Impact of pharmacy services on cystic fibrosis medication adherence.

Pediatr Pulmonol. 2017 Jun 13;:

Authors: Zobell JT, Schwab E, Collingridge DS, Ball C, Nohavec R, Asfour F

Abstract
OBJECTIVES: The purpose of this study is to characterize the impact of pharmacy services on medication adherence and hospitalizations for pediatric cystic fibrosis (CF) patients.
METHODS: A retrospective health insurance claims analysis and patient medical charts review from January 1, 2014 to December 31, 2016 of patients from the Pediatric Intermountain CF Center was performed. Adherence to dornase alfa and hospital admissions for pulmonary exacerbations pre and post the implementation of an integrated pharmacy team were reviewed. Dornase alfa adherence was measured by the medication possession ratio (MPR) both monthly and yearly.
RESULTS: Fifty-four patients met inclusion criteria. The mean dornase alfa yearly MPR improved from 0.75 (2014) to 0.92 (2016). Patients were 2.8 times more likely to be adherent to dornase alfa when followed by integrated pharmacy team model (P < 0.001), and 2.4 times more likely to be adherent when followed by a dedicated CF clinic pharmacist only (P = 0.001).
CONCLUSION: The study demonstrated that pharmacy services improved adherence to dornase alfa.

PMID: 28608652 [PubMed - as supplied by publisher]

Cystic fibrosis year in review 2016.

Pediatr Pulmonol. 2017 Jun 13;:

Authors: Savant AP, McColley SA

Abstract
In this article, we highlight cystic fibrosis (CF) research and case reports published in Pediatric Pulmonology during 2016. We also include articles from a variety of journals that are thematically related to these articles, or are of special interest to clinicians.

PMID: 28608632 [PubMed - as supplied by publisher]

Four case reports of Chinese cystic fibrosis patients and literature review.

Pediatr Pulmonol. 2017 Jun 13;:

Authors: Xu J, Yin Y, Zhang L, Zhang J, Yuan S, Zhang H

Abstract
AIM: Cystic fibrosis (CF) is an extremely rare disease in Asians. Here, we report four Chinese children with CF and review the literature about Chinese CF patients.
METHODS: The cystic fibrosis transmembrane conductance regulator (CFTR) gene testing was performed on four suspected patients for CF screening. We also reviewed the literature about Chinese CF patients from 1970s. The clinical data of all these CF patients were summarized.
RESULTS: We diagnosed four CF patients who had mutations in the CFTR gene. We identified six different mutations in the four patients. The c.1766+5G>T, c.595C>T, c.2909G>A, and c.4056G>C had been reported already. The two splicing mutations of c.579+1_579+2insACAT and c.1117-1G>C were novel mutations. There have been 46 Chinese CF patients reported in literature from 1974 up to present (2016.12). The clinical manifestations of CF involved several systems. The most common symptom was recurrent pulmonary infections. Thirty-three different mutations were identified; c.1766 + 5G>T was the most common mutation among Chinese CF patients. Only one of these mutations (R553X) was in the Caucasian CF screening panel. The spectrum of CFTR mutations in Chinese was highly different from that of Caucasian.
CONCLUSIONS: There was a high risk of misdiagnosis or delayed diagnosis of CF even in suspected cases in China. It is necessary to educate Chinese clinicians about the signs, symptoms, and diagnosis of cystic fibrosis and promote the implementation of the sweat chloride test.

PMID: 28608624 [PubMed - as supplied by publisher]

Mechanisms of pyocyanin toxicity and genetic determinants of resistance in Staphylococcus aureus.

J Bacteriol. 2017 Jun 12;:

Authors: Noto MJ, Burns WJ, Beavers WN, Skaar EP

Abstract
Pseudomonas aeruginosa and Staphylococcus aureus are commonly isolated from polymicrobial infections, such as wound infections and chronic respiratory infections of persons with cystic fibrosis. Despite their co-isolation, P. aeruginosa produces substances toxic to S. aureus, including pyocyanin, a blue pigmented molecule that functions in P. aeruginosa virulence. Pyocyanin inhibits S. aureus respiration, forcing it to derive energy from fermentation and adopt a small colony variant (SCV) phenotype. The mechanisms by which S. aureus sustains infection in the presence of pyocyanin are not clear. We sought to clarify the mechanisms of pyocyanin toxicity in S. aureus as well as identify the staphylococcal factors involved in resistance to pyocyanin toxicity. Non-respiring S. aureus SCVs are inhibited by pyocyanin through pyocyanin-dependent reactive oxygen species (ROS) production, indicating that pyocyanin toxicity is mediated through respiratory inhibition and ROS generation. Selection on pyocyanin yielded a menadione auxotrophic SCV capable of growth on high concentrations of pyocyanin. Genome sequencing of this isolate identified mutations in four genes including saeS, menD, NWMN_0006, and qsrR QsrR is a quinone-sensing repressor of quinone detoxification genes. Inactivation of qsrR resulted in significant pyocyanin resistance and additional pyocyanin resistance was achieved through combined inactivation of qsrR and menadione biosynthesis. Pyocyanin-resistant S. aureus has enhanced capability to inactivate pyocyanin, suggesting QsrR-regulated gene products may degrade pyocyanin to alleviate toxicity. These findings demonstrate pyocyanin-mediated ROS generation as an additional mechanism of pyocyanin toxicity, and define QsrR as a key mediator of pyocyanin resistance in S. aureusImportance Many bacterial infections occur in the presence of other microbes, where interactions between different microbes and the host impact disease. In patients with cystic fibrosis, chronic lung infection with multiple microbes results in the most severe disease manifestations. Staphylococcus aureus and Pseudomonas aeruginosa are prevalent CF pathogens, and infection with both is associated with worse outcomes. These organisms have evolved mechanisms of competing with one another. For example, P. aeruginosa produces pyocyanin which inhibits S. aureus growth. Our research has identified how pyocyanin inhibits S. aureus growth and how S. aureus can adapt to survive in the presence of pyocyanin. Understanding how S. aureus sustains infection in the presence of P. aeruginosa may identify means of disrupting these microbial communities.

PMID: 28607159 [PubMed - as supplied by publisher]

Gel-forming mucins form distinct morphologic structures in airways.

Proc Natl Acad Sci U S A. 2017 Jun 12;:

Authors: Ostedgaard LS, Moninger TO, McMenimen JD, Sawin NM, Parker CP, Thornell IM, Powers LS, Gansemer ND, Bouzek DC, Cook DP, Meyerholz DK, Abou Alaiwa MH, Stoltz DA, Welsh MJ

Abstract
Gel-forming mucins, the primary macromolecular components of airway mucus, facilitate airway clearance by mucociliary transport. In cystic fibrosis (CF) altered mucus properties impair mucociliary transport. Airways primarily secrete two closely related gel-forming mucins, MUC5B and MUC5AC. However, their morphologic structures and associations in airways that contain abundant submucosal glands and goblet cells are uncertain. Moreover, there is limited knowledge about mucins in airways not affected by inflammation, infection, or remodeling or in CF airways. Therefore, we examined airways freshly excised from newborn non-CF pigs and CF pigs before secondary manifestations develop. We found that porcine submucosal glands produce MUC5B, whereas goblet cells produce predominantly MUC5AC plus some MUC5B. We found that MUC5B emerged from submucosal gland ducts in the form of strands composed of multiple MUC5B filaments. In contrast, MUC5AC emerged from goblet cells as wispy threads and sometimes formed mucin sheets. In addition, MUC5AC often partially coated the MUC5B strands. Compared with non-CF, MUC5B more often filled CF submucosal gland ducts. MUC5AC sheets also accumulated in CF airways overlying MUC5B strands. These results reveal distinct morphology and interactions for MUC5B and MUC5AC and suggest that the two mucins make distinct contributions to mucociliary transport. Thus, they provide a framework for understanding abnormalities in disease.

PMID: 28607090 [PubMed - as supplied by publisher]

Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial.

Lancet Respir Med. 2017 Jun 08;:

Authors: Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, Milla CE, Robinson PD, Waltz D, Davies JC, VX14-809-109 investigator group

Abstract
BACKGROUND: Lumacaftor and ivacaftor combination treatment showed efficacy in patients aged 12 years or older with cystic fibrosis homozygous for F508del-cystic fibrosis transmembrane conductance regulator (CFTR) in placebo-controlled studies and patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR in an open-label study. We report efficacy and safety of lumacaftor and ivacaftor in patients with cystic fibrosis aged 6-11 years homozygous for F508del-CFTR.
METHODS: In this phase 3, randomised, double-blind, placebo-controlled, multicentre study, patients were enrolled at 54 hospitals and medical centres in nine countries (the USA, Australia, Belgium, Canada, Denmark, France, Germany, Sweden, and the UK). Eligible patients weighed at least 15 kg, with a confirmed diagnosis of cystic fibrosis, percent predicted forced expiratory volume in 1 s (FEV1) of 70 or more, and lung clearance index2·5 (LCI2·5) of 7·5 or more at screening (values less than these thresholds were permitted at day 1). All patients were tested for CFTR genotype at screening; eligible patients had to have the F508del-CFTR mutation on both alleles. Exclusion criteria included any comorbidity or laboratory abnormality that might confound the study results or pose additional risk to the patient. Patients were stratified by weight (<25 kg vs ≥25 kg) and ppFEV1 severity (<90 vs ≥90) determined at the screening visit, and randomly assigned 1:1 to treatment using an interactive web response system to receive 200 mg lumacaftor and 250 mg ivacaftor every 12 hours or placebo for 24 weeks. Patients, all site personnel including the investigator and the site monitor, and the study team were blinded, with the exception of site personnel needing this information in the event of medical emergency or pregnancy and patient safety and regulatory affairs personnel to meet serious adverse event reporting requirements. The primary endpoint was the mean absolute change in LCI2·5 from all on-treatment study visits up to and including week 24. All randomly assigned patients who were exposed to any amount of study drug, with treatment assignment as assigned were included in primary and other efficacy analyses. All patients who were exposed to any amount of study drug, with treatment assignment as treated, were included in the safety analysis. This study was registered with ClinicalTrials.gov, number NCT02514473.
FINDINGS: Between July 23, 2015, and Sept 20, 2016, a total of 206 patients were enrolled and randomly assigned to receive lumacaftor and ivacaftor (n=104) or placebo (n=102). Two randomly assigned patients were never dosed with study drug (one in the placebo arm due to ineligibility arising from a streptococcal throat infection and one in the lumacaftor and ivacaftor arm due to withdrawal based on refusal to provide blood tests) and were not included in the analyses. 103 patients received at least one dose of lumacaftor and ivacaftor and 101 patients received at least one dose of placebo. For the primary endpoint, the average absolute change in LCI2·5 from baseline over all study visits up to and including the week 24 visit, least squares mean difference was -1·09 units (95% CI -1·43 to -0·75, p<0·0001) for lumacaftor and ivacaftor versus placebo. For the key secondary endpoint of sweat chloride concentration, the least squares mean difference versus placebo was -20·8 mmol/L (95% CI -23·4 to -18·2, average absolute change at day 15/week 4; p<0·0001). The least squares mean difference compared with placebo in absolute change in ppFEV1 from all on-treatment study visits until week 24 was 2·4 (95% CI 0·4-4·4, p=0·0182). 196 (96%) of 204 patients reported adverse events, most of which were mild (87 [43%]) or moderate (98 [48%]). Treatment was discontinued due to adverse events in three (3%) of 103 patients in the lumacaftor and ivacaftor group and two (2%) of 101 patients in the placebo group. Serious adverse events were reported in 13 (13%) of 103 patients in the lumacaftor and ivacaftor group and 11 (11%) of 101 patients in the placebo group.
INTERPRETATION: Treatment with lumacaftor and ivacaftor was associated with statistically significant improvements in lung function, as measured by LCI2·5 and ppFEV1, versus placebo in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR. The overall safety profile was consistent with previous phase 3 studies of lumacaftor and ivacaftor.
FUNDING: Vertex Pharmaceuticals.

PMID: 28606620 [PubMed - as supplied by publisher]

Cystic fibrosis transmembrane conductance-regulator modulators for children.

Lancet Respir Med. 2017 Jun 08;:

Authors: Colombo C

PMID: 28606619 [PubMed - as supplied by publisher]

Aortic Elastic Properties in Preschool Children Born Preterm.

Arterioscler Thromb Vasc Biol. 2016 Nov;36(11):2268-2274

Authors: Odri Komazec I, Posod A, Schwienbacher M, Resch M, Pupp Peglow U, Kiechl S, Baumgartner D, Kiechl-Kohlendorfer U

Abstract
OBJECTIVE: Preterm birth predisposes children to the development of cardiovascular diseases in adulthood. The aim of this study was to characterize elastic properties of the aorta at preschool age and test the hypothesis that prematurity is associated with decreased aortic distensibility and increased stiffness, both of which are predictors of increased cardiovascular risk.
APPROACH AND RESULTS: In an observational study of 76 five- to seven-year-old children born at a gestational age <32 weeks and 79 term-born controls, elastic parameters of the ascending and descending abdominal aorta were determined noninvasively by means of M mode echocardiographic tracings and calculated using computerized wall contour analysis. Compared with children born at term, the preterm group showed significantly reduced distensibility and increased stiffness of the descending abdominal aorta. These results remained significant under multivariable adjustment for birth weight z score, maternal smoking in pregnancy, maternal education, family history of cardiovascular disease, breastfeeding, childhood nutrition, and current body mass index z score (multivariable odds ratios and 95% confidence intervals 5.1, 1.7-15.9; P=0.005 and 2.8, 1.0-7.9; P=0.046, respectively). Further adjustment for intravenous lipid therapy attenuated the strength of association. Elastic properties of the ascending aorta did not differ between the 2 study groups.
CONCLUSIONS: Children born preterm are characterized by decreased elastic properties of the descending abdominal aorta potentially attributable to impaired viscoelastic properties of and lipid damage to the aorta. Clinical follow-up of preterm infants with a focus on aortic elastic properties may be useful for tailoring early prevention programs and counteracting cardiovascular risk in adulthood.

PMID: 27659099 [PubMed - indexed for MEDLINE]

Biogenic selenium nanoparticles: characterization, antimicrobial activity and effects on human dendritic cells and fibroblasts.

Microb Biotechnol. 2016 Nov;9(6):758-771

Authors: Cremonini E, Zonaro E, Donini M, Lampis S, Boaretti M, Dusi S, Melotti P, Lleo MM, Vallini G

Abstract
Tailored nanoparticles offer a novel approach to fight antibiotic-resistant microorganisms. We analysed biogenic selenium nanoparticles (SeNPs) of bacterial origin to determine their antimicrobial activity against selected pathogens in their planktonic and biofilm states. SeNPs synthesized by Gram-negative Stenotrophomonas maltophilia [Sm-SeNPs(-)] and Gram-positive Bacillus mycoides [Bm-SeNPs(+)] were active at low minimum inhibitory concentrations against a number of clinical isolates of Pseudomonas aeruginosa but did not inhibit clinical isolates of the yeast species Candida albicans and C. parapsilosis. However, the SeNPs were able to inhibit biofilm formation and also to disaggregate the mature glycocalyx in both P. aeruginosa and Candida spp. The Sm-SeNPs(-) and Bm-SeNPs(+) both achieved much stronger antimicrobial effects than synthetic selenium nanoparticles (Ch-SeNPs). Dendritic cells and fibroblasts exposed to Sm-SeNPs(-), Bm-SeNPs(+) and Ch-SeNPs did not show any loss of cell viability, any increase in the release of reactive oxygen species or any significant increase in the secretion of pro-inflammatory and immunostimulatory cytokines. Biogenic SeNPs therefore appear to be reliable candidates for safe medical applications, alone or in association with traditional antibiotics, to inhibit the growth of clinical isolates of P. aeruginosa or to facilitate the penetration of P. aeruginosa and Candida spp. biofilms by antimicrobial agents.

PMID: 27319803 [PubMed - indexed for MEDLINE]

An efficient system for selectively altering genetic information within mRNAs.

Nucleic Acids Res. 2016 Dec 01;44(21):e157

Authors: Montiel-González MF, Vallecillo-Viejo IC, Rosenthal JJ

Abstract
Site-directed RNA editing (SDRE) is a strategy to precisely alter genetic information within mRNAs. By linking the catalytic domain of the RNA editing enzyme ADAR to an antisense guide RNA, specific adenosines can be converted to inosines, biological mimics for guanosine. Previously, we showed that a genetically encoded iteration of SDRE could target adenosines expressed in human cells, but not efficiently. Here we developed a reporter assay to quantify editing, and used it to improve our strategy. By enhancing the linkage between ADAR's catalytic domain and the guide RNA, and by introducing a mutation in the catalytic domain, the efficiency of converting a U A: G premature termination codon (PTC) to tryptophan (U G: G) was improved from ∼11 % to ∼70 %. Other PTCs were edited, but less efficiently. Numerous off-target edits were identified in the targeted mRNA, but not in randomly selected endogenous messages. Off-target edits could be eliminated by reducing the amount of guide RNA with a reduction in on-target editing. The catalytic rate of SDRE was compared with those for human ADARs on various substrates and found to be within an order of magnitude of most. These data underscore the promise of site-directed RNA editing as a therapeutic or experimental tool.

PMID: 27557710 [PubMed - indexed for MEDLINE]

Long-term safety and efficacy of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes.

Diabetes Obes Metab. 2017 Jun 13;:

Authors: Kadowaki T, Inagaki N, Kondo K, Nishimura K, Kaneko G, Maruyama N, Nakanishi N, Watanabe Y, Gouda M, Iijima H

Abstract
AIM: To evaluate the long-term safety and efficacy of canagliflozin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy.
METHODS: This open-label 52-week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included the changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight from baseline to week 52 (with last observation carried forward).
RESULTS: Overall, 153 patients entered the treatment period and 142 completed the study. The overall incidence of AEs and drug-related AEs was 69.9% and 22.9%, respectively. Most AEs and drug-related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean (95% confidence interval) changes in HbA1c, FPG, and body weight were -0.99% (-1.12% to -0.85%), -38.6 mg/dL (-43.4 to -33.9 mg/dL), and -3.92% (-4.53% to -3.31%), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52.
CONCLUSIONS: No new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG, and body weight were observed. The findings suggest that long-term co-administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese T2DM patients with inadequate glycaemic control on teneligliptin alone.

PMID: 28608617 [PubMed - as supplied by publisher]

Risk factors for adverse drug reactions in pediatric inpatients: a systematic review.

Ther Adv Drug Saf. 2017 Jun;8(6):199-210

Authors: Andrade PHS, Santos ADS, Souza CAS, Lobo IMF, da Silva WB

Abstract
BACKGROUND: The main objective of the present systematic review is to identify potential risk factors for adverse drug reactions (ADRs) through prospective cohort studies in pediatric inpatients.
METHODS: The data search was done in the following electronic databases PubMed/MEDLINE; Scopus; LILACS and Web of Science from the earliest record until 31 May 2015. Two reviewers independently screened each study and one of them assessed the methodological quality according to the Newcastle-Ottawa scale for cohort studies. The data extraction was conducted according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative for cohort studies.
RESULTS: The only risk factor observed in all studies was the increase in the number of prescription drugs. However, other factors were identified, such as the increase in the length of stay or the number of low- or high-risk drugs prescribed, use of general anesthesia and oncological diagnosis. The cumulative incidence of ADR was 16.4% (95% confidence interval: 15.6 to 17.2). The main professional responsible for ADR identification was the pharmacist and the dominant category among the ADRs were gastrointestinal disorders. In addition, analgesics, antibacterial agents and corticosteroids were the drug classes commonly associated with ADRs. The methodology used in this study was tried to homogenize the data extracted; however, this was not sufficient to correct the discrepancies so it was not possible to perform a meta-analysis.
CONCLUSIONS: The increase in the number of prescription drugs was the main risk factor in this population. However, additional studies are required to identify the risk factors for ADRs in pediatric inpatients.

PMID: 28607669 [PubMed - in process]

Identification of enzymes responsible for nitrazepam metabolism and toxicity in human.

Biochem Pharmacol. 2017 Jun 09;:

Authors: Konishi K, Fukami T, Gotoh S, Nakajima M

Abstract
Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity in rodents. In humans, NZP is primarily metabolized to 7-aminonitrazepam (ANZP) by reduction and subsequently to 7-acetylamino nitrazepam (AANZP) by acetylation. ANZP can be regenerated from AANZP by hydrolysis in rodents, but it is still unclear whether this reaction occurs in humans. In rodents, AANZP may be associated with teratogenicity, while in humans, it is known that drug-induced liver injuries may be caused by NZP reactive metabolite(s). In this study, we attempted to identify the enzymes responsible for NZP metabolism to obtain a basic understanding of this process and the associated metabolite toxicities. We found that the NZP reductase activity in human liver cytosol (HLC) was higher than that in human liver microsomes (HLM). We purified the responsible enzyme(s) from HLC and found that the NZP reductase was aldehyde oxidase 1 (AOX1). The role of AOX1 was confirmed by an observed increase in the NZP reductase activity upon addition of N(1)-methylnicotinamide, an electron donor of AOX1, as well as inhibition of this activity in HLC in the presence of AOX1 inhibitors. ANZP was acetylated to form AANZP by N-acetyltransferase (NAT) 2. An experiment using recombinant esterases in an inhibition study using HLM revealed that AANZP is hydrolyzed by arylacetamide deacetylase (AADAC) in the human liver. N-Hydroxylamino NZP, which is suspected to be a reactive metabolite, was detected as a conjugate with N-acetyl-L-cysteine through NZP reduction and ANZP hydroxylation reactions. In the latter reaction, the conjugate was readily formed by recombinant CYP3A4 among the various P450 isoforms tested. In sum, we found that AOX1, NAT2, AADAC, and CYP3A4 are the determinants for the pharmacokinetics of NZP and that they confer interindividual variability in sensitivity to NZP side effects.

PMID: 28606603 [PubMed - as supplied by publisher]

Inferring Genes and Biological Functions That Are Sensitive to the Severity of Toxicity Symptoms.

Int J Mol Sci. 2017 Apr 02;18(4):

Authors: Kim J, Shin M

Abstract
The effective development of new drugs relies on the identification of genes that are related to the symptoms of toxicity. Although many researchers have inferred toxicity markers, most have focused on discovering toxicity occurrence markers rather than toxicity severity markers. In this study, we aimed to identify gene markers that are relevant to both the occurrence and severity of toxicity symptoms. To identify gene markers for each of four targeted liver toxicity symptoms, we used microarray expression profiles and pathology data from 14,143 in vivo rat samples. The gene markers were found using sparse linear discriminant analysis (sLDA) in which symptom severity is used as a class label. To evaluate the inferred gene markers, we constructed regression models that predicted the severity of toxicity symptoms from gene expression profiles. Our cross-validated results revealed that our approach was more successful at finding gene markers sensitive to the aggravation of toxicity symptoms than conventional methods. Moreover, these markers were closely involved in some of the biological functions significantly related to toxicity severity in the four targeted symptoms.

PMID: 28368331 [PubMed - indexed for MEDLINE]

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study.

Gastroenterology. 2017 Apr;152(5):1078-1089

Authors: Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, Barnhart HX, Bondon-Guitton E, Hayashi PH, Bessone F, Carvajal A, Cascorbi I, Cirulli ET, Chalasani N, Conforti A, Coulthard SA, Daly MJ, Day CP, Dillon JF, Fontana RJ, Grove JI, Hallberg P, Hernández N, Ibáñez L, Kullak-Ublick GA, Laitinen T, Larrey D, Lucena MI, Maitland-van der Zee AH, Martin JH, Molokhia M, Pirmohamed M, Powell EE, Qin S, Serrano J, Stephens C, Stolz A, Wadelius M, Watkins PB, Floratos A, Shen Y, Nelson MR, Urban TJ, Daly AK, International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium

Abstract
BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors.
METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs.
RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10(-8)) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10(-9)). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10(-9)). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10(-9)). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224.
CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.

PMID: 28043905 [PubMed - indexed for MEDLINE]

Potential drug-drug interactions in paediatric outpatient prescriptions in Nigeria and implications for the future.

Expert Rev Clin Pharmacol. 2016 Nov;9(11):1505-1515

Authors: Oshikoya KA, Oreagba IA, Godman B, Oguntayo FS, Fadare J, Orubu S, Massele A, Senbanjo IO

Abstract
BACKGROUND: Information regarding the incidence of drug-drug interactions (DDIs) and adverse drug events (ADEs) among paediatric patients in Nigeria is limited.
METHODS: Prospective clinical audit among paediatric outpatients in four general hospitals in Nigeria over a 3-month period. Details of ADEs documented in case files was extracted.
RESULTS: Among 1233 eligible patients, 208 (16.9%) received prescriptions with at least one potential DDI. Seven drug classes were implicated with antimalarial combination therapies predominating. Exposure mostly to a single potential DDI, commonly involved promethazine, artemether/lumefantrine, ciprofloxacin and artemether/lumefantrine. Exposure mostly to major and serious, and moderate and clinically significant, potential DDIs. Overall exposure similar across all age groups and across genders. A significant association was seen between severity of potential DDIs and age. Only 48 (23.1%) of these patients presented at follow-up clinics with only 15 reporting ADEs.
CONCLUSION: There was exposure to potential DDIs in this population. However, potential DDIs were associated with only a few reported ADEs.

PMID: 27592636 [PubMed - indexed for MEDLINE]

Under-reporting of harm in clinical trials.

Lancet Oncol. 2016 May;17(5):e209-19

Authors: Seruga B, Templeton AJ, Badillo FE, Ocana A, Amir E, Tannock IF

Abstract
Appropriate safety evaluations of anticancer drugs are crucial to assess their benefit-risk ratio. Substantial evidence shows that clinicians under-report harm in clinical trials, and at least three factors contribute to this problem: assessment of harm by clinicians might not represent the experience of patients; harm might be detected within trials, but is not reported appropriately by investigators or reporting is influenced by sponsors; and short-term follow-up might not detect long-term and potentially serious toxicities. Additionally, because of the selection of patients with good functional status in clinical trials, study results might not apply to patients treated in everyday clinical practice. New approaches for the conduct, oversight, and reporting of clinical trials should include patient-reported assessment of side-effects. Effective pharmacovigilance programmes and large-scale observational studies are needed to improve understanding of the tolerability of anticancer drugs in a real world setting.

PMID: 27301048 [PubMed - indexed for MEDLINE]

Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial.

Lancet Oncol. 2016 May;17(5):612-21

Authors: Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, Etienne G, Nicolini FE, le Coutre P, Clark RE, Stenke L, Andorsky D, Oehler V, Lustgarten S, Rivera VM, Clackson T, Haluska FG, Baccarani M, Cortes JE, Guilhot F, Hochhaus A, Hughes T, Kantarjian HM, Shah NP, Talpaz M, Deininger MW, EPIC investigators

Abstract
BACKGROUND: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia.
METHODS: The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805.
FINDINGS: Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib.
INTERPRETATION: The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established.
FUNDING: ARIAD Pharmaceuticals.

PMID: 27083332 [PubMed - indexed for MEDLINE]

Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial.

Lancet Oncol. 2016 May;17(5):632-41

Authors: Mir O, Cropet C, Toulmonde M, Cesne AL, Molimard M, Bompas E, Cassier P, Ray-Coquard I, Rios M, Adenis A, Italiano A, Bouché O, Chauzit E, Duffaud F, Bertucci F, Isambert N, Gautier J, Blay JY, Pérol D, PAZOGIST study group of the French Sarcoma Groupe-Groupe d'Etude des Tumeurs Osseuses (GSF-GETO)

Abstract
BACKGROUND: Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Imatinib followed by sunitinib and regorafenib is the standard sequence of treatment for advanced disease. Pazopanib is effective in soft tissue sarcomas but has never been assessed in advanced GIST in a randomised trial. We aimed to assess the efficacy and safety of pazopanib in patients with previously treated advanced GIST.
METHODS: In this randomised, open-label phase 2 study, we enrolled adults (aged ≥18 years) with advanced GIST resistant to imatinib and sunitinib from 12 comprehensive cancer centres or university hospitals in France and randomly assigned them 1:1 using an interactive web-based centralised platform to 800 mg oral pazopanib once daily in 4-week cycles plus best supportive care or best supportive care alone. Randomisation was stratified by the number of previous treatment regimens (2 vs ≥3); no-one was masked to treatment group allocation. Upon disease progression, patients in the best supportive care group were allowed to switch to pazopanib as compassionate treatment. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat. All randomised participants who received at least one dose of pazopanib were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01323400.
FINDINGS: Between April 12, 2011, and Dec 9, 2013, 81 patients were enrolled and randomly assigned to pazopanib plus best supportive care (n=40) or best supportive care alone (n=41). The median follow-up was 26·4 months (IQR 22·0-37·8) in the pazopanib plus best supportive care group and 28·9 months (22·0-35·2) in the best supportive care group. 4-month investigator-assessed progression-free survival was 45·2% (95% CI 29·1-60·0) in the pazopanib plus best supportive care group versus 17·6% (7·8-30·8) in the best supportive care group (hazard ratio [HR] 0·59, 95% CI 0·37-0·96; p=0·029). Median progression-free survival was 3·4 months (95% CI 2·4-5·6) with pazopanib plus best supportive care and 2·3 months (2·1-3·3) with best supportive care alone (HR 0·59 [0·37-0·96], p=0·03). 36 (88%) of the patients originally assigned to the best supportive care group switched to pazopanib following investigator-assessed disease progression; these patients had a median progression-free survival from pazopanib initiation of 3·5 months (95% CI 2·2-5·2). 55 (72%) of the 76 pazopanib-treated patients had pazopanib-related grade 3 or worse adverse events, the most common of which was hypertension (15 [38%] in the pazopanib plus best supportive care group and 13 [36%] in the best supportive care group). 20 (26%) patients had pazopanib-related serious adverse events (14 [35%] in the pazopanib plus best supportive care group and six [17%] in the best supportive care group), including pulmonary embolism in eight (9%) patients (five [13%] in the pazopanib plus best supportive care group and three [7%] in the best supportive care group). Three pazopanib-related deaths occurred (two pulmonary embolisms [one in each group] and one hepatic cytolysis [in the best supportive care group]). Three adverse event-related but not pazopanib-related deaths occurred in the best supportive care group after switch to pazopanib; these deaths were from hyperammonaemic encephalopathy, pneumopathy, and respiratory failure.
INTERPRETATION: Pazopanib plus best supportive care improves progression-free survival compared with best supportive care alone in patients with advanced GIST resistant to imatinib and sunitinib, with a toxicity profile similar to that reported for other sarcomas. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting for these patients.
FUNDING: GlaxoSmithKline, French National Cancer Institute, EuroSARC (FP7-278742), Centre Léon Bérard.

PMID: 27068858 [PubMed - indexed for MEDLINE]

Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial.

Lancet Oncol. 2016 May;17(5):622-31

Authors: Younes A, Berdeja JG, Patel MR, Flinn I, Gerecitano JF, Neelapu SS, Kelly KR, Copeland AR, Akins A, Clancy MS, Gong L, Wang J, Ma A, Viner JL, Oki Y

Abstract
BACKGROUND: Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and PI3K enzymes, which are members of common oncogenic pathways in haematological malignancies. We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy in patients with relapsed or refractory lymphoma and multiple myeloma.
METHODS: This open-label, first-in-man, phase 1 trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres. CUDC-907 was orally administered in a standard 3 + 3 dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for 5 days followed by a 2-day break (5/2), in 21-day cycles. Dosing started at 30 mg for the once-daily schedule and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66% of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. We assessed safety in all patients who received at least one dose of study drug. This ongoing trial is registered at ClinicalTrials.gov, number NCT01742988.
FINDINGS: Between Jan 23, 2013, and July 27, 2015, we enrolled 44 patients, of whom ten were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to three-times-weekly (MTD 150 mg), and seven to the 5/2 dosing schedule (MTD 60 mg). 37 (84%) patients had discontinued study drug as a result of progressive disease or clinical signs of progressive disease at the data cutoff. Four DLTs occurred in three of 40 DLT-evaluable patients (diarrhoea and hyperglycaemia in one patient on 60 mg once daily, hyperglycaemia in one patient on 150 mg twice weekly, and diarrhoea in one patient on 150 mg three times weekly); no DLTs were reported in patients on the 5/2 schedule. Grade 3 or worse adverse events occurred in 19 (43%) of 44 patients, the most common of which were thrombocytopenia (in nine [20%] of 44 patients), neutropenia (three [7%]), and hyperglycaemia (three [7%]). 11 (25%) of 44 patients had serious adverse events, three of which were regarded as treatment related (epistaxis and the DLTs of diarrhoea and hyperglycaemia). Adverse events led to dose reductions in six (14%) patients and treatment discontinuation in seven (16%). Five (14%) of 37 response-evaluable patients achieved an objective response (two complete responses and three partial responses). All five responses occurred in the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; n=9), and three occurred in those with transformed follicular lymphoma DLBCL (n=5). 21 (57%) of 37 response-evaluable patients had stable disease, including those with DLBCL, Hodgkin's lymphoma, and multiple myeloma. On the basis of these findings, we selected CUDC-907 60 mg on the 5/2 dosing schedule as the recommended phase 2 dose.
INTERPRETATION: The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60 mg 5/2 dosing schedule, alone and in combination with other therapies. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular, is ongoing.
FUNDING: Curis, Inc, and the Leukemia and Lymphoma Society.

PMID: 27049457 [PubMed - indexed for MEDLINE]