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Aims: To investigate the exposure–response (E‐R) relationship, including exposure–efficacy and exposure–safety, of ropeginterferon alfa‐2b treatment in patients with polycythaemia vera (PV). Methods: Based on the results of the phase II trial A20‐202 regarding ropeginterferon alfa‐2b in patients with PV, E‐R analyses were performed to evaluate the efficacy and safety of the given dosing regimen. The E‐R analyses were based on logistic and linear regression and the relationship between exposure to ropeginterferon alfa‐2b and key efficacy and safety variables. The key efficacy variables included complete haematologic response (CHR) and reduction of the driver mutation JAK2V617F. The safety variable was treatment‐related adverse events (TRAEs). Results: A clear relationship between the exposure to ropeginterferon alfa‐2b and CHR was observed, with an increase in drug exposure resulting in an increased probability of achieving CHR. Similar CHR probabilities were observed in the third and fourth quantiles of the average concentration at Week 24. The results from the exposure–JAK2V617F model indicated that the JAK2V617F allele burden decreased with increasing exposure to ropeginterferon alfa‐2b and baseline body surface area. Exposure–safety analysis revealed a risk of AEs associated with transaminase abnormalities, which were not associated with clinical significance. Conclusions: Our analyses have shown that patients with PV treated with ropeginterferon alfa‐2b had an increased probability of achieving CHR and a molecular response with acceptable safety risks at the 250–350–500 μg titration dosing regimen. This study has provided the relevant data for the application of a biologics licence of ropeginterferon alfa‐2b for PV treatment in China. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Common genetic variations in the nitric oxide synthase‐1 adaptor protein (NOS1AP) gene are associated with QT‐interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT‐interval shortening in digoxin users. As QT‐interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes.We included 11 377 individuals from the prospective population‐based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time‐dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose‐dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non‐users.The median baseline age of the total study population was 62 (interquartile range [IQR] 58–71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow‐up of 11.5 (IQR 6.5–17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38–3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98–8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37–5.04] in the heterozygous TG and 2.56 [95%CI: 1.70–3.86] in the homozygous TT genotype groups. Compared to low‐ and moderate‐dose, high‐dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34–23.47]).Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin‐associated risk of SCD in a population of European ancestry. [ABSTRACT FROM AUTHOR]

Aims: Methotrexate (MTX) is used to induce and maintain remission in patients with steroid‐dependent Crohn's disease (CD). Despite its proven efficacy, its use is limited due to associated adverse events. Polymorphisms involving folate pathway genes might influence MTX efficacy and toxicity. We aimed to assess the impact of certain polymorphisms on the therapeutic outcomes of MTX in CD. Methods: Patients with CD who exclusively followed MTX monotherapy and fulfilled inclusion criteria were identified from the GETECCU ENEIDA registry. Variants of ATIC, DHFR, MTHFR, SLC19A1, ABCB1 and ABCC3 genes were analysed and their association with efficacy and toxicity was assessed. Results: A total of 129 patients were included in the analysis. MTX was used at a median weekly dose of 25 mg (interquartile range, 15–25 mg) and a median time of 14 months (interquartile range, 4–52 months). Thirty‐seven percent of the patients achieved disease remission with MTX monotherapy, while 34% were nonresponders (MTX failure). MTX‐related toxicity occurred in 40 patients (30%), leading to MTX discontinuation in 19%. DHFR rs408626 (odds ratio [OR] 3.12, 95% confidence interval [CI] 1.22–7.69; P =.017) and MTHFR rs1801133 (OR 2.86, 95% CI 1.23–6.68; P =.015) variants, and smoking (OR 2.61, 95% CI 1.12–6.05; P =.026) were associated with a higher risk of MTX failure. Additionally, the MTHFR rs1801131 variant was associated with a higher risk of MTX‐related adverse effects (OR 2.78, 95% CI 1.26–6.13, P =.011). Conclusion: Our study shows that variants of MTHFR and DHFR genes may be associated with MTX efficacy and adverse events in patients with CD. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to investigate the effects of tapentadol and oxycodone using the nociceptive withdrawal reflex and sensory evoked potentials. Methods: Twenty‐one healthy volunteers completed a cross‐over trial with oxycodone (10 mg), tapentadol (50 mg) extended‐release tablets, or placebo treatment administered orally BID for 14 days. Electrical stimulations were delivered on the plantar side of the foot to evoke a nociceptive withdrawal reflex at baseline and post‐interventions. Electromyography, recorded at tibialis anterior, and electroencephalography were recorded for analysis of: number of reflexes, latencies, and area under the curve of the nociceptive withdrawal reflex as well as latencies, amplitudes and dipole sources of the sensory‐evoked potential. Results: Tapentadol decreased the odds ratio of eliciting nociceptive withdrawal reflex by −0.89 (P =.001, 95% confidence interval [CI] −1.46, −0.32), whereas oxycodone increased the latency of the N1 component of the sensory‐evoked potential at the vertex by 12.5 ms (P =.003, 95% CI 3.35, 21.69). Dipole sources revealed that the anterior cingulate component moved caudally for all three interventions (all P <.02), and the insula components moved caudally in both the oxycodone and tapentadol arms (all P <.03). Conclusion: A decrease in the number of nociceptive withdrawal reflex was observed during tapentadol treatment, possibly relating to the noradrenaline reuptake inhibition effects on the spinal cord. Both oxycodone and tapentadol affected cortical measures possible due to μ‐opioid receptor agonistic effects evident in the dipole sources, with the strongest effect being mediated by oxycodone. These findings could support the dual effect analgesic mechanisms of tapentadol in humans as previously shown in preclinical studies. [ABSTRACT FROM AUTHOR]

Antiplatelet medications remain a cornerstone of therapy for atherosclerotic cardiovascular and cerebrovascular diseases. In primary prevention (patients with cardiovascular risk factors but no documented events, symptoms or angiographic disease), there is little evidence of benefit of any antiplatelet therapy, and such therapy carries the risk of excess bleeding. Where there is documented disease (secondary prevention), stable patients benefit from long‐term antiplatelet monotherapy, aspirin being first choice in those with coronary heart disease and clopidogrel in those with cerebrovascular disease; moreover, recent evidence shows that low‐dose rivaroxaban in combination with aspirin confers added benefit, in patients with stable cardiovascular and peripheral arterial disease. In patients with acute cerebrovascular disease, aspirin combined with clopidogrel reduces subsequent risk, while in acute coronary syndrome, dual antiplatelet therapy comprising aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) confers greater protection than aspirin monotherapy, with prasugrel and ticagrelor offering greater antiplatelet efficacy with faster onset of action than clopidogrel. Although greater antiplatelet efficacy is advantageous in preventing thrombotic events, this must be tempered by increased risk of bleeding, which may be a particular issue in certain patient groups, as will be discussed. We will also discuss possible future approaches to personalisation of antiplatelet therapy. [ABSTRACT FROM AUTHOR]

Aims: Ropeginterferon alfa‐2b is a novel, long‐acting pegylated interferon alfa‐2b. We aimed to evaluate its safety, pharmacokinetics (PK) and pharmacodynamics (PD). Methods: Thirty‐six subjects received single subcutaneous injection of ropeginterferon alfa‐2b at doses ranging from 24 to 270 μg, and 12 subjects received pegylated IFN alfa‐2a subcutaneously at 180 μg. Primary endpoints were safety/PK profiles of ropeginterferon alfa‐2b, while secondary endpoints were to compare PK/PD parameters with pegylated IFN alfa‐2a. Results: Adverse events in ropeginterferon alfa‐2b and pegylated IFN alfa‐2a groups were similar, and most of them were mild or moderate. Mean Cmax increased from 1.78 to 24.84 ng/mL along with the dose escalations in ropeginterferon alfa‐2b groups and was 12.95 ng/mL for pegylated IFN alfa‐2a. At 180 μg, ropeginterferon alfa‐2b showed statistically significant Cmax geometric mean ratio (1.76; P =.0275). Mean Tmax ranged from 74.52 to 115.69 h for ropeginterferon alfa‐2b groups, and was 84.25 h for pegylated IFN alfa‐2a. Mean AUC0‐t increased from 372.3 to 6258 ng•h/mL with the dose escalations in the ropeginterferon alfa‐2b groups, while for pegylated IFN alfa‐2a it was found to be 2706 ng•h/mL in pegylated IFN alfa‐2a. For neopterin and 2′,5′‐oligoadenylate synthase, mean Emax, Tmax and AUC0‐t of ropeginterferon alfa‐2b were similar to those of pegylated IFNα‐2a at 180 μg. Conclusion: Ropeginterferon alfa‐2b up to 270 μg was safe and well tolerated. The PK/PD parameters of ropeginterferon alfa‐2b showed increase in dose–response. Ropeginterferon alfa‐2b had higher drug exposures and showed similar safety profile when compared to pegylated IFN alfa‐2a at the same dose level. [ABSTRACT FROM AUTHOR]

Aims: In 2018, 1.07 million pregnant women received antiretroviral drugs, raising whether this affects pregnancy outcomes. We assessed the adverse pregnancy outcomes associated with prenatal antiretroviral drug exposure, notified to the French ANRS pharmacovigilance system. Methods: An exhaustive case report series has been performed using the ANRS pharmacovigilance database. All ANRS‐sponsored HIV clinical research studies using antiretroviral drugs either in pregnant women or women of childbearing age were eligible from 2004 to 2019. We analysed the following pregnancy outcomes: abortion, ectopic pregnancy, stillbirth, prematurity (<37 weeks of gestational age), low birth weight (<2500 g) and congenital abnormalities. A logistic regression was performed to assess the odds ratio (OR) for each outcome separately (if occurrence >50) compared to the outcome observed when exposed to non‐nucleoside‐reverse‐transcriptase‐inhibitor (NNRTI)‐based regimen as the reference. Results: Among the 34 studies selected, 918 deliveries occurred, of whom 88% had pregnancy outcomes documented. Pregnant women were mainly exposed to PI (n = 387, 48.6%), NNRTI (n = 331, 41.5%) and INI‐based combinations (n = 40, 5.0%, 18 on dolutegravir). Compared to NNRTI‐based combinations, there was no significant association observed with exposure to other antiretroviral combination for spontaneous abortion, prematurity or low birth weight, except an increased risk of low birth weight in new‐born exposed to exclusive nucleoside‐reverse‐transcriptase‐inhibitor (NRTI) combinations (n = 4; OR 7.50 [1.49–37.83]). Conclusions: Our study, mainly based on protease inhibitor (PI) and NNRTI‐based regimens, is overall reassuring on the risk of adverse pregnancy outcomes, except for NRTI which should be interpreted cautiously (small number, indication bias). In this study, the number of integrase inhibitor (INI)‐based combinations was too low to draw any conclusions. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to determine the differences and potential mechanistic rationale for observed adverse drug reactions (ADRs) between four approved PARP inhibitors (PARPi). Methods: The Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card drug analysis profiles and NHS secondary care medicines database enabled the identification of suspected ADRs associated with the PARPi in the UK from launch to 2020. The polypharmacology of the PARPi were data‐mined from several public data sources. Results: The overall ADRs per 100 000 Rx identified across the four PARPi are statistically significant (χ2 test, P <.001). Rucaparib has the greatest relative suspected ADRs, which can be explained by its least clean kinome and physicochemical properties. The suspected gastrointestinal ADRs of rucaparib and niraparib can be ascribed to their kinase polypharmacology. Suspected blood and lymphatic system ADRs of PARPi can be linked to their high volume of distribution (Vd). The thrombocytopenia rate of niraparib > rucaparib > olaparib tracked with the Vd trend. Hypertension is only associated with niraparib and could be explained by the therapeutically achievable inhibition of DYRK1A and/or transporters. Arrhythmia cases are potentially linked to the structural features of hERG ion‐channel inhibition found in rucaparib and niraparib. Enhanced psychiatric/nervous disorders associated with niraparib can be interpreted from the diverse neurotransporter off‐targets reported. Conclusions: Despite their similar mode of action, the differential polypharmacology of PARP inhibitors influences their ADR profile. [ABSTRACT FROM AUTHOR]

Aims: Kisangani is an area with intense malaria transmission and sulfadoxine–pyrimethamine resistance. Alternative antimalaria prophylaxis medication and protocols are needed, particularly with pregnant individuals. In this study, we compare the tolerance and effectiveness of mefloquine regimen as a split dose with a meal vs. sulfadoxine–pyrimethamine for the intermittent preventive treatment in pregnant individuals in Kisangani. Methods: This study was conducted from 15 May to 30 November 2019 as a single‐blind, randomized clinical trial comparing 2 regimens of intermittent preventive treatment during pregnancy. The first regimen consisted of 4 doses of sulfadoxine–pyrimethamine, and the second of 2 doses of mefloquine taken as a split dose with meal. Results: The occurrence of major or minor side‐effects among patients treated with mefloquine and those treated with sulfadoxine–pyrimethamine were not statistically significant (major side effects: Fisher exact = 0.5014; minor side effects: P =.0961). Intermittent preventive treatment using mefloquine significantly reduced the risk of placental malaria (risk ratio [RR]: 0.4315, 95% confidence interval [CI]: 0.2201–0.8460), maternal peripheral parasitaemia (RR: 0.4397, 95% CI: 0.2377–0.8132) and low birth weight (RR: 0.4708, 95% CI: 0.2455–0.9029). Conclusion: Splitting dose and intake with a meal increased mefloquine tolerability while keeping its efficacy higher compared to sulfadoxine–pyrimethamine. Intermittent preventive treatment during pregnancy using mefloquine reduces the risk of placental malaria, maternal peripheral parasitaemia and low birth weight, compared to sulfadoxine–pyrimethamine. Thus, mefloquine is a good alternative to intermittent preventive treatment in pregnancy. [ABSTRACT FROM AUTHOR]

Aims: Accurately estimating kidney function is essential for the safe administration of renally cleared drugs such as ganciclovir. Current practice recommends adjusting renally eliminated drugs according to the Cockcroft–Gault equation. There are no data on the utility of the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equations in ganciclovir dosing. To evaluate which renal function equation best predicts ganciclovir clearance. Methods: The performance of the Cockcroft–Gault equation, isotope dilution mass spectrometry (IDMS)‐traceable 4‐variable MDRD study (MDRD4‐IDMS) equation and CKD‐EPI equation in determining ganciclovir clearance were assessed retrospectively in patients treated with ganciclovir from 2004–2015. The MDRD4‐IDMS and CKD‐EPI equations adjusted to individual body surface area (MDRD4‐IDMS·BSA and CKD‐EPI·BSA, respectively) were also evaluated. Patients with intravenous ganciclovir peak and trough concentrations in their medical records were included in the study. Ganciclovir clearance was calculated from serum concentrations using a one‐compartment model. The five equations were compared based on their predictive ability, the coefficient of determination, through a linear regression analysis. The results were validated in a group of patients. Results: One hundred patients were included in the final analysis. Seventy‐four patients were analysed in the learning group and 26 in the validation group. The coefficient of determination was 0.281 for Cockcroft–Gault, 0.301 for CKD‐EPI·BSA, 0.308 for MDRD4‐IDMS·BSA, 0.324 for MDRD4‐IDMS and 0.360 for CKD‐EPI. Subgroup analysis also showed that CKD‐EPI is a better predictor of ganciclovir clearance. Analysis of the validation group confirmed these results. Conclusions: The CKD‐EPI equation correlates better with ganciclovir clearance than the Cockcroft‐Gault and MDRD4‐IDMS equations, even the clinical difference between the equations is scarce. [ABSTRACT FROM AUTHOR]

Aims: There are no specific criteria for a step‐down or withdrawal dose of omalizumab (OMA). Our purpose was to evaluate the viability of a protocol for OMAlizumab DOse REduction (the OMADORE study) in severe allergic asthma (SAA). Methods: The study population included 35 SAA patients treated during a minimum period of 1 year with oral corticosteroids (OC) equivalent to a mean daily dose of 4 mg of methyl‐prednisolone. To qualify for the protocol, the patients had to have received treatment with OMA for at least one and a half years, OC dose had to have reached the lowest tolerated dose and spirometry had to be greater than or equal to that at entry. The interventions were (a) OMA dose was reduced by half; (b) if patients were clinically stable after 6 months, the dose was halved again; (c) if repeated OC boosters were needed and/or spirometry worsened by more than 10%, OMA dose was raised to the previous figure until stabilization. Results: Mean age was 52.5 (17) years, median monthly OC dose was 120 (IQR: 225) mg. Pulmonary function: FVC: 79.7 (20.2)%; FEV1: 64.8 (21.7)%; FEV1/ FVC: 61.7(13.8)%. OMA could be withdrawn in 34.3% of the patients; 22.9% tolerated a reduction, and in 42.9% the dose could not be modified. Follow‐up time after reduction or withdrawal ranged from 12 to 30 months. There were no severe exacerbations requiring emergency assistance or admission. Conclusions: The OMADORE study found that in more than 50% of SAA patients on OC, OMA dose can be safely reduced or withdrawn based on a progressive dose reduction protocol. [ABSTRACT FROM AUTHOR]

Aims To investigate the association between use of β-blockers and β-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. Methods Data from two prospective studies were used, including community-dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B-PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time-varying β-blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between β-blocker use, their characteristics - selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism - and fall risk. The results of the studies were combined using meta-analyses. Results In total 2917 participants encountered a fall during a total follow-up time of 89 529 years. Meta-analysis indicated no association between use of any β-blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 [95% confidence interval (CI) 0.88-1.06]. Use of a selective β-blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83-1.01). Use of a nonselective β-blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01-1.48). Other β-blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk. Conclusion Our study suggests that use of a nonselective β-blocker, contrary to selective β-blockers, is associated with an increased fall risk in an older population. In clinical practice, β-blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a β-blocker in this age group, and the pros and cons for β-blocker classes should be taken into consideration. [ABSTRACT FROM AUTHOR]

Aims Adherence to medicines is vital in treating diseases. Initial medication non-adherence (IMNA) - defined as not obtaining a medication the first time it is prescribed - has been poorly explored. Previous studies show IMNA rates between 6 and 28% in primary care (PC). The aims of this study were to determine prevalence and predictive factors of IMNA in the most prescribed and expensive pharmacotherapeutic groups in the Catalan health system. Methods This is a retrospective, register-based cohort study which linked the Catalan PC System (Spain) prescription and invoicing databases. Medication was considered non-initiated when it was not collected from the pharmacy by the end of the month following the one in which it was prescribed. IMNA prevalence was calculated using July 2013-June 2014 prescription data. Predictive factors related to patients, general practitioners and PC centres were identified through multilevel logistic regression analyses. Missing data were attributed using simple imputation. Results Some 1.6 million patients with 2.9 million prescriptions were included in the study sample. Total IMNA prevalence was 17.6% of prescriptions. The highest IMNA rate was observed in anilides (22.6%) and the lowest in angiotensin-converting-enzyme (ACE) inhibitors (7.4%). Predictors of IMNA are younger age, American nationality, having a pain-related or mental disorder and being treated by a substitute/resident general practitioner in a resident-training centre. Conclusions The rate of IMNA is high when all medications are taken into account. Attempts to strengthen trust in resident general practitioners and improve motivation to initiate a needed medication in the general young and older immigrant population should be addressed in Catalan PC. [ABSTRACT FROM AUTHOR]

Aim The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects. Methods The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)-pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg-1, phenytoin 300 mg, (S)-ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II). Pain measurements were performed at baseline and up to 10 h post-dose. Endpoints were analysed using a mixed model analysis of variance. Results Sixteen subjects (8 female) completed each part. The pain tolerance threshold (PTT) for electrical stimulation was increased (all P < 0.05) compared to placebo for (S)-ketamine (+10.1%), phenytoin (+8.5%) and pregabalin (+10.8%). The PTT for mechanical pain was increased by pregabalin (+14.1%). The cold pressor PTT was increased by fentanyl (+17.1%) and pregabalin (+46.4%). Normal skin heat pain detection threshold was increased by (S)-ketamine (+3.3%), fentanyl (+2.8%) and pregabalin (+4.1%). UVB treated skin pain detection threshold was increased by fentanyl (+2.6%) and ibuprofen (+4.0%). No differences in conditioned pain modulation were observed. Conclusion This study shows that these pain models are able to detect changes in pain thresholds after administration of different classes of analgesics in healthy subjects. The analgesic compounds all showed a unique profile in their effects on the pain tasks administered. [ABSTRACT FROM AUTHOR]

Aim Xen2174 is a synthetic 13-amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects. Methods This was a randomized, blinded, placebo-controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks). Results Twenty-five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration-time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post-lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg-placebo (95% confidence interval), 22.2% (−5.0%, 57.1%); P = 0.1131]. Conclusions At the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed. [ABSTRACT FROM AUTHOR]

Aims Opioids and antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) are recognized as analgesics to treat severe and moderate pain, but their mechanisms of action in humans remain unclear. The present study aimed to explore how oxycodone (an opioid) and venlafaxine (an SNRI) modulate spinal and supraspinal sensory processing. Methods Twenty volunteers were included in a randomized, double-blinded, three-way (placebo, oxycodone, venlafaxine), crossover study. Spinal and full scalp cortical evoked potentials (EPs) to median nerve stimulation were recorded before and after 5 days of treatment. Assessment of the central effects of the three treatments involved: (i) amplitudes and latencies of spinal EPs (spinal level); (ii) amplitudes and latencies of the P14 potential (subcortical level); (iii) amplitudes and latencies of early and late cortical EPs (cortical level); (iv) brain sources underlying early cortical Eps; and (v) brain networks underlying the late cortical EPs. Results In the venlafaxine arm, the spinal P11 and the late cortical N60-80 latencies were reduced by 1.8% [95% confidence interval (CI) 1.7%, 1.9%) and 5.7% (95% CI 5.3%, 6.1%), whereas the early cortical P25 amplitude was decreased by 7.1% (95%CI 6.1%, 8.7%). Oxycodone increased the subcortical P14 [+25% (95% CI 22.2%, 28.6%)], early cortical N30 [+12.9% (95% CI 12.5%, 13.2%)] amplitudes and the late cortical N60-80 latency [+2.9% (95% CI 1.9%, 4.0%)]. The brainstem and primary somatosensory cortex source strengths were increased by 66.7% (95% CI 62.5%, 75.0%) and 28.8% (95% CI 27.5%, 29.6%) in the oxycodone arm, whereas the primary somatosensory cortex strength was decreased in the venlafaxine arm by 18.3% (95% CI 12.0%, 28.1%). Conclusions Opioids and SNRI drugs exert different central effects. The present study contributed to the much-needed human models of the mechanisms of action of drugs with effects on the central nervous system. [ABSTRACT FROM AUTHOR]

Aims The aim was to perform a systematic review of the efficacy of traditional Chinese medicines (TCM) in cardiovascular disease. Methods Electronic databases were searched up to 11 November 2015 for all randomized-controlled trials evaluating the effect of TCM in hypertension, ischaemic stroke, heart failure, coronary heart disease and type 2 diabetes mellitus. Pooled odds ratios (ORs) were calculated using a fixed-effects model. Results Four hypertension studies were eligible for statistical analysis and included 133 patients receiving TCM and 130 control patients. There were significant reductions in systolic blood pressure in patients receiving TCM, comparable to results achieved with pharmaceutical medicines. An OR of 3.781 (95% confidence interval 2.392, 5.977; P = 0.000) was observed for the anti-hypertensive effect of TCM. Significant heterogeneity was present ( P = 0.011), with a tendency towards publication bias that did not reach significance ( P = 0.05275). Outcome measures for other cardiovascular diseases were inconsistent. Conclusions Certain TCM compounds appear to have significant anti-hypertensive effects, and although some are associated in some studies with improved outcomes in coronary heart disease, heart failure and type 2 diabetes mellitus, the data are inconsistent and will require large-scale randomized-controlled trials to allow full evaluation of any potential therapeutic benefit in these areas. [ABSTRACT FROM AUTHOR]

The author reflects on the organized crime against the academic peer review system of the journal. Topics discussed include meta-analysis of the effect of recombinant brain natriuretic peptide on in-hospital mortality, quality of data pooled in a published meta-analysis, and inadequacies regarding the study-design.

Clinical pharmacology is a medical specialty whose practitioners teach, undertake research, frame policy, give information and advice about the actions and proper uses of medicines in humans and implement that knowledge in clinical practice. It involves a combination of several activities: drug discovery and development, training safe prescribers, providing objective and evidence-based therapeutic information to ethics, regulatory and pricing bodies, supporting patient care in an increasingly subspecialized arena where co-morbidities, polypharmacy, altered pharmacokinetics and drug interactions are common and developing and contributing to medicines policies for Governments. Clinical pharmacologists must advocate drug quality and they must also advocate for sustainability of the Discipline. However for this they need appropriate clinical service and training support. This Commentary discusses strategies to ensure the Discipline is supported by teaching, training and policy organizations, to communicate the full benefits of clinical pharmacology services, put a monetary value on clinical pharmacology services and to grow the clinical pharmacology workforce to support a growing clinical, academic and regulatory need. [ABSTRACT FROM AUTHOR]

Aims Selective serotonin re-uptake inhibitors (SSRIs), specifically citalopram and escitalopram, are thought to cause QTc prolongation, although studies have shown contradictory results. Nevertheless, a maximum citalopram dosage of 20 mg in high risk patients (e.g. >60 years of age) is recommended. We aimed to investigate the association between use of (individual) SSRIs and QTc in a population-based study in older adults. Methods This study, which was part of the prospective Rotterdam Study (period 1991-2012), included participants with up to five electrocardiograms (ECGs). We used linear mixed models to compare QTcF (QT corrected according to Fridericia) measured during use of individual SSRIs with QTcF measured during non-use of any antidepressant. For citalopram, analyses were additionally restricted to a maximum dosage of 20 mg in participants aged 60 years and older. Results We included 12 589 participants with a total of 26 620 ECGs of which 436 ECGs were made during SSRI use. The mean QTcF was similar during use of any drugs from the SSRI class and during non-use. After stratifying to individual SSRIs, ECGs recorded during use of citalopram had the longest QTc compared with ECGs recorded during non-use (+12.8 ms, 90% CI 7.5, 18.2). This result remained similar in the analysis comprising participants aged 60 years and older with a maximum prescribed daily dosage of 20 mg citalopram. Conclusions Although no SSRI class effect was observed, use of citalopram was associated with a longer QTcF, even after considering the recommended restrictions. Other SSRIs may not give a clinically relevant QTcF prolongation. [ABSTRACT FROM AUTHOR]

Aims Antiplatelet therapy reduces the incidence of ischaemic stroke. Platelet-mediated thrombosis contributes variably to the major subtypes of stroke as defined by the TOAST criteria: large artery atherosclerosis (LAA), cardioembolic (CE) and small vessel occlusion (SVO). The effect of antiplatelet therapy on the incidence of each subtype is unknown and is the subject of this meta-analysis. Methods Electronic databases were searched for articles comparing the effect of antiplatelet therapy on the incidence of stroke according to aetiological subtype. Studies containing subjects prescribed anticoagulant therapy or solely investigating subjects with atrial fibrillation were excluded. Pooled odds ratios (ORs) were calculated using a fixed effects model. Results Nine studies were included ( n = 5739). In patients who had an ischaemic stroke, pre-event antiplatelet therapy was associated with significantly decreased incidence of LAA (OR 0.88, 95% CI 0.79, 0.99; P = 0.026), increased incidence of CE (OR 1.23, 95% CI 1.08, 1.41; P = 0.002) and no effect on SVO (OR 0.99, 95% CI 0.88, 1.11; P = 0.806). Concordant non-significant trends were observed in primary prevention populations ( n = 751): LAA (OR 0.81, 95% CI 0.57, 1.15; P = 0.240), CE (OR 1.29, 95% CI 0.89, 1.87; P = 0.179) and SVO (OR 0.99, 95% CI 0.73, 1.36; P = 0.970). Subgroup analysis of aspirin monotherapy ( n = 3786) demonstrated a significant reduction in LAA (OR 0.87, 95% CI 0.76, 1.00; P = 0.046), but non-significant effects on the incidence of CE (OR 1.17, 95% CI 0.99, 1.39; P = 0.068) and SVO (OR 1.04, 95% CI 0.91, 1.20; P = 0.570). Probability of publication bias was low ( P > 0.05). Conclusions Antiplatelet therapy preferentially reduces the incidence of LAA stroke compared with CE and SVO subtypes. [ABSTRACT FROM AUTHOR]

Aims The aims were to analyze the dynamics of the medicines formulary in a middle-income country and to analyze the concordance of the included medicines with the national Clinical Practices Guidelines ( CPG). Methods Medicines and their indications of use included in the Mexican Reference Drug List ( Mex- RDL) from 1996 to 2013 were analyzed. The top 10 indications with the highest number of medicines in 2013 were analyzed retrospectively until 1996 in order to identify the increase in the number of medicines to treat each one, as well as the progressive specificity of the indication according to the International statistical Classification of Diseases ( ICD-10). The concordance between the CPG and medicines approved for the top 10 indications was studied. Results The number of medicines included in the Mex- RDL kept constantly growing from 454 drugs in 1996 to 811 in 2013. Up to 26.3% of these medicines were approved to treat only 10 indications (1.5% of all possible indications of use). Many of these new medicines had been approved for more and more specific indications, while the oldest ones had been approved for general indications. Up to 27.6% of the medicines approved for these top 10 indications do not appear in the updated recommendations of the specific CPG for those indications. Conclusions During the last 18 years, the new medicines and indications included in the Mex- RDL were redundant and concentrated into few similar clinical conditions. This is a factor that promotes an irrational use of these medicines and, thus, unnecessarily raises the price of health care, undermines the quality of the health system and probably increases the uncertainty of treatments. [ABSTRACT FROM AUTHOR]

Aims Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects. Methods Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2, and blood was taken to measure arachidonic acid ( AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting. Results In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance. Conclusions In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker. [ABSTRACT FROM AUTHOR]

The authors examine whether nutraceuticals can be considered as the contemporary equivalent of panacea, a herbal remedy dispensed to humans by Panacea, daughter of Greek god of medicine, Asclepius. They discuss clinical evidence on nutraceuticals, prevention of cardiovascular disease as one application of nutraceuticals, and perspectives on nutraceuticals.

Aim The PlA1/ A2 polymorphism of glycoprotein IIIa ( GPIIIa) has been associated with both antiplatelet drug resistance and increased cardiovascular events. The aim of this study was to conduct the first meta-analysis investigating the association between carriage of the PlA2 allele and resistance to currently licensed antiplatelet drugs. Methods Electronic databases ( MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where antiplatelet resistance was measured using validated techniques, pooled odds ratios ( ORs) were calculated using fixed effects and random effects models. Results Sixteen studies were eligible for statistical analysis and included 1650 PlA1 homozygous subjects and 668 carriers of the PlA2 allele. For carriers of the PlA2 allele, OR 0.924 ( n = 2318; 95% CI 0.743, 1.151; P = 0.481) was observed for resistance to any antiplatelet drug, OR 0.862 ( n = 2085; 95% CI 0.685, 1.086; P = 0.208) for resistance to aspirin and OR 1.429 ( n = 233; 95% CI 0.791, 2.582; P = 0.237) for resistance to clopidogrel. In the aspirin cohort, sub-group analysis revealed no statistical association in either healthy subjects or those with cardiovascular disease. PlA2 carriage was marginally associated with aspirin sensitivity using the fixed effects model when identified by the PFA-100 assay ( n = 1151; OR 0.743, 95% CI 0.558, 0.989; P = 0.041) but with significant heterogeneity ( I2 = 55%; P = 0.002). Significance was lost with analysis using a random effects model. Conclusions The totality of published data does not support an association between carriage of the PlA2 allele and antiplatelet drug resistance. Significant heterogeneity indicates the need for larger studies using validated and standardized assays. [ABSTRACT FROM AUTHOR]

An introduction to the journal is presented in which the editors discuss its publication of articles in 2013 related to clinical pharmacology such as first in man (FIM) research of chemical entities and biologics as well as old drugs.

The anaesthetic 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 (4-14 days) show long-term analgesic effects up to 3 months following infusion. The side effects of ketamine 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, haemodynamic, 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. [ABSTRACT FROM AUTHOR]

Aim β-adrenoceptor blockers have been used with caution in patients with obstructive lung diseases such as asthma or chronic obstructive pulmonary disease ( COPD), due to the potentially increased airway reactivity and risk of bronchial obstruction. Cardioselective β-adrenoceptor blockers have a more beneficial profile than non-cardioselective β-adrenoceptor blockers and can be safely prescribed to patients with both cardiovascular disease and COPD. We hypothesized that cardioselective β-adrenoceptor blockers also affect pulmonary function. Methods This study was performed within the Rotterdam Study, a prospective population-based cohort study. Effects of cardioselective and non-cardioselective β-adrenoceptor blockers on pulmonary function were analysed using regression techniques with multivariable adjustment for potential confounders. Results Current use of non-cardioselective β-adrenoceptor blockers was significantly associated with a lower forced expiratory volume in 1 s ( FEV1) of −198 ml (95% CI −301, −96), with a lower forced vital capacity ( FVC) of −223 ml (95% CI −367, −79) and with a decreased FEV1 : FVC of −1.38% (95% CI −2.74, −0.13%). Current use of cardioselective β-adrenoceptor blockers was significantly associated with a lower FEV1 of −118 ml (95% CI −157, −78) and with a lower FVC of −167 ml (95% CI −222, −111), but did not affect FEV1 : FVC. After exclusion of patients with COPD, asthma and heart failure the effects of cardioselective β-adrenoceptor blockers remained significant for FEV1 (−142 ml [95% CI −189, −96]) and for FVC (−176 ml [95% CI −236, −117]). Conclusion In our study both non-cardioselective and cardioselective β-adrenoceptor blockers had a clinically relevant effect on both FEV1 and FVC. In contrast to cardioselective β-adrenoceptor blockers, use of non-cardioselective β-adrenoceptor blockers was associated with a significantly lower FEV1 : FVC. [ABSTRACT FROM AUTHOR]

Aims The assessment of heart rate-corrected QT ( QTc) interval prolongation relies on the evidence of drug effects in healthy subjects. This study demonstrates the relevance of pharmacokinetic-pharmacodynamic (PKPD) relationships to characterize drug-induced QTc interval prolongation and explore the discrepancies between clinical trials and real-life conditions. Methods 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 a real-life conditions, respectively. Using modelling and simulation, drug effects at therapeutic doses were predicted in both populations. Results Inclusion criteria were shown to restrict the representativeness of the trial population in comparison to real-life conditions. A significant part of the typical patient population was excluded from trials due to weight and baseline QTc interval criteria. Relative risk was significantly different between sotalol users with and without heart failure, hypertension, diabetes and myocardial infarction ( P < 0.01). Although drug effects do cause an increase in the relative risk of QTc interval prolongation, the presence of diabetes represented an increase from 4.0 [95% confidence interval (CI) 2.7-5.8] to 6.5 (95% CI 1.6-27.1), whilst for myocardial infarction it increased from 3.4 (95% CI 2.3-5.13) to 15.5 (95% CI 4.9-49.3). Conclusions 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 the cardiovascular risk of medicinal products. [ABSTRACT FROM AUTHOR]

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 and extracellular matrix defects and results in kidney enlargement and interstitial fibrosis. Since its first description over 200 years ago, ADPKD has been considered an untreatable condition and its management is 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. [ABSTRACT FROM AUTHOR]

Aims Nevirapine ( NVP) is a non-nucleoside reverse transcriptase inhibitor used for chronic human immunodeficiency virus 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. Methods Concentrations were measured on a routine basis in 94 children aged 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. Results Nevirapine 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. Estimates of apparent clearance and volume of distribution were 3.9 l h−1 (70 kg)−1 and 140 l (70 kg)−1, respectively. Based on simulations of European Medicines Agency ( EMA) and World Health Organization ( WHO) dosing recommendations, the probability of observing minimal concentrations below the efficacy target of 3 mg l−1 is higher following the EMA recommendations than the WHO recommendations. However, NVP underdosing persists for the 3-6 and 6-10 kg weight ranges following the WHO recommendations. Conclusions It is suggested to increase doses to 75 and 100 mg twice daily for the 3-6 and 6-10 kg weight ranges, respectively, in order to obtain more than 95% of children with concentrations above 3 mg l−1. [ABSTRACT FROM AUTHOR]

Aim The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared. Methods Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days −2 and −1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT ( QTcM) on day 7 was the primary endpoint. Results QTcM differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one-sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one-sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QTc was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QTcM for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration− QTc change observed was consistent with the literature. Conclusion Atomoxetine was not associated with a clinically significant change in QTc. However, a statistically significant increase in QTc was associated with increasing plasma concentrations. [ABSTRACT FROM AUTHOR]

Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physician's use of opioids to morphine. Although this approach is recognized as cost-effective in most cases there is solid evidence that, on an individual patient basis, opioids are not all equal. Therefore it is important to have an armamentarium of strong analgesics in clinical practice to ensure a personalized approach in patients who do not respond to standard treatment. In this review we highlight differences between opioids in human studies from a pharmacological, experimental, clinical and health economics point of view. We provide evidence that individuals respond differently to opioids, and that general differences between classes of opioids exist. We recommend that this recognition is used to individualize treatment in difficult cases allowing physicians to have a wide range of treatment options. In the end this will reduce pain and side effects, leading to improved quality of life for the patient and reduce the exploding pain related costs. [ABSTRACT FROM AUTHOR]

The article offers information on several topics published in the journal in 2012 that are selected by the editors. One topic tackles on defining and validating biomarkers that enhance understanding of pharmacokinetics (PK) and pharmacodynamics (PD). Another topics include the diversity of the data-modelling-prediction-dosing (DMPD) paradigm and the drug safety.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Proprietary Chinese medicines (pCMs), generally considered to be natural and harmless, are commonly used for many indications, including diabetes mellitus. Adulteration of pCMs with undeclared pharmaceuticals has been reported previously. However, a detailed study investigating the problem of adulterated herbal antidiabetic products and their associated toxicities is largely lacking. WHAT THIS STUDY ADDS • This study shows the severity of the under-recognized problem of adulteration of herbal antidiabetic products with undeclared pharmaceuticals, including both registered and banned drugs. Potentially fatal adverse effects could result from the use of these illicit products. AIMS The current study aims to examine the problem of adulteration of herbal antidiabetic products with undeclared pharmaceuticals, including both registered and banned drugs. METHODS All cases involving use of adulterated herbal antidiabetic products referred to a tertiary centre for clinical toxicology analysis from 2005 to 2010 inclusive were retrospectively reviewed. The patients' demographic characteristics, clinical presentations, medical history, drug history and the analytical findings of the herbal antidiabetic products were studied. RESULTS A total of 27 cases involving use of 29 adulterated herbal antidiabetic products were identified. Seventeen of the patients (63%) had clinical toxicities associated with the illicit products. Hypoglycaemia was the most common adverse effect, followed by lactic acidosis. Analysis of the 29 illicit herbal antidiabetic products revealed eight undeclared registered or banned oral antidiabetic agents, namely glibenclamide ( n= 22), phenformin ( n= 18), metformin ( n= 6), rosiglitazone ( n= 6), gliclazide ( n= 2), glimepiride ( n= 2), nateglinide ( n= 1) and repaglinide ( n= 1). Non-antidiabetic drugs were also detected in some products. Up to four adulterants were detected within the same product. CONCLUSIONS Adulteration of herbal antidiabetic products with undeclared pharmaceuticals is a significant yet under-recognized problem. Patients taking these illicit products could be at risk of potentially fatal adverse effects. It is important to educate the public to avoid taking pCMs of dubious source. Effective regulatory measures should be put in place to address the problem. [ABSTRACT FROM AUTHOR]

An introduction is presented which discusses various research works including one related to drug and patient safety, second related a core drug list of 100 commonly-used or important drugs, and last related to uropharmacology.

In this article, the authors examine beliefs regarding the substitution of drug treatments to optimize spending headed by a group of European healthcare experts. The authors argue that the necessity to reduce and manage costs is significant for healthcare systems throughout the world, since generic substitution is widely adopted across Europe. Moreover, they say that best practice is the solution for issues associated with both therapeutic and generic substitution.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Coumarin anticoagulants and selective serotonin re-uptake inhibitors (SSRIs) have been reported to cause bleeding. Combination of these drug groups might enhance this risk. Case reports showed an increase of prothrombin time for the combination of warfarin with fluvoxamine and fluoxetine. This has not yet been confirmed by population based studies. WHAT THIS STUDY ADDS • Fluvoxamine and venlafaxine increased prothrombin time in users of acenocoumarol above a critical value which is associated with an increased bleeding risk. The other SSRIs had no influence on acenocoumarol effectiveness, however numbers of drug users were low. The combination of fluvoxamine and venlafaxine with acenocoumarol should be monitored by measurements of the international normalized ratio to avoid overanticoagulation. AIM The aim of this study was to investigate the effects of co-medication with selective serotonin re-uptake inhibitors (SSRIs) on overanticoagulation during acenocoumarol maintenance treatment. METHODS All subjects from The Rotterdam Study who received acenocoumarol maintenance treatment between April 1 1991 and September 9 2009 were followed for the event of an international normalized ratio (INR) ≥6, until death, end of treatment or end of the study period. With the Andersen-Gill extension of the Cox proportional hazards model, risks for repeated events of overanticoagulation in relation to concomitant SSRI use were calculated. RESULTS The risk for overanticoagulation during acenocoumarol maintenance treatment was increased in combination with fluvoxamine (HR 2.63, 95% CI 1.49, 4.66) and venlafaxine (HR 2.19, 95% CI 1.21, 3.99). There was no increase in risk for the other SSRIs, but numbers of exposed cases were low for all SSRIs except paroxetine. CONCLUSION Fluvoxamine and venlafaxine were associated with a more than double risk of INR values ≥6 in acenocoumarol treated subjects. [ABSTRACT FROM AUTHOR]

Thrombogenic and inflammatory activity are two distinct aspects of platelet biology, which are sustained by the ability of activated platelets to interact with each other (homotypic aggregation) and to adhere to circulating leucocytes (heterotypic aggregation). These two events are regulated by distinct biomolecular mechanisms that are selectively activated in different pathophysiological settings. They can occur simultaneously, for example, as part of a pro-thrombotic/pro-inflammatory response induced by vascular damage, or independently, as in certain clinical conditions in which abnormal heterotypic aggregation has been observed in the absence of intravascular thrombosis. Current antiplatelet drugs have been developed to target specific molecular signalling pathways mainly implicated in thrombus formation, and their ever increasing clinical use has resulted in clear benefits in the treatment and prevention of arterial thrombotic events. However, the efficacy of currently available antiplatelet drugs remains suboptimal, most likely because their therapeutic action is limited to only few of the signalling pathways involved in platelet homotypic aggregation. In this context, modulation of heterotypic aggregation, which is believed to contribute importantly to acute thrombotic events, as well to the pathophysiology of atherosclerosis itself, may offer benefits over and above the classical antiplatelet approach. This review will focus on the distinct biomolecular pathways that, following platelet activation, underlie homotypic and heterotypic aggregation, aiming potentially to identify novel therapeutic targets. [ABSTRACT FROM AUTHOR]

• Lopinavir/ritonavir pharmacokinetics have been fully investigated in adults and children. • Lopinavir/ritonavir population pharmacokinetics in 96 neonates and infants from birth to less than 2 years (1.16 to 10.4 kg) showed that CL/ F and V/F were dependent on body weight on an allometric basis and post-menstrual age. Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg. Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach. A one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/ F) and distribution volume ( V/ F) estimates were 5.87 l h 70 kg and 91.7 l 70 kg. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks. Size and PMA explained some CL/ F and V/ F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h, 80 mg 12 h and 120 mg 12 h in the 1-2 kg, 2-6 kg and 6-10 kg group, respectively. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) effects of acute alcohol administration have been frequently assessed. Such studies often use a wide range of methods to study each of these effects. Unfortunately, the sensitivity of these tests has not completely been ascertained. A literature search was performed to recognize the most useful tests (or biomarkers) for identifying the acute CNS effects of alcohol in healthy volunteers. All tests were grouped in clusters and functional domains. Afterwards, the effect of alcohol administration on these tests was scored as improvement, impairment or as no effect. Furthermore, dose-response relationships were established. A total number of 218 studies, describing 342 different tests (or test variants) were evaluated. Alcohol affected a wide range of CNS domains. Divided attention, focused attention, visuo-motor control and scales of feeling high and of subjective drug effects were identified as the most sensitive functional biomarkers for the acute CNS effects of alcohol. The large number of CNS tests that are used to determine the effects of alcohol interferes with the identification of the most sensitive ones and of drug-response relationships. Our results may be helpful in selecting rational biomarkers for studies investigating the acute CNS effects of alcohol or for future alcohol- interaction studies. [ABSTRACT FROM AUTHOR]

This review aims to present an overview of recent clinical trials targeting biomarkers in advanced prostate cancer. We searched ClinicalTrials.gov for early phase clinical trials on treatments of prostate cancer that have been recently completed, are ongoing or are actively recruiting participants. Drug targets and their mechanism of actions were assessed and summarized. Trials were categorized according to prostate cancer biomarkers that have potential as therapeutic targets. A total of 19 new therapeutic agents for the treatment of prostate cancer are included in this review. Trials are summarized according to the targeted biomarkers and are categorized into five therapeutic approaches: prostate cancer vaccine, epigenetic therapy, pro-apoptotic agents, prostate cancer antibodies and anti-angiogenesis approach. Some of the therapeutic agents reviewed showed promising results, warranting further investigation in late phase clinical trials. Recent novel prostate cancer biomarkers that made it through clinical trials and their relevance as drug targets are summarized. This review emphasizes the importance of specific prostate cancer biomarkers and their potentials as targets of the disease. Some clinical trials of targeted treatments in prostate cancer show promising results. Better understanding of disease mechanisms should potentially lead to more specific treatments for individual patients. [ABSTRACT FROM AUTHOR]

Adulteration of over-the-counter proprietary medications has been reported previously. However, to date a detailed study specifically on illicit slimming products has been lacking. This study showed the presence of a wide variety of illicit weight-reducing agents in over-the-counter slimming products, including registered or banned drugs and pharmaceutical analogues. These products may result in significant toxicities and even mortality. To provide an overview of illicit weight-reducing agents found in over-the-counter slimming products ingested by poisoned patients. The clinical details and analytical findings of slimming products involved in poisoning cases between 2004 and 2009 were reviewed. Sixty-six (including one fatal) poisoning cases were encountered. Eighty-one products were analysed and found to contain undeclared prescription weight-loss drugs, drug analogues, banned drugs, drugs used for an inappropriate indication or animal thyroid tissue, with up to six illicit agents within the same product. Many products were readily available from shops or the Internet. A rich diversity of illicit, potentially harmful weight-reducing agents was found in over-the-counter slimming products. [ABSTRACT FROM AUTHOR]

The article offers the author's insights on topics related to clinical pharmacology. The author mentions the assessment of risk in patients who take antipsychotic and antidepressant drugs. The author relates the topical debate on lifestyle and generic drugs that received attention in the journal. The author also tackles the topic on bispecific monoclonal antibodies called trifunctional antibodies which has the capacity of activating various immune effector cells and anti-tumour immune response.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • At rest, β-adrenoreceptor antagonists lower peripheral systolic blood pressure (SBP) but have less effect on central SBP. • Effects of β-adrenoreceptor antagonists on central and peripheral blood pressure during exercise are unknown. WHAT THIS STUDY ADDS • This study shows that acute β-blockade in healthy normotensive subjects markedly reduces peripheral SBP by ∼ 20 mmHg during moderate exercise but has no significant effect on central SBP. • The differential effect of β-blockade on central and systolic blood pressure is not completely explained by reduction in heart rate. Beta-blockade may blunt dilation of muscular arteries, influencing peripheral amplification during exercise. BACKGROUND Differential effects of β-adrenoreceptor antagonists (β-ARB) on central and peripheral blood pressure may relate to change in heart rate and/or vasodilator tone and thus be exaggerated during exercise. AIMS To examine acute effects of selective and nonselective β-ARB on central and peripheral blood pressure, cardiac output and peripheral vascular resistance during exercise. METHODS Healthy volunteers ( n= 20, 18 men, 19–54 years) received propranolol 80 mg, bisoprolol 20 mg, and placebo 1 h before bicycle ergometry (50, 75 and 100 W each for 3 min) in a randomized, cross-over study. Cardiac output was determined by pulmonary uptake of soluble and inert gas tracers (InnoCor, Innovision). Central systolic blood pressure (SBP) was determined from the late systolic shoulder of the digital artery pressure waveform (Finometer, Finopres). RESULTS At rest, both β-ARB reduced brachial but not central SBP (compared with placebo). During exercise, β-ARB reduced brachial SBP (reductions of 19.9 ± 4.3 mmHg and 23.2 ± 2.7 mmHg for propranolol and bisoprolol, respectively, at 100 W, each P < 0.0001) but not central SBP. The difference between peripheral and central SBP was reduced, relative to that during placebo, by 21.5 mmHg (95% confidence interval 8.8, 34.1) and 26.4 mmHg (18.1, 34.8) for propranolol and bisoprolol, respectively, at 100 W (each P < 0.01). There was no significant effect of β-ARB on diastolic blood pressure or peripheral vascular resistance. CONCLUSIONS Despite reducing brachial blood pressure, acute β-adrenoreceptor blockade in man at rest and during exercise does not reduce central blood pressure. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • MMF has been proposed as a treatment of steroid-dependent nephrotic syndrome and in the recent years, several studies have suggested its positive effect in preventing relapses. WHAT THIS PAPER ADDS • The population pharmacokinetics of MPA was first evaluated in children with idiopathic nephrotic syndrome and data fitted well with a two-compartment model with first-order absorption and lag time. • Body weight and serum albumin had a significant impact on oral clearance. • A three-point (T0, T1 and T4h) Bayesian estimator of AUC0–12 was developed. AIMS To develop a population pharmacokinetic model for mycophenolic acid (MPA) in children with idiopathic nephrotic syndrome (INS) treated with mycophenolate mofetil (MMF), identify covariates that explain variability and determine the Bayesian estimator of the area under the concentration–time curve over 12 h (AUC0–12). METHODS The pharmacokinetic model of MMF was described from 23 patients aged 7.4 ± 3.9 years (range 2.9–14.9) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag–time and first-order absorption and elimination was developed. The final model was validated using visual predictive check. Bayesian estimator was validated using circular permutation method. RESULTS The population pharmacokinetic parameters were apparent oral clearance 9.7 l h−1, apparent central volume of distribution 22.3 l, apparent peripheral volume of distribution 250 l, inter-compartment clearance 18.8 l h−1, absorption rate constant 5.16 h−1, lag time 0.215 h. The covariate analysis identified body weight and serum albumin as individual factors influencing the apparent oral clearance. Accurate Bayesian estimation of AUC0–12 was obtained using the combination of three MPA concentrations measured just before (T0), 1 and 4 h (T1 and T4) after drug intake with a small error of 0.298 µg h−1 ml−1 between estimated and reference AUC0–12. CONCLUSIONS The population pharmacokinetic model of MPA was developed in children with INS. A three-point (T0, T1 and T4h) Bayesian estimator of AUC0–12 was developed and might be used to investigate the relation between MPA pharmacokinetic and pharmacodynamics in children with INS and determine if there is any indication to monitor MPA exposure in order to improve patient outcome based on individual AUC-controlled MMF dosing. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The acute effects of alcohol are often studied after oral administration, and alcohol exposure is controlled by adaptation of the dose to weight, and sometimes to sex or demographic variables. • Measurements of the alcohol effects are usually performed at fixed time intervals after intake. • In only a few studies has alcohol been administered intravenously to by-pass the variability in absorption, but plasma levels often vary after administration and efforts to maintain constant levels are rare. WHAT THIS STUDY ADDS • The pharmacodynamic central nervous system (CNS) effects of alcohol or drug–alcohol interactions can be more accurately investigated if alcohol is administered intravenously and alcohol levels are kept within tightly controlled limits. • In the current study we introduce a clamping procedure to study the acute effects of a constant alcohol level of 0.6 g l−1 for 5 h on a wide range of CNS domains. • The obtained pseudo-steady-state levels with very little inter- and intravariability allow the separation of concentration- and time-dependent changes in alcohol effects. AIM In determining the acute effects of alcohol, it is helpful if alcohol concentrations are maintained at stable levels, to facilitate the interpretation of the results. Recently, an alcohol clamping method was developed that resulted in stable alcohol concentrations for hours. The aim of this study was to test a range of central nervous system (CNS) effects under pseudo-steady-state conditions. METHODS To achieve a pseudo-steady state of 0.6 g l−1, breath alcohol concentrations (BrAC) were frequently measured and fed back into a spreadsheet-based program to guide intravenous dosing. CNS effects were frequently measured throughout the clamp. RESULTS The clamping paradigm resulted in a pseudo-steady-state BrAC of 0.61 g l−1 (coefficient of variation 6.2%). A plateau was maintained from 25 to 300 min and caused significant effects on smooth pursuit eye movements [−9.7%, 95% confidence interval (CI) −12.4, −7.1], adaptive tracking (−3.4%, 95% CI −4.5, −2.2), visual analogue scale (VAS) alertness (−13 mm, 95% CI −20, −6), VAS alcohol effects (16 mm, 95% CI 7, 25) and body sway (21.3%, 95% CI 1.8, 45). Some effects (like smooth pursuit eye movements) closely followed the relatively stable alcohol concentrations, whereas others (such as body sway and VAS alcohol effects) fluctuated during the plateau phase. CONCLUSIONS Most CNS effects of alcohol showed a trend to change over time, despite stable concentrations. Other variables remained stable under pseudo-steady-state conditions. The intravenous clamping method provides precise control over BrAC levels and allows frequent repetition of different CNS measurements. These features make this technique eminently suitable to study the complex pharmacodynamic effects of acute alcohol administration. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Thyroid hormone free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death. • The association between hyperthyroidism and ventricular arrhythmias or sudden cardiac death has been reported in several case reports. WHAT THIS STUDY ADDS • We investigated in a prospective population-based cohort study and in a case–control study whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of sudden cardiac death. • Use of antithyroid drugs was associated with a threefold increased risk of sudden cardiac death. • Although this might be due to antithyroid drug use, it could be more readily explained by underlying hyperthyroidism. AIM Thyroid free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death (SCD). Hyperthyroidism has been associated with SCD in case reports, but there are no population-based studies confirming this. The aim was to investigate whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of SCD. METHODS We studied the occurrence of SCD in a two-step procedure in two different Dutch populations. First, the prospective population-based Rotterdam Study including 7898 participants (≥55 years old). Second, we used the Integrated Primary Care Information (IPCI) database, which is a longitudinal general practice research database to see whether we could replicate results from the first study. Drug use at the index date was assessed with prescription information from automated pharmacies (Rotterdam Study) or drug prescriptions from general practices (IPCI). We used a Cox proportional hazards model in a cohort analysis, adjusted for age, gender and use of QTc prolonging drugs (Rotterdam Study) and conditional logistic regression analysis in a case–control analysis, matched for age, gender, practice and calendar time and adjusted for arrhythmia and cerebrovascular ischaemia (IPCI). RESULTS In the Rotterdam Study, 375 participants developed SCD during follow-up. Current use of antithyroid drugs was associated with SCD [adjusted hazard ratio 3.9; 95% confidence interval (CI) 1.7, 8.7]. IPCI included 1424 cases with SCD and 14 443 controls. Also in IPCI, current use of antithyroid drugs was associated with SCD (adjusted odds ratio 2.9; 95% CI 1.1, 7.4). CONCLUSIONS Use of antithyroid drugs was associated with a threefold increased risk of SCD. Although this might be directly caused by antithyroid drug use, it might be more readily explained by underlying poorly controlled hyperthyroidism, since treated patients who developed SCD still had low thyroid-stimulating hormone levels shortly before death. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several antidepressants are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). • The variant allele CYP2D6* 4 is the main polymorphism resulting in decreased enzyme activity in Caucasians. • Decreased CYP2D6 enzyme activity potentially leads to higher plasma concentrations of antidepressants. • Consequently, patients carrying the * 4 allele are more likely to suffer from adverse drug reactions such as hyponatraemia. WHAT THIS STUDY ADDS • The association between CYP2D6 genotype and serum sodium concentration in users of antidepressants has not been examined thoroughly, and most studies suffer from small numbers of poor metabolizers (PMs) of CYP2D6. • This study shows that serum sodium concentrations in users of tricyclic antidepressive drugs are lower in CYP2D6 PMs than in extensive metabolizers. AIM To study the effect of the CYP2D6* 4 polymorphism on serum sodium concentration in users of antidepressants [selective serotonin reuptake inhibitors and tricyclic antidepressants (TCAs)]. METHODS In this population-based cohort study, all subjects in the Rotterdam Study were included who used an antidepressant at baseline and from whom a blood sample was available in which CYP2D6 genotype and serum sodium concentration could be determined ( n= 76). Multivariate linear regression was used to study the association between CYP2D6* 4 and serum sodium concentration. RESULTS CYP2D6 poor metabolizers (PMs) (* 4/* 4) had a significantly lower mean serum sodium concentration in comparison with CYP2D6 extensive metabolizers (EMs) (* 1/* 1) [difference −3.9 mmol l−1; 95% confidence interval (CI) −0.86, −7.03; P= 0.013]. In CYP2D6* 4 heterozygotes (* 1/* 4) serum sodium concentration was 1.7 mmol l−1 (95% CI −3.48, 0.18) lower compared with CYP2D6 EMs, but this difference was not statistically significant ( P= 0.077). CONCLUSIONS The serum sodium concentration in PMs was lower in users of an antidepressant, especially in TCA users. Therefore CYP2D6 PMs might be at increased risk of developing symptoms of hyponatraemia. [ABSTRACT FROM AUTHOR]