Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly.

J Med Genet. 2018 Mar 07;:

Authors: Shabbir RMK, Nalbant G, Ahmad N, Malik S, Tolun A

Abstract
BACKGROUND: Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N-acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNA MIR3922 had been detected in a woman with hand/foot malformation and malignant lymphoproliferative disease. Chst11-deficient mouse has severe chondrodysplasia, congenital arthritis and neonatal lethality. We searched for the causative variant for the unusual combination of limb malformations with variable expressivity accompanied by skeletal defects in a consanguineous Pakistani kindred.
METHODS: We performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect.
RESULTS: The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in CHST11. Novel variant c.467_481del (p.L156_N160del) is deduced to lead to the deletion of five evolutionarily highly conserved amino acids and predicted as damaging to protein by in silico analysis. Our findings confirm the crucial role of CHST11 in skeletal morphogenesis and show that CHST11 defects have variable manifestations that include a variety of limb malformations and skeletal defects.

PMID: 29514872 [PubMed - as supplied by publisher]

Life-threatening drug interactions: what the physician needs to know.

Intern Med J. 2017 May;47(5):501-512

Authors: Day RO, Snowden L, McLachlan AJ

Abstract
Adverse drug-drug interactions are a significant cause of adverse events and outcomes. Their incidence is rising, with more patients taking more drugs, and newer, more precise but often more hazardous drugs becoming available. Despite considerable information, including computerised alerts about potential adverse drug-drug interactions, prescribers increasingly override alerts, possibly symptomatic of the immense problem of evaluating the risk of an interaction in a particular patient. Many reports emanate from small studies often of normal and young volunteers, entirely different from the real world where, more often, older patients with multiple health conditions are receiving many more than the two drugs identified in the drug interaction report. Focusing on those drug-drug interactions that are clinically relevant is necessary, and increasingly, tools and reliable sources of this information are easily accessible.

PMID: 28503886 [PubMed - indexed for MEDLINE]

A decade of adverse drug events in Portuguese hospitals: space-time clustering and spatial variation in temporal trends.

BMC Pharmacol Toxicol. 2017 May 10;18(1):34

Authors: Scripcaru G, Mateus C, Nunes C

Abstract
BACKGROUND: The aim of this study is to identify the distribution by municipalities of adverse drug events (ADE) in Portugal, including adverse drug reactions (ADR) and accidental poisoning by drugs (AP), on municipality/years ADE rate clustering. Also we identify areas with different trends in time.
METHODS: We used a national dataset of public hospital discharges in Continental Portugal from 2004 to 2013. Events were identified based on codes: from E930 to E949.9 (ADR) and from E850 to E858.9 (AP). Space-time clustering and spatial variation in temporal trends methods were applied in three different time-periods: globally, by year and grouped in 2 classes (periods of 5 years).
RESULTS: A total of 9,320,076 patients were discharged within this period, with 133,688 patients (1.46%) having at least one ADE, 4% of them related with AP. Critical space-time identified clusters (p < 0.001) were the municipalities from Lisbon metropolitan area and Centro region area. The global rate increased at a 7.8% mean annual percentage change, with high space-time heterogeneity and variation in time trends clusters (p < 0.001). For whole period, 2004-2013, all clusters presented increasing trends. However when analyzed by period of 5 years we identified two clusters with decreasing trends in time in 2004-2008.
CONCLUSION: The impact of ADE is huge, with widely variations within country and in time, and represents an increasing challenge. Future research using individual and contextual risk factors are urgently needed to understand this spatiotemporal variability in order to promote local tailored and updated actions of prevention.

PMID: 28486949 [PubMed - indexed for MEDLINE]

A Bayesian analysis of quantal bioassay experiments incorporating historical controls via Bayes factors.

Stat Med. 2017 May 30;36(12):1907-1923

Authors: León Novelo LG, Womack A, Zhu H, Wu X

Abstract
This paper addresses model-based Bayesian inference in the analysis of data arising from bioassay experiments. In such experiments, increasing doses of a chemical substance are given to treatment groups (usually rats or mice) for a fixed period of time (usually 2 years). The goal of such an experiment is to determine whether an increased dosage of the chemical is associated with increased probability of an adverse effect (usually presence of adenoma or carcinoma). The data consists of dosage, survival time, and the occurrence of the adverse event for each unit in the study. To determine whether such relationship exists, this paper proposes using Bayes factors to compare two probit models, the model that assumes increasing dose effects and the model that assumes no dose effect. These models account for the survival time of each unit through a Poly-k type correction. In order to increase statistical power, the proposed approach allows the incorporation of information from control groups from previous studies. The proposed method is able to handle data with very few occurrences of the adverse event. The proposed method is compared with a variation of the Peddada test via simulation and is shown to have higher power. We demonstrate the method by applying it to the two bioassay experiment datasets previously analyzed by other authors. Copyright © 2017 John Wiley & Sons, Ltd.

PMID: 28106916 [PubMed - indexed for MEDLINE]

Long-term (52-week) safety and efficacy of Sacubitril/valsartan in Asian patients with hypertension.

Hypertens Res. 2017 May;40(5):472-476

Authors: Supasyndh O, Sun N, Kario K, Hafeez K, Zhang J

Abstract
Sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor-neprilysin inhibitor, demonstrated significant reductions in office and 24 h ambulatory blood pressure (BP) over 8 weeks in Asian patients with hypertension. This 52-week extension to the 8-week core study was aimed at evaluating the long-term safety, tolerability and efficacy of sacubitril/valsartan. Patients who completed an 8-week randomized study (the core study) were enrolled in this 52-week open-label study and received sacubitril/valsartan 200 mg QD. The sacubitril/valsartan dose was uptitrated to 400 mg QD if BP was uncontrolled (>140/90 mm Hg) after 4 weeks. Subsequently, in patients with uncontrolled BP, treatment was intensified every 4 weeks with amlodipine 5-10 mg followed by hydrochlorothiazide 6.25-25 mg. Of the 341 patients enrolled, 7 (2.1%) discontinued the study drug due to adverse events (AEs). The incidence of AEs and serious AEs were 63.9 and 3.8%, respectively, and no deaths were reported in this study. The most frequent AEs were nasopharyngitis (18.2%) and dizziness (8.8%). Events that were potentially indicative of low BP were infrequent. One patient reported mild transient angioedema (lasting 2.5 h) that resolved without treatment but led to study drug discontinuation. The sacubitril/valsartan-based regimen provided clinically significant mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-24.7/-16.2 mm Hg). The overall BP control, msSBP and msDBP response rates were 75.3, 90.6 and 87.6%, respectively. Long-term use of sacubitril/valsartan was generally safe and well-tolerated in patients with hypertension and provided significant BP reductions from baseline.

PMID: 27853163 [PubMed - indexed for MEDLINE]

Assessment of Drug Therapy-Related Issues in an Outpatient Heart Failure Population and the Potential Impact of Pharmacist-Driven Intervention.

J Pharm Pract. 2017 Jun;30(3):318-323

Authors: Dempsey JT, Matta LS, Carter DM, Stevens CA, Stevenson LW, Desai AS, Cheng JW

Abstract
BACKGROUND: The Ambulatory Cardiac Triage, Intervention, and Education (ACTIVE) infusion unit is an outpatient center that aims to provide heart failure (HF) patients with comprehensive multidisciplinary interventions.
OBJECTIVE: To describe the patient population served in ACTIVE and to document the prevalence of comorbidities and drug therapy-related issues (DRIs) in order to define the most effective role of a pharmacist in the unit.
METHODS: Patients who have been interviewed by a pharmacist in ACTIVE were included. Comprehensive medical and medication profile reviews were performed. Patient comorbidities were documented, and DRIs were classified.
RESULTS: Sixty patients were included. Most prevalent cardiac comorbidities included hypertension (73%) and hyperlipidemia (62%). Top 3 noncardiac comorbidities included chronic kidney disease (60%), diabetes (50%), and obesity (35%). The prevalence of DRI was reported as follows: (1) needs additional/alternative therapy (untreated indication [37] or suboptimal therapeutic choice [46]), (2) wrong drug (major drug-drug interaction [90], contraindication [11], or duplicate therapy [1]), (3) suboptimal dosing (17), (4) dose exceeds recommended maximum (9), and (5) adverse drug reaction (93). In 63 (22%) of the DRIs, a pharmacist made recommendations to modify the regimen.
CONCLUSION: The prevalence of DRI is high even among HF patients managed in a subspecialty cardiovascular practice. Pharmacists in this setting play a vital role in more effectively resolving DRI.

PMID: 27080398 [PubMed - indexed for MEDLINE]

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"Rare Diseases"[Mesh] OR "orphan disease"

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pharmacogenomics

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"systems biology"

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Next generation sequencing-based emerging trends in molecular biology of gastric cancer.

Am J Cancer Res. 2018;8(2):207-225

Authors: Verma R, Sharma PC

Abstract
Gastric cancer (GC) is one of the leading causes of cancer related mortality in the world. Being asymptomatic in nature till advanced stage, diagnosis of gastric cancer becomes difficult in early stages of the disease. The onset and progression of gastric cancer has been attributed to multiple factors including genetic alterations, epigenetic modifications, Helicobacter pylori and Epstein-Barr Virus (EBV) infection, and dietary habits. Next Generation Sequencing (NGS) based approaches viz. Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), RNA-Seq, and targeted sequencing have expanded the knowledge base of molecular pathogenesis of gastric cancer. In this review, we highlight recent NGS-based advances covering various genetic alterations (Microsatellite Instability, Single Nucleotide Variations, and Copy Number Variations), epigenetic changes (DNA methylation, histone modification, microRNAs) and differential gene expression during gastric tumorigenesis. We also briefly discuss the current and future potential biomarkers, drugs and therapeutic approaches available for the management of gastric cancer.

PMID: 29511593 [PubMed]

The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug.

Am J Cancer Res. 2018;8(2):317-331

Authors: Juarez M, Schcolnik-Cabrera A, Dueñas-Gonzalez A

Abstract
Drug repositioning is a highly studied alternative strategy to discover and develop anticancer drugs. This drug development approach identifies new indications for existing compounds. Ivermectin belongs to the group of avermectins (AVM), a series of 16-membered macrocyclic lactone compounds discovered in 1967, and FDA-approved for human use in 1987. It has been used by millions of people around the world exhibiting a wide margin of clinical safety. In this review, we summarize the in vitro and in vivo evidences demonstrating that ivermectin exerts antitumor effects in different types of cancer. Ivermectin interacts with several targets including the multidrug resistance protein (MDR), the Akt/mTOR and WNT-TCF pathways, the purinergic receptors, PAK-1 protein, certain cancer-related epigenetic deregulators such as SIN3A and SIN3B, RNA helicase, chloride channel receptors and preferentially target cancer stem-cell like population. Importantly, the in vitro and in vivo antitumor activities of ivermectin are achieved at concentrations that can be clinically reachable based on the human pharmacokinetic studies done in healthy and parasited patients. Thus, existing information on ivermectin could allow its rapid move into clinical trials for cancer patients.

PMID: 29511601 [PubMed]

Atypical chronic myeloid leukaemia: A case of an orphan disease-A multicenter report by the Polish Adult Leukemia Group.

Hematol Oncol. 2018 Mar 07;:

Authors: Drozd-Sokołowska J, Mądry K, Waszczuk-Gajda A, Biecek P, Szwedyk P, Budziszewska K, Raźny M, Dutka M, Obara A, Wasilewska E, Lewandowski K, Piekarska A, Bober G, Krzemień H, Stella-Hołowiecka B, Kapelko-Słowik K, Sawicki W, Paszkowska-Kowalewska M, Machowicz R, Dwilewicz-Trojaczek J

Abstract
Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses. Thirteen patients were male, median age 64.6 years (range 40.4-80.9). The median parameters at diagnosis were as follows: white blood cell count 97 × 109 /L (23.8-342) with immature progenitors amounting at 27.5% (12-72), haemoglobin 8.6 g/dL (3.9-14.9), and platelet count 66 × 109 /L (34-833). Cytoreductive treatment was used in all patients, and 2 patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival was 14.1 months (95% CI, 7.2), with median acute myeloid leukaemia-free survival of 13.3 months (95% CI, 3.6-22.6). Cumulative incidence of acute myeloid leukaemia transformation after 1 year in aCML group was 12.5% (95% CI, 0%-29.6%). To conclude, aCML harbours a poor prognosis. Treatment options are limited, with allogeneic hematopoietic stem cell transplantation being the only curative method at present, although only a minority of patients are transplant eligible. Educational measures are needed to improve the quality of diagnoses.

PMID: 29512182 [PubMed - as supplied by publisher]

The Direct Cost of Managing a Rare Disease: Assessing Medical and Pharmacy Costs Associated with Duchenne Muscular Dystrophy in the United States.

J Manag Care Spec Pharm. 2017 Jun;23(6):633-641

Authors: Thayer S, Bell C, McDonald CM

Abstract
BACKGROUND: A Duchenne muscular dystrophy (DMD) cohort was identified using a claims-based algorithm to estimate health care utilization and costs for commercially insured DMD patients in the United States. Previous analyses have used broad diagnosis codes that include a range of muscular dystrophy types as a proxy to estimate the burden of DMD.
OBJECTIVE: To estimate DMD-associated resource utilization and costs in a sample of patients identified via a claims-based algorithm using diagnosis codes, pharmacy prescriptions, and procedure codes unique to DMD management based on DMD clinical milestones.
METHODS: DMD patients were selected from a commercially insured claims database (2000-2009). Patients with claims suggestive of a non-DMD diagnosis or who were aged 30 years or older were excluded. Each DMD patient was matched by age, gender, and region to controls without DMD in a 1:10 ratio (DMD patients n = 75; controls n = 750). All-cause health care resource utilization, including emergency department, inpatient, outpatient, and physician office visits, and all-cause health care costs were examined over a minimum 1-year period. Costs were computed as total health-plan and patient-paid amounts of adjudicated medical claims (in annualized U.S. dollars).
RESULTS: The average age of the DMD cohort was 13 years. Patients in the DMD cohort had a 10-fold increase in health care costs compared with controls ($23,005 vs. $2,277, P < 0.001). Health care costs were significantly higher for the DMD cohort across age strata and, in particular, for DMD patients aged 14-29 years ($40,132 vs. $2,746, P < 0.001).
CONCLUSIONS: In the United States, resource use and medical costs of DMD are substantial and increase with age.
DISCLOSURES: Funding for this study (GHO-10-4441) was provided by GlaxoSmithKline (GSK). Optum was contracted by GSK to conduct the study. Thayer was an employee of Optum Health Economics and Outcomes Research at the time of this study and was not compensated for her participation as an author of this manuscript. Bell is an employee and shareholder of GSK. McDonald has been a consultant for GSK, Sarepta, PTC Therapeutics, Biomarin, and Catabasis on clinical trials regarding Duchenne muscular dystrophy clinical trial design, endpoint selection, and data analysis; Mitobridge for drug development; and Eli Lilly as part of a steering committee for clinical trials. Study concept and design were contributed primarily by Bell, along with Thayer and McDonald. Thayer collected the data, and data interpretation was performed by Thayer and Bell, along with McDonald. The manuscript was written by Thayer and Bell, along with McDonald, and revised by all the authors.

PMID: 28530521 [PubMed - indexed for MEDLINE]

Orphan drug policies and use in pediatric nephrology.

Pediatr Nephrol. 2017 Jan;32(1):1-6

Authors: Karpman D, Höglund P

Abstract
Orphan drugs designed to treat rare diseases are often overpriced per patient. Novel treatments are sometimes even more expensive for patients with ultra-rare diseases, in part due to the limited number of patients. Pharmaceutical companies that develop a patented life-saving drug are in a position to charge a very high price, which, at best, may enable these companies to further develop drugs for use in rare disease. However, is there a limit to how much a life-saving drug should cost annually per patient? Government interventions and regulations may opt to withhold a life-saving drug solely due to its high price and cost-effectiveness. Processes related to drug pricing, reimbursement, and thereby availability, vary between countries, thus having implications on patient care. These processes are discussed, with specific focus on three drugs used in pediatric nephrology: agalsidase beta (for Fabry disease), eculizumab (for atypical hemolytic uremic syndrome), and cysteamine bitartrate (for cystinosis). Access to and costs of orphan drugs have most profound implications for patients, but also for their physicians, hospitals, insurance policies, and society at large, particularly from financial and ethical standpoints.

PMID: 27738765 [PubMed - indexed for MEDLINE]

Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment.

Semin Fetal Neonatal Med. 2018 Feb 24;:

Authors: Lewis TR, Shelton EL, Van Driest SL, Kannankeril PJ, Reese J

Abstract
Patent ductus arteriosus (PDA) is a frequent, complex, and difficult to treat clinical syndrome among preterm infants in the neonatal intensive care unit. In addition to known clinical risk factors, there are emerging data about genetic predisposition to PDA in both animal and human models. Clinical response and toxicity from drugs used to treat PDA are highly variable. Developmental and genetic aspects of pharmacokinetics and pharmacodynamics influence exposure and response to pharmacologic therapies. Given the variable efficacy and toxicity of known drug therapies, novel therapeutic targets for PDA treatment offer the promise of precision medicine. This review addresses the known genetic contributions to prolonged ductal patency, variability in response to drug therapy for PDA, and potential novel drug targets for future PDA treatment discovery.

PMID: 29510900 [PubMed - as supplied by publisher]

Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial.

Clin Lymphoma Myeloma Leuk. 2018 Feb 08;:

Authors: Rinaldetti S, Pfirrmann M, Manz K, Guilhot J, Dietz C, Panagiotidis P, Spiess B, Seifarth W, Fabarius A, Müller M, Pagoni M, Dimou M, Dengler J, Waller CF, Brümmendorf TH, Herbst R, Burchert A, Janβen C, Goebeler ME, Jost PJ, Hanzel S, Schafhausen P, Prange-Krex G, Illmer T, Janzen V, Klausmann M, Eckert R, Büschel G, Kiani A, Hofmann WK, Mahon FX, Saussele S

Abstract
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated.
MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated.
RESULTS: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (‰) was retained as the only significant variable (P = .02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P = .04). Patients with an ABCG2/GUSB transcript level >4.5‰ (n = 93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (≤4.5‰; n = 39) had a 12-month TFR rate of 72% (95% CI, 55%-82%).
CONCLUSION: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation.

PMID: 29510895 [PubMed - as supplied by publisher]

PEGylation of tobramycin improves mucus penetration and antimicrobial activity against Pseudomonas aeruginosa biofilms in vitro.

Mol Pharm. 2018 Mar 07;:

Authors: Bahamondez-Canas TF, Zhang H, Tewes F, Leal J, Smyth HDC

Abstract
Pseudomonas aeruginosa is the predominant pathogen in the persistent lung infections of cystic fibrosis (CF) patients among other diseases. One of the mechanisms of resistance of P. aeruginosa infections is the formation and presence of biofilms. Previously, we demonstrated that PEGylated-tobramycin (Tob-PEG) had superior antimicrobial activity against P. aeruginosa biofilms compared to tobramycin (Tob). The goal of this study was to optimize the method of PEGylation of Tob and assess its activity in an in vitro CF-like mucus barrier biofilm model. Tob was PEGylated using three separate chemical conjugation methods and analyzed by 1H NMR. A comparison of the Tob-PEG products from the different conjugation methods showed significant differences in reduction of biofilm proliferation after 24h of treatment. In the CF-like mucus barrier model, Tob-PEG was significantly better than Tob in reducing P. aeruginosa proliferation after only 5 h of treatment (p<0.01). Finally, Tob-PEG caused a higher reduction in the number of surviving P. aeruginosa biofilm colonies compared to Tob (p<0.0001). We demonstrate the significantly improved antimicrobial activity of Tob-PEG against P. aeruginosa biofilms compared to Tob using two PEGylation methods. Tob-PEG had better in vitro activity compared to Tob against P. aeruginosa biofilms growing in a CF-like mucus barrier model.

PMID: 29514003 [PubMed - as supplied by publisher]