Drug repositioning for novel antitrichomonas from known antiprotozoan drugs using hierarchical screening.

Future Med Chem. 2018 Mar 28;:

Authors: Meneses-Marcel A, Marrero-Ponce Y, Ibáñez-Escribano A, Gómez-Barrio A, Escario JA, Barigye SJ, Terán E, García-Jacas CR, Machado-Tugores Y, Nogal-Ruiz JJ, Arán-Redó VJ

Abstract
AIM: Metronidazole is the most widely used drug in trichomoniasis therapy. However, the emergence of metronidazole-resistant Trichomonas vaginalis isolates calls for the search for new drugs to counter the pathogenicity of these parasites.
RESULTS: Classification models for predicting the antitrichomonas activity of molecules were built. These models were employed to screen antiprotozoal drugs, from which 20 were classified as active. The in vitro experiments showed moderate to high activity for 19 of the molecules at 10 μg/ml, while 3 compounds yielded higher activity than the reference at 1 μg/ml. The 11 most active chemicals were evaluated in vivo using Naval Medical Research Institute (NMRI) mice.
CONCLUSION: Benznidazole showed similar results as metronidazole, and can thus be considered as a potential candidate in antitrichomonas therapy.

PMID: 29589477 [PubMed - as supplied by publisher]

Personalised drug repositioning for Clear Cell Renal Cell Carcinoma using gene expression.

Sci Rep. 2018 Mar 27;8(1):5250

Authors: Koudijs KKM, Terwisscha van Scheltinga AGT, Böhringer S, Schimmel KJM, Guchelaar HJ

Abstract
Reversal of cancer gene expression is predictive of therapeutic potential and can be used to find new indications for existing drugs (drug repositioning). Gene expression reversal potential is currently calculated, in almost all studies, by pre-aggregating all tumour samples into a single group signature or a limited number of molecular subtype signatures. Here, we investigate whether drug repositioning based on individual tumour sample gene expression signatures outperforms the use of tumour group and subtype signatures. The tumour signatures were created using 534 tumour samples and 72 matched normal samples from 530 clear cell renal cell carcinoma (ccRCC) patients. More than 20,000 drug signatures were extracted from the CMAP and LINCS databases. We show that negative enrichment of individual tumour samples correlated (Spearman's rho = 0.15) much better with the amount of differentially expressed genes in drug signatures than with the tumour group signature (Rho = 0.08) and the 4 tumour subtype signatures (Rho 0.036-0.11). Targeted drugs used against ccRCC, such as sirolimus and temsirolimus, which could not be identified with the pre-aggregated tumour signatures could be recovered using individual sample analysis. Thus, drug repositioning can be personalized by taking into account the gene expression profile of the individual's tumour sample.

PMID: 29588458 [PubMed - in process]

The Horizon of a Therapy for Rare Genetic Diseases: A "Druggable" Future for Fibrodysplasia Ossificans Progressiva.

Int J Mol Sci. 2018 Mar 26;19(4):

Authors: Cappato S, Giacopelli F, Ravazzolo R, Bocciardi R

Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation.

PMID: 29587443 [PubMed - in process]

Spectrum of CFTR gene sequence variants in a northern Portugal population.

Pulmonology. 2018 Jan - Feb;24(1):3-9

Authors: Grangeia A, Alves S, Gonçalves L, Gregório I, Santos AC, Barros H, Barros A, Carvalho F, Moura C

Abstract
In Portugal, the spectrum of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene variants is not known. The main objective of this work was to determine the type and frequency of CFTR variants in a sample from northern Portugal by the complete analysis of the CFTR coding sequencing performed in 512 Portuguese children. A total of 30 different CFTR sequence variants, already reported as cystic fibrosis (CF) or CFTR related disorders variants, were detected. Ninety-two children (18.0%; 95%CI: 14.7-21.6) were found to be carriers of one sequence variant and 8 (1.6%; 95%CI: 0.7-3.1) had two sequence variants. Taking into consideration only variants that may cause CF when combined with a pathogenic CF variant, the CF pathogenic variant carrier frequency was 3.3% (95%CI: 1.9-5.3). One (0.2%; 95%CI: 0.01-0.7) child presented two CF pathogenic variants.
CONCLUSIONS: The majority of CFTR variants detected have been associated with a less severe CF phenotype. A wide spectrum of CFTR variants was identified, confirming the highest CFTR allelic heterogeneity previously reported in Mediterranean country. Additionally, better knowledge about the CFTR sequence variation spectrum may contribute to more efficient genetic testing in the Portuguese population.

PMID: 29589582 [PubMed - in process]

Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis and non-cystic fibrosis bronchiectasis.

Electron Physician. 2018 Jan;10(1):6273-6278

Authors: Alyasin S, Moghtaderi M, Farjadian S, Babaei M, Teshnizi SH

Abstract
Background: Aspergillus sensitization (AS) and allergic bronchopulmonary aspergillosis (ABPA) can occur as a cause of permanent lung damage in patients with cystic fibrosis (CF) and non-CF bronchiectasis.
Objective: The aim of this study was to determine the frequency of AS and ABPA in patients with CF and non-CF bronchiectasis in southwestern Iran.
Methods: This cross-sectional study was conducted on 33 patients with CF and 27 patients with non-CF bronchiectasis from southwestern Iran who were referred to Namazi Hospital affiliated to Shiraz University of Medical Sciences from July 2015 to February 2016. Skin prick test to Aspergillus fumigatus, peripheral blood eosinophil count, total serum IgE, specific IgE and IgG against Aspergillus fumigatus as well as radiologic chest studies were done for each patient. Statistical analysis was done by Mann-Whitney U test, Fisher Exact test, and Kappa weighted in SPSS software version 18. Level of significance was set at p<0.05.
Results: Nine patients with CF (27.3%) and one patient with non-CF bronchiectasis (3.7%) had positive skin tests to Aspergillus. There was 81.2% agreement between positive skin test and specific IgE to Aspergillus fumigatus (p<0.001). Three patients with CF (9%) met the diagnostic criteria for ABPA, whereas ABPA was not seen in patients with non-CF bronchiectasis.
Conclusion: ABPA was low in this study, considering more frequency of AS in patients with cystic fibrosis, clinicians should keep in mind the diagnosis of ABPA for those CF patients that do not respond to usual medical therapy and have positive skin tests to Aspergillus allergens.

PMID: 29588830 [PubMed]

Mixed Communities of Mucoid and Nonmucoid Pseudomonas aeruginosa Exhibit Enhanced Resistance to Host Antimicrobials.

MBio. 2018 Mar 27;9(2):

Authors: Malhotra S, Limoli DH, English AE, Parsek MR, Wozniak DJ

Abstract
Pseudomonas aeruginosa causes chronic pulmonary infections in patients with cystic fibrosis (CF). P. aeruginosa mucoid conversion, defined by overproduction of the exopolysaccharide alginate, correlates with accelerated decline in CF patient lung function. Recalcitrance of the mucoid phenotype to clearance by antibiotics and the immune response is well documented. However, despite advantages conferred by mucoidy, mucoid variants often revert to a nonmucoid phenotype both in vitro and in vivo Mixed populations of mucoid isolates and nonmucoid revertants are recovered from CF lungs, suggesting a selective benefit for coexistence of these variants. In this study, cocultures of mucoid and nonmucoid variants exhibited enhanced resistance to two host antimicrobials: LL-37, a cationic antimicrobial peptide, and hydrogen peroxide (H2O2). Alginate production by mucoid isolates protected nonmucoid variants in consortia from LL-37, as addition of alginate exogenously to nonmucoid variants abrogated LL-37 killing. Conversely, nonmucoid revertants shielded mucoid variants from H2O2 stress via catalase (KatA) production, which was transcriptionally repressed by AlgT and AlgR, central regulators of alginate biosynthesis. Furthermore, extracellular release of KatA by nonmucoid revertants was dependent on lys, encoding an endolysin implicated in autolysis and extracellular DNA (eDNA) release. Overall, these data provide a rationale to study interactions of P. aeruginosa mucoid and nonmucoid variants as contributors to evasion of innate immunity and persistence within the CF lung.IMPORTANCEP. aeruginosa mucoid conversion within lungs of cystic fibrosis (CF) patients is a hallmark of chronic infection and predictive of poor prognosis. The selective benefit of mixed populations of mucoid and nonmucoid variants, often isolated from chronically infected CF patients, has not been explored. Here, we show that mixed-variant communities of P. aeruginosa demonstrate advantages in evasion of innate antimicrobials via production of shared goods: alginate and catalase. These data argue for therapeutically targeting multiple constituents (both mucoid and nonmucoid variants) within diversified P. aeruginosa communities in vivo, as these variants can differentially shield one another from components of the host response.

PMID: 29588399 [PubMed - in process]

[Influenza vaccination and cystic fibrosis. Impact of an incentivisation campaign about influenza vaccination for patients attending the Dunkerque cystic fibrosis treatment centre and their health care workers].

Rev Mal Respir. 2018 Mar 24;:

Authors: Scalbert-Dujardin M, Boldron A, Leroy E, Bazin J, Froment-Leclercq E

Abstract
INTRODUCTION: The main aim of this study is to evaluate the effectiveness of preventive actions regarding influenza in the studied populations. The secondary objective is to analyze and understand the mechanisms which bring about a behavioural change regarding influenza vaccination.
METHODS: The interventional and prospective study was undertaken in the form of an anonymous questionnaire about influenza vaccination coverage and about the reasons for vaccinating or not vaccinating. The studied populations were patients followed for cystic fibrosis (n=67) in the Dunkerque cystic fibrosis treatment centre and their health care workers (n=117), before (April 2014) and after (April 2015) an information campaign and primary prevention actions (vaccination in the workplace with expanded time slots) in collaboration with the department of occupational medicine.
RESULTS: In 2015, the vaccination coverage rate of health care workers rose to 65.63%, that is to say 2.38 times more than in 2014 (27.55%). This difference is significant (χ2[1]=29.17, P<0.0001). However, no significant difference between 2014 and 2015 was observed among patients (children and adults) (χ2[1]=0.24, NS) whose vaccination coverage was already optimal before the study.
CONCLUSIONS: Raising awareness among health care workers about vaccination against influenza increases the coverage rate and decreases outbreaks of virus infection in the care services and among patients at risk. Three main levers were identified: the necessity of providing information on influenza vaccination to health care workers, the ease of vaccination access and the attitude towards vaccination of supervisory staff (health executives/doctors).

PMID: 29588090 [PubMed - as supplied by publisher]

Serum (1→3)-β-D-glucan and galactomannan levels in patients with cystic fibrosis: a retrospective cohort study.

BMC Pulm Med. 2018 Mar 27;18(1):52

Authors: Träger J, Melichar VO, Meyer R, Rauh M, Bogdan C, Held J

Abstract
BACKGROUND: Aspergillus fumigatus is frequently encountered in sputum samples of patients with cystic fibrosis (CF), which traditionally has been interpreted as saprophytic airway colonization. However, this mere bystander role has been challenged by recent data. There is now evidence that Aspergillus fumigatus accelerates the decline of pulmonary function. (1→3)-β-D-glucan (BDG) and galactomannan (GM) are highly sensitive fungal biomarkers that are used to diagnose invasive fungal disease. However, their diagnostic value in CF patients is largely unknown.
METHODS: We conducted a retrospective cohort study on 104 CF patients to determine whether serum BDG and GM levels correlate with parameters such as Aspergillus-positive sputum cultures and lung function.
RESULTS: Aspergillus fumigatus was persistently detected in 22 of the 104 CF patients (21%). Mean serum BDG and GM levels in the Aspergillus-positive patients were significantly higher than in those without persistent Aspergillus detection (89 versus 40 pg/ml [p = 0.022] and 0.30 versus 0.15 ODI [p = 0.013], respectively). 27 and 7 patients had elevated BDG (≥ 60 pg/ml) or GM levels (> 0.5 ODI), respectivly. BDG and GM levels showed a significant correlation (p = 0.004). Patients with increased serum concentrations of BDG were more frequently Aspergillus-positive (40.7 versus 14.3%, p = 0.004) and had a significantly lower forced expiratory volume in one second (FEV1) than patients with a normal BDG (61.6 versus 77.1%, p = 0.007). In the multivariate analysis, BDG but not GM or the growth of A. fumigatus, proved to be an independent predictor for the FEV1.
CONCLUSIONS: CF patients with persistent Aspergillus detection have elevated BDG and GM levels which ranged between healthy and invasively infected patients. Serum BDG may be superior to GM and fungal culture in predicting an impaired lung function in CF patients.

PMID: 29587700 [PubMed - in process]

p.Val804Met, the most frequent pathogenic mutation in RET, confers a very low lifetime risk of medullary thyroid cancer.

J Clin Endocrinol Metab. 2018 Mar 23;:

Authors: Loveday C, Josephs K, Chubb D, Gunning A, Izatt L, Tischkovitz M, Ellard S, Turnbull C

Abstract
Context: To date, penetrance figures for medullary thyroid cancer (MTC) for variants in RET have been estimated from families ascertained on account of presence of MTC.
Objective: To gain estimates of penetrance unbiased by ascertainment, we analyzed 61 RET mutations assigned as disease-causing by the ATA in population whole exome sequencing data.
Design: For the 61 RET mutations, we used analyses of the observed allele frequencies in ∼51,000 individuals from non-TCGA ExAC, assuming lifetime penetrance for MTC of 90%, 50% and unbounded.
Setting: Population-based. Patients or other participants/Interventions. NA.
Results: 10/61 ATA disease-causing RET mutations were present in the non-TCGA ExAC population with observed frequency consistent with penetrance for MTC of >90%. For p.Val804Met, the lifetime penetrance for MTC estimated from the allele frequency observed was 4% (95% CI: 0.9-8%).
Conclusions: Based on penetrance analysis in carrier relatives of p.Val804Met-positive cases of MTC, p.Val804Met is currently understood to have high lifetime penetrance for MTC (87% by age 70), albeit of later onset of MTC than other RET mutations. Given our unbiased estimate of penetrance for RET p.Val804Met of 4% (95% CI: 0.9-8%), current recommendation by the American Thyroid Association of prophylactic thyroidectomy as standard for all RET mutation carriers is likely inappropriate.

PMID: 29590403 [PubMed - as supplied by publisher]

Additive Effect of Variably Penetrant 22q11.2 Duplication and Pathogenic Mutations in Autism Spectrum Disorder: To Which Extent Does the Tree Hide He Forest?

J Autism Dev Disord. 2018 Mar 27;:

Authors: Demily C, Lesca G, Poisson A, Till M, Barcia G, Chatron N, Sanlaville D, Munnich A

Abstract
The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.

PMID: 29589274 [PubMed - as supplied by publisher]

Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia.

J Clin Immunol. 2018 Mar 27;:

Authors: Alodayani AN, Al-Otaibi AM, Deswarte C, Frayha HH, Bouaziz M, AlHelale M, Le Voyer T, Nieto-Patlan A, Rattina V, AlZahrani M, Halwani R, Al Sohime F, Al-Mousa H, Al-Muhsen S, Alhajjar SH, Dhayhi NS, Abel L, Casanova JL, Bin-Hussain I, AlBarrak MS, Al-Jumaah SA, Bustamante J

Abstract
PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30).
METHODS: Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain.
RESULTS: Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect.
CONCLUSIONS: This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.

PMID: 29589181 [PubMed - as supplied by publisher]

Genetic test utilization and diagnostic yield in adult patients with neurological disorders.

Neurogenetics. 2018 Mar 28;:

Authors: Bardakjian TM, Helbig I, Quinn C, Elman LB, McCluskey LF, Scherer SS, Gonzalez-Alegre P

Abstract
To determine the diagnostic yield of different genetic test modalities in adult patients with neurological disorders, we evaluated all adult patients seen for genetic diagnostic evaluation in the outpatient neurology practice at the University of Pennsylvania between January 2016 and April 2017 as part of the newly created Penn Neurogenetics Program. Subjects were identified through our electronic medical system as those evaluated by the Program's single clinical genetic counselor in that period. A total of 377 patients were evaluated by the Penn Neurogenetics Program in different settings and genetic testing recommended. Of those, 182 (48%) were seen in subspecialty clinic setting and 195 (52%) in a General Neurogenetics Clinic. Genetic testing was completed in over 80% of patients in whom it was recommended. The diagnostic yield was 32% across disease groups. Stratified by testing modality, the yield was highest with directed testing (50%) and array comparative genomic hybridization (45%), followed by gene panels and exome testing (25% each). In conclusion, genetic testing can be successfully requested in clinic in a large majority of adult patients. Age is not a limiting factor for a genetic diagnostic evaluation and the yield of clinical testing across phenotypes (almost 30%) is consistent with previous phenotype-focused or research-based studies. These results should inform the development of specific guidelines for clinical testing and serve as evidence to improve reimbursement by insurance payers.

PMID: 29589152 [PubMed - as supplied by publisher]

Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2.

Epilepsia Open. 2018 Mar;3(1):81-85

Authors: Akamine S, Sagata N, Sakai Y, Kato TA, Nakahara T, Matsushita Y, Togao O, Hiwatashi A, Sanefuji M, Ishizaki Y, Torisu H, Saitsu H, Matsumoto N, Hara T, Sawa A, Kano S, Furue M, Kanba S, Shaw CA, Ohga S

Abstract
Advance in the exome-wide sequencing analysis contributes to identifying hundreds of genes that are associated with early-onset epileptic encephalopathy and neurodevelopmental disorders. On the basis of massive sequencing data, functional interactions among different genes are suggested to explain the common molecular pathway underlying the pathogenic process of these disorders. However, the relevance of such interactions with the phenotypic severity or variety in an affected individual remains elusive. In this report, we present a 45-year-old woman with neurofibromatosis type 1 (NF1), infantile-onset epileptic encephalopathy, and severe developmental delay. Whole-exome sequencing identified de novo pathogenic mutations in NF1 and the Schaaf-Yang syndrome-associated gene, MAGEL2. Literature-curated interaction data predicted that NF1 and MAGEL2 proteins were closely connected in this network via their common interacting proteins. Direct conversion of fibroblasts into neurons in vitro showed that neuronal cells from 9 patients with NF1 expressed significantly lower levels of MAGEL2 (54%, p = 0.0047) than those from healthy individuals. These data provide the first evidence that pathogenic mutations of NF1 deregulate the expression of other neurodevelopmental disease-associated genes. De novo mutations in multiple genes may lead to severe developmental phenotypes through their cumulative effects or synergistic interactions.

PMID: 29588991 [PubMed]

Primaquine Pharmacokinetics in Lactating Women and Breastfed Infant Exposures.

Clin Infect Dis. 2018 Mar 24;:

Authors: Ellen Gilder M, Hanpithakphong W, Hoglund RM, Tarning J, Htun Win H, Hilda N, Chu CS, Bancone G, Carrara VI, Singhasivanon P, White NJ, Nosten F, McGready R

Abstract
Background: Primaquine is the only drug providing radical cure of Plasmodium vivax malaria. It is not recommended for breastfeeding women as it causes hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals, and breast milk excretion and thus infant exposure are not known.
Methods: Healthy G6PD normal breastfeeding women with previous P.vivax infection and their healthy G6PD normal infants between 28 days and 2 years old were enrolled. Mothers took primaquine 0.5 mg/kg/day for 14 days. Primaquine and carboxyprimaquine concentrations were measured in maternal venous plasma, capillary plasma, and breast milk samples and infant capillary plasma samples taken on days 0, 3, 7, and 13.
Results: In 20 mother-baby pairs primaquine concentrations were below measurement thresholds in all but one infant capillary plasma sample (that contained primaquine 2.6 ng/mL) and carboxyprimaquine was likewise unmeasurable in the majority of infant samples (maximum value 25.8 ng/mL). The estimated primaquine dose received by infants, based on measured breast milk levels, was 2.98 µg/kg/day (i.e. ~0.6% of a hypothetical infant daily dose of 0.5 mg/kg). There was no evidence of drug-related hemolysis in the infants. Maternal levels were comparable to non-lactating patients, and adverse events in mothers were mild.
Conclusions: The concentrations of primaquine in breast milk are very low and therefore very unlikely to cause adverse effects in the breast-feeding infant. Primaquine should not be withheld from mothers breastfeeding infants or young children. More information is needed in neonates.

PMID: 29590311 [PubMed - as supplied by publisher]

Liver and statins: a critical appraisal of the evidence.

Curr Med Chem. 2018 Mar 26;:

Authors: Licata A, Giammanco A, Minissale MG, Pagano S, Petta S, Averna M

Abstract
Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

PMID: 29589533 [PubMed - as supplied by publisher]

Potentially inappropriate medication in the elderly: a systematic review of validated explicit criteria.

Eur J Clin Pharmacol. 2018 Mar 27;:

Authors: Motter FR, Fritzen JS, Hilmer SN, Paniz ÉV, Paniz VMV

Abstract
PURPOSE: Potentially inappropriate medication (PIM) use causes preventable adverse drug reactions in older patients. Several assessment tools have been published to identify and avoid PIM use. In this systematic literature review, we aim to provide summaries and comparisons of validated PIMs lists published between 1991 and 2017 internationally.
METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA), we performed a systematic review of articles describing the development and validation of criteria for identification of PIMs among older people published between January 1991 and April 2017. The searches were conducted on PUBMED, AgeLine, Academic Search, Academic Search Premier, and CINAHL. We identified the most common medications/classes described as PIM. We also identified the drug-disease interactions and drug-drug interactions reported among criteria.
RESULTS: From 2933 articles screened, 36 met our inclusion criteria. The majority used the Delphi method to validate their criteria. We identified 907 different medications/classes, 536 different drug disease interactions involving 84 diseases/conditions, and 159 drug-drug interactions. Benzodiazepines and nonsteroidal anti-inflammatory drugs were the medications most commonly reported as potentially inappropriate for older people.
CONCLUSION: Although approaches aimed at detecting inappropriate prescribing have intensified in recent years, we observed limited overlap between different PIM lists. Additionally, some PIM lists did not provide special considerations of use and alternative therapies to avoid PIMs. These facts may compromise the use of PIM lists in clinical practice. Future PIM lists should integrate information about alternative therapies and special considerations of use in order to help clinicians in the drug prescription.

PMID: 29589066 [PubMed - as supplied by publisher]

Severe immune thrombocytopaenia in a patient taking benznidazole for chronic Chagas disease.

BMJ Case Rep. 2018 Mar 27;2018:

Authors: Crespillo-Andújar C, Calbacho Robles M, Norman FF, Pérez-Molina JA

Abstract
Chagas disease is a parasitic disease that mostly affects Latin American countries, but it has currently become a worldwide epidemic due to migration. Both drugs marketed for its treatment (benznidazole and nifurtimox) are associated with a high rate of adverse reactions. Benznidazole is preferred initially because of its more favourable toxicity profile and perceived greater efficacy. Hypersensitivity dermatological reactions, gastrointestinal and neurological disturbances represent the most common drug-related adverse events. General symptoms such as fever, arthralgia, myalgia or bone marrow depression (leucopaenia) are seen less frequently. We describe the case of a 33-year-old woman with chronic Chagas disease who presented with acute gingival bleeding and severe thrombocytopaenia, probably related to benznidazole treatment. Temporal association with drug initiation and recovery after treatment withdrawal were demonstrated. Clinicians should be aware of the possible association between immune thrombocytopaenia and benznidazole, even though the pathogenesis remains unclear at present.

PMID: 29588298 [PubMed - in process]

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