Literature Watch
Towards better understanding of patient centric drug product development in an increasingly older patient population.
Towards better understanding of patient centric drug product development in an increasingly older patient population.
Int J Pharm. 2016 Oct 30;512(2):334-342
Authors: Stegemann S
Abstract
The substantial reduction in premature death and longevity is an achievement of modern societies and advances in technology, medical and pharmaceutical sciences. Derived from the effective management of acute and chronic diseases throughout the lifetime the typical age related, later life stage diseases will become more dominant characteristics in future patients as well as other age related impairments or life conditions. Naturally, this leads to patients with complex clinical and functional patterns that are accompanied by the necessity of therapeutic interventions and polypharmacy. With the increasing number of older people and especially those with very high age in the society, new distinct older patient populations are evolving that require patient centered therapies and drug products to maintain safety and efficacy as well as effectiveness. Understanding how the patient populations and their characteristics change from a clinical, daily functioning and a patient perspective is crucial to move towards patient centric drug products.
PMID: 26807529 [PubMed - indexed for MEDLINE]
Notice of Change in Award Budget for RFA-AA-17-016 "Alcohol-PTSD Comorbidity: Preclinical Studies of Models and Mechanisms (R01)"
Limited Competition: Data Coordinating Center for Type 1 Diabetes TrialNet (UC4)
Notice of Correction to RFA-DA-18-005 "Expanding Medication Assisted Treatment for Opioid Use Disorders in the Context of the SAMHSA Opioid STR Grants (R21/R33)"
Systematic review of the safety and efficacy of palivizumab among infants and young children with cystic fibrosis.
Systematic review of the safety and efficacy of palivizumab among infants and young children with cystic fibrosis.
Pharmacotherapy. 2017 Apr 19;:
Authors: Kua KP, Lee SWH
Abstract
BACKGROUND: Respiratory syncytial virus (RSV) is a common pathogen in infants with cystic fibrosis (CF). The use of palivizumab prophylaxis for RSV infection as the standard of care for infants with CF remains controversial.
OBJECTIVE: To evaluate the efficacy of palivizumab in reducing the incidence of RSV hospitalization in children with CF who are younger than 2 years of age.
METHODS: Four electronic databases (PubMed, Embase, CINAHL, and CENTRAL) were searched from inception until January 31, 2017 for clinical studies investigating the use of palivizumab in infants with CF aged less than 2 years. The primary outcome was hospitalization rate due to RSV infection. Secondary outcomes included hospitalization for respiratory illness, length of hospital stay, safety (adverse effects), and cost-effectiveness of palivizumab prophylaxis.
RESULTS: The review included a total of ten studies (six cohort studies, two before-and-after studies, one cross-sectional study, and one randomized controlled trial) involving 3,891 patients with CF. Seven studies reported that palivizumab prophylaxis had a positive impact on the rate of RSV hospitalization. Five studies (n=3,404) reported that palivizumab prophylaxis significantly reduced the rate of hospitalization due to RSV infection compared to no prophylaxis. One study (n=5) demonstrated patients with CF who received palivizumab had no RSV hospitalization. Another study showed infants with CF receiving palivizumab (n=117) had a lower risk of hospitalization for RSV infection compared with premature infants (gestational age <35 completed weeks) who received palivizumab (n=4,880).
CONCLUSIONS: Evidence from the literature suggests that palivizumab may have a potential role in reducing RSV hospitalization in children aged less than 2 years with CF. Given the lack of overall data, additional research is warranted to better understand the efficacy and safety of prophylactic palivizumab in infants with CF. This article is protected by copyright. All rights reserved.
PMID: 28423192 [PubMed - as supplied by publisher]
Adult Onset Cystic Fibrosis Liver Disease: Diagnosis and characterization of an underappreciated entity.
Adult Onset Cystic Fibrosis Liver Disease: Diagnosis and characterization of an underappreciated entity.
Hepatology. 2017 Apr 19;:
Authors: Koh C, Sakiani S, Surana P, Zhao X, Eccleston J, Kleiner DE, Herion D, Liang TJ, Hoofnagle JH, Chernick M, Heller T
Abstract
BACKGROUND & AIMS: Cystic fibrosis liver disease (CFLD), a leading cause of death in cystic fibrosis (CF), is mostly described in pediatric populations. Adult-onset CFLD lacks sufficient characterization and diagnostic tools.
METHODS: A cohort of CF patients without CFLD during childhood were followed for up to 38 years with serologic testing, imaging, and noninvasive fibrosis markers. Historical CFLD diagnostic criteria were compared with a newly proposed CFLD criteria.
RESULTS: 36 CF patients were followed for a median of 24.5 years(IQR=15.6, 32.9). By the last follow-up, 11(31%) had died. With conventional criteria, 8(22%) patients had CFLD, and by new criterion, 17 (47%) had CFLD at a median age of 36.6 years(IQR=26.5, 43.2). By new criterion, those with CFLD had higher median ALT(42 vs 27, p=0.005), AST(26 vs 21, p=0.01), direct bilirubin(0.13 vs 0.1, p=0.01), PT(14.4 vs 12.4, p=0.002), and APRI(0.31 vs 0.23, p=0.003) over the last two years of follow-up. Subjects with a Fibroscan® >6.8kPa had higher ALT(42 vs 28U/L, p=0.02), AST(35 vs 25U/L, p=0.02), APRI(0.77 vs 0.25, p=0.0004), FIB-4(2.14 vs 0.74, p=0.0003) and lower platelet counts(205 vs 293, p=0.02). One CFLD patient had nodular regenerative hyperplasia. Longitudinally, mean platelet counts significantly declined in the CFLD group(310 to 230U/L, p=0.0005). Deceased CFLD patients had lower platelet counts than those alive with CFLD(143 vs 258 U/L, p=0.004) or those deceased with no CFLD(143 vs 327U/L, p=0.006).
CONCLUSION: Adult-onset CFLD may be more prevalent than previously described which suggests a later wave of CFLD that impacts morbidity. Routine liver tests, radiologic imaging, noninvasive fibrosis markers and fibroscan® can be utilized algorithmically to identify adult CFLD. Further evaluation in other CF cohorts should be performed for validation. This article is protected by copyright. All rights reserved.
PMID: 28422310 [PubMed - as supplied by publisher]
Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection.
Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection.
Mucosal Immunol. 2017 Apr 19;:
Authors: Codagnone M, Cianci E, Lamolinara A, Mari VC, Nespoli A, Isopi E, Mattoscio D, Arita M, Bragonzi A, Iezzi M, Romano M, Recchiuti A
Abstract
Pseudomonas aeruginosa lung infection is a main cause of disability and mortality worldwide. Acute inflammation and its timely resolution are crucial for ensuring bacterial clearance and limiting tissue damage. Here, we investigated protective actions of resolvin (Rv) D1 in lung infection induced by the RP73 clinical strain of P. aeruginosa. RvD1 significantly diminished bacterial growth and neutrophil infiltration during acute pneumonia caused by RP73. Inoculum of RP73, immobilized in agar beads, resulted in persistent lung infection up to 21 days, leading to a non resolving inflammation reminiscent of human pathology. RvD1 significantly reduced bacterial titer, leukocyte infiltration, and lung tissue damage. In murine lung macrophages sorted during P. aeruginosa chronic infection, RvD1 regulated the expression of Toll-like receptors, downstream genes, and microRNA (miR)-21 and 155, resulting in reduced inflammatory signaling. In vitro, RvD1 enhanced phagocytosis of P. aeruginosa by neutrophils and macrophages, recapitulating its in vivo actions. These results unveil protective functions and mechanisms of action of RvD1 in acute and chronic P. aeruginosa pneumonia, providing evidence for its potent pro-resolution and tissue protective properties on airway mucosal tissue during infection.Mucosal Immunology advance online publication 19 April 2017; doi:10.1038/mi.2017.36.
PMID: 28422188 [PubMed - as supplied by publisher]
Susceptibility of Candida albicans from Cystic Fibrosis Patients.
Susceptibility of Candida albicans from Cystic Fibrosis Patients.
Mycopathologia. 2017 Apr 18;:
Authors: Sabino R, Carolino E, Moss RB, Banaei N, Verissimo C, Stevens DA
Abstract
Candida albicans is a common microbe, colonizer and potential pathogen found in respiratory cultures of cystic fibrosis (CF) patients. Because of possible development of resistance in patient isolates resulting from residence in the abnormal milieu of CF patient airways, or from exposure to antifungals, and considering the possibility of patient-to-patient spread of microbes and reports of elevated resistance to other fungal pathogens, it was important to assay the susceptibility of isolates of Candida and compare that profile to isolates from the community. In our center, and unlike another fungal pathogen, no increase in resistance of Candida isolates of the CF cohort was found.
PMID: 28421452 [PubMed - as supplied by publisher]
In vivo and In vitro Interactions between Pseudomonas aeruginosa and Staphylococcus spp.
In vivo and In vitro Interactions between Pseudomonas aeruginosa and Staphylococcus spp.
Front Cell Infect Microbiol. 2017;7:106
Authors: Hotterbeekx A, Kumar-Singh S, Goossens H, Malhotra-Kumar S
Abstract
The significance of polymicrobial infections is increasingly being recognized especially in a biofilm context wherein multiple bacterial species-including both potential pathogens and members of the commensal flora-communicate, cooperate, and compete with each other. Two important bacterial pathogens that have developed a complex network of evasion, counter-inhibition, and subjugation in their battle for space and nutrients are Pseudomonas aeruginosa and Staphylococcus aureus. Their strain- and environment-specific interactions, for instance in the cystic fibrosis lung or in wound infections, show severe competition that is generally linked to worse patient outcomes. For instance, the extracellular factors secreted by P. aeruginosa have been shown to subjugate S. aureus to persist as small colony variants (SCVs). On the other hand, data also exist where S. aureus inhibits biofilm formation by P. aeruginosa but also protects the pathogen by inhibiting its phagocytosis. Interestingly, such interspecies interactions differ between the planktonic and biofilm phenotype, with the extracellular matrix components of the latter likely being a key, and largely underexplored, influence. This review attempts to understand the complex relationship between P. aeruginosa and Staphylococcus spp., focusing on S. aureus, that not only is interesting from the bacterial evolution point of view, but also has important consequences for our understanding of the disease pathogenesis for better patient management.
PMID: 28421166 [PubMed - in process]
The Diverse Cellular and Animal Models to Decipher the Physiopathological Traits of Mycobacterium abscessus Infection.
The Diverse Cellular and Animal Models to Decipher the Physiopathological Traits of Mycobacterium abscessus Infection.
Front Cell Infect Microbiol. 2017;7:100
Authors: Bernut A, Herrmann JL, Ordway D, Kremer L
Abstract
Mycobacterium abscessus represents an important respiratory pathogen among the rapidly-growing non-tuberculous mycobacteria. Infections caused by M. abscessus are increasingly found in cystic fibrosis (CF) patients and are often refractory to antibiotic therapy. The underlying immunopathological mechanisms of pathogenesis remain largely unknown. A major reason for the poor advances in M. abscessus research has been a lack of adequate models to study the acute and chronic stages of the disease leading to delayed progress of evaluation of therapeutic efficacy of potentially active antibiotics. However, the recent development of cellular models led to new insights in the interplay between M. abscessus with host macrophages as well as with amoebae, proposed to represent the environmental host and reservoir for non-tuberculous mycobacteria. The zebrafish embryo has also appeared as a useful alternative to more traditional models as it recapitulates the vertebrate immune system and, due to its optical transparency, allows a spatio-temporal visualization of the infection process in a living animal. More sophisticated immunocompromised mice have also been exploited recently to dissect the immune and inflammatory responses to M. abscessus. Herein, we will discuss the limitations, advantages and potential offered by these various models to study the pathophysiology of M. abscessus infection and to assess the preclinical efficacy of compounds active against this emerging human pathogen.
PMID: 28421165 [PubMed - in process]
The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice.
The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice.
Sci Signal. 2017 Apr 18;10(475):
Authors: Sun L, Ren X, Wang IC, Pradhan A, Zhang Y, Flood HM, Han B, Whitsett JA, Kalin TV, Kalinichenko VV
Abstract
Goblet cell metaplasia and excessive mucus secretion associated with asthma, cystic fibrosis, and chronic obstructive pulmonary disease contribute to morbidity and mortality worldwide. We performed a high-throughput screen to identify small molecules targeting a transcriptional network critical for the differentiation of goblet cells in response to allergens. We identified RCM-1, a nontoxic small molecule that inhibited goblet cell metaplasia and excessive mucus production in mice after exposure to allergens. RCM-1 blocked the nuclear localization and increased the proteasomal degradation of Forkhead box M1 (FOXM1), a transcription factor critical for the differentiation of goblet cells from airway progenitor cells. RCM-1 reduced airway resistance, increased lung compliance, and decreased proinflammatory cytokine production in mice exposed to the house dust mite and interleukin-13 (IL-13), which triggers goblet cell metaplasia. In cultured airway epithelial cells and in mice, RCM-1 reduced IL-13 and STAT6 (signal transducer and activator of transcription 6) signaling and prevented the expression of the STAT6 target genes Spdef and Foxa3, which are key transcriptional regulators of goblet cell differentiation. These results suggest that RCM-1 is an inhibitor of goblet cell metaplasia and IL-13 signaling, providing a new therapeutic candidate to treat patients with asthma and other chronic airway diseases.
PMID: 28420758 [PubMed - in process]
Modulation of TMEM16A Channel Activity by the Von Willebrand Factor Type A (VWA) domain of the Calcium-Activated Chloride Channel Regulator 1 (CLCA1).
Modulation of TMEM16A Channel Activity by the Von Willebrand Factor Type A (VWA) domain of the Calcium-Activated Chloride Channel Regulator 1 (CLCA1).
J Biol Chem. 2017 Apr 18;:
Authors: Sala-Rabanal M, Yurtsever Z, Berry KN, Nichols CG, Brett TJ
Abstract
Calcium-activated chloride channels (CaCCs) are key players in transepithelial ion transport and fluid secretion, smooth muscle constriction, neuronal excitability, and cell proliferation. The CaCC regulator 1 (CLCA1) modulates the activity of the CaCC TMEM16A/Anoctamin 1 (ANO1) by directly engaging the channel at the cell surface, but the exact mechanism is unknown. Here, we demonstrate that the von Willebrand factor type A (VWA) domain within the cleaved CLCA1 N-terminal fragment is necessary and sufficient for this interaction. TMEM16A protein levels on the cell surface were increased in HEK293T cells transfected with CLCA1 constructs containing the VWA domain, and TMEM16A-like currents were activated. Similar currents were evoked in cells exposed to secreted VWA domain alone, and these currents were significantly knocked down by TMEM16A siRNA. VWA-dependent TMEM16A modulation was not modified by the S357N mutation, a VWA domain polymorphism associated with more severe meconium ileus in cystic fibrosis (CF) patients. VWA-activated currents were significantly reduced in the absence of extracellular Mg2+, and mutation of residues within the conserved metal ion-dependent adhesion site (MIDAS) motif impaired the ability of VWA to potentiate TMEM16A activity, suggesting that CLCA1-TMEM16A interactions are Mg2+- and MIDAS-dependent. Increase in TMEM16A activity occurred within minutes of exposure to CLCA1 or after a short treatment with nocodazole, consistent with the hypothesis that CLCA1 stabilizes TMEM16A at the cell surface by preventing its internalization. Our study hints at the therapeutic potential of the selective activation of TMEM16A by the CLCA1 VWA domain in loss-of-function chloride channelopathies, such as CF.
PMID: 28420732 [PubMed - as supplied by publisher]
Nutritional management of cystic fibrosis an update for the 21st century.
Nutritional management of cystic fibrosis an update for the 21st century.
Paediatr Respir Rev. 2017 Mar 14;:
Authors: Collins S
Abstract
Nutritional management is an essential part of multidisciplinary care for infants, children and adults with cystic fibrosis (CF). In 2016 two updated nutritional consensus guidelines were published [1,2]. This review will explore some of the key points in the nutritional management of people with CF in the 21st Century.
PMID: 28420572 [PubMed - as supplied by publisher]
Dry powders for the inhalation of ciprofloxacin or levofloxacin combined with a mucolytic agent for cystic fibrosis patients.
Dry powders for the inhalation of ciprofloxacin or levofloxacin combined with a mucolytic agent for cystic fibrosis patients.
Drug Dev Ind Pharm. 2017 Apr 19;:1-35
Authors: Akdag Cayli Y, Sahin S, Buttini F, Balducci AG, Montanari S, Vural I, Oner L
Abstract
OBJECTIVE: This study aimed to design and characterize an inhalable dry powder of ciprofloxacin or levofloxacin combined with the mucolytics acetylcysteine and dornase alfa for the management of pulmonary infections in patients with cystic fibrosis.
METHODS: Ball milling, homogenization in isopropyl alcohol, and spray drying processes were used to prepare dry powders for inhalation. Physico-chemical characteristics of the dry powders were assessed via thermogravimetric analysis, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry, and scanning electron microscopy. The particle size distribution, dissolution rate, and permeability across Calu-3 cell monolayers were analyzed. The aerodynamic parameters of dry powders were determined using the Andersen cascade impactor (ACI).
RESULTS: After the micronization process, the particle sizes of the raw materials significantly decreased. X-ray and DSC results indicated that although ciprofloxacin showed no changes in its crystal structure, the structure of levofloxacin became amorphous after the micronization process. FT-IR spectra exhibited the characteristic peaks for ciprofloxacin and levofloxacin in all formulations. The dissolution rates of micro-homogenized and spray-dried ciprofloxacin were higher than that of untreated ciprofloxacin. ACI results showed that all formulations had a mass median aerodynamic diameter less than 5 µm; however, levofloxacin microparticles showed higher respirability than ciprofloxacin powders did. The permeability of levofloxacin was higher than those of the ciprofloxacin formulations.
CONCLUSION: Together, our study showed that these methods could suitably characterize antibiotic and mucolytic-containing dry powder inhalers.
PMID: 28420285 [PubMed - as supplied by publisher]
Infections With Biofilm Formation: Selection of Antimicrobials and Role of Prolonged Antibiotic Therapy.
Infections With Biofilm Formation: Selection of Antimicrobials and Role of Prolonged Antibiotic Therapy.
Pediatr Infect Dis J. 2016 06;35(6):695-7
Authors: Beaudoin T, Waters V
PMID: 26986772 [PubMed - indexed for MEDLINE]
A rare case of necrotizing fasciitis caused by Vibrio cholerae O8 in an immunocompetent patient.
A rare case of necrotizing fasciitis caused by Vibrio cholerae O8 in an immunocompetent patient.
Wien Klin Wochenschr. 2016 Oct;128(19-20):728-730
Authors: Dobrović K, Rudman F, Ottaviani D, Šestan Crnek S, Leoni F, Škrlin J
Abstract
We report a case of necrotizing fasciitis of the leg caused by Vibrio cholerae O8 in a 63-year-old immunocompetent man after he had been fishing in a lake on a Croatian island. The strain was cytotoxic, invasive and adhesive and contained a fragment of the gene for El Tor-like hemolysin (El Tor hlyA). After surgical and antibiotic treatment, the patient fully recovered.
PMID: 27604649 [PubMed - indexed for MEDLINE]
Early life antibiotic use and the risk of asthma and asthma exacerbations in children.
Early life antibiotic use and the risk of asthma and asthma exacerbations in children.
Pediatr Allergy Immunol. 2017 Apr 19;:
Authors: Ahmadizar F, Vijverberg SJH, Arets HGM, de Boer A, Turner S, Devereux G, Arabkhazaeli A, Soares P, Mukhopadhyay S, Garssen J, Palmer CNA, de Jongste JC, Jaddoe VW, Duijts L, van Meel ER, Kraneveld AD, Maitland-van der Zee AH
Abstract
BACKGROUND: The use of antibiotic therapy early in life might influence the risk of developing asthma. Studies assessing the influence of early life antibiotic use on the risk of asthma exacerbations are limited, and the results are inconsistent. Therefore, the aim of this study was to assess the association between use of antibiotic during the first three years of life and the risk of developing childhood asthma and the occurrence of asthma exacerbations.
METHODS: Data from four large childhood cohorts were used; two population-based cohorts to study the risk of developing asthma: Generation R (n=7,393, the Netherlands) and SEATON (n=891, Scotland, UK), and two asthma cohorts to assess the risk of asthma exacerbations: PACMAN (n=668, the Netherlands) and BREATHE (n=806, Scotland, UK). Odds ratios (ORs) were derived from logistic regression analysis within each database followed by pooling the results using a fixed- or random-effect model.
RESULTS: Antibiotic use in early life was associated with an increased risk of asthma in a meta-analysis of the Generation R and SEATON data (OR: 2.18, 95% CI: 1.04-4.60; I(2) : 76.3%). There was no association between antibiotic use in early life and risk of asthma exacerbations later in life in a meta-analysis of the PACMAN and BREATHE data (OR: 0.93, 95% CI: 0.65-1.32; I(2) : 0.0%).
CONCLUSION: Children treated with antibiotic in the first three years of life are more likely to develop asthma, but there is no evidence that the exposure to antibiotic is associated with increased risk of asthma exacerbations. This article is protected by copyright. All rights reserved.
PMID: 28423467 [PubMed - as supplied by publisher]
Androgen receptor-regulated miRNA-193a-3p targets AJUBA to promote prostate cancer cell migration.
Androgen receptor-regulated miRNA-193a-3p targets AJUBA to promote prostate cancer cell migration.
Prostate. 2017 Apr 19;:
Authors: Jia L, Gui B, Zheng D, Decker KF, Tinay I, Tan M, Wang X, Kibel AS
Abstract
Background Dysregulation of microRNA (miRNA) expression is implicated in cancer development and progression by modulating oncogenes or tumor suppressors at the post-transcriptional level. Methods To investigate the role of miRNAs in prostate cancer (PCa) progression, we performed small RNA-sequencing (RNA-seq) analysis in androgen-dependent LNCaP cells and LNCaP-derived castration-resistant prostate cancer (CRPC) C4-2B cells. For functional validation, we specifically investigated miR-193a-3p, which is highly upregulated in C4-2B cells and modulated by the androgen receptor (AR). We elucidated the role of miR-193a-3p and its downstream target gene in PCa cell migration using biochemical approaches. Results We identified a subset of differentially expressed miRNAs in C4-2B cells compared to LNCaP cells. Computational analysis shows that the targets of upregulated miRNAs are significantly associated with downregulated protein-coding mRNAs in C4-2B cells. Gene Ontology analysis further reveals that these downregulated mRNAs are significantly enriched in cell-cell adhesion functions. Downregulation of these miRNA-targeted genes may change PCa cell motility resulting in the acquisition of metastatic potential. We then focus on miR-193a-3p and demonstrate overexpression of miR-193a-3p increases cell migration through downregulating its target AJUBA. AJUBA is a LIM domain protein and contributes to the formation and stability of cadherin-mediated cell-cell adhesion. Loss of AJUBA enhances PCa migration and downregulation of AJUBA expression is observed in metastatic PCa tumors. Conclusions Our results suggest a novel AR/miR-193a-3p/AJUBA pathway implicated in PCa progression. MiR-193a-3p is a potential therapeutic target for metastatic PCa.
PMID: 28422308 [PubMed - as supplied by publisher]
Clinical-pharmacogenetic models for personalized cancer treatment: application to malignant mesothelioma.
Clinical-pharmacogenetic models for personalized cancer treatment: application to malignant mesothelioma.
Sci Rep. 2017 Apr 19;7:46537
Authors: Goričar K, Kovač V, Dolžan V
Abstract
Large interindividual differences in treatment outcome are observed in cancer patients undergoing chemotherapy. Our aim was to develop and validate clinical-pharmacogenetic prediction models of gemcitabine/cisplatin or pemetrexed/cisplatin treatment outcome and develop an algorithm for genotype-based treatment recommendations in malignant mesothelioma (MM). We genotyped 189 MM patients for polymorphisms in gemcitabine, pemetrexed and cisplatin metabolism, transport and drug target genes and DNA repair pathways. To build respective clinical-pharmacogenetic models, pharmacogenetic scores were assigned by rounding regression coefficients. Gemcitabine/cisplatin model was based on training group of 71 patients and included CRP, histological type, performance status, RRM1 rs1042927, ERCC2 rs13181, ERCC1 rs3212986, and XRCC1 rs25487. Patients with higher score had shorter progression-free (PFS) and overall survival (P < 0.001). This model's sensitivity was 0.615 and specificity 0.812. In independent validation group of 66 patients the sensitivity and specificity were 0.667 and 0.641, respectively. Pemetrexed/cisplatin model was based on 57 patients and included CRP, MTHFD1 rs2236225, and ABCC2 rs2273697. Patients with higher score had worse response and shorter PFS (P < 0.001). This model's sensitivity was 0.750 and specificity 0.607. In independent validation group of 20 patients the sensitivity and specificity were 0.889 and 0.500, respectively. The proposed algorithm based on these models could enable the choice of the most effective chemotherapy for 85.5% of patients and lead to improved treatment outcome in MM.
PMID: 28422153 [PubMed - in process]
The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics.
The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics.
Cardiol Res Pract. 2017;2017:8062796
Authors: Amin AM, Sheau Chin L, Azri Mohamed Noor D, Sk Abdul Kader MA, Kah Hay Y, Ibrahim B
Abstract
Dual antiplatelet therapy of aspirin and clopidogrel is pivotal for patients undergoing percutaneous coronary intervention. However, the variable platelets reactivity response to clopidogrel may lead to outcome failure and recurrence of cardiovascular events. Although many genetic and nongenetic factors are known, great portion of clopidogrel variable platelets reactivity remain unexplained which challenges the personalization of clopidogrel therapy. Current methods for clopidogrel personalization include CYP2C19 genotyping, pharmacokinetics, and platelets function testing. However, these methods lack precise prediction of clopidogrel outcome, often leading to insufficient prediction. Pharmacometabolomics which is an approach to identify novel biomarkers of drug response or toxicity in biofluids has been investigated to predict drug response. The advantage of pharmacometabolomics is that it does not only predict the response but also provide extensive information on the metabolic pathways implicated with the response. Integrating pharmacogenetics with pharmacometabolomics can give insight on unknown genetic and nongenetic factors associated with the response. This review aimed to review the literature on factors associated with the variable platelets reactivity response to clopidogrel, as well as appraising current methods for the personalization of clopidogrel therapy. We also aimed to review the literature on using pharmacometabolomics approach to predict drug response, as well as discussing the plausibility of using it to predict clopidogrel outcome.
PMID: 28421156 [PubMed]
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