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Xia Yang, Wei Liu, Allie Lyons, Zaiwei Song, ,
Published: 27 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 181-182; https://doi.org/10.1007/s00228-017-2355-7

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Youhua Wang, Rulin Zhao, Ben Wang, Qiaoyun Zhao, Zhen Li, Liya Zhu-Ge, Wenzhu Yin,
Published: 8 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 1-13; https://doi.org/10.1007/s00228-017-2347-7

Abstract:
Sequential and concomitant therapies are two innovative therapies for Helicobacter pylori (H. pylori) eradication. However, the comparative efficacy and safety of these treatments are controversial. Therefore, we aimed to conduct an updated systematic review and meta-analysis of studies that compared these two treatments.
Correction
Published: 26 October 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1457-1457; https://doi.org/10.1007/s00228-017-2358-4

Abstract:
In the 3rd paragraph and 2nd line of the Conclusion section the correct sentence should be: It is now important to encourage policy and decision makers to facilitate and accommodate future linkage of data.
, , Martina Vallin, Maria Juhasz-Haverinen, Eva Andersén-Karlsson, Kristina Ateva, Lars L Gustafsson, Malena Jirlow, Pia Bastholm-Rahmner
Published: 23 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 131-138; https://doi.org/10.1007/s00228-017-2354-8

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Published: 24 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 171-179; https://doi.org/10.1007/s00228-017-2351-y

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Feng Xiao, Feng Zhang, Ling-Ling Zhang,
Published: 19 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 69-77; https://doi.org/10.1007/s00228-017-2342-z

Abstract:
Objective The aim of this study was to investigate the safety, maximum tolerated dose and pharmacokinetics (PK) of iguratimod and the effect of food on PK parameters in healthy adult volunteers. Methods This phase 1 study consisted of four parts. Part 1 was a single-ascending dose (3.125, 6.25, 12.5, 25, 50, 75 mg) study to assess the maximum tolerated dose and safety of iguratimod. Part 2 was a single-ascending dose study to analyze the pharmacokinetic (PK) parameters of iguratimod; subjects were divided into three groups, with each group receiving iguratimod at a different dose (25, 50 or 75 mg). Part 3 was designed to compare the pharmacokinetic parameters of iguratimod between single-dose and multiple-dose administration; subjects were divided into two groups, with one group receiving a single dose of 50 mg on day 1 and the other group receiving a multiple dose of 50 mg, once every day, until a stable plasma concentration had been achieved. The aim of part 4 was to evaluate the effect of food on the pharmacokinetic parameters of iguratimod; subjects were divided into two groups, namely a fed group and a fasted group, with each group receiving a single 50 mg dose of iguratimod on day 1. Following a 14-day washout period, the two groups were crossed-over and received a single dose of 50 mg iguratimod on day 15. Results In part 1 of the study, iguratimod at doses ranging from 3.125 to 50 mg were well tolerated, with most adverse effects (AEs) being mild; no severe AEs occurred. In part 2, there were no significant differences in Tmax, T1/2, Ka and V/F among volunteers receiving doses of 25, 50 and 75 mg iguratimod. The Cmax and AUC0-last in volunteers receiving 75 mg iguratimod were higher than those in volunteers receiving 25 and 50 mg. The Cmax was linear from 25 to 75 mg, with a correlation coefficient (r2) of 0.9808. The AUC0-last was also linear from 25 to 75 mg, with an r2 of 0.9839. In part 3, in subjects receiving multiple doses of 50 mg, the T1/2 was 10.25 h, Tmax was 3.63 h, Cmax was 1.88 mg/L, AUC0-last was 31.88 mg/L h, Vd was 1.16 L and Ka was 0.87 1/h.There were no significant differences in the Cmax, AUC0-last, Ka and V/F between the single-dose and multiple-dose groups; there were, however, significant differences in Tmax and T1/2 between the two groups. In part 4, there were no significant differences in T1/2, AUC0-last, Ka and V/F between the fed group and fasted group; however, food may promote the absorption of iguratimod. Conclusions The maximum tolerated dose for iguratimod was confirmed to be 50 mg. The ingestion of food was able to increase the peak concentration of iguratimod and shorten the time to peak concentration. Therefore, based on our results, iguratimod can be administered with food. The PK profile and metabolic effects of iguratimod support further clinical development for its application in treating autoimmune diseases.
, on behalf of the Italian Group for Appropriate Drug prescription in the Elderly (I-GrADE), , , , , , , , , et al.
Published: 18 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 119-129; https://doi.org/10.1007/s00228-017-2352-x

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, Guadalupe García-Pino, Esther Vergara, Sonia Mota-Zamorano, Montserrat García-Cerrada,
Published: 18 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 53-60; https://doi.org/10.1007/s00228-017-2353-9

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Xuan Zhou, Yang-Yang Gao, Jian-Yong Hu, Yu Dong, Hai-Zhu Zhang,
Published: 6 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 37-44; https://doi.org/10.1007/s00228-017-2346-8

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Takahiro Suzuki, , Takahiro Uotani, Mihoko Yamade, , , , Ken Sugimoto, Hiroaki Miyajima,
Published: 6 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 45-52; https://doi.org/10.1007/s00228-017-2324-1

Abstract:
Vonoprazan, a novel potassium-competitive acid blocker, elicits potent acid inhibition and hypergastrinemia at a dose of 20 mg. Its recommended maintenance dose for gastro-esophageal reflux disease is 10 mg, which is sometimes insufficient for preventing nocturnal acid breakthrough (NAB). Concomitant use of a histamine 2 receptor antagonist (H2RA) is effective for NAB. However, further acid inhibition by addition of H2RA has concern of hypergastrinemia again. Lafutidine (H2RA) is known to stimulate somatostatin release.
, Jadwiga Twardosz, Anna Kasprzyk, , Krzysztof Kałwak,
Published: 3 October 2017
European Journal of Clinical Pharmacology, Volume 74, pp 79-89; https://doi.org/10.1007/s00228-017-2344-x

Abstract:
Purpose There is an increasing interest in use of treosulfan (TREO), a structural analogue of busulfan, as an agent in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT), both in pediatric and adult populations. The aim of this study was to develop a population pharmacokinetic model and to establish limited sampling strategies (LSSs) enabling accurate estimation of exposure to this drug. Methods The study included 15 pediatric patients with malignant and non-malignant diseases, undergoing conditioning regimens prior to HSCT including TREO administered as a 1 h or 2 h infusion at daily doses of 10, 12, or 14 g/m2. A population pharmacokinetic model was developed by means of non-linear mixed-effect modeling approach in Monolix® software. Multivariate regression analysis and Bayesian method were used to develop 2- and 3-point strategies for estimation of exposure to TREO. Results Pharmacokinetics of TREO was best described with a two-compartmental linear model with proportional residual error. Following sampling schedules allowed accurate estimation of exposure to TREO: 1 h and 6 h or 1 h, 2 h, and 6 h for a TREO dose 12 g/m2 in a 1 h infusion, or at 2 h and 6 h or 2 h, 4 h, and 8 h for a TREO dose of 12 g/m2 and 14 g/m2 in a 2 h infusion. Conclusions A two-compartmental population pharmacokinetic model of TREO was developed and successfully used to establish 2- and 3-point LSSs for accurate and precise estimation of TREO AUC0→∞.
, Zhan-Zhang Wang, Hai-Tang Hu, Xiao-Jia Ni, Hao-Yang Lu, , Ling-Fang Shen, , Yue-Feng Zhang, Huan Peng
Published: 3 October 2017
European Journal of Clinical Pharmacology, Volume 74; https://doi.org/10.1007/s00228-017-2340-1

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, Jian Cheng, Chunjian Li
Published: 30 September 2017
European Journal of Clinical Pharmacology, Volume 74, pp 29-35; https://doi.org/10.1007/s00228-017-2338-8

Abstract:
Early and intensive atorvastatin treatment can decrease nonsustained ventricular tachycardia (nsVT) in patients with ST-segment elevation myocardial infarction (STEMI). The objective of this study was to compare the effects of hydrophilic rosuvastatin and lipophilic atorvastatin on nsVT in STEMI patients treated with primary percutaneous coronary intervention (PCI). The data from a cohort of patients undergoing primary PCI at Jinhua Municipal Central Hospital from January 1, 2013 through June 30, 2016 were analyzed. The patients were divided into the rosuvastatin group and the atorvastatin group based on which kind of statins that they had received. The endpoint of the study was the occurrence of nsVT on either electrocardiogram monitoring or Holter monitoring. A total of 301 patients were enrolled in the study (rosuvastatin group: n = 103; atorvastatin group: n = 198). The baseline and procedural characteristics were similar between the two groups, except that total ischemic time in the rosuvastatin group was markedly longer than that in the atorvastatin group (8 (5-16) h vs. 6 (4-12) h; P = 0.001). The administration of rosuvastatin was significantly associated with lower occurrence of nsVT than that of atorvastatin (9.71 vs. 19.70%; P = 0.026). Multivariable logistic regression analysis suggested that the independent predictors of nsVT included rosuvastatin (odds ratio (OR) 0.397, 95% confidence interval (CI) 0.176-0.894), current smoking (OR 2.307, 95% CI 1.011-5.262), and left ventricular ejection fraction (LVEF) (OR 1.060, 95% CI 1.023-1.098). The effects of rosuvastatin on nsVT might be better than that of atorvastatin in STEMI patients undergoing primary PCI.
Reinier Smit, , Nathalie C. Péquériaux, Daan A. Hollander, Michiel W. P. Bleeker, Yasamin Latify, Walter A. Hermens, Hieronymus J. Derijks
Published: 27 September 2017
European Journal of Clinical Pharmacology, Volume 74, pp 139-140; https://doi.org/10.1007/s00228-017-2339-7

Zoe Oesterreicher, Iris Minichmayr, Robert Sauermann, Daniela Marhofer, Edith Lackner, , Alexandra Maier-Salamon, Richard Schwameis, Charlotte Kloft,
Published: 17 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1609-1613; https://doi.org/10.1007/s00228-017-2327-y

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, T. Hortobágyi, G. Van Staveren, K. Taxis, F. Boersma, , W. J. R. Bossers, C. G. Blankevoort, E. J. A. Scherder, E. A. Van Der Zee, et al.
Published: 18 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1633-1642; https://doi.org/10.1007/s00228-017-2319-y

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Qasim Khan, , Iqbal Haider, Inam Ul Haq, Sidra Noor
Published: 12 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1511-1518; https://doi.org/10.1007/s00228-017-2321-4

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, G. Francis, J. Martin, M. Boyce
Published: 15 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1551-1555; https://doi.org/10.1007/s00228-017-2329-9

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, Marta Karaźniewicz-Łada, Anna Komosa, Paweł Burchardt, Maciej Lesiak, , Agnieszka Graczyk-Szuster,
Published: 15 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1623-1632; https://doi.org/10.1007/s00228-017-2334-z

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, , Julie H. Schiavo
Published: 13 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1523-1537; https://doi.org/10.1007/s00228-017-2325-0

Abstract:
Drug-induced oral lichenoid reactions (DIOLRs) have been extensively reported in the literature, but the validity of the causality relationship between any drug and the oral lichenoid lesions (OLLs) still remains questionable. We sought to determine whether this causality relationship really exists, whether a resolution of the oral lesions upon withdrawal occurs, and what the most common alleged offending medications are. Nine electronic databases from January 1966 to December 2016 were systematically searched to identify all relevant studies selected with specific inclusion criteria (a clinical and histopathological diagnosis of DIOLRs, and clearly statement on the systemic offending medication). Searched terms included but not limited to oral lichen planus/oral lichenoid lesions/oral lichenoid reactions, the adverse effects of medication, and drug-induced. Statistical analyses conducted. The search retrieved a total of 817 articles, of which only 46 were included into a qualitative synthesis: 40 case reports/series and 6 studies. The causality assessment was done only in 14.8% of cases with the C-D-R protocol. The Naranjo algorithm was not reported in the majority of cases (98.2%). Culprit medication was withdrawn in 68.5% of the cases, obtaining a partial or complete resolution without treatment in 16.7% of cases and with treatment in 27.7% of cases. The median number of culprit medication(s) described was 1 with the most frequent ones being Methyldopa (20.37%), Interferon (IFN)-alpha (11.11%), and Imatinib and Infliximab (9.26%). This systematic review demonstrated that there is no strong scientific evidence to support the causal relationship between any drug and oral lichenoid lesions; therefore, in all reviewed cases, we must question whether the DIOLRs represent a real and separate clinical entity. Further and more thorough investigations using one of the available algorithms for adverse drug reaction are warranted.
, Antonio J. Carcas, Xavier Carné
Published: 12 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1557-1563; https://doi.org/10.1007/s00228-017-2332-1

Abstract:
Purpose General notification offers a possible alternative to written informed consent for pragmatic randomized controlled trials (pRCTs). It involves patients being informed through brochures, posters, and letters that research is being conducted simultaneously to providing clinical care and that patients will be enrolled in pRCTs without study-specific consent. A previous survey found that a substantial minority of respondents endorsed general notification. We aimed to know who is willing to enroll in this type of trials using general notification rather than written consent. Methods The previous study was a cross-sectional, probability-based survey, with a 2 × 2 factorial design. Two scenarios were assessed: two low-risk pRCTs in hypertension, one comparing two drugs with similar benefit/risk ratio and the other taking the same drug in the morning or at night. Each scenario had two routes: written consent vs verbal consent and written consent vs general notification. In this study, we were interested in the latter route in both scenarios. Respondents’ preferences were measured based on their recommendation to the research ethics committee and the respondent’s personal preference. We aimed to investigate the characteristics of those supporting general notification in either outcome or the variables explaining consistency and inconsistency between their personal preference and their recommendation. Based on the results of the original survey, we aimed to have at least 200 inconsistent respondents; to this end, the sample size was increased accordingly in a second wave of the survey. Results One thousand six hundre and ten respondents were included; 1003 from the original survey and 607 new ones belonging to the second wave. Thirty-nine percent of respondents chose general notification as personal preference and/or recommendation. Respondents with lower education levels were more prone to accept general notification than those holding a university degree [OR (95% CI)], primary school [2.959 (2.069–4.232)], secondary school [2.899 (2.09–4.021)], or high school [1.620 (1.184–2.217)]. Also unemployed [1.372 (1.064–1.770)] and retired [1.445 (1.049–1.990)], but not students, showed preference for general notification in comparison with those employed. Individuals more than 24 years old and having received high school or university (or postgraduate) education were statistically significantly more consistent in their decisions. Conclusions Thirty-nine percent of respondents is open to not to be asked for their informed consent in low-risk pRCTs; of these, those being less educated and not having current job or being retired are significantly more open to general notification. The use of this alternative method to written consent for simultaneous conduct of pRCTs and care should be considered and educational programs settled up to, in the case of public acceptance, ensure its ethical appropriateness.
Published: 11 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1665-1672; https://doi.org/10.1007/s00228-017-2333-0

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, O. Della Pasqua,
Published: 11 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1219-1236; https://doi.org/10.1007/s00228-017-2301-8

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Caterina Bigi,
Published: 2 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1379-1387; https://doi.org/10.1007/s00228-017-2309-0

Abstract:
The reporting of suspected adverse drug reactions (ADRs) is starting to become routine to nurses. The aim of this review is to underline the role of clinical and community health nurses in pharmacovigilance and to promote their effective participation in ADR reporting in different countries and for patients of different ages.
Published: 1 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1467-1474; https://doi.org/10.1007/s00228-017-2312-5

Abstract:
Purpose The purpose of this study is to investigate whether there is an association between anticholinergic burden and mortality or rehospitalization in older adults discharged from hospital. Methods Prospective multicenter cohort study carried out with patients aged 65 and older discharged from seven acute care hospitals. The primary outcomes of the study were rehospitalization and mortality within 1 year after discharge. The study population was classified in three groups according to the anticholinergic exposure measured by the Anticholinergic Risk Scale (ARS) and Durán’s list at the time of hospital discharge: without risk (ARS/Durán = 0), low risk (ARS/Durán = 1), and high risk (ARS/Durán ≥ 2). Predictors of hospitalizations and mortality were examined using regression models adjusting for important covariates. Results The mean age of the 921 participants was 81.2 years (SD = 7.4 years). Prevalence of exposure to medications with anticholinergic activity ranged from 19.6% with ARS to 32.1% with Durán’s list. During the follow-up period, 30.4% of participants were hospitalized and 19.4% died. Multivariate regression analysis showed that low anticholinergic burden quantified according to Durán’s list was significantly associated with all-cause mortality (OR 1.69, 95% CI 1.02–2.82). This association was not present after adjustment when using ARS. No statistically significant association was found between anticholinergic burden and hospitalizations. Conclusions Taking medications with anticholinergic activity is associated with greater risk of mortality in older adults discharged from acute care hospitals. Strategies to reduce anticholinergic burden in vulnerable elders could be useful to improve health outcomes. Further research is required to assess the association between anticholinergic burden and hospitalizations in older patients.
M. Ehrnebo, S. Agurell, B. Jalling
Published: 1 September 1971
European Journal of Clinical Pharmacology, Volume 3, pp 189-193; https://doi.org/10.1007/bf00565004

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E. E. Ohnhaus, U. Münch, J. Meier
Published: 1 January 1982
European Journal of Clinical Pharmacology, Volume 22, pp 247-251; https://doi.org/10.1007/bf00545223

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, J. Miettunen, S. Sneck, H. Lehtiniemi, O. Tenhunen,
Published: 5 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1539-1549; https://doi.org/10.1007/s00228-017-2330-3

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Carmen Walter, Bruno G. Oertel, Lisa Felden, Ulrike Nöth, Johannes Vermehren, Ralf Deichmann,
Published: 2 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1579-1587; https://doi.org/10.1007/s00228-017-2331-2

Abstract:
Background Considering the increasing acknowledgment of the human sense of smell as a significant component of the quality of life, olfactory drug effects gain potential clinical importance. A recent observation in a human experimental context indicated that Δ9-tetrahydrocannabinol (THC) impaired the subject’s performance in olfactory tests. To further analyze the role of THC in human olfaction, the present report addresses its effects on the central processing of olfactory stimuli. Methods Employing a placebo-controlled randomized crossover design, an oral dose of 20 mg THC was administered in 15 healthy volunteers. The central processing of olfactory input, consisting of short pulses of gaseous vanillin or hydrogen sulfide, and for comparison, of non-odorous but painful carbon dioxide, were investigated before and after administration of THC or placebo in a pharmacological functional magnet resonance imaging study. Results Following THC administration, the vanillin stimuli lost their pleasantness and became hedonically inert. This observation had its functional correlate in reduced stimulus-associated brain activations located in the left amygdala, the hippocampus and superior temporal pole (peak MNI coordinates x = − 27, y = − 1, z = − 26 mm p = 0.039). Differences in amygdala activations were significantly correlated with the corresponding differences in vanillin pleasantness (p = 0.025). By contrast, no effects were observed on the perception of processing of H2S stimuli. Conclusions The results support that THC induced a modulation of the central processing of olfactory input. The THC-induced reduction in the pleasantness of a pleasurable odor was accompanied by reduced activations in the limbic system. Results agree with previous observation of negative effects of cannabinoids on the human sense of smell and strengthen the evidence that THC-based medications will be among drugs with olfactory side effects.
, Yohann Mansiaux, Ana Jarné, , Cécile Pageot, Julien Bezin, Andy Smith, Bernard Bégaud
Published: 2 September 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1655-1663; https://doi.org/10.1007/s00228-017-2326-z

Abstract:
Purpose In 2011, pioglitazone was withdrawn from the French market owing to a potential risk of bladder cancer. This study aimed at assessing the impact of this pioglitazone withdrawal (PW) considering (i) trends in antidiabetic uses and (ii) changes in hospitalization/death rates in diabetic patients following PW. Methods We first considered the general population of the Echantillon Généraliste des Bénéficiaires (EGB), a 1/97th representative sample of the French healthcare insurance system beneficiaries, for the 2010–2014 period. In this, for each non-insulinic antidiabetic drug class, changes within the numbers of monthly supplied drug units for 1000 subjects were studied through times series and Unobserved Component Models. Second, we identified from the EGB a cohort of patients who were delivered a non-insulinic antidiabetic between 01 April 2011 and 01 August 2011 (date of PW). In this, post-withdrawal incidences of all-cause hospitalization and death were compared amongst pioglitazone users and non-users using proportional subdistribution hazards models. Results PW was accompanied by an increase in metformin (+ 11.7; 95% CI 1.1–22.3) and glinide (+ 11.0; 95% CI 1.2–20.8) numbers of monthly supplied units for 1000 subjects. No significant change was found for GLP-1 agonists, DPP-4 inhibitors, sulphonylureas or alpha-glucosidase inhibitors. In the cohort of non-insulinic antidiabetic users at the time of PW (1093 pioglitazone users, 17,900 non-users), being a pioglitazone user at PW was not associated with a subsequently higher rate of hospitalization. Conclusions If PW was accompanied with significant changes in the use of some antidiabetics, no adverse impact of PW on hospitalization or death rates of diabetic type 2 patients was found.
Hsien-Feng Lin, Kuan-Fu Liao, Ching-Mei Chang, Cheng-Li Lin,
Published: 30 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1615-1621; https://doi.org/10.1007/s00228-017-2328-x

Abstract:
Few studies have reported the association of the use of selective serotonin reuptake inhibitors (SSRIs) with acute pancreatitis. We conducted a population-based case-control study to explore this relationship.
A. B. Sanchez Spitman, D. J. A. R. Moes, H. Gelderblom, V. O. Dezentje, ,
Published: 28 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1589-1598; https://doi.org/10.1007/s00228-017-2323-2

Abstract:
Background Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this study is to investigate the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. Methods DNA from 667 women enrolled in the CYPTAM study (NTR1509) was genotyped (CYP2D6, CYP3A4*22, and CYP3A5*3). Tamoxifen and metabolite concentrations were measured in serum, and metabolic ratios were calculated. The effect of the CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes in addition to the CYP2D6 genotypes was examined by multiple linear regression analysis. Results CYP3A4*22 carriers reached significant higher concentrations of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-tamoxifen compared to non-carriers, whereas a tendency toward increased endoxifen levels was observed (p = 0.088). The metabolic ratio tamoxifen/N-desmethyl-tamoxifen was significantly higher in CYP3A4*22 individuals (0.59 vs. 0.52, p < 0.001). At the same time, CYP3A4*22 genotype contributed to improving the inter-variability [R2 of the (log-transformed) metabolic ratio tamoxifen/N-desmethyl-tamoxifen improved from 21.8 to 23.9%, p < 0.001]. CYP3A5*3 marginally improved the explained variability of the (log transformed) metabolic ratio 4-hydroxy-tamoxifen/endoxifen (from 44.9 to 46.2%, p < 0.038). Conclusion Our data demonstrate that CYP3A genotype has a minor effect to explaining the variability between patients in tamoxifen metabolism and has no added value in addition to CYP2D6 genotype.
, ShuSen Sun, Xi Ling, Kai Chen, ,
Published: 29 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1599-1607; https://doi.org/10.1007/s00228-017-2313-4

Abstract:
Purpose Combined intravenous and intraventricular administration of vancomycin into the cerebrospinal fluid (CSF) has been increasingly utilized for neurosurgical patients, but little is known about the population pharmacokinetics of vancomycin in the plasma and CSF. The aim of our study was to identify significant factors associated with plasma and CSF vancomycin concentrations to guide clinicians with vancomycin dosing. Methods Patients with an indwelling ventricular drainage catheter who received intravenous and intraventricular vancomycin were enrolled in this study. Blood and CSF samples were collected at scheduled times and vancomycin concentrations determined. A three-compartmental model (central, peripheral and CSF compartments) was proposed to describe the in vivo behavior of vancomycin. CSF outflow resulted in vancomycin loss, and the clearance of CSF compartment (CLCSF) was used to describe this loss. The nonlinear mixed-effects modeling method was applied to structure the population model, and the stepwise incorporation of seven covariates into the final model was attempted. Simulation was performed with the goal of CSF concentrations reaching or exceeding the minimum inhibitory concentration during therapy. Results Serum creatinine clearance had a significant influence on clearance of the central compartment. CLCSF had a positive correlation with drainage amount and a negative correlation with elapsed time. Model validation (bootstrap and visual predictive check) demonstrated the stability and performance of the proposed population model. A simple-to-use dosage regimen table was created based on the simulation results. Conclusions The proposed final model may be used to guide clinicians with vancomycin dosing in this specific patient population.
, I. Diemberger, M. De Ridder, A. Koci, M. Clo, A. Oteri, S. Pecchioli, I. Bezemer, , S. Pilgaard Ulrichsen, et al.
Published: 22 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1499-1510; https://doi.org/10.1007/s00228-017-2317-0

The publisher has not yet granted permission to display this abstract.
, Kimie Sai, Chisato Fukazawa, Yasushi Hinomura, Ryosuke Nakamura, Yoshimi Okamoto-Uchida, Katsunori Segawa, Yoshiro Saito
Published: 22 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1643-1653; https://doi.org/10.1007/s00228-017-2320-5

Abstract:
Purpose It has been reported recently that immune reactions are involved in the pathogenesis of certain types of adverse drug reactions (ADRs). We aimed to determine the associations between infections and drug-induced interstitial lung disease (DILD), rhabdomyolysis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), or drug-induced liver injury (DILI) using a spontaneous adverse drug event reporting database in Japan. Methods The reported cases were classified into three categories (anti-infectious drug group, concomitant infection group, and non-infection group) based on the presence of anti-infectious drugs (either as primary suspected drug or concomitant drug) and infectious disease. We assessed the association between four severe ADRs and the presence and seriousness of infection using logistic regression analysis. Results We identified 177,649 cases reported in the study period (2009–2013). Logistic regression analysis showed significant positive associations between infection status and onset of SJS/TEN or DILI (SJS/TEN: anti-infectious drug group: odds ratio (OR) 2.04, 95% CI [1.85–2.24], concomitant infection group: OR 2.44, 95% CI [2.21–2.69], DILI: anti-infectious drug group: OR 1.27, 95% CI [1.09–1.49], concomitant infection group: OR 1.25, 95% CI [1.04–1.49]), compared to the non-infection group. By contrast, there were negative or no associations between infection and DILD or rhabdomyolysis. A significantly positive association between infection and SJS/TEN seriousness (OR 1.48, 95% CI [1.10–1.98]) was observed. Conclusions This study suggested that infection plays an important role in the development of SJS/TEN and DILI. For the patients with infection and/ or anti-infectious drugs, careful monitoring for severe ADRs, especially SJS/TEN, might be needed.
, Changtao Jiang
Published: 22 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1337-1339; https://doi.org/10.1007/s00228-017-2322-3

The publisher has not yet granted permission to display this abstract.
Published: 17 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1449-1455; https://doi.org/10.1007/s00228-017-2310-7

Abstract:
Introduction Administrative health data, such as pharmacy claims data, present a valuable resource for conducting pharmacoepidemiological and health services research. Often, data are available for whole populations allowing population level analyses. Moreover, their routine collection ensures that the data reflect health care utilisation in the real-world setting compared to data collected in clinical trials. Setting and methods The Irish Health Service Executive-Primary Care Reimbursement Service (HSE-PCRS) community pharmacy claims database is described. The availability of demographic variables and drug-related information is discussed. The strengths and limitations associated using this database for conducting research are presented, in particular, internal and external validity. Examples of recently conducted research using the HSE-PCRS pharmacy claims database are used to illustrate the breadth of its use. Results and conclusions The HSE-PCRS national pharmacy claims database is a large, high-quality, valid and accurate data source for measuring drug exposure in specific populations in Ireland. The main limitation is the lack of generalisability for those aged <70 years and the lack of information on indication or outcome.
Ju-E Liu, Xiao-Ying Liu, Sheng Chen, Yan Zhang, Li-Yun Cai, Min Yang, Wei-Hua Lai, Bin Ren,
Published: 15 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1409-1416; https://doi.org/10.1007/s00228-017-2318-z

Abstract:
Purpose This nested case–control study aimed to evaluate the association of candidate genetic variants with statin-induced myotoxicity in Chinese patients with coronary artery disease (CAD). Methods One hundred forty-eight Chinese patients experiencing statin-induced myotoxicity were included in our study, and 255 patients without muscular side effects served as controls. Five SNPs in CYP3A5, SLCO1B1, and APOE were genotyped. The effect of genetic variants on statin-induced myotoxicity was assessed. Results Patients who carried at least one SLCO1B1 521C allele had a higher risk for myotoxicity (OR = 1.69, 95%CI = 1.07–2.67, P = 0.024). Significant association was found between SLCO1B1 521C mutant allele mutation and risk of myotoxicity in individuals that received rosuvastatin (OR = 3.67, 95%CI = 1.42–9.47, P = 0.007). However, non-significant association was observed between 521C mutant allele and risk of myotoxicity (P > 0.5) in patients that received atorvastatin and simvastatin. The other four single nucleotide polymorphisms (SNPs), namely rs776746, rs2306283, rs7412, and rs429358, showed no significant association with any statin induced myotoxicity (P > 0.5). Conclusions SLCO1B1 (rs4149056, 521T > C) is associated with statin-induced myotoxicity in Chinese patients with coronary artery disease. In addition, SLCO1B1 521C mutant allele increased the risk of rosuvastatin-associated myotoxicity.
, Yukihiro Hamada, Yujiro Geka, Shiori Kuwana, Koji Hirai, Mai Ishibashi, Yutaka Fukaya, Toshimi Kimura
Published: 9 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1491-1497; https://doi.org/10.1007/s00228-017-2316-1

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, Christopher Cabib, Francisco Javier Barón,
Published: 5 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1389-1398; https://doi.org/10.1007/s00228-017-2314-3

Abstract:
Antipsychotics (APs) are commonly used to manage neuropsychiatric symptoms (NPS) in elderly patients with dementia, even though several large studies have demonstrated an association between AP treatment and increased morbidity and mortality in people with dementia. The aim of this study is to review the scientific literature of the use of AP in the elderly with dementia and to propose an algorithm to assist in decision-making regarding the withdrawal of APs. A computerized literature search (MEDLINE: 1966 to December 2016, EMBASE: 1982 to December 2016) was used to locate relevant literature. Keywords in the search included terms from Medical Subject Headings (MESH) and EMBASE thesaurus (EMTREE). The following terms were used in the MESH database and EMTREE thesaurus: Aged, Antipsychotic Agents, Behavioral Symptoms and Dementia. Earlier studies of APs used in elderly patients with dementia suggest that, in most elderly demented patients, APs can be withdrawn with no effect on behaviour. These patients are likely to benefit from the algorithm we propose to assist clinicians in the withdrawal of APs. In this paper, we review the potential risks and benefits of discontinuing AP treatment in elderly demented patients with NPS and propose an algorithm to assist in decision-making regarding AP withdrawal.
, Antje Groth, Andreas Fuchs, Matthias Pfannkuche, Ulf Maywald
Published: 5 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1437-1447; https://doi.org/10.1007/s00228-017-2307-2

Abstract:
Purpose The aim of this study was to describe persistence with vitamin K antagonist (VKA) treatment in German atrial fibrillation (AF) patients and to identify factors which may be associated with early discontinuation of VKA therapy. Methods We did a retrospective cohort study based on an anonymized German claims dataset with VKA treatment-naïve AF patients, who received at least one VKA prescription. VKA therapy discontinuation was defined as a gap >180 days. Results We identified 38,076 VKA patients who started a VKA therapy (mean age 76.13 years; 56.08% female; mean CHA2DS2-VASc-Score 4.49; mean Charlson Comorbidity Index (CCI) 3.91). After four quarters since start of VKA treatment, 14,889 (39.10%) of observed patients had discontinued their VKA treatment (after eight quarters: 54.61%). Mean time until treatment discontinuation was 390.55 days. Risk of VKA discontinuation increased with the diagnosis of dementia within the first two quarters of VKA treatment [HR 1.35 (95% CI 1.29–1.40)], diagnosed alcohol or drug abuse in the baseline period [HR 1.25; 95% CI 1.18–1.33)], female gender [HR 1.08; 95% CI 1.05–1.10)], higher age (HR 1.03; 95% CI 1.03–1.03), higher CCI (HR 1.05; 95% CI 1.04–1.05), any prescription of NSAID (HR 1.07; 95% CI 1.04–1.10), and number of surgeries in the first two quarters of VKA treatment (HR 1.05; 95% CI 1.04–1.05). At least one yearly visit to a cardiologist since start of VKA treatment decreased the risk of non-persistence [HR 0.90; 95% CI 0.88–0.93] and a cancer diagnosis in the baseline period (HR 0.92; 95% CI 0.89–0.96). Conclusion Non-persistence related to VKA therapy is common in AF patients. Older more comorbid female patients as well as patients who face surgeries and who do not visit a cardiologist regularly face a higher therapy discontinuation risk.
J. K. Berbee, L. A. Lammers, , J. C. Fischer,
Published: 7 August 2017
European Journal of Clinical Pharmacology, Volume 73, pp 1459-1465; https://doi.org/10.1007/s00228-017-2311-6

Abstract:
Purpose A patient was identified with severe metabolic acidosis, a high anion gap and 5-oxoproline accumulation, probably caused by the simultaneous use of paracetamol (acetaminophen) and flucloxacillin. We wanted to investigate the necessity to control the interaction between both drugs with an automatic alert system. Methods To investigate the relevance of the interaction of paracetamol and flucloxacillin, a retrospective study was conducted. Data on paracetamol and flucloxacillin prescriptions and laboratory data (pH, Na+, HCO3, Cl, albumin and 5-oxoproline levels) were combined to assess the prevalence of acidosis, calculate the anion gap and analyse 5-oxoproline levels in clinically admitted patients using both drugs simultaneously. Results In the 2-year study period, approximately 53,000 admissions took place in our hospital. One thousand and fifty-seven patients used paracetamol and flucloxacillin simultaneously, of which 51 patients (4.8%) had a serum pH ≤ 7.35. One patient, the same patient as presented in the case report, had a high anion gap and a toxic level of 5-oxoproline. Conclusion The prevalence of metabolic acidosis is very low and the only patient identified with the interaction was recognised during normal clinical care. We conclude that automatic alerts based on simultaneous use of paracetamol and flucloxacillin will generate too many signals. To recognise patients earlier and prevent severe outcomes, a warning system (clinical rule) based on paracetamol, flucloxacillin and pH measurement may be helpful. Early calculation of the anion gap can narrow the differential diagnosis of patients with metabolic acidosis and measurement of 5-oxoproline can explain acidosis due the interaction of paracetamol and flucloxacillin.
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