA and other medicines regulators in the future.
Antibiotics are a key resource for the management of infectious diseases in neonatology and their evaluation is particularly challenging. We reviewed medical literature to assess the characteristics and quality of randomized controlled trials on antibiotics in neonatal infections.
We performed a systematic search of PubMed, Embase and the Cochrane Library from January 1995 to March 2010. Bibliographies of relevant articles were also hand-searched. We included all randomized controlled trials that involved neonates and evaluated the use of an antibiotic agent in the context of a neonatal infectious disease. Methodological quality was evaluated using the Jadad scale and the Cochrane Risk of Bias Tool. Two reviewers independently assessed studies for inclusion and evaluated methodological quality.
A total of 35 randomised controlled trials were evaluated. The majority were conducted in a single hospital institution, without funding. Median sample size was 63 (34-103) participants. The most frequently evaluated antibiotic was gentamicin. Respectively, 18 (51%) and 17 (49%) trials evaluated the therapeutic or prophylactic use of antibiotics in various neonatal infections. Overall, the methodological quality was poor and did not improve over the years. Risk of bias was high in 66% of the trials.
Design and reporting of randomised controlled trials of antibacterial agents in neonates should be improved. Nevertheless, the necessity of implementing such trials when antibacterial efficacy has already been established in other age groups may be questioned and different methods of evaluation should be further developed.
Junior doctors write the majority of hospital prescriptions but many indicate they feel underprepared to assume this responsibility and around 10% of prescriptions contain errors. Medical smartphone apps are now widely used in clinical practice and present an opportunity to provide support to inexperienced prescribers. This study assesses the contemporary range of smartphone apps with prescribing or related content.
Six smartphone app stores were searched for apps aimed at the healthcare professional with drug, pharmacology or prescribing content.
306 apps were identified. 34% appeared to be for use within the clinical environment in order to aid prescribing, 14% out with the clinical setting, and 51% of apps were deemed appropriate for both clinical and non-clinical use. Apps with drug reference material, such as textbooks, manuals or medical apps with drug information were the commonest app found (51%), followed by apps offering drug or infusion rate dose calculation (26%). 68% of apps charged for download, with a mean price of £14.25 per app and a range of £0.62 – 101.90.
A diverse range of pharmacology-themed apps are available and there is further potential for the development of contemporary apps to improve prescribing performance. Personalised app stores may help universities/healthcare organisations offer high-quality apps to students to aid in pharmacology education. Users of prescribing apps must be aware of the lack of information regarding the medical expertise of app developers; this will enable them to make informed choices about the use of such apps in their clinical practice.
Investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature.
Three studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four-way, double-blind, randomised, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H1- and H2-antagonists. Flare and itch were assessed in all studies.
Histamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol/min) infused (mean (SEM) infused arm vs. control: 26.8 (5.3) vs. 2.6 ml min-1 100 ml-1; p<0.0001). Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H2-antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol/min histamine: -11.9 ml min-1 100 ml-1 (-4.0 to -19.8), p<0.0001) and flare (mean (95% CI) difference from placebo: -403.7 cm2 (-231.4 to 576.0), p<0.0001). No reduction in FBF or flare was observed in response to the H1-antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor.
Histamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H2-receptors are important in this process. Our results support further exploration of combined H1- and H2-antagonist therapy in acute allergic syndromes.
Cannabinoid 1 receptor (CB1R) has a well-established role in appetite regulation. Central CB1R antagonists, notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals, but were discontinued due to psychiatric side-effects. CB1R is also expressed peripherally, where its effects include promoting liver fat accumulation, consuming ATP. Type 2 diabetes in obese subjects is linked to excess liver fat, whilst there is a negative correlation between hepatic ATP content and insulin resistance. A decreased hepatic ATP/AMP ratio increases food intake by signals via the vagus nerve to the brain. The hepatic cannabinoid system is highly upregulated in obesity, and the effects of hepatic CB1R activation include increased activity of lipogenic and gluconeogenic transcription factors. Thus, blocking hepatic CB1Rs could contribute significantly to the weight-reducing and insulin-sensitising effects of CB1R antagonists. Additionally, upregulation of the hepatic CB1R may contribute to chronic liver inflammation, fibrosis and cirrhosis from causes including obesity, alcoholism and viral hepatitis.
Peripheral CB1R antagonists induce weight loss and metabolic improvements in obese rodents; however, as there is evidence that hepatic CB1Rs are predominately intracellular, due to high intrinsic clearance, many drugs may not effectively block these receptors and therefore have limited efficacy. Hepatoselective CB1R antagonists may be effective at reducing hepatic steatosis, insulin resistance and body weight in obese, diabetic patients, with far fewer side-effects than first-generation CB1R antagonists. Additionally, such compounds may effective in treating inflammatory liver disease, e.g. non-alcoholic steatohepatitis (NASH), reducing the likelihood of disease progression to cirrhosis or cancer.
Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee surgery and under development for treatment of venous thrombosis. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple-dose apixaban.
This double-blind, randomized, placebo-controlled, parallel-group, multiple-dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily (BID) and 10 and 25 mg once daily (QD) – with 8 healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT).
Forty-eight subjects were randomized and treated (apixaban, n=36; placebo, n=12); one subject receiving 2.5 mg BID discontinued due to AEs (headache and nausea). No dose-limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by Day 3, with an accumulation index of 1.3–1.9. Peak-to-trough ratios were lower for BID versus QD regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile.
Animal and in vitro studies suggest that the use of bisphosphonates (BP) may be associated with reduced risk for colorectal cancer (CRC). However, results from these studies have been inconsistent. The aim of our study was to review and summarize the evidence provided by longitudinal studies on the association between BP use and CRC risk.
A comprehensive literature search for articles published up to October 2012 was performed. Prior to performing a meta-analysis, the studies were evaluated for publication bias and heterogeneity. Relative risk (RR) or odds ratios (OR) were calculated.
Six reports (4 case–control studies and two cohort studies), published between 2010 and 2012 were identified. There was evidence of an association between any use of BP and CRC risk using fixed-effects model (RR = 0.80, 95% CI = 0.74, 0.85), and the random-effects model (RR = 0.80, 95% CI = 0.71, 0.90). However, we did not observe any evidence of a trend with increasing duration of use.
Our findings indicate that there is evidence of an association between any use of BP and CRC risk. However, this subject deserves further investigation.
Chronic kidney diseases share common pathogenic mechanisms that, independently from the initial injury, lead to glomerular hyperfiltration, proteinuria, and progressive renal scarring and function loss. Consistent experimental evidence supports the crucial role of proteinuria in accelerating kidney disease progression to end-stage renal failure through multiple pathways, including induction of tubular chemokine expression and complement activation. These events, on turn, lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis. The extent of proteinuria is widely recognized as a marker of the severity of chronic kidney disease and as a predictor of future decline in glomerular filtration rate. More importantly, a reduction in proteinuria invariably translates into a protection from renal function decline in patients with diabetic and nondiabetic renal disease. Recent evidence showed also the existance of a relatioship between proteinuria levels and cardiovascular risk, which extends to the range of urinary albumin excretion that was previously thought ‘normal’. Thus, proteinuria should be considered a valuable surrogate end point for clinical trials in patients with chronic renal diseases and a target for reno- and cardioprotecive strategies.
This book is part of the Advances in Cardiology series, and specifically looks at the current status of antiplatelet therapy in two important cardiac diseases, namely acute coronary syndrome (ACS) and atrial fibrillation (A-Fib).
The first chapter gives a potted summary of the usefulness and place of antiplatelet therapy in ACS and A-Fib; essentially concluding (rightly) that modern antiplatelet regimens have an important and ever increasing place in ACS treatment, whereas their usefulness in A-Fib is now considered very limited indeed (whereas by contrast anticoagulation is now considered a much superior treatment option in A-Fib). These themes are explored in detail in subsequent chapters, which deal successively with aspirin, clopidogrel, prasugrel and ticagrelor. There then follows a chapter on dipyridamole, exploring not so much its antiplatelet actions but its anti-thrombotic, anti-inflammatory, free radical scavenging and other pleiotropic effects; but one comes away from this chapter rather thinking, does any of this translate into anything clinically meaningful?
Many monoclonal antibodies (MAbs) have been studied in healthy volunteers in phase 1, but few data have been published on the safety of that practice. We aimed to review the available data, and thereby to estimate the risks of participation in phase 1 trials of MAbs.
We searched PubMed, the ClinicalTrials.gov database, and Google, using the search terms ‘monoclonal antibody’, ‘phase 1’ and ‘healthy volunteers’.
We identified 70 completed trials of MAbs in healthy volunteers, but the published data were too sparse to allow confident assessment of the risks of MAbs in healthy volunteers. Our best estimate of risk of a life-threatening adverse event was between 1:425 and 1:1700 volunteer-trials, but all such events occurred in a single trial (of TGN1412).
In a phase 1 trial of a small-molecule, the risk of death or a life-threatening adverse event appears to be 1:100,000–1,000,000 volunteer-trials, which is similar to the risk of many ordinary daily activities. Most people would consider that level of risk to be ‘minimal’ or ‘negligible’, and, therefore, acceptable. On that basis, the safety record of MAbs in healthy volunteers has been ruined by the TGN1412 disaster. However, that experience is unlikely to be repeated, because of improvements in governance and practice of phase 1 trials. If the experience of TGN1412 is disregarded, it seems reasonable to continue using healthy volunteers in phase 1 trials of MAbs, provided that there are scientific and medical reasons to conclude that the risk is truly minimal.
Rifampicin profoundly reduces lopinavir concentrations. Doubled doses of lopinavir/ritonavir compensate for the effect of rifampicin in adults, but fail to provide adequate lopinavir concentrations in young children on rifampicin-based antituberculosis therapy. The objective of this study was to develop a population pharmacokinetic model describing the pharmacokinetic differences of lopinavir and ritonavir, with and without rifampicin, between children and adults.
An integrated population pharmacokinetic model developed in NONMEM 7 was used to describe the pharmacokinetics of lopinavir and ritonavir in 21 HIV infected adults, 39 HIV infected children and 35 HIV infected children with tuberculosis, of whom established on lopinavir/ritonavir-based antiretroviral therapy with and without rifampicin-containing antituberculosis therapy.
The bioavailability of lopinavir was reduced by 25% in adults whereas children on antituberculosis treatment experienced a 59% reduction, an effect that was moderated by the dose of ritonavir. Conversely, rifampicin increased oral clearance of both lopinavir and ritonavir to a lesser extent in children than in adults. Rifampicin therapy in administered doses increased CL of lopinavir by 58% in adults and 48% in children, and CL of ritonavir by 34% and 22% for adults and children respectively. In children, the absorption half-life of lopinavir and the mean transit time of ritonavir were lengthened, compared to those in adults.
The model characterized important differences between adults and children in the effect of rifampicin on the pharmacokinetics of lopinavir and ritonavir. As adult studies cannot reliably predict their magnitude in children, drug-drug interactions should be evaluated in paediatric patient populations.
Preterm infants are deprived of the normal intrauterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials.
Melatonin was administered to eighteen preterm infants in doses ranging from 0.04-0.6 micrograms/kilograms, over 0.5-6 hours. Pharmacokinetic profiles were analysed individually and by population methods.
Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 micrograms/kilogram/hour for 2 hours showed a median half-life of 15.82 hours and median maximum plasma concentration of 203.3 picograms/millilitre. On population pharmacokinetics, clearance was 0.045 litre/hour, volume of distribution 1.098 litres and elimination half-life 16.91 hours with gender (p=0.047) and race (p<0.0001) as significant covariates.
A two-hour infusion of 0.1 micrograms/kilogram/hour increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can used to guide therapeutic clinical trials of melatonin in preterm infants.
To investigate whether the use of carbamazepine is associated with reduced risk of Parkinson's disease.
We conducted a population-based matched case-control study of patients randomly selected from the UK General Research Practice Database (GPRD). We identified 8,549 patients with Parkinson's disease using diagnosis criteria with a positive predictive value of 90%. These patients were compared with 42,160 controls matched for age, sex, and general practice.
Overall, 3.0% of cases (257/8,549) had at least one recorded prescription for carbamazepine compared to 2.5% (1,050/42,160) of controls. The crude odds ratio (OR) for the association between Parkinson's disease and carbamazepine was 1.22 (95% confidence interval [CI]: 1.06-1.40), but this reduced to 0.93 (95%CI: 0.81-1.08, p=0.34) after adjusting for annual consultation rate. Further adjustment for body mass index, smoking status, alcohol consumption, or use of calcium channel blockers did not affect results. There was no evidence that risk decreased with higher doses or longer duration of carbamazepine use.
There was little to no evidence that use of carbamazepine is associated with reduced risk of Parkinson's disease. Although the study was underpowered, it does indicate that any effect of carbamazepine is likely to be small.
To confirm by means of pentagastrin, a synthetic gastrin agonist, that netazepide is a gastrin/CCK2 receptor antagonist in healthy subjects, and that antagonism persists during repeated dosing.
We did two studies in which we infused pentagastrin 0.6 μg/kg/h intravenously, aspirated gastric secretion, and measured volume, pH and H+ secretion rate of gastric aspirate. First, we carried out a double-blind, 5-way crossover study (n=10) to assess the effect of single oral doses of netazepide 1, 5, 25 and 100 mg and placebo on the response to pentagastrin. Then, we did a single-blind, placebo-controlled study (n=8) to assess the effect of the first and last oral doses of netazepide 100 mg twice daily for 13 doses on the response to pentagastrin.
Netazepide was well tolerated. After placebo, pentagastrin increased volume and H+ secretion rate, and reduced pH, of gastric aspirate. Compared with placebo, single doses of netazepide caused dose-dependent inhibition of the pentagastrin response (p<0.02); netazepide 100 mg abolished the response. After 13 doses, the reduction in volume and H+ secretion rate persisted (p<0.001), but the pH effect was mostly lost.
Netazepide is an orally active, potent, competitive antagonist of human gastrin/CCK2 receptors. Antagonism is dose-dependent and persists during repeated dosing, despite tolerance to the effect on pH. Further studies are required to explain that tolerance. Netazepide is a tool to study the physiology and pharmacology of gastrin, and merits studies in patients, to assess its potential to treat gastric acid-related conditions and the trophic effects of hypergastrinaemia.
Both rituximab and plasmapheresis can be associated in the treatment of immune mediated kidney diseases. The real impact of plasmapheresis on rituximab pharmacokinetics is unknown. The aim of this study was to compare rituximab pharmacokinetics between patients requiring plasmapheresis and others without plasmapheresis.
The study included 20 patients receiving one or several infusions of rituximab. In 10 patients, plasmapheresis sessions were also performed (from two to six sessions per patient). Rituximab concentrations were measured in blood samples in all patients and in discarded plasma obtained by plasmapheresis using an ELISA method. Data were analyzed according to a population pharmacokinetic approach.
The mean percentage of rituximab removed during the first plasmapheresis session ranged between 47% and 54% when plasmapheresis was performed between 24 and 72 hours after rituximab infusion. Rituximab pharmacokinetics was adequately described by a two-compartment model with first-order elimination. Plasmapheresis had a significant impact on rituximab pharmacokinetics with an increase of rituximab clearance by a factor of 261 (95% Confidence Interval: 146 – 376): i.e., from 6.64 to 1733 mL.h-1. Plasmapheresis performed 24 hours after rituximab infusion decreased the rituximab area under the curve (AUC) by 26%.
Plasmapheresis removes an important amount of rituximab when performed less than three days after infusion. The removal of rituximab led to a significant decrease of AUC. This pharmacokinetic observation should be taken into account for rituximab dosing: e.g., an additional third rituximab infusion may be recommended when three plasmapheresis sessions are performed after the first rituximab infusion.
Crosstalk between the nervous, endocrine and immune systems exists via regulator molecules such as neuropeptides, hormones and cytokines. A number of neuropeptides have been implicated in the genesis of inflammation, such as tachykinins and calcitonin gene-related peptide. Development of their receptor antagonists could be a promising approach to the anti-inflammatory pharmacotherapy. Anti-inflammatory neuropeptides such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, alpha-melanocyte–stimulating hormone, urocortin, adrenomedullin, somatostatin, cortistatin, ghrelin, galanin and opioid peptides are also released and act on own receptors on the neurons as well as on different inflammatory and immune cells. The aim of the present review is to summarize the the most prominent data of preclinical animal studies concerning the main pharmacological effects of ligands acting on the neuropeptide receptors. Promising therapeutic impacts of these compounds as potential candidates for the development novel type of anti-inflammatory drugs are also discussed.
To administer repeated oral doses of netazepide to healthy subjects for the first time, to assess safety, tolerability, pharmacokinetics, and effect on 24-h gastric pH and plasma gastrin.
We did two randomised, double-blind, parallel-group studies. The first compared netazepide 25 and 100 mg 12-hourly, omeprazole 20 mg once daily, and placebo for 7 days. On Day 7 only, we measured pH and assayed plasma gastrin. The second study compared netazepide 5, 10 and 25 mg and placebo once daily for 14 days. We measured pH on Days 1, 7 and 14, and assayed plasma gastrin on Days 1 and 14. We compared treatments by time gastric pH ≥4 during 0–4, 4–9, 9–13 and 13–24h after the morning dose, and by plasma gastrin. P<0.05 was significant.
Netazepide was well tolerated. On Day 7 of the first study, netazepide increased pH significantly only during 9–13h after the 100 mg dose, whereas omeprazole raised pH significantly during all periods. But, both netazepide and omeprazole increased plasma gastrin significantly. Netazepide had linear pharmacokinetics. In the second study, netazepide caused dose-dependent, sustained increases in pH on Day 1, but as in the first study, netazepide had little effect on pH on Days 7 and 14. Again, netazepide increased plasma gastrin significantly.
Although repeated doses of netazepide led to tolerance to its effect on pH, the accompanying increase in plasma gastrin is consistent with continued inhibition of acid secretion, via gastrin receptor antagonism and gene up-regulation.
The anesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low-dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N-methyl-D-aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti-inflammatory effects at central sites. Current data on short-term infusions indicate that ketamine produces potent analgesia during administration only, while three studies on the effect of prolonged infusion (10-14 days) show long-term analgesic effects up to 3 months following infusion. Ketamine's side-effects noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation, and in a minority of patients hepatoxicity. The recreational use of ketamine is increasing and comes with a variety of additional risks ranging from bladder and renal complications to persistent psychotypical behaviour and memory defects. Blind extrapolation of these risks to clinical patients is difficult, because of the variable, high and recurrent exposure to the drug in ketamine abusers and the high frequency of abuse of other illicit substances in this population. In clinical settings, ketamine is well tolerated, especially when benzodiazepines are used to tame the psychotropic side-effects. Irrespective, close monitoring of patients receiving ketamine is mandatory, particularly aimed at CNS, hemodynamic, renal and hepatic symptoms as well as abuse. Further research is required to assess whether the benefits outweigh the risks and costs. Until definite proof is obtained ketamine administration should be restricted to patients with therapy-resistant severe neuropathic pain.
The disturbed circadian rhythm in hemodialysis patients results in perturbed sleep. Short-term melatonin supplementation has alleviated these sleep problems. Our aim was to investigate the effects of long-term melatonin supplementation on quality of life and sleep.
In this randomized double-blind placebo-controlled trial hemodialysis patients suffering from subjective sleep problems received melatonin 3 mg/day versus placebo during 12 months. The primary endpoint quality of life parameter ‘vitality’ was measured with Medical Outcomes Study Short Form-36. Secondary outcomes were improvement of three sleep parameters measured by actigraphy and nighttime salivary melatonin concentrations.
Sixty-seven patients were randomised. Forty-two patients completed the trial. With melatonin, no beneficial effect on vitality was seen. Other quality of life parameters showed both advantageous and disadvantageous effects of melatonin. Considering sleep, at 3 months sleep efficiency and actual sleep time had improved with melatonin compared to placebo on hemodialysis days (difference: 7.6%, 95%CI [0.77;14.4] and 49 minutes 95%CI [2.1;95.9] respectively). At 12 months none of the sleep parameters differed significantly from placebo. Melatonin salivary concentrations at 6 months had significantly increased in the melatonin group compared to placebo.
The high drop-out rate limits the strength of our conclusions. However, although a previous study reported beneficial short-term effects of melatonin on sleep in hemodialysis patients, in this long-term study the positive effects disappeared during follow up (6-12 months). Also the quality of life parameter vitality did not improve. Efforts should be made to elucidate the mechanism responsible for the loss of effect with chronic use.
Pharmacology occupies an unusual position within the life sciences: unlike physiology, biochemistry or anatomy for example, it wouldn't have a function at all if we didn't take medicines or drugs. Of course, clinical practice today without such resources is inconceivable. Drugs constitute one of the principal ways of combating and mitigating disease: according to the ABPI (2011), over a thousand million prescriptions are written each year in the UK averaging some 20 per head of the population [1]. Biological organisms are intricate chemical machines. As the cosmologist Martin Rees has noted [2], we know more about what goes on in the centre of a star than we do in the brain of an insect. In attempting to fathom the complexity of the cell or the physiology of a multicellular organism we are faced with huge challenges, but we are even more at a disadvantage when it comes to understanding drug action. One reason why pharmacology is so fascinating is because each drug interacts with living systems in a unique manner.
]]>To develop a list of prescribing indicators specific for the hospital setting that would facilitate the prospective collection of high severity and/or high frequency prescribing errors, which are also amenable to electronic clinical decision support (CDS).
A two-stage consensus technique (electronic Delphi) was carried out with 20 experts across England. Participants were asked to score prescribing errors using a five-point Likert scale for their likelihood of occurrence and the severity of the most likely outcome. These were combined to produce risk scores, from which median scores were calculated for each indicator across the participants in the study. The degree of consensus between the participants was defined as the proportion that gave a risk score in the same category as the median. Indicators were included if a consensus of 80% or more was achieved.
A total of 80 prescribing errors were identified by consensus as being high or extreme risk. The most common drug classes named within the indicators were antibiotics (n=13), antidepressants (n=8), non-steroidal anti-inflammatory drugs (n=6), and opioid analgesics (n=6).The most frequent error type identified as high or extreme risk were those classified as clinical contraindications (n=29/80).
80 high-risk prescribing errors in the hospital setting have been identified by an expert panel. These indicators can serve as a standardised, validated tool for the collection of prescribing data in both paper-based and electronic prescribing processes. This can assess the impact of safety improvement initiatives such as the implementation of electronic clinical decision support.
Although knowledge of human renal cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes and their role in xenobiotic and endobiotic metabolism is limited compared to hepatic drug and chemical metabolism, accumulating evidence indicates that human kidney has significant metabolic capacity. Of the drug metabolising P450s in families 1 to 3, there is definitive evidence for only CYP 2B6 and 3A5 expression in human kidney. CYP 1A1, 1A2, 1B1, 2A6, 2C19, 2D6 and 2E1 are not expressed in human kidney, while data for CYP 2C8, 2C9 and 3A4 expression are equivocal. It is further known that several P450 enzymes involved in the metabolism of arachidonic acid and eicosanoids are expressed in human kidney; CYP 4A11, 4F2, 4F8, 4F11 and 4F12. With the current limited evidence of drug substrates for human renal P450s drug-endobiotic interactions arising from inhibition of renal P450s, particularly effects on arachidonic acid metabolism, appear unlikely. With respect to the UGTs, 1A5, 1A6, 1A7, 1A9, 2B4, 2B7 and 2B17 are expressed in human kidney, whereas UGT 1A1, 1A3, 1A4, 1A8, 1A10, 2B10, 2B11 and 2B15 are not. The most abundantly expressed renal UGTs are 1A9 and 2B7, which play a significant role in the glucuronidation of drugs, arachidonic acid, prostaglandins, leukotrienes and P450 derived arachidonic acid metabolites. Modulation by drug substrates (e.g. NSAIDs) of the intrarenal activity of UGT1A9 and UGT2B7 has the potential to perturb the metabolism of renal mediators including aldosterone, prostaglandins and 20-hydroxyeicosatetraenoic acid, thus disrupting renal homeostasis.
We compared, and determined the reasons for any differences in, the review and approval times of tyrosine kinase inhibitors (TKI) by the FDA and the EMA/CHMP. Applications for these novel cancer drugs were submitted to them within a mean of 31.2 days of each other, providing a fair basis for comparison. The FDA had granted priority review to 12 TKIs but the EMA/CHMP did not grant the equivalent accelerated assessment to any. The FDA granted accelerated approvals to 6 (38%) and CHMP granted (the equivalent) conditional approvals to 4 (29%) of these agents. On average, the review and approval times were 205.3 days in the US compared to 409.6 days in the EU. The active 225.4 days in the EU and 205.3 days in the US). Since oncology drug development lasts about 7 years, the 20-days difference in review times between the two agencies is inconsequential. Clock stops during review and the time required to issue an approval had added the extra 184.2 days to review times, however were comparable (review time in the EU. We suggest possible solutions to expedite the EU review and approval processes. However, post-marketing emergence of adverse efficacy and safety data on gefitinib and lapatinib, respectively, indicate potential risks of expedited approvals. We challenge the widely prevalent myth that early approval translates into early access or beneficial impact on public health. Both the agencies collaborate closely but conduct independent assessments and make decisions based on distinct legislation, procedures, precedents, and societal expectations.
To evaluate the comparative efficacy (50% reduction in seizure frequency) and tolerability (premature withdrawal due to adverse events) of antiepileptic drugs (AEDs) for refractory epilepsy.
We searched Cochrane Central Register of Controlled Trials (Cochrane Library 2009, issue 2) including Epilepsy Group's specialised register; MEDLINE (1950 to March 2009); EMBASE (1980 to March 2009); and Current Contents Connect (1998 to March 2009) to conduct a systematic review of published studies, developed a treatment network and undertook a network meta-analysis.
Forty-two eligible trials with 6346 patients and 12 interventions, including placebo, contributed to the analysis. Only two direct drug comparator trials were identified, the remaining 40 trials being placebo-controlled. Conventional random-effects meta-analysis indicated all drugs were superior in efficacy to placebo (overall odds ratio [OR] 3.78 [95% CI 3.14 to 4.55]) but did not permit firm distinction between drugs on the basis of the efficacy or tolerability. A Bayesian network meta-analysis prioritised oxcarbazepine, topiramate and pregabalin on the basis of short-term efficacy. However, sodium valproate, levetiracetam, gabapentin and vigabatrin were prioritised on the basis of short-term efficacy and tolerability, with the caveat that vigabatrin is recognised as being associated with serious visual disturbance with chronic use.
Of the wide range of AEDs licensed for the treatment of refractory epilepsy, sodium valproate, levetiracetam, and gabapentin demonstrated the best balance of efficacy and tolerability. Until regulators mandate greater use of active-comparator trials with longer term follow-up, network meta-analysis provides the only available means to quantify these clinically important parameters.
Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterise the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc-interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin.
Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT-interval duration. A threshold of > 10 ms was used to explore the probability of prolongation after drug administration.
A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs were statistically significant different from humans. Despite such differences, our results show that the probability of QTc prolongation > 10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans.
Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk for QTc prolongation can be expressed in terms of the probability associated with an increase > 10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule.
To assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone.
This randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days.
Opicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 hours. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such half-life translates into a putative underlying rate constant that is comparable to the estimated dissociation rate constant of the COMT-opicapone complex.
Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once-daily regimen.
rAAV vectors mediating long-term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in the clinics, more efficient vectors deriving from the rh10 serotype are currently being evaluated and other serotypes are likely to be tested in the near future. In addition, aside from the currently used stereotaxy-guided intraparenchymal delivery, new techniques for global brain transduction (by intravenous or intra-cerebrospinal injections) are very promising.
Various strategies for therapeutic gene delivery to the CNS have been explored in human clinical trials in the past decade. Canavan disease, a genetic disease caused by an enzymatic deficiency, was the first to be approved. Three gene transfer paradigms for Parkinson's disease have been explored : converting L-dopa into dopamine through AADC gene delivery in the putamen ; synthesizing GABA through GAD gene delivery in the overactive subthalamic nucleus; and providing neurotrophic support through Neurturin gene delivery in the nigro-striatal pathway.
These pioneer clinical trials demonstrated the safety and tolerability of rAAV delivery in the human brain at moderate doses. Therapeutic effects however, were modest, emphasizing the need for higher doses of the therapeutic transgene product which could be achieved using more efficient vectors or expression cassettes. This will require re-addressing pharmacological aspects, with attention to which cases require either localized and cell-type specific expression or efficient brain-wide transgene expression, and when it is necessary to modulate or terminate the administration of transgene product. The ongoing development of targeted and regulated rAAV vectors is described.
This was an open-label, multicenter phase I trial to study the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in African American patients with type 2 diabetes mellitus (T2DM).
Forty-one African American patients with type 2 diabetes mellitus were included in this study. Patients were admitted to a study clinic and administered 5 mg linagliptin once-daily for 7 days, followed by 7 days of outpatient evaluation.
Primary endpoints were area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), and plasma DPP-4 trough inhibition at steady state. Linagliptin geometric mean AUC was 194 nmol/L·h (geometric coefficient of variation, 26%), with a Cmax of 16.4 nmol/L (41%). Urinary excretion was low (0.5% and 4.4% of the dose excreted over 24 hours, days 1 and 7). The geometric mean DPP-4 inhibition at steady state was 84.2% at trough and 91.9% at maximum. The exposure range and overall pharmacokinetic/pharmacodynamic profile of linagliptin in this study of African Americans with T2DM was comparable with that in other populations. Laboratory data, vital signs, and physical exams did not show any relevant findings. No safety concerns were identified.
The results of this study in African American patients with T2DM support the use of the standard 5 mg dose recommended in all populations.
To assess the cardiovascular effects of a new inhaled long-acting beta agonist PF-00610355 in COPD Patients.
13,062 heart rate measurements collected in 10 clinical studies from 579 healthy volunteers, asthma, and COPD patients, were analyzed. The relationship between heart rate profiles and predicted plasma concentration profiles, patient status, demographics, and concomitant medication was evaluated using non-linear mixed-effects models. The median heart rate increase in COPD patients for doses of PF-00610355 up to 280 μg QD was simulated with the final pharmacokinetics/pharmacodynamics (PKPD) model.
An EMAX model accounting for delayed on- and offset of the PF-00610355-induced change in heart rate was developed. The predicted potency in COPD patients was 3-fold lower compared to healthy volunteers, while no difference in maximum drug effect was identified. Simulations suggested a maximum placebo-corrected increase of 2.7 (0.90-4.82) bpm in COPD patients for a PF-00610355 dose of 280 μg QD, with 19% subjects experiencing a heart rate increase of more than 20 bpm compared to 8% in the placebo group.
This PKPD analysis supports the clinical observation that no relevant effects of PF-00610355 on heart rate in COPD patients should be expected for doses up to 280 μg QD.
Metformin pharmacokinetics depends on presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms.
Twenty-four healthy volunteers received metformin 500 mg tid for 10 days and trimethoprim 200 mg bid from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analyzed.
In the population as a whole trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l/h, renal metformin clearance from 31 to 21 l/h, and prolonged half-life from 2.7 to 3.6 h (all P<0.01). This resulted in an increase in Cmax by 38% and in AUC by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml/min (P<0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol/l (P=0.016).
The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin.
To describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the postpartum period.
IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through 6-12 weeks postpartum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks postpartum. PK targets were the estimated 10th percentile IDV AUC (12.9 μg.h/mL) in non-pregnant historical Thai adults and a trough concentration of 0.1 μg/mL, the suggested minimum target.
Twenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC0-12 and Cmax during the second trimester and postpartum (ante/post ratios) were 0.58 (0.49-0.68) and 0.73 (0.59-0.91), respectively; third trimester/postpartum AUC0-12 and Cmax ratios were 0.60 (0.53-0.68) and 0.63 (0.55-0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load <40 copies/mL at delivery. All twenty-six infants were confirmed HIV negative.
IDV exposure during the second and third trimesters was significantly reduced compared to postpartum and ∼30% of women fail to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations.
The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2).
The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers.
Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] –28% to 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23% to 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44% to 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29% to 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136% to 182%] for a 400 mg once-daily dose) and ritonavir (153% increase [95% CI 134% to 174%]).
Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination.
An algorithm based on the CYP3A5 genotype to predict tacrolimus clearance to inform the optimal initial dose was derived using data from the DeKAF study (Passey, et al. Br J Clin Pharm 2011;72:948) but was not tested in an independent cohort of patients. Our aim was to test whether the DeKAF dosing algorithm could predict estimated tacrolimus clearance in renal transplant recipients at our centre.
Predicted tacrolimus clearance based on the DeKAF algorithm was compared to dose-normalised trough whole blood concentrations (estimated clearance) on day 7 after transplantation in a single centre cohort of 255 renal transplant recipients.
There was a weak correlation (r=0.431) between clearance based on dose-normalised trough whole blood concentrations and DeKAF algorithm predicted clearance. The means of the tacrolimus clearance predicted by the DeKAF algorithm and the estimated tacrolimus clearance based on the dose-normalised trough blood concentrations were plotted against the differences in the clearance as a Bland-Altman Plot. Log transformation was performed due to the increased difference in tacrolimus clearance as the mean clearance increased. There was a highly significant systematic error (p<0.0005) characterised by a sloped regression line (gradient 0.88 (95% Confidence Interval 0.75 to 1.01)) on the Bland-Altman Plot.
The DeKAF algorithm was unable to accurately predict the estimated tacrolimus clearance based on actual tacrolimus doses and blood concentrations in our cohort of patients. Other genes are known to influence the clearance of tacrolimus and a polygenic algorithm may be more predictive than those based on a single genotype.
This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor.
This single-centre, non-randomized, non-blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child–Pugh classification, and gender-matched healthy subjects (n = 16).
Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in area under the plasma concentration–time curve (AUC). The least-squares (LS)-mean values for AUC were 1.15-fold (90% confidence interval [CI] 0.85–1.57) and 2.27-fold (90% CI 1.68–3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect–time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, versus healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment.
Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used for chronic HIV infections in adults and children. The aims of this study were to investigate the population pharmacokinetics of NVP in children, establish factors that influence NVP pharmacokinetics and evaluate the current dosing recommendations.
Concentrations were measured on a routine basis in 94 children from 2 months to 17 years. A total of 390 NVP plasma concentrations were retrospectively collected and a population pharmacokinetic model was developed with MONOLIX 4.0.
NVP pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. After standardization to a 70 kg adult using allometry, postmenstrual age had a significant effect on the bioavailability. Apparent clearance and volume of distribution estimates were respectively 3.9 L.h-1 70 kg-1 and 140 L 70 kg-1. Based on simulations of EMA and WHO dosing recommendations, the probability to observe minimal concentrations below the efficacy target of 3 mg/L is higher following the EMA recommendations than the WHO recommendations. However NVP under-dosing persists for the 3-6 kg and 6-10 kg weight ranges following the WHO recommendations.
It is suggested to increase doses to 75 mg BID and 100 mg BID for the 3-6 kg and 6-10 kg weight ranges respectively in order to obtain more than 95% of children with concentrations above 3 mg/L.
For approximately six years, the only commercially available direct renin inhibitor aliskiren, which inhibits the renin-angiotensin-aldosterone system at the initial rate limiting step, has been marketed for the treatment of hypertension. Concurrently, much attention has been given the possibility that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need for improved treatment and prognosis in these patients. Several short term studies have been performed in diabetic nephropathy, showing consistent effect on the surrogate endpoint lowering of albuminuria, both as monotherapy and in combination with other blockers of the renin-angiotensin-aldosterone system. In addition, combination treatment seemed safe and effective also in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but was terminated early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic kidney disease by reporting of the studies published so far as well as perspective on the future possibilites.
Cannabinoid receptor type 1 (CB1) antagonists are developed for the treatment of obesity and associated risk factors. Surinabant is a high affinity CB1 antagonist in vitro. The aim of this study was to assess the magnitude of inhibition by surinabant of CNS effects and heart rate induced by Δ9-tetrahydrocannabinol (THC) in humans.
This was a double blind, placebo-controlled, randomized, four-period six-sequence cross-over study. Thirty healthy young male occasional cannabis users (<1/week) were included. A single oral dose of surinabant (5, 20 or 60 mg) or placebo was administered followed 1.5 hours later by four intrapulmonary THC doses (2, 4, 6 and 6 mg) or vehicle, administered at 1h intervals. The wash-out period was 14-21 days. Subjective and objective pharmacodynamic (PD) measurements were performed. A population PK-PD model for THC and surinabant quantified PK and PD effects.
Surinabant 20 and 60 mg inhibited all THC-induced PD effects in a similar range for both doses with inhibition ratios ranging from 68.3% (95%CI = 32.5, 104.2; heart rate) to 91.1% (95%CI = 30.3, 151.8; body sway). IC50 ranged from 22.0 ng/ml (relative standard error = 45.2%; body sway) to 58.8 ng/ml (RSE = 44.2%; internal perception). Surinabant 5 mg demonstrated no significant effects.
The dose-related inhibition by surinabant, without any effect of its own, suggests that this compound behaves as a CB1 receptor antagonist in humans at these concentrations. A single surinabant dose between 5 to 20 mg and above was able to antagonize THC-induced effects in humans.
Acamprosate is effective pharmacotherapy for relapse prevention in alcohol dependence. Although this has been known for almost two decades and has been confirmed in several meta-analyses, evidence regarding its mechanism of action has accrued more slowly. In 1995, John Littleton proposed that acamprosate prevents relapse in alcohol dependence by decreasing sub-clinical withdrawal symptoms that may cause an individual to crave alcohol for relief - ‘negative reinforcement’ (1). Its effectiveness in reducing measurable alcohol craving has been less impressive. Here, we summarise the evidence, and consider to what extent it is consistent with acamprosate suppressing craving related to negative reinforcement.
]]>Exposure-response (ER) analysis has emerged as an important tool to interpret QT data from thorough QT (TQT) studies and allow the prediction of effects in the targeted patient population. Recently, ER analysis has also been applied to data from early clinical pharmacology studies, such as single and multiple ascending dose studies, in which high plasma levels often are achieved. In line with this, there is an on-going discussion between sponsors, academicians and regulators on whether ‘Early QT assessment’ can provide sufficiently high confidence in assessment of QT prolongation to replace the TQT study. In this article, we discuss how QT assessment can be applied to early clinical studies (‘Early QT assessment’) and what we believe is needed to achieve the same high confidence in the data as we currently obtain in data from the TQT study. The power to exclude a QTc effect exceeding 10 ms in small sample sizes using ER analysis will be discussed and compared with time-matched analysis, as described in the ICH E14 guidance. Two examples of Early QT assessment are shared; one negative and one positive, and the challenge in terms of demonstrating assay sensitivity in the absence of a pharmacological positive control will be discussed. Finally, we describe a recent research proposal, which may generate data to support the replacement of the TQT study with data from QT assessment in early phase 1 studies.
In children with acute lymphoblastic leukaemia (ALL) bone marrow activity can influence red blood cell (RBC) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT) measurements. The aim of this study was to investigate TPMT phenotype-genotype concordance in ALL, and the influence of TPMT on thiopurine metabolite formation.
We measured TPMT (activity as units/ml packed RBCs, and genotype) at diagnosis (n=1150) and TPMT and thioguanine nucleotide (TGN) and methylmercaptopurine nucleotide (MeMPN) metabolites (pmol/8x108 RBCs) during chemotherapy (n=1131) in children randomised to thioguanine or mercaptopurine on the United Kingdom trial ALL97.
Median TPMT activity at diagnosis (8.5units) was significantly lower than during chemotherapy (13.8units, median difference 5.1units, 95% confidence interval, CI, 4.8 to 5.4, P<0.0001). At diagnosis genotype-phenotype was discordant. During chemotherapy the overall concordance was 92%, but this fell to 55% in the intermediate activity cohort (45% had wild-type genotypes). For both thiopurines TGN concentrations differed by TPMT status. For mercaptopurine, median TGNs were higher in TPMT heterozygous genotype (754pmol) than wild-type (360pmol) patients; median difference 406pmol, 95% CI 332 to 478, P<0.0001, whilst median MeMPNs, products of the TPMT reaction, were higher in wild-type (10,650pmol) than heterozygous patients (3,868pmol); P<0.0001. In TPMT intermediate activity patients with a wild-type genotype, TGN (median 366pmol) and MeMPN (median 8590pmol) concentrations were similar to those in wild-type, high activity patients.
In childhood ALL, TPMT activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN accumulation during chemotherapy.
Numerous pre-clinical studies have implicated endothelin-1 in the pathogenesis of diabetic and nondiabetic chronic kidney disease (CKD). Renal endothelin-1 production is almost universally increased in kidney disease. The pathologic effects of endothelin-1, including vasoconstriction, proteinuria, inflammation, cellular injury and fibrosis, are likely mediated by the endothelin A (ETA) receptor. ETA antagonism alone, and/or combined ETA/B blockade, reduces CKD progression. Based on the strong pre-clinical data, several clinical trials using ETA antagonists were conducted. Small trials involving acute intravenous endothelin receptor blockade suggest that ETA, but not ETB, blockade exerts protective renal and vascular effects in CKD patients. A large phase 3 trial (ASCEND) examined the effects of avosentan, an endothelin receptor antagonist, on renal disease progression in diabetic nephropathy. Proteinuria was reduced after 3-6 months of treatment, however the study was terminated due to increased morbidity and mortality associated with avosentan-induced fluid retention. Several phase 2 trials using avosentan at lower doses than in ASCEND, atrasentan or sitaxsentan (the latter two being highly ETA-selective) showed reductions in proteinuria on top of renin-angiotensin system blockade; infrequent and clinically insignificant fluid retention was observed at the most effective doses. Additional trials using ETA blockers are ongoing or being planned in patients with diabetic nephropathy or focal segmental glomerulosclerosis. Moving forward, such studies must be conducted with careful patient selection and attention to dosing in order to minimize adverse side effects. Nonetheless, there is cause for optimism that this class of agents will ultimately prove to be effective for the treatment of CKD.
The purpose of this study was to establish safety and tolerability of a single intravenous (IV) infusion of a p38 MAP-kinase inhibitor, losmapimod, to obtain therapeutic levels rapidly for a potential acute coronary syndrome (ACS) indication. Pharmacokinetics (PK) following IV dosing were characterized and pharmacokinetic/pharmacodynamic (PK/PD) relationships between losmapimod and pHSP27 and hsCRP were explored.
Healthy volunteers received 1mg losmapimod IV over 15 minutes (n=4) or 3mg IV over 15 minutes followed by a washout period and then 15mg orally (PO) (n=12). PK parameters were calculated by non-compartmental methods. PK/PD relationships were explored using modelling and simulation.
There were no deaths, non-fatal SAEs, or AEs leading to withdrawal. Headache was the only AE reported more than once, n=3 following oral dosing. Following 3mg IV and 15 mg PO, Cmax was 59.4 μg/L and 45.9 μg/L and AUC0-inf was 171.1 μg·hr/L and 528.0 μg·hr/L, respectively. Absolute oral bioavailability was 0.62 (90% CI 0.56, 0.68). Following 3mg IV and 15mg PO, maximum reductions in pHSP27 were 44% (95% CI 38%, 50%) and 55% (95% CI 50%, 59%) occurring at 30 minutes and 4 hours, respectively. There was a 17% decrease (95% CI 9%, 24%) in hsCRP 24 hours following oral dosing. A direct link maximum-inhibitory effect model related plasma concentrations to pHSP27 concentrations..
A single IV infusion of losmapimod in healthy volunteers was safe and well tolerated, and may potentially serve as an initial loading dose in ACS as rapid exposure is achieved.
Modelling and simulation (M&S)-based approaches have been proposed to support paediatric drug development in order to efficiently design and analyze clinical studies. Development of anti-cancer drugs in the paediatric population is particularly challenging due to ethical and practical constraints. We aimed to review the application of M&S in the development of anti-cancer drugs in the paediatric population, and to identify where M&S-based approaches could provide additional support in paediatric drug development of anti-cancer drugs. A structured literature search on PubMed was performed. The majority of identified M&S-based studies aimed to use population PK modelling approaches to identify determinants of inter-individual variability, in order to optimize dosing regimens and to develop therapeutic drug monitoring strategies. Prospective applications of M&S approaches for PK-bridging studies have scarcely been reported for paediatric oncology. Based on recent developments of M&S in drug development there are several opportunities where M&S could support more informative bridging between children and adults, and increase efficiency of the design and analysis of paediatric clinical trials, which should ultimately lead to further optimization of drug treatment strategies in this population.
The present article reviews whether available efficacy and safety data support the pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD) in patients with concurrent substance use disorders (SUD). Arguments for and against treating adult ADHD with active SUD are discussed. Findings from 19 large open studies and controlled clinical trials show that the use of atomoxetine or extended-release methylphenidate formulations, together with psychological therapy, yield promising though inconclusive results about short-term efficacy of these drugs in the treatment of adult ADHD in patients with SUD and no other severe mental disorders. However, the efficacy of these drugs is scant or lacking for treating concurrent SUD. No serious safety issues have been associated with these drugs in patients with co-morbid SUD-ADHD, given their low risk of abuse and favourable side-effect and drug-drug interaction profile. The decision to treat adult ADHD in the context of active SUD depends on various factors, some directly related to SUD-ADHD co-morbidity (e.g., degree of diagnostic uncertainty for ADHD) and other factors related to the clinical expertise of the medical staff and availability of adequate resources (e.g., the means to monitor compliance with pharmacological treatment). Our recommendation is that clinical decisions be individualized and based on a careful analysis of the advantages and disadvantages of pharmacological treatment for ADHD on a case-by-case basis in the context of active SUD.
The UK's Clinical Practice Research Datalink (CPRD) is increasingly used to investigate suicide- related adverse drug reactions. No studies have comprehensively validated the recording of suicide and non-fatal self-harm in the CPRD. We validated GP's recording of these outcomes using linked Office for National Statistics (ONS) mortality and hospital episode statistics (HES) admission data.
We identified cases of suicide and self-harm recorded using appropriate Read codes in the CPRD between 1998 and 2010 in patients aged ≥ 15 years. Suicides were defined as patients with Read codes for suicide recorded within 95 days of their death. ICD codes were used to identify suicides/hospital admissions for self-harm in the linked ONS and HES datasets. We compared CPRD derived cases/incidence of suicide and self-harm with those identified from linked ONS mortality and HES data, national suicide incidence rates and published self-harm incidence data.
Only 26.1% (n=590) of the ‘true’ (ONS-confirmed) suicides were identified using Read codes. Furthermore, only 55.5% of Read code identified suicides were confirmed as suicide by the ONS data. 68.4% of HES-identified cases of self–harm were identified in the CPRD using Read codes. CPRD self-harm rates based on Read codes had similar age and sex distributions to rates observed in self-harm hospital registers although rates were underestimated in all age groups.
CPRD recording of suicide using Read codes is unreliable, with significant inaccuracy (over and under-reporting). Future CPRD suicide studies should use linked ONS mortality data. The under-reporting of self-harm appears to be less marked.
The safety of trial subjects is the tenet that guides the regulatory assessment of a Clinical Trial Authorisation application and applies equally to trials involving small molecules and those with biological/biotechnological products, including Advanced Therapy Medicinal Products (ATMPs). The objective of a Regulator is to ensure that the potential risk faced by a trial subject is outweighed by the potential benefit to them from taking part in the trial. The focus of the application review is to assess whether risks have been identified and appropriate steps taken to alleviate these are as much as possible. Other factors are also taken into account during a review, such as regulatory requirements, and emerging non-clinical and clinical data from other trials on the same or similar products. This paper examines the regulatory review process of a Clinical Trial Authorisation application from the perspectives of Quality, Non-Clinical and Clinical Regulatory Assessors at the MHRA. It should be noted that each perspective has highlighted specific issues from their individual competence and that these can be different between the disciplines.
Imagine a medicine that is expected to have very limited effects based upon knowledge of pharmacology and (patho)physiology, is studied in the wrong population, with low quality studies that use a surrogate endpoint that relates to the clinical endpoint in a partial manner at most. Such a medicine would surely not be recommended. Recombinant human erythropoietin (rHuEPO) use to enhance performance in cycling is very common. A qualitative systematic review of the available literature was performed to look at the evidence for these ergogenic properties of this drug normally used to treat anaemia in chronic renal failure patients.
The results of this literature search show there is no scientific basis to conclude rHuEPO has performance enhancing properties in elite cyclists. The reported studies have many shortcomings regarding translation of the results to professional cycling endurance performance. Additionally, the possibly harmful side-effects have not been adequately researched for this population but appear to be worrying at least.
rHuEPO use in cycling is rife but scientifically unsupported by evidence and its use in sports is medical malpractice. What its use would have been, if the involved team physicians had been trained in clinical pharmacology and had investigated this properly, remains a matter of speculation. A single well controlled trial in athletes under real life circumstances would give a better indication of the real advantages and risk factors of rHuEPO use, but it would be an oversimplification that this would eradicate its use.
This study assessed the effect of differences in renal function on the pharmacokinetics and pharmacodynamics of dapagliflozin, an SGLT2 inhibitor for treatment of type 2 diabetes mellitus (T2DM).
A single 50-mg dose of dapagliflozin was used to assess pharmacokinetics and pharmacodynamics in five groups: healthy nondiabetic subjects; patients with T2DM and normal kidney function; and patients with T2DM and mild, moderate or severe renal impairment based on estimated creatinine clearance. Subsequently, 20-mg once-daily multiple doses were evaluated in the patients with T2DM. Formation rates of dapagliflozin 3-O-glucuronide (D3OG), an inactive metabolite, were evaluated using isolated human kidney and liver microsomes.
Plasma concentrations of dapagliflozin and D3OG were incrementally increased with declining kidney function. Steady-state Cmax for dapagliflozin were 4%, 6% and 9% higher and for D3OG were 20%, 37% and 52% higher in patients with mild, moderate, and severe renal impairment, respectively, compared to normal function. AUC0-τ was likewise higher. D3OG formation in kidney microsomes was 3-fold higher than liver and 109-fold higher than intestine. Compared to patients with normal renal function, pharmacodynamic effects were attenuated with renal impairment. Steady-state renal glucose clearance was reduced by 42%, 83%, and 84% in patients with mild, moderate, or severe renal impairment, respectively.
These results indicate that both kidney and liver significantly contribute to dapagliflozin metabolism, resulting in higher systemic exposure with declining kidney function. Dapagliflozin pharmacodynamics in diabetic subjects with moderate to severe renal impairment are consistent with the observation of reduced efficacy in this patient population.
Dabigatran etexilate (DE), an oral direct thrombin inhibitor, is a substrate for P-glycoprotein (P-gp) and its reflux can be modulated by other drugs that either induce or inhibit P-gp.
The aim of this study was to develop a PK/PD model to assess drug-drug interactions between dabigatran and P-gp modulators, using the example of clarithromycin, a strong inhibitor of P-gp.
Ten healthy male volunteers were randomised to receive in the first treatment period a single 300 mg dose of DE and in the second treatment period 500 mg of clarithromycin twice daily during 3 days and then 300 mg of DE plus 500 mg of clarithromycin on the fourth day, or the same treatments in the reverse sequence. Dabigatran plasma concentration and ecarin clotting time (ECT) were measured on 11 blood samples. Models were built using a non-linear mixed effect modelling approach.
The best PK model was based on an inverse Gaussian absorption process with two compartments. The relationship between dabigatran concentration and ECT was implemented as a linear function. No continuous covariate was associated with a significant decrease in the objective function. The concomitant administration of clarithromycin induced a significant change only in DE bioavailability, which increased from 6.5% to 10.1% in the presence of clarithromycin. Clarithromycin increased peak concentration and AUC of 60.2% and 49.1% respectively.
The model proposed effectively describes the complex PK of dabigatran and takes into account drug-drug interactions with P-gp activity modulators, such as clarithromycin.
Vancomycin is widely used to treat late-onset coagulase-negative Staphylococcus (CoNS) sepsis in very-low-birth-weight (VLBW) infants. Although vancomycin is associated with a risk of toxicity and bacterial resistance, the appropriate duration of use has not been established. This study sought to investigate the association between the duration of vancomycin therapy and clinical outcome in VLBW infants with CoNS sepsis.
The files of all VLBW infants treated for CoNS sepsis at a tertiary pediatric medical center in 1995-2003 were reviewed for clinical data, laboratory variables, and outcome. Only patients with 2 positive diagnostic blood cultures were included. The findings were analyzed by duration of vancomycin treatment after the last positive blood culture.
The study cohort included 126 infants: 48 treated for 5 days, 32 for 6-7 days, 31 for 8-10 days, and 15 for >10 days. There were no differences among the groups in perinatal characteristics, central catheter dwell time, laboratory data including hematologic, renal, and liver function tests, or rate of complications of prematurity. Five infants were diagnosed with infective endocarditis or aortic thrombus and were treated for >10 days. CoNS sepsis recurred in 2 infants (1.6%). No toxicity of vancomycin treatment was observed.
The catechol-O-methyltransferase (COMT) Val158Met polymorphism affected healthy volunteers’ pain sensitivity upon experimental pain stimuli. The relevance of these findings in morphine-treated postoperative cardiac patients undergoing painful healthcare procedures is unknown. Therefore, the aim of this study was to investigate whether the COMT Val158Met polymorphism increases pain sensitivity in morphine-treated patients undergoing an unavoidable painful routine procedure after cardiac surgery.
117 postoperative cardiac patients in the intensive care (ICU) were genotyped for the COMT Val158Met polymorphism. All patients were treated with continuous morphine infusions for pain at rest, and received a bolus of morphine (2.5 or 7.5 mg) before a painful procedure (turning and/or chest drain removal) on the first postoperative day. Numeric rating scale (NRS) scores were evaluated at four time points; at baseline (at rest), and before, during, and after the painful procedure.
Overall mean NRS scores were significantly higher in patients carrying the Met-variant allele. During the painful procedure, the mean NRS score was significantly higher for Met/Met patients compared to Val/Met and Val/Val patients (mean NRS 3.4 ± 2.8, 2.7 ± 2.4 and 1.7 ± 1.7, respectively; p=0.04). In Met/Met patients, the increase in NRS scores during the painful procedure compared with baseline NRS score was clinically relevant (ΔNRS≥1.3) and statistically significant and appeared independent of sex and the morphine bolus dose.
Activation of angiotensin II receptor type 1 (AT1) has been shown to mediate the structural and electrical remodelling of the atrial myocardium associated with atrial fibrillation.
We hypothesized that AT1 genotypic variation is associated with atrial fibrillation or diseases predisposing to atrial fibrillation such as hypertension, heart failure, ischemic heart disease, and myocardial infarction in the general population.
We re-sequenced the AT1 gene in 760 individuals with atrial fibrillation and identified 2 non-synonymous variants (I103T and A244S) which were subsequently genotyped in the prospective Copenhagen City Heart Study (n=10,603) and the prospective Copenhagen General Population Study (n=60,647).
Risk of atrial fibrillation for heterozygotes for AT1 genetic variants A244S and I103T/A244S versus non-carriers was increased by 2.7 (1.5-5.1) and 2.6 fold (95% CI: 1.6-4.2) for men.
Heterozygosity for the non-synonymous AT1 genetic variants A244S and I103T/A244S associated with increased risk of atrial fibrillation in men. The AT1 might be a target for the pharmaceutical industry. This finding needs to be validated in independent studies.
For people seeking treatment, the course of heroin addiction tends to be chronic and relapsing, and longer duration of treatment is associated with better outcomes. Heroin addiction is strongly associated with deviant behaviour and crime, and the objectives in treating heroin addiction have been a blend of humane support, rehabilitation, public health intervention, and crime control. Reduction in street heroin use is the foundation on which all these outcomes are based. The pharmacological basis of maintenance treatment of dependent individuals is minimizing withdrawal symptoms, and attenuating the reinforcing effects of street heroin, leading to reduction or cessation of street heroin use. Opioid maintenance treatment can be moderately effective in suppressing heroin use, although deviations from evidence-based approaches, particularly the use of suboptimal doses, have meant that treatment as delivered in practice may have resulted in poorer outcomes than predicted by research. Methadone treatment has been “programmatic”, with a one-size-fits-all approach which in part reflects the perceived need to impose discipline on deviant individuals. However, differences in pharmacokinetics and in side-effects mean that many patients do not respond optimally to methadone. Injectable diamorphine (heroin) provides a more reinforcing medication for some “non-responders”, and can be a valuable option in the rehabilitation of demoralised, socially-excluded individuals. Buprenorphine, a partial agonist, is a less reinforcing medication with different side-effects and less risk of overdose. It represents not only a different medication, but can also be used in a different paradigm of treatment, office-based opioid treatment, with less structure and offering greater patient autonomy.
This review examines the effectiveness of detection methods in terms of their ability to identify and accurately determine medication-related problems in hospitals.
A search was conducted of databases from inception to June 2012. The following keywords were used in combination: medication error or adverse drug event or adverse drug reaction, comparison, detection, hospital and method. Seven detection methods were considered: chart review; claims data review; computer monitoring; direct care observation; interviews; prospective data collection; and incident reporting.
Forty relevant studies were located. Detection methods that were better able to identify medication-related problems compared with other methods tested in the same study included chart review, computer monitoring, direct care observation and prospective data collection. However, only small numbers of studies were involved in comparisons with direct care observation (n=5) and prospective data collection (n=6). There was little focus on detecting medication-related problems during various stages of the medication process, and comparisons associated with the seriousness of medication-related problems were examined in 19 studies. Only 17 studies involved appropriate comparisons with a gold standard, which provided details about sensitivities and specificities.
In view of the relatively low identification of medication-related problems with incident reporting, use of this method in tracking trends over time should be met with some scepticism. Greater attention should be placed on combining methods, such as chart review and computer monitoring in examining trends. More research is needed on the use of claims data, direct care observation, interviews and prospective data collection as detection methods.
Fostamatinib (R788) is an orally-dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of fostamatinib and R406.
Three clinical studies were conducted in healthy subjects: (A) A single ascending-dose study for R406 with doses ranging from 80–600 mg, (B) A single and multiple-dose study of fostamatinib in aqueous suspension, with single doses ranging from 80–400 mg and multiple doses at 160 mg bid, and (C) A study comparing suspension and tablet of fostamatinib, with the latter tested in both fed and fasted states.
These studies demonstrated that when administered as a solution, R406 was rapidly absorbed. Increases in exposure were observed with doses up to 400 mg. A terminal half-life of 12–21 h was observed. Similar R406 exposure could be achieved with fostamatinib suspension, and steady-state was achieved after 3–4 days following twice-daily administration. Fostamatinib tablet and suspension exhibited similar R406 exposure. Upon coadministration with food, a delay in peak time and lower peak concentrations of R406 were observed, at the same time the overall exposure did not change.
Fostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK. Solid dosage forms of fostamatinib overcome the challenge of low aqueous solubility of R406. The PK profile of R406 could potentially allow once-daily or twice-daily oral administration of fostamatinib.
Despite considerable effort, application of monoclonal antibody technology has had only modest success in improving treatment-outcomes in patients with solid tumors. Enhancing the cancer cell-killing activity of antibodies through conjugation to highly potent cytotoxic “payloads” to create ADCs offers a strategy for developing anti-cancer drugs of great promise. Early ADCs exhibited side-effect profiles similar to those of “classical” chemotherapeutic agents, and their performance in clinical trials in cancer patients was generally poor. However, the recent clinical development of ADCs that have highly potent tubulin-acting agents as their payloads have profoundly changed the outlook for ADC technology. Twenty-five such ADCs are in clinical development, and one, brentuximab vedotin, was approved by FDA in August, 2011, for the treatment of Hodgkin lymphoma patients, and patients with anaplastic large cell lymphoma, based on a high rate of durable responses in single arm phase II clinical trials. More recently, a second ADC, trastuzumab emtansine, has shown excellent anti-tumor activity with the presentation of results of a 991-patient randomized phase III trial in patients with HER2-positive metastatic breast cancer. Treatment with this ADC (single agent) resulted in a significantly improved progression-free survival of 9.6 months compared with 6.4 months for lapatinib plus capecitabine in the comparator arm and significantly prolonged overall survival. Besides demonstrating excellent efficacy, these ADCs were remarkably well tolerated. Thus these, and other ADCs in development, promise to achieve the long-sought goal of ADC technology, that is, of having compounds with high anti-tumor activity at doses where adverse effects are generally mild.
Prasugrel is a novel thienopyridine P2Y12 adenosine diphosphate (ADP) receptor antagonist that inhibits ADP-mediated platelet activation and aggregation. Accordingly, it may be useful in reducing platelet-related isc haemia in sickle cell disease (SCD). Exposure to prasugrel's active metabolite (Pras-AM) and its antiplatelet activity in SCD have not been investigated.
Thirteen adult patients with SCD and an equal number of matched healthy control subjects were studied before and after 12 days of 5.0 mg/day or 7.5 mg/day prasugrel treatment. Platelet reactivity was assessed by light transmission aggregometry (LTA), impedance aggregometry (MEA), VerifyNow® P2Y12, vasodilator-stimulated phosphoprotein (VASP) phosphorylation and Plateletworks. Exposure to Pras-AM was also assessed.
At baseline, patients with SCD showed increased platelet reactivity versus healthy controls with VerifyNow (408 vs. 323 PRU, respectively, P=0.003) and MEA (106 vs. 77 AU.min, P=0.002); lower platelet reactivity index with VASP flow cytometry (59% vs. 79% PRI, P=0.018); and no significant differences with LTA, VASP ELISA, or Plateletworks. Relative to baseline, prasugrel significantly reduced platelet reactivity by all assays in both populations (all p<0.05). Prasugrel was well tolerated, with no bleeding-related events in patients with SCD. The mean concentration-time profiles of Pras-AM were comparable between healthy subjects and patients with SCD following the one-time 10 mg prasugrel dose, and following the 12th dose of 7.5 mg or 5 mg prasugrel.
Results demonstrate that in response to prasugrel, patients with SCD and healthy subjects have similar degrees of platelet inhibition and exposure to Pras-AM, and provide a basis for further study of prasugrel in patients with SCD.
To characterize the romiplostim dose response in subjects with low- or intermediate-1 risk myelodysplastic syndromes (MDS) receiving subcutaneous romiplostim.
Data from 44 MDS subjects receiving subcutaneous romiplostim (dose range: 300-1500 μg/week) were used to develop a pharmacodynamic model consisting of a romiplostim-sensitive progenitor cell compartment linked to the peripheral blood compartment through four transit compartments representing the maturation in the bone marrow from megakaryocytes to platelets. A kinetics of drug effect model was used to quantify the stimulatory effect of romiplostim on the proliferation of sensitive progenitor cells and pharmacodynamics-mediated disposition was modeled by assuming the kinetics of drug effect constant (kDE) to be proportional to the change in platelet count relative to baseline.
The estimated values (between-subject variability) for baseline platelet count, mean transit time, and kDE were 24x109/L (47%), 9.6 days (44%), and 0.28 days-1, respectively. MDS subjects had a shorter platelet lifespan (42h) than healthy subjects (257h). Romiplostim response was described for responders (78%) and non-responders (22%). The average weekly stimulatory effect of romiplostim on the sensitive progenitor cells at baseline was 269% per 100 μg/week for responders. Body weight, age, sex, and race were not statistically related to romiplostim pharmacodynamic parameters. Visual predictive checks confirmed the model adequacy.
The time course of platelet counts in MDS subjects receiving subcutaneous administration of a titrated dose of romiplostim was characterized and evidenced a linear dose response for romiplostim to increase the platelet counts.
There has been in increasing focus on drug induced QT prolongation including research on drug development and QT prolongation, following the removal of drugs due to Torsades de Pointes (TdP). Although this has improved our understanding of drug-induced QT prolongation there has been much less research aimed at helping clinicians assess risk in individual patients with drug induced QT prolongation. This review will focus on assessment of drug-induced QT prolongation in clinical practice using a simple risk assessment approach. Accurate measurement of the QT interval is best done manually, and not using the measurement of standard ECG machines. Correction for heart rate (HR) using correction formulae such as Bazett's is often inaccurate. These formulae underestimate and overestimate the duration of cardiac repolarisation at low and high heart rates, respectively. Numerous cut-offs have been suggested as an indicator of an abnormal QT, but are problematic in clinical practice. An alternative approach is the QT nomogram which is a plot of QT versus HR. The nomogram has an “at risk” line and QT-HR pairs above this line have been shown in a systematic study to be associated with TdP and the line is more sensitive and specific than Bazett's QTc of 440msec or 500msec. Plotting the QT-HR pair for patients on drugs suspected or known to cause QT prolongation allows assessment of the QT interval based on normal population QT variability. This risk assessment then allows the safer commencement of drugs therapeutically or management of drug induced effects in overdose.
It was our pleasure to read an excellent review by Lidder and Webb about the nitrate-nitrite-nitric oxide pathway [1]. These authors summarized the whole spectrum of nitrite and nitrate effects and provided a review of clinical trials using dietary nitrate interventions as well as suggesting nitrite/nitrate dose standardization.
We would like to comment on the nitrite effect on platelet function. In this part, the older reports cited by Lidder and Webb show that nitrite addition to platelet preparations had no effect on platelet function. We recently reported [2] that this is correct when only platelet rich plasma or similar pure platelet preparations are used. However, we showed that addition of red blood cells to such preparations combined with hypoxia had significant effect on platelet functioning – inhibition of platelet aggregation was observed upon nitrite addition. These data are in agreement with the hypothesis that added nitrite is reduced to nitric oxide by hypoxic red blood cells and with our recent observation of altered platelet aggregation by dietary nitrate manipulation – mice fed low nitrate diet had better platelet aggregation than mice on standard diet (Park JW, unpublished data). This could be important start for future investigations in clinical settings when enhanced platelet aggregation is either required or to be avoided.
The cytochrome P450 (CYP) 3A4*22 allelic status influences the pharmacokinetics of tacrolimus independently of an individual's CYP3A5 genotype. In their recent publication, Passey et al described an algorithm that predicts tacrolimus apparent clearance (CL/F) by taking into account the age and CYP3A5 genotype of a patient, time after kidney transplantation, whether the transplantation was performed at a steroid-sparing center or not and whether the patient was treated with a calcium channel blocker (CCB). However, as the effect of the CYP3A4*22 allele was only recently reported, these authors did not consider this variable as a potential predictive factor for tacrolimus CL/F.
]]>All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, AJW is due to receive shares in ‘Beet It’, though as yet no share certificate has been received and no other relationships or activities that could appear to have influenced the submitted work.
]]>While asthma is a chronic inflammatory disorder that is managed with inhaled controller and reliever drugs, there remains a large unmet need at the severe end of the disease spectrum. Here a novel stratified approach to its treatment is reviewed based upon identification of causal pathways with a focus on biologics.
A systematic search of the literature was made using Medline and publications selected on the basis of their relevance to the topic.
Despite strong preclinical data for many of the more recently identified asthma targets especially those relating to the Th2 allergic pathway, clinical trials with specific biologics in moderate to severe asthma as a group has been disappointing. However, subgroup analyses based upon pathway-specific biomarkers suggest specific endotypes that are responsive. Application of hypothesis-free analytical approaches (the ‘omics) to well defined phenotypes is leading to the stratification of asthma along causal pathways. Refinement of this approach is likely to be the future for diagnosing and treating this group of diseases as well as helping define new causal pathways.
The identification of responders and non-responders to targeted asthma treatments provides a new way of looking at asthma diagnosis and management especially with biologics that are costly. The identification of novel biomarkers linked to well phenotyped patients provides a stratified approach to disease management beyond simple disease severity and involving causal pathways. In order to best achieve this, a closer interaction will be required between industry (therapeutic and diagnostic), academia and health workers.
The paediatric aspects of Travel Medicine can be complex, and individual advice is often required. Nonetheless, children are much more likely to acquire common infections than exotic tropical diseases whilst travelling. Important exceptions are malaria and tuberculosis, which are more frequent and severe in children. Overall, travellers’ diarrhoea is the most common illness affecting travelers.
This review will discuss vaccines and medications that may be indicated for children who are travelling overseas. It will focus on immunisations that are given as part of the routine schedule as well as those that are more specific to travel. Malaria and travellers’ diarrhoea will also be discussed.
To review current evidence on the effect of paracetamol on blood pressure, the quality of the previous studies and the validity of the results, and to summarise these findings.
A systematic literature review was performed by searching PubMed, the Cochrane library and EMBASE for publications between the years 1963 and 2012.
We identified three case reports, seven prospective observational trials, six randomised controlled trials, one commentary and two reviews. Some, but not all, of the observational studies, which included over 147,000 patients, showed an increased risk of hypertension with paracetamol use. The randomised studies were generally small and the results were inconsistent; three studies, which included 104 patients, showed an increase of systolic BP by ∼4mmHg, two studies, which included 27 patients, reported no change in BP, and one study, which included 21 patients, reported a fall in BP although no placebo arm was included for comparison.
The overall effect of paracetamol on BP is unclear. Given that paracetamol is often suggested as a safer alternative to non-steroidal anti-inflammatory drugs (NSAIDs), it would seem that further prospective evidence is now needed to address the effect of paracetamol on BP. This would be best done with larger studies in relevant cohorts using BP measured by ABPM as the primary endpoint.
To update and summarise the scientific knowledge on the long-term outcomes of the different pharmacological treatment options for opioid dependence currently available and to provide a critical discussion on the different treatment options based on these results.
We performed a literature search using the PubMed databases and the reference lists of the identified articles.
Data from research show that the three pharmacological options reviewed are effective treatments for opioid dependence with positive long-term outcomes. However, each one has its specific target population and setting. While methadone and buprenorphine are first-line options, heroin-assisted treatment is a second-line option for those patients refractory to treatment with methadone with concomitant severe physical, mental, social and/or functional problems. Buprenorphine seems to be the best option for use in primary care offices.
The field of opioid dependence treatment is poised to undergo a process of reinforcement and transformation. Further efforts from researchers, clinicians, and authorities should be made to turn new pharmacological options into clinical reality and to overcome the structural and functional obstacles that maintenance programmes face in combatting opioid dependence.
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, impaired diastolic and systolic function. Abnormal sympathetic-parasympathetic balance is a potential stimulus for left ventricular hypertrophy in HCM patients. Beta-blockers are routinely used in HCM for their strong negative inotropic effect, however these drugs also influence the sympathetic-parasympathetic balance. This study aimed to determine the autonomic control of the cardiovascular system and the autonomic effects of beta-blockers in HCM patients treated or untreated with beta-blockers.
Among 51 HCM outpatient patients (18-70 years old; 29 men) there were 19 individuals with no medication and 32 subjects treated with beta-blocker. Additionally, 14 age- and gender-matched (23-70 years old; 9 men) healthy volunteers were enrolled in the control group. Continuous, noninvasive finger blood pressure was recorded in supine rest for 30 minutes. Autonomic regulation of the cardiovascular system was measured by heart rate variability (HRV) and spontaneous baroreflex function (cross-correlation sequence method).
The mean pulse interval, time domain and spectral measures of HRV and baroreflex sensitivity were comparable between HCM patients treated or not with beta-blockers, and the control group. However, the delay of baroreflex was significantly longer in HCM patients untreated with beta-blockers (2.0 (1.6-2.3) s) in comparison with HCM patients on beta-blockers (1.4 (1.1-1.8) s; p=0.0072) or control subjects (1.2 (0.8-1.8) s; p=0.0025). This delay did not differ between HCM patients treated with beta-blockers and the control group.
HCM not treated with beta-blockers is accompanied by prolonged baroreflex delay. The use of beta-blockers normalizes this delay.
This study examined the effects of grapefruit juice on the new P2Y12 inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein.
In a randomized crossover study, ten healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for four days. On day three, they ingested a single 90-mg dose of ticagrelor.
Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (Cmax) to 165% (95% confidence interval, 147-184%) and area under the concentration–time curve (AUC0-∞) to 221% of control (95% confidence interval, 200-245%). The Cmax and AUC0-34h (P < 0.05) but not the AUC0-∞ of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity.
Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice-ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.
Invasive fungal infections, although relatively rare, are life-threatening diseases in premature infants and immunocompromised children. While many advances have been made in antifungal therapeutics in the last two decades, knowledge of the pharmacokinetics and pharmacodynamics of antifungal agents in infants and children remains incomplete. This review summarises the pharmacology and clinical utility of currently available antifungal agents, and discusses the opportunities and challenges for future research.
To characterise the pharmacokinetics of abacavir in infants, toddlers and children, and assess the influence of covariates on drug disposition across these populations.
Abacavir concentration data from three clinical studies in HIV-infected children (n=69) were used for model building. The children received either a weight-normalised dose of 16 mg/kg/day or the WHO recommended dose based on weight-bands. A population pharmacokinetic analysis was performed using NONMEM VI. The influence of age, gender, body weight and formulation was evaluated. The final model was selected according to graphical and statistical criteria.
A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Body weight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state Cmax and AUC0-12 of standard b.i.d. regimen were 2.5 mg/L and 6.1 mg●h/L for toddlers and infants, and 3.6 mg/L and 8.7 mg●h/L for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and as such can be used to support therapeutic drug monitoring in conjunction with sparse sampling.
The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny.
Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management - benzodiazepine tapering - is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABAA –benzodiazepine receptor antagonist/partial agonist flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for four days significantly reduced acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.
Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism.
We sequenced AKR1C3 exon 5 and genotyped 7 functional SNPs in CBR3, ABCB1, and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin-containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics.
Two previously reported AKR1C3 intronic variants, IVS4-212 C>G and IVS4+218 G>A were detected. AKR1C3 IVS4-212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocyte 2.49±1.57x109/L vs 3.85±3.42x109/L, p=0.007) and neutrophil count (mean neutrophil 0.70±1.01x109/L vs 1.56±2.80x109/L, p=0.008), and significant improvement of progression-free survival (mean PFS 49.0 [95% CI 42.2-55.8] vs 31.0 [95% CI 20.7-41.2] months, p=0.017) and overall survival (mean OS 64.4 [95% CI 58.3-70.5] vs 46.3 [95% CI 35.1-57.5] months, p=0.006) compared to those carrying at least one C allele. There was no significant association between AKR1C3 IVS4-212 C>G and doxorubicin pharmacokinetics. For the other 7 SNPs genotyped, CBR3 G11A correlated with doxorubicinol AUC and OS, ABCB1 G2677T/A with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59T>G correlated with OS. AKR1C3 IVS4-212C>G remained significantly correlated with both PFS and OS on multivariate analysis with clinical prognosticators.
AKR1C3 IVS4-212 GG genotype was associated with greater hematologic toxicity, longer progression-free and overall survival after doxorubicin-based therapy, suggesting potential interaction of this variant with doxorubicin metabolism.
To investigate the CYP3A4 inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of fluticasone furoate (FF) and vilanterol trifenatate (VI).
Two double-blind, randomised, placebo-controlled, two-way crossover studies in healthy subjects. In study 1 subjects received single doses of ketoconazole (400mg) or placebo on Days 1 to 6 with a single dose of inhaled VI (25mcg) on Day 5. PD and PK data were obtained up to 48h following the VI dose. In study 2 subjects received once daily ketoconazole (400mg) or placebo for 11 days with FF/VI (200/25mcg) for the final 7 days. PD and PK data were obtained up to 48h following the Day 11 dose.
In study 1 there was no effect of co-administration of ketoconazole and VI on PD or PK parameters. In study 2, co-administration of ketoconazole and FF/VI had no effect on 0-4h maximum heart rate or minimum blood potassium (treatment difference (90%CI) -0.6bpm (-5.8, 4.5) and 0.04mmol/L (-0.03, 0.11), respectively) whilst there was a 27% decrease in 24h weighted mean serum cortisol (treatment ratio (90%CI) 0.73 (0.62, 0.86)). Co-administration of ketoconazole increased (percent change (90%CI)) FF AUC (0-24) and Cmax by 36% (16, 59) and 33% (12, 58) and VI AUC(0-t’) and Cmax by 65% (38, 97) and 22% (8, 38), respectively.
Co-administration of FF/VI or VI with ketoconazole resulted in a less than two-fold increase in systemic exposure to FF and VI. There was no increase in beta-agonist systemic pharmacodynamic effects while serum cortisol was decreased by 27%. Co-administration of FF/VI with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol which could lead to an increase in the potential for adverse reactions.
To report the first three studies with SCH 900435, a selective glycine-1 reuptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects.
Three double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the single and multiple dose study SCH 900435 (0.5-30mg) was given to healthy males and frequent pharmacokinetic and pharmacodynamic measurements were performed. The visual effects study incorporated visual electrophysiological measures of macular, retinal and intracranial visual pathway function.
In the single dose study (highest difference,95%CI,P) increases in smooth pursuit eye movements (8, 12 (-6.09,-10.14 - -2.04,0.013), 30mg), pupil/iris ratio (20 and 30mg (-0.065,-0.09 - -0.04,<0.0001)), VAS colour perception (30mg (-9.48,-13.05 - -5.91,<0.0001)) and changes in spontaneous reports of visual disturbance were found, while FSH (8 (0.42,0.18 – 0.66,0.0015), 12, 20mg), LH (8-30mg (1.35,0.65 – 2.05,0.0003)) and EEG alpha2 activity decreased (12, 20, 30mg (0.27,0.14 – 0.41,0.0002)). A subsequent dedicated visual effects study demonstrated that visual effects were transient without underlying electrophysiological changes. This provided enough safety information for starting a multiple ascending dose study, showing less visual symptoms after twice daily dosing and titration, possibly due to tolerance.
Several CNS effects and gonadotropic changes resulted from administration of 8mg and higher, providing evidence for CNS penetration and pharmacological activity of SCH 900435. Antipsychotic activity in patients, specificity of the reported effects for this drug class and possible tolerance to visual symptoms remain to be established.
The large inter-individual variability in clopidogrel response is attributed to pharmacokinetics. Although, being used since late 1990's the pharmacokinetic fate of clopidogrel and its metabolites are poorly explained. The variable response by clopidogrel is believed to be multi-factorial, caused both by genetic and non-genetic factors. In this study, we examined whether inactive-metabolite can alter the plasma protein binding of the active-metabolite; thus explaining the large inter-individual variability associated with clopidogrel response.
Female subjects (n=28) with stable coronary disease who are not taking clopidogrel were recruited. Serial blood samples were collected following 300mg oral dose of clopidogrel, plasma was isolated and quantified for total and free concentrations of active- and inactive-metabolites. Inhibition of platelet aggregation was measured using phosphorylated vasodilator stimulated phosphoprotein (VASP) assay.
Significant correlation was observed between VASP and both free (r=0.49; p<0.05) and total (r=0.49; p<0.05) concentrations of active-metabolite. Surprisingly, we observed a significant correlation to both free (r=0.42; p<0.05) and total (r=0.67; p<0.001) concentrations of inactive-metabolite as well. Free fractions of active-metabolite elevated with increasing protein binding of inactive-metabolite (p<0.05).
The above in vivo data suggest that inactive-metabolite displaces active-metabolite from binding sites. Thus, the inactive-metabolite might increase the free concentration of the active-metabolite leading to enhanced inhibition of platelet aggregation. The plasma protein binding mechanism would offer additional therapeutic strategies to optimize clopidogrel pharmacotherapy.
To compare plasma 4β-hydroxycholesterol/cholesterol to urinary 6β-hydroxycortisol/cortisol as markers of CYP3A4 activity before and after treatment with rifampicin for two weeks.
6β-Hydroxycortisol and cortisol were determined by LC-MS/MS and 4β-hydroxycholesterol was determined by GC-MS in 3 groups of healthy volunteers.
Induction ratios for 6β-hydroxycortisol/cortisol were 1.8, 3.9 and 4.5 for 20 mg/day, 100 mg/day or 500 mg/day of rifampicin, respectively. The corresponding ratios for 4β-hydroxycholesterol /cholesterol were 1.5, 2.4 and 3.8.
Plasma 4β-hydroxycholesterol/cholesterol gave similar induction ratios as urinary 6β-hydroxycortisol/cortisol.
The complex relationships between cardiovascular, renal, and bone disease are increasingly recognised but not yet clearly understood. Vascular calcification (VC) represents a common endpoint between these interlinked systems. It is highly prevalent in chronic kidney disease (CKD) and is responsible for much of the excess cardiovascular death seen in this condition. There is much interest in developing therapeutic agents to stop its development or reverse its progression. Traditionally considered to be due abnormalities in calcium and phosphate metabolism alone, VC is now known to be the product of active, dynamic processes within the vessel wall. Primary prevention of VC is possible through successful prevention or reversal of progressive renal dysfunction, hypertension and hyperlipidaemia, but is challenging given the increasing global prevalence of these risk factors. Secondary prevention of VC through tight control of calcium and phosphate, can be achieved by dietary or pharmacological means. Both the modification of haemodialysis duration or methods, and the use of renal transplantation have an effect. Novel drugs such cinacalcet were hoped to halt calcification but results have been mixed, and no intervention has yet been shown to reliably reverse calcification. A new range of experimental targets involved in the putative mediatory pathways between bone and vascular disease has emerged. Aiming to manipulate the active mechanisms involved in calcium deposition, these hold hope for reversal of calcification, but are still theoretical or in early animal or human experimentation.
Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid-addicted patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in intramuscular or implantable polymers that release naltrexone for 1-7 months have become available for clinical use and - research.
This qualitative review of the literature provides an overview of the technologies currently available for sustained release naltrexone (SRX) and their effectiveness in reducing opioid use and other relevant outcomes.
The majority of studies indicate that SRX is effective in reducing heroin use, and the most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on mortality and morbidity. In some studies, SRX also seems to affect other outcomes like concomitant substance use, vocational training attendance, needle use, and risk behaviour for blood-borne diseases like Hepatitis or HIV. There is a general need for more controlled studies, in particular comparing SRX with agonist maintenance treatment, combinations of SRX with behavioural interventions, and with at-risk groups like prison inmates or opioid addicted pregnant patients.
The literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid addiction.
With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called ‘gene doping’. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place.
With the European economy in the midst of the deepest recession since the 1930s and countries struggling to weigh up national and community interests, one may overlook accomplishments made in other areas of the European co-operation. Since the start of the European Union (EU) medicines approval system in 1995, the European regulatory environment has faced many challenges, but also made ample progress. Significant achievements are seen in unifying and improving regulatory practices, streamlining the way of bringing medicinal products to the clinic, thereby improving that new medicines become available to patients in the EU in an harmonized and evidence-based way.[1, 2] With the European Medicines Agency (EMA) coordinating a wide array of regulatory procedures, EU member states are contributing in many ways to the regulatory network, e.g. as rapporteur of individual dossiers, by work-sharing, guideline development, and cross learning. Recently, both the EMA and the Heads of Medicines Agencies (HMA) published their future strategy papers (i.e. European Medicines Agency Road Map to 2015: The Agency's contribution to Science, Medicines, Health and the HMA; A Strategy for the Heads of Medicines Agencies 2011-2015), aiming at strengthening the European regulatory network and its contribution to patients’ access to medicinal products, public health and innovation.[3, 4]
T cells are a multifaceted family pivotal in the operations of the immune system and many of its associated diseases. The pathway to understanding T cells has been marked by several pharmacological advances including the discoveries of Cyclosporin, Tacrolimus and the mTOR inhibitors which revolutionised transplant therapy along with providing relief for severe eczema, asthma and other immunological disorders towards the end of the last century. This article will revisit the current understanding and new developments in T cell pharmacology 10 years on from the TeGenero (TGN142) debacle and look at more recent successes with ex vivo antigen presenting cell incubation technologies; T cell receptor (TCR) engineering and adoptive T cell therapy both with chimaeric antibodies and also with modified T cell receptors themselves. Features of T cell biology will be explored and processes often highly unique to humans will be used to highlight what many are beginning to see as a an exciting new monoclonal (T cell) frontier for drug development.
Substance use disorders represent a serious public health and social issue worldwide. Recent advances in our understanding of the neurobiological basis of the addictive processes have led to the development of a growing number of pharmacological agents to treat addictions. Despite this progress, there are no approved pharmacological treatments for cocaine, methamphetamine, and cannabis addiction. Moving treatment development to the next stage will require novel ways of approaching substance use disorders. One such novel approach is targeting individual vulnerabilities, such as cognitive function, sex differences, and psychiatric comorbidities. This review provides a summary of promising pharmacotherapies for alcohol, opiate, stimulant and nicotine addictions. Many medications that target positive and negative reinforcement of drugs, as well individual vulnerabilities to addiction are in different phases of development. Clinical trials testing the efficacy of these medications for substance use disorder are warranted.
Mipomersen is a second generation antisense oligonucleotide that targets apolipoprotein B. It has been studied thoroughly in clinical trials (more than 800 subjects), including four randomized double blind placebo controlled phase 3 studies involving 391 patients, and is in registration for the treatment of severe hypercholesterolemia. The pharmacokinetic and pharmacodynamic properties of mipomersen are well characterized. Mipomersen is rapidly and extensively absorbed after subcutaneous administration and has an elimination half-life of approximately 30 days across species. It is cleared by nuclease metabolism and renal excretion of the metabolites. Mipomersen reduces all apolipoprotein B containing atherogenic particles and displays dose dependent reductions between 50-400 mg/week, both as a single agent and in the presence of maximal lipid lowering therapy. No drug-drug interactions have been identified. Mipomersen is a representative of second generation antisense drugs all of which have similar properties and is thus representative of the behavior of the class of drugs.
Pathological gambling (PG) is a relatively common and often disabling psychiatric condition characterized by intrusive urges to engage in deleterious gambling behavior. Although common and financially devastating to individuals and families, there currently exist no formally approved pharmacotherapeutic interventions for this disorder. This review seeks to examine the history of medication treatments for PG.
A systematic review of the 18 double-blind, placebo-controlled pharmacotherapy studies conducted for the treatment of pathological gambling was conducted. Study outcome and the mean dose of medication administered was documented in an effort to determine a preferred medication choice in this population.
A variety of medication classes have been examined in the treatment of PG with varying results. Antidepressants, atypical antipsychotics, and mood stabilizers have demonstrated mixed results in controlled clinical trials. Although limited information is available, opioid antagonists and glutamatergic agents have demonstrated efficacious outcomes, especially for individuals with PG suffering from intense urges to engage in the behavior.
Given that several studies have demonstrated their efficacy in treating the symptoms associated with PG, opioid antagonists should be considered the first-line treatment for PG at this time. Most published studies, however, have employed relatively small sample sizes, are of limited duration, and involve possibly non-representative clinical groups (e.g., those without co-occurring psychiatric disorders. Response measures have varied across studies. Heterogeneity of PG treatment samples may also complicate identification of effective treatments. Identification of factors related to treatment response will help inform future studies and advance treatment strategies for PG.
Despite being a relatively effective and safe treatment, the clinical management of alcohol abuse/dependence by oral naltrexone can be compromised due to the patient's noncompliance with daily use of this medication. Over the past decade an increasing body of research has suggested that the use of sustained release depot naltrexone preparations can overcome this issue and deliver improved clinical outcomes. However, at the same time, research findings from diverse areas of pharmacogenetics, neurobiology and behavioural psychology have also been converging to identify variables including genetic markers, patient psychosocial characteristics and drug use history differences, or clusters of these variables that play a major role in mediating the response of alcohol abuse/dependent persons to treatment by naltrexone. While this article does not attempt to review all available data pertaining to an individual alcohol dependent patient's response to treatment by naltrexone, it does identify relevant research areas and highlights the importance of data arising from them. The characterization of clinical markers, to identify those patients who are most likely to benefit from naltrexone and to tailor a more individual naltrexone treatment, will ultimately provide significant benefit to both patients and clinicians by optimizing treatment outcome.
The benzodiazepines (BZDs) are anxiolytics, hypnotics, anticonvulsants, muscle-relaxants and induce anaesthesia. Adverse effects comprise sedation subjectively and cognitive and psychomotor impairment objectively Complex skills such as driving can be compromised. Paradoxical excitement can have forensic implications. Long-term use beyond the licensed durations is common but both efficacy and adverse effects associated with this have been poorly documented.
Withdrawal and dependence have excited particular concern, and even polemic. Perhaps a third of long-term (Beyond 6 months) users experience symptoms and signs on attempting to withdraw – anxiety, insomnia, muscle spasms and tension, and perceptual hypersensitivity. Uncommonly, fits or a psychosis may supervene. The patterns following withdrawal vary widely. The usual method of withdrawal is slow tapering but it may not obviate the problems completely. BZDs are also drugs of abuse either on their own or in conjunction with opioids and stimulants.
Claims have been made that the use of BZDs is associated with increased mortality. This is a concern in view of the widespread usage of these drugs, particularly in the elderly. All of these factors impinge on the risk/benefit ratio and the severity of the indications.
Harm reduction should focus on choice of alternative treatments both psychological and pharmacological. Guidelines emphasise that BZDs are not drugs of first choice and should only be used short-term. Schedules are available to educate about methods of withdrawal in current users, emphasising the slow rate of taper. General principles of harm minimisation in the addiction field are appropriate to BZD abuse.
Metabolic diseases are associated with activation of the innate immune system in various tissues and characterised by elevated inflammatory factors and the presence of immune cells. Type 2 diabetes develops when islet beta-cells are deficient in producing sufficient insulin to overcome peripheral insulin resistance. Intra-islet IL-1β activity diminishes beta-cell function and survival and governs islet inflammation. Targeting the IL-1 system with the IL-1 receptor antagonist IL1Ra improved insulin secretion, glycemia and reduced systemic inflammation in a proof of concept study with patients with type 2 diabetes. Currently, long lasting and specific IL-1β blocking antibodies are evaluated in clinical trials and this may lead to a novel cytokine-based treatment for type 2 diabetes.
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
Aim: The contribution of selective serotonin reuptake inhibitors (SSRIs) to injurious fall risk in patients with dementia has not been quantified precisely until now. Our objective was to determine whether a dose-response relationship exists for the use of SSRIs and injurious falls in a population of nursing home residents with dementia.
Methods: Daily drug use and daily falls were recorded in 248 nursing home residents with dementia from 1 January 2006 until 1 January 2008. For each resident and for each day of the study period, data on drug use were abstracted from the prescription database, and information on falls and subsequent injuries was retrieved from a standardised incident report system, resulting in a dataset of 85,074 person-days.
Results: We found a significant dose-response relationship between injurious falls and the use of SSRIs. The risk of an injurious fall increased significantly with 31% at 0.25 of the Defined Daily Dose (DDD) of a SSRI, 73% at 0.50 DDD, and 198% at 1.00 DDD (Hazard Rate = 2.98; 95% confidence interval 1.94-4.57). The risk increased further in combination with a hypnotic or sedative.
Conclusions: Even at low doses, SSRIs are associated with increased risk of an injurious fall in nursing home residents with dementia. Higher doses increase the risk further with a threefold risk at 1.00 DDD. New treatment protocols might be needed that take into account the dose-response relationship between SSRIs and injurious falls.
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
Background: Interest in patient adherence has increased in recent years, with a growing literature that shows the pervasiveness of poor adherence to appropriately prescribed medications. However, four decades of adherence research has not resulted in uniformity in the terminology used to describe deviations from prescribed therapies.
Objectives: To PROPOSE A NEW TAXONOMY, IN WHICH ADHERENCE TO MEDICATIONS IS CONCEPTUALIZED, BASED ON BEHAVIOURAL AND PHARMACOLOGICAL SCIENCE, AND WHICH WILL SUPPORT QUANTIFIABLE PARAMETERS.
Methods: A systematic literature review was performed using MEDLINE, EMBASE, CINAHL, the Cochrane Library and PsycINFO from database inception to 1 April 2009. The objective was to identify the different conceptual approaches to adherence research. Definitions were analysed according to time and methodological perspectives. A taxonomic approach was subsequently derived, evaluated, and discussed with international experts.
Results: More than ten different terms describing medication-taking behaviour were identified through the literature review, often with differing conceptual meanings. The conceptual foundation for a new, transparent taxonomy relies on three elements, which make a clear distinction between processes that describe actions through established routines (“Adherence to medications”, “Management of adherence”) and the discipline that studies those processes (“Adherence-related sciences”). “Adherence to medications” is the process by which patients take their medication as prescribed, further divided into three quantifiable phases: “Initiation”, “Implementation”, and “Discontinuation”.
Conclusions: In response to the proliferation of ambiguous or unquantifiable terms in the literature on medication adherence, this research has resulted in a new conceptual foundation for a transparent taxonomy. The terms and definitions are focused on promoting consistency and quantification in terminology and methods to aid in the conduct, analysis, and interpretation of scientific studies of medication adherence.
What is already known about this subject
• Cannabis based medicines are registered as a treatment for various indications, such as pain and spasms in multiple clerosis (MS) patients, and anorexia and nausea in patients with HIV or cancer treatment.
• Pharmacokinetics of the various administration routes of cannabis and cannabis based medicines are variable and dosing is hard to regulate.
What this study adds
• Namisol is a new tablet containing pure THC (>98%) that has a beneficial pharmacokinetic profile after oral administration.
• Namisol gives a quick onset of pharmacodynamic effects in healthy volunteers, which implies a rapid initiation of therapeutic effects in patients.
Aims Among the main disadvantages of currently available Δ9-tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of Namisol®.
Methods This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomised, cross-over study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5-, 8.0 mg or matching placebo in a randomised, cross-over, rising dose study during panel II. PD measurements were: body sway; visual analogue scales (VAS) mood, psychedelic; heart rate. THC and 11-OH-THC population PK analysis was performed.
Results Sublingual administration showed a flat concentration profile compared to oral. Oral THC apparent t1/2 was 72-80 min, Tmax was 39-56 min, and Cmax 2.92-4.69 ng mL-1. THC affected body sway (60.8%;95%CI 29.5-99.8), external perception (0.078 log mm;95%CI 0.019-0.137), alertness (-2,7 mm;95%CI -4.5-/-0.9) feeling high (0.256 log mm;95%CI 0.093-0.418), and heart rate (5.6 BPM;95%CI 2.7-6.5). Namisol® was well tolerated.
Conclusions Oral Namisol® showed promising PK and PD characteristics. Variability and Tmax of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.
What this adds:
What is already known about this subject
Paclitaxel and rosiglitazone are primarily metabolized by CYP2C8 and their in vitro metabolism by human liver microsomes is correlated. Probe assays that quantify the in vivo activity of CYP enzymes which are important in drug metabolism have been developed for use in clinical pharmacology research. A probe of CYP2C8 that is easy to administer and interpret may be valuable for individualized dosing of paclitaxel.
What this study adds
This pilot study demonstrates for the first time that there is an in vivo correlation between paclitaxel and rosiglitazone exposure. The finding, that a single rosiglitazone plasma concentration after oral dosing may explain significant variance in paclitaxel exposure, suggests that rosiglitazone may satisfy the requirements of a clinically useful in vivo probe. However, it is acknowledged that there is a need for further studies evaluating the use of rosiglitazone as a CYP2C8 probe and quantifying the relationship, in order to guide dosing of narrow therapeutic index drugs metabolized primarily by CYP2C8, such as paclitaxel.
Aims: Evaluate the use of rosiglitazone and the Erythromycin Breath Test (ERMBT), as probes of CYP2C8 and CYP3A4, respectively, to explain inter-individual variability in paclitaxel exposure.
Methods: 3-hour rosiglitazone concentration and ERMBT results were included in a regression model to explain the variability in paclitaxel exposure in 14 subjects.
Results: Rosiglitazone concentration was significantly correlated with paclitaxel exposure (p = 0.018) while ERMBT had no predictive value (p = 0.47).
Conclusions: The correlation between the exposure of rosiglitazone and paclitaxel likely reflects mutual dependence on the activity of CYP2C8. Rosiglitazone or similar agents may have value as in vivo probes of CYP2C8 activity.
What this paper adds
What is already known about this subject: Nevirapine pharmacokinetics is affected by several factors including CYP2B6 Single Nucleotide Polymorphisms. These genetic profiles are more common in African patients and they affect the drug clearance being associated to higher trough concentrations. PK/PG studies are difficult to perform in remote areas where refrigeration is not available, although dried plasma and dried blood methods have been validated.
What this study adds: Dried plasma spots are useful tools for studying nevirapine PK with a good association to plasma levels and they can be used in rural areas since cold chain is not necessary. Dried blood spots can be used to store and analyse patients’ DNA for pharmacogenetic polymorphisms. Nevirapine trough levels in Burundese patients, not studied so far, are above the target concentration (3000 ng/ml) in 84% of patients. CYP2B6 (both at position 516 and 983) but not ABCB1 (3435 and 1236) SNPs as well as age correlate to higher nevirapine exposure.
Aims: Pharmacokinetics and pharmacogenetics of nevirapine have been studied in rich and limited-resource countries: CYP2B6 SNPs have been associated to decreased drug clearance. We evaluated the pharmacogenetic determinants of nevirapine trough concentrations in a rural cohort in Burundi using easy-to-store and transport dried sample spot devices.
Methods. A cross-sectional analysis in HIV-positive nevirapine-treated patients in Kiremba, north of Burundi, was performed in 2009. After blood withdrawal whole blood was stored on dried blood spots and plasma (after centrifugation) was placed on dried plasma spot devices and stored at room temperature. Nevirapine plasma and dried sample spot concentrations were compared to test the clinical usefulness of the tool. Single nucleotide polymorphisms in CYP2B6 and ABCB1 (using a real time PCR technique) were analysed and associated to nevirapine plasma trough levels.
Results. Nevirapine concentrations measured on dried plasma spot devices were highly related to plasma ones in sixty patients, although a negative bias was observed (-18%). Nevirapine trough levels were above the target concentration (3000 ng/ml) in 84% of patients and they were associated to CYP2B6 SNPs (both at position 516 and 983); no effect of ABCB1 SNPs was noted.
Conclusions. Dried plasma spot devices are accurate tools for measuring nevirapine concentrations in rural settings where refrigeration is not available, despite a moderate underestimation bias. They allowed the evaluation of nevirapine concentration in a cohort of HIV-infected people in rural Burundi, confirming very good exposure and correlation to pharmacogenetic polymorphisms in the CYP2B6 encoding gene.
Self-poisoning with pesticides or plants is a major clinical problem in rural Asia, killing several hundred thousand people every year. Over the last 17 years, our clinical toxicology and pharmacology group has carried out clinical studies in the North Central Province of Sri Lanka to improve treatment and reduce deaths. Studies have looked at the effectiveness of anti-digoxin Fab in cardiac glycoside plant poisoning, multiple dose activated charcoal in all poisoning, and pralidoxime in moderate toxicity organophosphorus insecticide poisoning. More recently, using a Haddon matrix as a guide, we have started conducting public health and animal studies to find strategies that may work outside of the hospital. Based on the 2009 GSK Research in Clinical Pharmacology prize lecture, this review shows the evolution of the group's research from a clinical pharmacology approach to one that studies possible interventions at multiple levels, including the patient, the community and government legislation.
]]>Diabetic retinopathy, a common complication of diabetes, develops in 75% of patients with type 1 and 50% of patients with type 2 diabetes, progressing to legal blindness in about 5%. In the recent years, considerable efforts have been put into finding treatments for this condition. It has been discovered that peptidergic mechanisms (neuropeptides and their analogues, activating a diverse array of signal transduction pathways through their multiple receptors) are potentially important for consideration in drug development strategies. A considerable amount of knowledge has been accumulated over the last three decades on human retinal neuropeptides and those elements in the pathomechanisms of diabetic retinopathy which might be related to peptidergic signal transduction. Here, human retinal neuropeptides and their receptors are reviewed, along with the theories relevant to the pathogenesis of diabetic retinopathy both in humans and in experimental models. By collating this information, the curative potential of certain neupeptides and their analogues/antagonists can also be discussed, along with the existing clinical treatments of diabetic retinopathy. The most promising peptidergic pathways for which treatment strategies may be developed at present are stimulation of the somatostatin-related pathway and the pituitary adenylyl cyclase-activating polypeptide-related pathway or inhibition of angiotensinergic mechanisms. These approaches may result in the inhibition of vascular endothelial growth factor production and neuronal apoptosis; therefore, both the optical quality of the image and the processing capability of the neural circuit in the retina may be saved.
]]>Aldosterone antagonists (AldoAs) have been used to treat severe chronic heart failure (CHF).There is uncertainty regarding the efficacy of using AldoAs in mild to moderate CHF with New York Heart Association (NYHA) classifications of I to II. This study summarizes the evidence for the efficacy of spironolactone (SP), eplerenone (EP) and canrenone in mild to moderate CHF patients.
PubMed, MEDLINE, EMBASE and OVID databases were searched before June 2012 for randomized and quasi-randomized controlled trials assessing AldoA treatment in CHF patients with NYHA classes I to II. Data concerning the study's design, patients' characteristics and outcomes were extracted. Risk ratio (RR) and weighted mean differences (WMD) or standardized mean difference were calculated using either fixed or random effects models.
Eight trials involving 3929 CHF patients were included. AldoAs were superior to the control in all cause mortality (RR 0.79, 95% CI 0.66, 0.95) and in re-hospitalization for cardiac causes (RR 0.62, 95% CI 0.52, 0.74), the left ventricular ejection fraction was improved by AldoA treatment (WMD 2.94%, P = 0.52). Moreover, AldoA therapy decreased the left ventricular end-diastolic volume (WMD −14.04 ml, P < 0.00001),the left ventricular end-systolic volume (WMD −14.09 ml, P < 0.00001). A stratified analysis showed a statistical superiority in the benefits of SP over EP in reducing LVEDV and LVESV. AldoAs reduced B-type natriuretic peptide concentrations (WMD −37.76 pg ml−1, P < 0.00001), increased serum creatinine (WMD 8.69 μmol l−1, P = 0.0003) and occurrence of hyperkalaemia (RR 1.78, 95% CI 1.43, 2.23).
Additional use of AldoAs in CHF patients may decrease mortality and re-hospitalization for cardiac reasons, improve cardiac function and simultaneously ameliorate LV reverse remodelling.
Conjugation to antithrombin III ATIII-binding pentasaccharides has been proposed as a novel method to extend the half-life of therapeutic proteins. We aim to validate this technological concept in man by performing a first-in-human study using CarboCarrier® insulin (SCH 900948) as an example. A rising single dose phase 1 study was performed assessing safety, tolerability, pharmacokinetics and relative bioactivity of CarboCarrier® insulin. Safety, tolerability and pharmacokinetics (PK) of single doses of CarboCarrier® insulin in healthy volunteers were explored, and the dose–response relationship and relative bioactivity of CarboCarrier® insulin in subjects with type 2 diabetes were investigated.
After an overnight fast, subjects were randomized to a treatment sequence. PK and pharmacodynamic (glucose, insulin and C-peptide) samples were obtained for up to 72 h post-dose. Effects of CarboCarrier® insulin were compared with those of NPH-insulin.
CarboCarrier® insulin was safe and well-tolerated and no consistent pattern of adverse events occurred. CarboCarrier® insulin exposure (Cmax and AUC) increased proportionally with dose. The mean terminal elimination half-life ranged between 3.11 and 5.28 h. All CarboCarrier® insulin dose groups showed decreases in the mean change from baseline of plasma glucose concentrations compared with the placebo group.
CarboCarrier® insulin is pharmacologically active showing features of insulin action in man. The elimination half-life of the molecule was clearly extended compared with endogenous insulin, indicating that conjugation to ATIII-binding pentasaccharides is a viable approach to extend the half-life of therapeutic proteins in humans. This is an important step towards validation of the CarboCarrier® technology by making use of CarboCarrier® insulin as an example.
To ascertain the tolerability profile of single and repeated oral doses of methanesulfonyl fluoride (MSF, SNX-001) in healthy aged subjects, and to determine the degree of erythrocyte acetylcholinesterase (AChE) inhibition induced by MSF after single and repeated oral doses.
To calculate properly the kinetics and the duration of AChE inhibition, the effects of MSF were also studied in rodents. These experiments suggested that MSF administered three times per week should provide safe and efficacious AChE inhibition. In a randomized placebo-controlled phase I study, 3.6 mg, 7.2 mg or 10.8 mg MSF were then orally administered to 27 consenting healthy volunteers (aged 50 to 72 years). After a single dose phase and a 1 week wash-out period, the subjects received the same doses three times per week for 2 weeks.
Twenty-two out of the 27 subjects completed the study. Four patients withdrew due to adverse events (AEs) and one for non-compliance. Erythrocyte AChE was inhibited by a total of 33%, 46%, and 62% after 2 weeks of 3.6 mg, 7.2 mg and 10.8 mg MSF, respectively. No serious AEs occurred. The most frequent AEs were headache (27%), nausea (11%) and diarrhoea (8%).
MSF proved to be well tolerated even with repeated oral dosing. It is estimated that MSF provided a degree of AChE inhibition that should effectively enhance memory. This molecule deserves to be tested for efficacy in a pilot randomized controlled study in patients with Alzheimer's disease.
To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans.
Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2–600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women).
Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4–6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40–80 h. The area under the curve0-24 hours (AUC0–24 h), concentration at 24 hours (C24 h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC0–24 h, Cmax,day1, Cmax,overall and C24 h relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of −66% and urine NTx/creatinine (uNTx/Cr) of −51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (−70%) and uNTx/Cr (−78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction.
Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.
To assess the bioequipotency of equimolar doses of idraparinux (2.5 mg) and idrabiotaparinux (3.0 mg).
In a phase I study, 48 healthy male volunteers were randomized to a single subcutaneous injection of idrabiotaparinux or idraparinux, followed by plasma sampling over 27 days. In a prospective substudy of the phase III EQUINOX trial, 228 patients treated for acute symptomatic deep vein thrombosis received idrabiotaparinux or idraparinux once weekly for 6 months. Plasma sampling was performed within 5 days following the last injection. The primary pharmacodynamic endpoint was the inhibition of activated factor X (FXa) activity. Maximal anti-FXa activity (Amax) and area under anti-FXa activity vs. time curve (AAUC) were calculated. Safety and tolerability were also assessed.
In both studies, pharmacodynamic anti-FXa vs. time profiles of idrabiotaparinux and idraparinux were superimposable. Ratio estimates (90% confidence intervals [CIs]) for idrabiotaparinux : idraparinux were 0.96 (0.89, 1.04) for Amax and 0.95 (0.87, 1.04) for AAUC in the phase I study, and 1.11 (1.00, 1.22) for Amax and 1.06 (0.96, 1.16) for AAUC at month 6 in the EQUINOX substudy. Idrabiotaparinux and idraparinux were considered bioequipotent because 90% CIs were within the pre-specified interval (0.80, 1.25). Study treatments were well tolerated.
Pharmacodynamic parameters reported after single dose in healthy volunteers and after repeated once weekly dosing in patients demonstrated the bioequipotency of idrabiotaparinux and idraparinux based on FXa inhibition. These outcomes support the use of an idrabiotaparinux dose bioequipotent to an idraparinux dose in large clinical trials, and the possibility to substitute idrabiotaparinux to idraparinux for the treatment of venous thromboembolism.
To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition.
Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling.
A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (−12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h−1 for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h−1 and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46.
Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.
To predict simultaneously the area under the concentration−time curve during one dosing interval [AUC(0,12 h)] for mycophenolic acid (MPA) and tacrolimus (TAC), when concomitantly used during the first month after transplantation, based on common blood samples.
Data were from two different sources, real patient pharmacokinetic (PK) profiles from 65 renal transplant recipients and 9000 PK profiles simulated from previously published models on MPA or TAC in the first month after transplantation. Multiple linear regression (MLR) and Bayesian estimation using optimal samples were performed to predict MPA and TAC AUC(0,12 h) based on two concentrations.
The following models were retained: AUC(0,12 h) = 16.5 + 4.9 × C1.5 + 6.7 × C3.5 (r2 = 0.82, rRMSE = 9%, with simulations and r2 = 0.66, rRMSE = 24%, with observed data) and AUC(0,12 h) = 24.3 + 5.9 × C1.5 + 12.2 × C3.5 (r2 = 0.94, rRMSE = 12.3%, with simulations r2 = 0.74, rRMSE = 15%, with observed data) for MPA and TAC, respectively. In addition, Bayesian estimators were developed including parameter values from final models and values of concentrations at 1.5 and 3.5 h after dose. Good agreement was found between predicted and reference AUC(0,12 h) values: r2 = 0.90, rRMSE = 13% and r2 = 0.97, rRMSE = 5% with simulations for MPA and TAC, respectively and r2 = 0.75, rRMSE = 11% and r2 = 0.83, rRMSE = 7% with observed data for MPA and TAC, respectively.
Statistical tools were developed for simultaneous MPA and TAC therapeutic drug monitoring. They can be incorporated in computer programs for patient dose individualization.
To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 5825 following single-dose intravenous (i.v.) and subcutaneous (s.c.) administration in healthy and healthy atopic subjects.
Sixty-four subjects received a single dose of placebo or CNTO 5825 (0.1, 0.3, 1.0, 3.0, or 10 mg kg−1 i.v. in a dose-escalating manner, or 3.0 mg kg−1 s.c. in healthy subjects; and 10 mg kg−1 i.v. in healthy atopic subjects). Subjects were observed for 96 h postadministration and followed for 16 weeks. Safety and tolerability were monitored, and serum samples were collected to measure CNTO 5825 concentrations, antibodies to CNTO 5825 and PD biomarkers.
Most adverse events were mild to moderate in severity and considered to be unrelated to CNTO 5825, with no dose-dependent trends seen. The two serious adverse events were considered to be unrelated to CNTO 5825. After i.v. administration, CNTO 5825 exhibited linear PK, with a terminal half-life of ∼22–32 days. After a single 3 mg kg−1 s.c. dose in healthy subjects, CNTO 5825 was absorbed into the systemic circulation with a median time to maximum serum concentration (tmax) of 5.45 days and absolute bioavailability of ∼75%. The PK profile of CNTO 5825 at 10 mg kg−1 was similar in both healthy and healthy atopic subjects. No antibodies to CNTO 5825 were detected through week 16. In the CNTO 5825-treated healthy atopic subjects, there was a significant reduction in serum IgE and C-C motif chemokine ligand 17 (P = 0.028 and 0.068 vs. placebo, respectively).
CNTO 5825 was well tolerated, had an acceptable safety profile, exhibited linear PK characteristics, and no detected antibodies to CNTO 5825.
The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting.
Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design.
ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure.
Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients.
Vitamin D deficiency is prevalent in HIV-infected patients and has been associated with osteopenia and HIV disease progression. Our aims were to investigate the pharmacokinetics of 25-hydroxycholecalciferol [25(OH)D], the effect of antiretroviral treatment (ARV) and others factors that may influence the pharmacokinetics, and to determine a vitamin D3 dosing scheme to reach the 30 ng ml−1 threshold (defined as 25(OH)D sufficiency).
This monocentric retrospective study included 422 HIV-infected patients aged 16 to 85 years. A total of 723 25(OH)D concentrations were available for pharmacokinetic evaluation and a population pharmacokinetic model was developed with MONOLIX 3.2.
Median 25(OH)D at baseline was 16 ng ml−1 (interquartile range 11–23 ng ml−1) for the total population, 17% of patient had concentrations below 10 ng ml−1, 68% between 10 and 30 ng ml−1 and 15% above 30 ng ml−1. 25(OH)D pharmacokinetics were best described by a one compartment model with an additional endogenous production. The effects of season and skin phototype were significant on production rate. The endogenous production was 20% lower in non-white skin phototype patients and was decreased by 16% during autumn, winter and spring. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs (ARV). To obtain concentrations between 30 and 80 ng ml−1, the dosing recommendation was 100 000 IU every month.
Season and skin phototype had an influence on the endogenous production of 25(OH)D. However no effect of ARV was found. A dosing scheme to reach sufficient 25(OH)D concentrations is proposed.
No pharmacokinetic data exist on doses of ropivacaine larger than 300 mg for peripheral nerve block in man, although in clinical practice higher doses are frequently used. The purpose of the present study was to describe the pharmacokinetic profile in serum of 450 mg ropivacaine with and without epinephrine in patients undergoing anterior cruciate ligament reconstruction.
Twelve patients were randomly allocated to receive a single shot combined sciatic/femoral nerve block with 60 ml of either ropivacaine 0.75% alone (group R, n = 6) or ropivacaine 0.75% plus epinephrine 5 μg ml−1 (group RE, n = 6). Venous blood samples for total and free ropivacaine serum concentrations were obtained during 48 h following block placement. Pharmacokinetic parameters were calculated using a non-compartmental approach.
Results are given as mean (SD) for group R vs. group RE (95% CI of the difference). Total Cmax was 2.81 (0.94) μg ml−1 vs. 2.16 (0.21) μg ml−1 (95% CI −0.23, 1.53). tmax was 1.17 (0.30) h vs. 1.67 (0.94) h (95% CI −1.40, 0.40). The highest free ropivacaine concentration per patient was 0.16 (0.08) μg ml−1 vs. 0.12 (0.04) μg ml−1 (95% CI −0.04, 0.12). t1/2 was 6.82 (2.26) h vs. 5.48 (1.69) h (95% CI −1.23, 3.91). AUC was 28.35 (5.92) μg ml−1 h vs. 29.12 (7.34) μg ml−1 h (95% CI −9.35, 7.81).
Free serum concentrations of ropivacaine with and without epinephrine remained well below the assumed threshold of 0.56 μg ml−1 for systemic toxicity. Changes in pharmacokinetics with epinephrine co-administration did not reach statistical significance.
Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1/NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated.
In a blinded, randomized, placebo-controlled, two period crossover study, the pharmacokinetics and central nervous system (CNS) effects of single oral doses of 200 mg GSK1144814 were evaluated in 20 healthy volunteers, using a controlled alcohol infusion paradigm to maintain stable alcohol concentrations with subsequent analysis of eye movements, adaptive tracking, body sway, visual analogue scales, Epworth sleepiness scale and the verbal visual learning test.
Frequent adverse effects were mild somnolence, fatigue and headache. Plasma concentration of GSK1144814 in the presence of alcohol was maximal 1.5 h after dose administration. GSK1144814 did not affect alcohol pharmacokinetics. Co-administration of GSK1144814 and alcohol impaired saccadic reaction time and peak velocity, adaptive tracking, alertness, sleepiness, word recognition and recognition reaction time compared with administration of alcohol alone, but the size of the interaction was small.
Administration of GSK1144814 in the presence of alcohol was generally well tolerated and not likely to produce clinically relevant additional impairments after alcohol consumption.
To present a statistical model for defining interindividual variation in response to morphine and to use this model in a preliminary hypothesis-generating multivariate genetic association study.
Two hundred and sixty-four cancer patients taking oral morphine were included in a prospective observational study. Pain and morphine side-effect scores were examined using principal components analysis. The resulting principal components were used in an exploratory genetic association study of single nucleotide polymorphisms across the genes coding for the three opioid receptors, OPRM1, OPRK1 and OPRD1. Associations in multivariate models, including potential clinical confounders, were explored.
Two principal components corresponding to residual pain and central side-effects were identified. These components accounted for 42 and 18% of the variability in morphine response, respectively, were independent of each other and only mildly correlated. The genetic and clinical factors associated with these components were markedly different. Multivariate regression modelling, including clinical and genetic factors, accounted for only 12% of variability in residual pain on morphine and 3% of variability in central side-effects.
Although replication is required, this data-driven analysis suggests that pain and central side-effects on morphine may be two separate dimensions of morphine response. Larger study samples are necessary to investigate potential genetic and clinical associations comprehensively.
To describe cases of acute renal failure (ARF) and of renal failure (RF) from dronedarone retrieved in the general population during post-marketing surveillance through the Italian spontaneous ADR reporting database.
A case by case analysis was performed. Reports codified with the System Organ Class (SOC) term ‘urinary system disorders’ of the ADR terminology of the World Health Organization associated with dronedarone treatment were selected.
Out of 124 069 ADR reports, in 55 of them dronedarone was listed as the suspected drug. Among these reports, we identified four cases of ARF, two of RF and three cases of increase of blood creatinine submitted by physicians between October 2010 and December 2011. The patient age was from 61 to 84 years and most cases occurred within the first 13 days of initiation of dronedarone therapy (range 6 days – 2 months). Only one patient received a co-suspected drug labelled for causing ARF. In all reports but one, positive dechallenge was reported.
Clinicians should be made aware of the risk of ARF/RF associated with dronedarone and of the need to screen patients appropriately for ARF/RF risk factors before starting dronedarone therapy.
Studies of the carcinogenic potential of benzodiazepines and related drugs (BZRD) have been equivocal. A recent study reported a 35% excess cancer risk among users of hypnotics, including benzodiazepines.
Using Danish nationwide registers, we conducted a matched case–control study of the association between BZRD and cancer risk. During 1 January 2002 and 31 December 2009, we identified 152 510 cases with a first time cancer who were matched (1:8) by age and gender to 1 220 317 cancer-free controls. A new-user design was applied by excluding all subjects who had used anxiolytics, hypnotics or sedatives during the first 2 years of available prescription data (1995–6). Odds ratios (ORs) with 95% confidence intervals (CI) were estimated using conditional logistic regression, adjusting for potential confounders. In the primary analysis, long term use of BZRD was defined by a cumulative amount of ≥500 defined daily doses of BZRD within a period of 1 to 5 years prior to the index date.
The adjusted OR for cancer associated with BZRD use was 1.09 (95% CI 1.04, 1.14). ORs were close to unity for most cancer sites, except stomach 1.40 (95% CI 1.05, 1.88), oesophagus 1.43 (95% CI 1.01, 2.02), liver 1.81 (95% CI 1.18, 2.80), lung 1.38 (95% CI 1.23, 1.54), pancreas 1.35 (95% CI 1.02, 1.79) and kidney 1.39 (95% CI 1.01, 1.91). For tobacco-related cancers, the OR was 1.15 (95% CI 1.09, 1.22) and for the remaining cancer sites 1.01 (95% CI 0.94, 1.08). Sub-group analyses revealed only small differences between different levels of exposure or different patient subgroups.
BZRD use was not associated with an overall increase in cancer risk, except for what is likely explained by minor lifestyle confounding, e.g. smoking.