Funding Opportunity PA-18-739 from the NIH Guide for Grants and Contracts. The overall purpose of this funding opportunity announcement (FOA) is to assess the role of the microbiome in health and disease during aging. This initiative will support research projects designed to evaluate changes in the microbiota during lifetime and its influence in health and disease status in the elderly, including those from racial/ethnic minority and underserved populations and understand the underlying mechanisms of microbiota interactions in aged subjects as related to health and disease. This FOA will accept basic mechanistic, preclinical studies in animal models and human clinical trial proposals in accordance with the state of the science.

Notice NOT-CA-18-056 from the NIH Guide for Grants and Contracts

Have there been improvements in Alzheimer's disease drug discovery over the past 5 years?

Expert Opin Drug Discov. 2018 Apr 01;:1-16

Authors: Cacabelos R

Abstract
INTRODUCTION: Alzheimer's disease (AD) is the most important neurodegenerative disorder with a global cost worldwide of over $700 billion. Pharmacological treatment accounts for 10-20% of direct costs; no new drugs have been approved during the past 15 years; and the available medications are not cost-effective. Areas covered: A massive scrutiny of AD-related PubMed publications (ps)(2013-2017) identified 42,053ps of which 8,380 (19.60%) were associated with AD treatments. The most prevalent pharmacological categories included neurotransmitter enhancers (11.38%), multi-target drugs (2.45%), anti-Amyloid agents (13.30%), anti-Tau agents (2.03%), natural products and derivatives (25.58%), novel drugs (8.13%), novel targets (5.66%), other (old) drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and others (<1% each). Expert opinion: Unsuccessful outcomes in AD therapeutics are attributed to pathogenic misconceptions, erratic procedures in drug development and inappropriate regulations. Recommendations for the future are as follows: (i) the reconsideration of dominant pathogenic theories, (ii) the identification of reliable biomarkers, (iii) the redefinition of diagnostic criteria, (iv) new guidelines for disease management, (v) the reorientation of drug discovery programs, (vi) the updating of regulatory requirements, (vii) the introduction of pharmacogenomics in drug development and personalized treatments, and (viii) the implementation of preventive programs.

PMID: 29607687 [PubMed - as supplied by publisher]

Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke.

Pharmgenomics Pers Med. 2018;11:43-49

Authors: Kryukov AV, Sychev DA, Andreev DA, Ryzhikova KA, Grishina EA, Ryabova AV, Loskutnikov MA, Smirnov VV, Konova OD, Matsneva IA, Bochkov PO

Abstract
Introduction: Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke.
Patients and methods: Pharmacokinetics of apixaban in patients with acute stroke was studied earlier by Kryukov et al. The present study enrolled 17 patients with cardioembolic stroke, who received 5 mg of apixaban. In order to evaluate the pharmacokinetic parameters of apixaban, venous blood samples were collected before taking 5 mg of apixaban (point 0) and 1, 2, 3, 4, 10, and 12 hours after drug intake. Blood samples were centrifuged at 3000 rpm for 15 minutes. Separate plasma was aliquoted in Eppendorf tubes and frozen at -70°C until analysis. High-performance liquid chromatography mass spectrometry analysis was used to determine apixaban plasma concentration. Genotyping was performed by real-time polymerase chain reaction. CYP3A isoenzyme group activity was evaluated by determining urinary concentration of endogenous substrate of the enzyme and its metabolite (6-β-hydroxycortisol to cortisol ratio). Statistical analysis was performed using SPSS Statistics version 20.0. The protocol of this study was reviewed and approved by the ethics committee; patients or their representatives signed an informed consent.
Results: ABCB1 (rs1045642 and rs4148738) gene polymorphisms do not affect the pharmacokinetics of apixaban as well as CYP3A5 (rs776746) gene polymorphisms. Apixaban pharmacokinetics in groups with different genotypes did not differ statistically significantly. Correlation analysis showed no statistically significant relationship between pharmacokinetic parameters of apixaban and the metabolic activity of CYP3A.
Conclusion: Questions such as depending on genotyping results for apixaban dosing and implementation of express genotyping in clinical practice remain open for NOACs. Large population studies are required to clarify the clinical significance of genotyping for this drug class.

PMID: 29606886 [PubMed]

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Molecular epidemiology of blastocystosis in Malaysia: does seasonal variation play an important role in determining the distribution and risk factors of Blastocystis subtype infections in the Aboriginal community?

Parasit Vectors. 2017 Jul 31;10(1):360

Authors: Noradilah SA, Moktar N, Anuar TS, Lee IL, Salleh FM, Manap SNAA, Mohtar NSHM, Azrul SM, Abdullah WO, Nordin A, Abdullah SR

Abstract
BACKGROUND: Alternating wet and dry seasons may play an important role in the acquisition and distribution of Blastocystis subtype infection in the tropics. This cross-sectional study was therefore conducted to provide the prevalence of Blastocystis and to determine the potential risk factors associated with each subtype during the wet and dry seasons in the Aboriginal community, Pahang, Malaysia.
METHODS: A total of 473 faecal samples were collected: 256 (54.1%) and 217 (45.9%) samples were obtained during the wet (October-November 2014) and the dry season (June 2015), respectively. All fresh faecal samples were subjected to molecular analysis for subtype and allele identification.
RESULTS: Of the 473 samples, 42.6% and 37.8% were positive for Blastocystis ST1, ST2, ST3 and ST4 during wet and dry seasons, respectively. Prevalence of Blastocystis ST1 was significantly higher during the wet season compared to the dry season (Z = 2.146, P < 0.05). Analysis of the association of each Blastocystis subtype with socioeconomic characteristics showed the presence of other family members infected with Blastocystis ST3 and the use of stored river water for domestic activities were the significant risk factors for Blastocystis ST3 infections during both seasons. Untreated water supply and low monthly household income (less or equal to RM 500) were the other significant risk factors for Blastocystis ST3 infections during wet and dry season, respectively. The presence of other family members with Blastocystis ST1 and ST2 was the only significant risk factor associated with ST1 and ST2 infections during both seasons. We hypothesise that transmission of Blastocystis ST1, ST2 and ST3 occurred from person to person during both seasons. The waterborne transmission was also identified as a mode of transmission of Blastocystis ST3.
CONCLUSION: The significant risk factors identified in this study were important in the dynamic transmission of Blastocystis infections during both seasons. Provision of treated water supply and health education are affirmative actions to be taken to control Blastocystis infections in this community.

PMID: 28760145 [PubMed - indexed for MEDLINE]

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Lack of association between MTHFR A1298C polymorphism and outcome of methotrexate treatment in rheumatoid arthritis patients: evidence from a systematic review and meta-analysis.

Int J Rheum Dis. 2017 May;20(5):526-540

Authors: Fan H, Li Y, Zhang L, Li Y, Li W

Abstract
OBJECTIVES: The aim of this study was to evaluate the association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphism A1298C and methotrexate (MTX) outcome in rheumatoid arthritis (RA) patients.
METHODS: We conducted a meta-analysis of the relevant published literature through to May 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- and random-effect models.
RESULTS: A total of 1325 cases (10 studies) of MTX efficacy and 2777 cases (18 studies) of MTX toxicity in RA patients were analyzed. Pooled results showed that MTHFR gene A1298C polymorphism was not significantly related to MTX toxicity or efficacy in RA patients. However, subgroup analysis indicated a significant association between MTHFR gene A1298C polymorphism and decreased MTX efficacy in the South Asian population (CCvs. CA + AA: OR = 0.45, 95% CI = 0.23-0.89, P = 0.021). Also, MTHFR gene A1298C polymorphism in the partial folate supplementation group showed a relationship with decreased MTX efficacy (CCvs. CA + AA: OR = 0.43, 95% CI = 0.20-0.92, P = 0.029) and toxicity (CCvs. CA + AA: OR = 0.40, 95% CI = 0.17-0.96, P = 0.04; CCvs. AA: OR = 0.38, 95% CI = 0.16-0.94, P = 0.035).
CONCLUSIONS: Overall, our meta-analysis suggested no significant effect of MTHFR gene A1298C polymorphism on MTX outcome in RA patients. However, due to several limitations of our meta-analysis, the results should be interpreted cautiously and require further confirmation using high-quality studies.

PMID: 28544525 [PubMed - indexed for MEDLINE]

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A New CYP3A5*3 and CYP3A4*22 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach.

Clin Pharmacokinet. 2017 Aug;56(8):963-975

Authors: Andreu F, Colom H, Elens L, van Gelder T, van Schaik RHN, Hesselink DA, Bestard O, Torras J, Cruzado JM, Grinyó JM, Lloberas N

Abstract
BACKGROUND: Single nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes have been reported to be an important cause of variability in the pharmacokinetics of tacrolimus in renal transplant patients. The aim of this study was to merge all of the new genetic information available with tacrolimus pharmacokinetics to generate a more robust population model with data from renal transplant recipients.
METHODS: Tacrolimus exposure data from 304 renal transplant recipients were collected throughout the first year after transplantation and were simultaneously analyzed with a population pharmacokinetic approach using NONMEM® version 7.2.
RESULTS: The tacrolimus whole-blood concentration versus time data were best described by a two-open-compartment model with inter-occasion variability assigned to plasma clearance. The following factors led to the final model, which significantly decreased the minimum objective function value (p < 0.001): a new genotype cluster variable combining the CYP3A5*3 and CYP3A4*22 SNPs defined as extensive, intermediate, and poor metabolizers; the standardization of tacrolimus whole blood concentrations to a hematocrit value of 45%; and age included as patients <63 years versus patients ≥63 years. External validation confirmed the prediction ability of the model with median bias and precision values of 1.17 ng/mL (95% confidence interval [CI] -3.68 to 4.50) and 1.64 ng/mL (95% CI 0.11-5.50), respectively. Simulations showed that, for a given age and hematocrit at the same fixed dose, extensive metabolizers required the highest doses followed by intermediate metabolizers and then poor metabolizers.
CONCLUSIONS: Tacrolimus disposition in renal transplant recipients was described using a new population pharmacokinetic model that included the CYP3A5*3 and CYP3A4*22 genotype, age, and hematocrit.

PMID: 28050888 [PubMed - indexed for MEDLINE]

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CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients.

Clin Pharmacokinet. 2017 Aug;56(8):977-985

Authors: Barratt DT, Cox HK, Menelaou A, Yeung DT, White DL, Hughes TP, Somogyi AA

Abstract
OBJECTIVE: The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients.
METHODS: We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400-800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc).
RESULTS: CYP2C8*3 (n = 34) and *4 (n = 15) carriers had significantly higher (P < 0.01) and lower (P < 0.01) metabolic ratios, respectively, than CYP2C8*1/*1 (n = 147) patients (median ± standard deviation: 0.28 ± 0.08, 0.18 ± 0.06 and 0.22 ± 0.08, respectively). Plasma imatinib concentrations were consequently > 50% higher for CYP2C8*1/*4 than for CYP2C8*1/*1 and CYP2C8*3 carriers (2.18 ± 0.66 vs. 1.45 ± 0.74 [P < 0.05] and 1.36 ± 0.98 μg/mL [P < 0.05], respectively).
CONCLUSIONS: CYP2C8 genotype significantly alters imatinib metabolism in patients through gain- and loss-of-function mechanisms.

PMID: 27995529 [PubMed - indexed for MEDLINE]

Emerging biological therapies for treating chronic obstructive pulmonary disease: A pairwise and network meta-analysis.

Pulm Pharmacol Ther. 2018 Mar 30;:

Authors: Rogliani P, Matera MG, Puxeddu E, Mantero M, Blasi F, Cazzola M, Calzetta L

Abstract
Inflammation in chronic obstructive pulmonary disease (COPD) is often corticosteroid resistant and, thus, alternative anti-inflammatory approaches are needed. Since it is still not clear whether blocking specific pro-inflammatory factors may provide clinical benefit in COPD, we have performed a meta-analysis to quantify the impact of monoclonal antibodies (mABs) targeting the cytokine/chemokine-mediated inflammation in COPD. A pairwise and network meta-analyses were performed by extracting data from randomized clicnial trials on COPD concerning the impact of mABs vs. placebo on the risk of exacerbation, forced expiratory volume in 1 s (FEV1), and St. George's Respiratory Questionnaire (SGRQ). Data on the interleukin (IL)-1β antagonist canakinumab, IL-1R1 antagonist MEDI8986, IL-5 antagonist mepolizumab, IL-5R antagonist benralizumab, IL-8 antagonist ABX-IL8, and TNF-α antagonist infliximab were found. Overall, mAB therapy had a moderate impact on the risk exacerbation, but not on FEV1 and SGRQ. The pairwise meta-analysis performed in eosinophilic patients, and the network approach, indicated that mepolizumab elicited a beneficial effect against the risk of exacerbation, whereas benralizumab was more effective in improving both FEV1 and SGRQ. This study demonstrates that targeting the pathway activated by IL-5 may have a beneficial impact in eosinophilic COPD patients.

PMID: 29609004 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa Pyocyanin Production Reduced by Quorum-Sensing Inhibiting Nanocarriers.

Int J Pharm. 2018 Mar 30;:

Authors: Lu HD, Pearson E, Ristroph KD, Duncan GA, Ensign LM, Soo Suk J, Hanes J, Prud'homme RK

Abstract
Pseudomonas aeruginosa is an opportunistic gram-negative pathogen that causes a wide range of infections; it is becoming increasingly difficult to treat due to antibiotic resistance. Quorum-sensing (QS) based therapeutics, which function by disabling pathogen virulence without killing pathogens, are a promising class of drugs that may be used to treat bacterial infections without eliciting resistance development. The use of QS drugs to treat pulmonary P. aeruginosa infections, however, has been greatly limited due to the inability to deliver QS drugs at sufficiently high concentrations past physiological barriers such as pulmonary mucus. Here we apply a block-copolymer directed self-assembly process, Flash NanoPrecipitation, to develop a series of QS-active formulations that are fully water dispersible, stable, and mucus-penetrating. These formulations inhibit P. aeruginosa virulence without inhibiting cell growth. Particle size (70nm - 400 nm) and release rate (1 hr to 14 days) can be tuned by altering constructs' physical properties and formulation excipients. We also demonstrate, to the best of our knowledge, the first instance of a QS nanocarrier platform technology that can penetrate through human cystic fibrosis pulmonary mucus. This work highlights the need to incorporate nanoformulation strategies into the development of next-generation antimicrobial therapeutics.

PMID: 29608955 [PubMed - as supplied by publisher]

Regulation of carbohydrate degradation pathways in Pseudomonas involves a versatile set of transcriptional regulators.

Microb Biotechnol. 2018 Apr 02;:

Authors: Udaondo Z, Ramos JL, Segura A, Krell T, Daddaoua A

Abstract
Bacteria of the genus Pseudomonas are widespread in nature. In the last decades, members of this genus, especially Pseudomonas aeruginosa and Pseudomonas putida, have acquired great interest because of their interactions with higher organisms. Pseudomonas aeruginosa is an opportunistic pathogen that colonizes the lung of cystic fibrosis patients, while P. putida is a soil bacterium able to establish a positive interaction with the plant rhizosphere. Members of Pseudomonas genus have a robust metabolism for amino acids and organic acids as well as aromatic compounds; however, these microbes metabolize a very limited number of sugars. Interestingly, they have three-pronged metabolic system to generate 6-phosphogluconate from glucose suggesting an adaptation to efficiently consume this sugar. This review focuses on the description of the regulatory network of glucose utilization in Pseudomonas, highlighting the differences between P. putida and P. aeruginosa. Most interestingly, It is highlighted a functional link between glucose assimilation and exotoxin A production in P. aeruginosa. The physiological relevance of this connection remains unclear, and it needs to be established whether a similar relationship is also found in other bacteria.

PMID: 29607620 [PubMed - as supplied by publisher]

Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis.

Cochrane Database Syst Rev. 2018 Mar 30;3:CD001021

Authors: Smith S, Rowbotham NJ, Regan KH

Abstract
BACKGROUND: Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review.
OBJECTIVES: To evaluate the effects long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug sensitivity reactions and survival).
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries.Date of last search: 13 February 2018.
SELECTION CRITERIA: We selected trials if inhaled anti-pseudomonal antibiotic treatment was used for at least three months in people with cystic fibrosis, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic).
DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the quality of the evidence using the GRADE system.
MAIN RESULTS: The searches identified 333 citations to 98 trials; 18 trials (3042 participants aged between five and 56 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One of the trials (18 participants) compared to placebo and a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials.We found limited evidence that inhaled antibiotics improved lung function (four of the 11 placebo-controlled trials, n = 814). Compared to placebo, inhaled antibiotics also reduced the frequency of exacerbations (three trials, n = 946), risk ratio 0.66 (95% confidence interval (CI) 0.47 to 0.93). There were insufficient data for us to be able to report an effect on nutritional outcomes or survival and there were insufficient data for us to ascertain the effect on quality of life. There was no significant effect on antibiotic resistance seen in the two trials that were included in meta-analyses. Tinnitus and voice alteration were the only adverse events significantly more common in the inhaled antibiotics group. The overall quality of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates.Of the eight trials that compared different inhaled antibiotics or different antibiotic regimens, there was only one trial in each comparison. Forced expiratory volume at one second (FEV1) % predicted was only found to be significantly improved with aztreonam lysine for inhalation compared to tobramycin (n = 273), mean difference -3.40% (95% CI -6.63 to -0.17). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. No significant differences were found in the remaining comparisons with regard to lung function. Pulmonary exacerbations were measured in different ways, but one trial (n = 273) found that the number of people treated with antibiotics was lower in those receiving aztreonam than tobramycin, risk ratio 0.66 (95% CI 0.51 to 0.86). We found the quality of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high.
AUTHORS' CONCLUSIONS: Inhaled anti-pseudomonal antibiotic treatment probably improves lung function and reduces exacerbation rate, but pooled estimates of the level of benefit were very limited. The best evidence is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.

PMID: 29607494 [PubMed - as supplied by publisher]

Molecular dynamics simulation study on the structural instability of the most common cystic fibrosis-associated mutant ΔF508-CFTR.

Biophys Physicobiol. 2018;15:33-44

Authors: Odera M, Furuta T, Sohma Y, Sakurai M

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that belongs to the ATP binding cassette protein superfamily. Deletion of phenylalanine at position 508 (ΔF508) is the most common CF-associated mutation and is present in nearly 90% of CF patients. Currently, atomistic level studies are insufficient for understanding the mechanism by which the deletion of a single amino acid causes greatly reduced folding as well as trafficking and gating defects. To clarify this mechanism, we first constructed an atomic model of the inward-facing ΔF508-CFTR and performed allatom molecular dynamics (MD) simulations of the protein in a membrane environment. All of the computational methodologies used are based on those developed in our previous study for wild-type CFTR. Two important findings were obtained. First, consistent with several previous computational results, the deletion of F508 causes a disruption of a hydrophobic cluster located at the interface between the nucleotide binding domain 1 (NBD1) and intracellular loop 4 (ICL4). This exerts unfavorable influences on the correlated motion between ICLs and transmembrane domains (TMDs), likely resulting in gating defects. Second, the F508 deletion affected the NBD1-NBD2 interface via allosteric communication originating from the correlated motion between NBDs and ICLs. As a result, several unusual inter-residue interactions are caused at the NBD1-NBD2 interface. In other words, their correct dimerization is impaired. This study provided insight into the atomic-level details of structural and dynamics changes caused by the ΔF508 mutation and thus provides good insight for drug design.

PMID: 29607278 [PubMed]

Prevalence of severe fatigue among adults with cystic fibrosis: A single center study.

J Cyst Fibros. 2018 Mar 29;:

Authors: Nap-van der Vlist MM, Burghard M, Hulzebos HJ, Doeleman WR, Heijerman HGM, van der Ent CK, Nijhof SL

Abstract
BACKGROUND: With life expectancy increasing among patients with cystic fibrosis (CF), the prevalence of complications such as fatigue is also expected to increase. Our aim was to investigate the prevalence of severe fatigue among adults with CF and to identify factors associated with fatigue.
METHODS: Adult patients with CF receiving treatment at a single center were invited to complete three questionnaires. We then studied the associations between fatigue and clinically measured parameters and between fatigue and patient-reported outcomes.
RESULTS: A total of 77 patients (age 19-54 years; 56% males; mean FEV1: 63%) completed the questionnaires (43% response rate). The prevalence of severe fatigue among these patients was 26%. The variance in fatigue was explained partially by clinically measured parameters. However, patient-reported outcomes were stronger independently associated with fatigue and included the patients' reported respiratory symptoms, emotional functioning, and social functioning.
CONCLUSIONS: Fatigue is a clinically important and highly prevalent issue among adults with CF and is associated with a significant reduction in health-related quality of life and participation in society. In addition, fatigue is associated more strongly with the patient's perception of symptoms and well-being than with clinically measured parameters.

PMID: 29606526 [PubMed - as supplied by publisher]

Neoadjuvant degarelix with or without apalutamide followed by radical prostatectomy for intermediate and high-risk prostate cancer: ARNEO, a randomized, double blind, placebo-controlled trial.

BMC Cancer. 2018 Apr 02;18(1):354

Authors: Tosco L, Laenen A, Gevaert T, Salmon I, Decaestecker C, Davicioni E, Buerki C, Claessens F, Swinnen J, Goffin K, Oyen R, Everaerts W, Moris L, De Meerleer G, Haustermans K, Joniau S, P.E.A.R.L. (ProstatE cAncer Research Leuven)

Abstract
BACKGROUND: Recent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone.
OBJECTIVE: The primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints.
METHODS: ARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68Ga -PSMA-11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry.
DISCUSSION: ARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected.
TRIAL REGISTRATION: EUDRaCT number: 2016-002854-19 (authorization date 3rd August 2017). clinicalTrial.gov: NCT03080116 .

PMID: 29606109 [PubMed - in process]

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Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures.

Biol Psychiatry. 2017 Aug 01;82(3):224-232

Authors: Ben-Shalom R, Keeshen CM, Berrios KN, An JY, Sanders SJ, Bender KJ

Abstract
BACKGROUND: Variants in the SCN2A gene that disrupt the encoded neuronal sodium channel NaV1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect NaV1.2 function and neuronal excitability are unclear.
METHODS: We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry. Resultant data were incorporated into computational models of developing and mature cortical pyramidal cells that express NaV1.2.
RESULTS: In contrast to gain of function variants that contribute to seizure, we found that all ASD-associated variants dampened or eliminated channel function. Incorporating these electrophysiological results into a compartmental model of developing excitatory neurons demonstrated that all ASD variants, regardless of their mechanism of action, resulted in deficits in neuronal excitability. Corresponding analysis of mature neurons predicted minimal change in neuronal excitability.
CONCLUSIONS: This functional characterization thus identifies SCN2A mutation and NaV1.2 dysfunction as the most frequently observed ASD risk factor detectable by exome sequencing and suggests that associated changes in neuronal excitability, particularly in developing neurons, may contribute to ASD etiology.

PMID: 28256214 [PubMed - indexed for MEDLINE]

Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity.

J Vis Exp. 2018 Mar 16;(133):

Authors: Sheehan K, Sheth S, Mukherjea D, Rybak LP, Ramkumar V

Abstract
The systemic administration of protective agents to treat drug-induced ototoxicity is limited by the possibility that these protective agents could interfere with the chemotherapeutic efficacy of the primary drugs. This is especially true for the drug cisplatin, whose anticancer actions are attenuated by antioxidants which provide adequate protection against hearing loss. Other current or potential otoprotective agents could pose a similar problem, if administered systemically. The application of various biologicals or protective agents directly to the cochlea would allow for high levels of these agents locally with limited systemic side effects. In this report, we demonstrate a trans-tympanic method of delivery of various drugs or biological reagents to the cochlea, which should enhance basic science research on the cochlea and provide a simple way of directing the use of otoprotective agents in the clinics. This report details a method of trans-tympanic drug delivery and provides examples of how this technique has been used successfully in experimental animals to treat cisplatin ototoxicity.

PMID: 29608150 [PubMed - in process]

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Comparison of Two Versions of the Beers Criteria and Adverse Outcomes in Older Hospitalized Patients.

Consult Pharm. 2017 Dec 01;32(12):752-763

Authors: Ozalas SM, Huang V, Brunetti L, Reilly T

Abstract
OBJECTIVE: To compare the performance of the 2003 and 2012 Beers criteria (BC) to predict negative clinical outcomes associated with potentially inappropriate medications in hospitalized older adults.
DESIGN: Retrospective cohort study.
SETTING: Acute Care of Elders (ACE) unit in a community-based teaching hospital.
PARTICIPANTS: All patients admitted to an ACE unit who were older than 65 years of age and prescribed at least one medication upon hospital admission.
MAIN OUTCOME MEASURE(S): The primary outcome was hospital length of stay (LOS). Secondary outcomes included likelihood of experiencing adverse drug events (ADEs) and in-hospital mortality.
RESULTS: A total of 340 patients were included in this study. Inpatients prescribed a BC drug at any time had a longer hospital LOS than those not prescribed a BC drug (2003 BC: adjusted geometric mean, 5.93 vs. 5.50 days, P = 0.003; 2012 BC: adjusted geometric mean, 5.87 vs. 4.21 days, P < 0.001). Patients prescribed a 2003 BC drug had an increased risk of experiencing an ADE compared with those not prescribed a BC drug (odds ratio [OR] = 1.86, 95% confidence interval [CI] 1.11-3.11); however, this outcome was not statistically significant after adjusting for confounders (OR = 1.51, 95% CI 0.870-2.63). There was no statistically significant difference in ADEs when using the 2012 BC (adjusted OR = 1.27, 95% CI 0.689-2.33). There was no difference in hospital mortality regardless of the BC version used.
CONCLUSION: Prescription of BC drugs in an acute care setting is associated with an increased hospital LOS; however, there is no difference in the risk of ADEs or in-hospital mortality.

PMID: 29467068 [PubMed - indexed for MEDLINE]

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Clinical Alerts to Decrease High-Risk Medication Use in Older Adults.

J Gerontol Nurs. 2017 Jul 01;43(7):7-12

Authors: Lord-Adem W, Brandt NJ

Abstract
High-risk medications (HRMs) account for 14.6% to 54.6% of all medications used in older adults, and have been linked to >50% of adverse drug events (ADEs). HRM-related ADEs lead to increased morbidity and mortality, increased hospital length of stay, and financial costs for patients and health care systems. It has been well documented that incorporating information technology in patient care in the form of clinical alert systems can effectively decrease HRM use and improve patient safety. The current article seeks to identify and discuss clinical alert systems focusing on HRMs, their impact on prescribing for older adults, and challenges to the implementation of electronic decision systems. [Journal of Gerontological Nursing, 43(7), 7-12.].

PMID: 28651030 [PubMed - indexed for MEDLINE]

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Personalized Medicine: New Perspectives for the Diagnosis and the Treatment of Renal Diseases.

Int J Mol Sci. 2017 Jun 10;18(6):

Authors: Gluba-Brzózka A, Franczyk B, Olszewski R, Banach M, Rysz J

Abstract
The prevalence of renal diseases is rising and reaching 5-15% of the adult population. Renal damage is associated with disturbances of body homeostasis and the loss of equilibrium between exogenous and endogenous elements including drugs and metabolites. Studies indicate that renal diseases are influenced not only by environmental but also by genetic factors. In some cases the disease is caused by mutation in a single gene and at that time severity depends on the presence of one or two mutated alleles. In other cases, renal disease is associated with the presence of alteration within a gene or genes, but environmental factors are also necessary for the development of disease. Therefore, it seems that the analysis of genetic aspects should be a natural component of clinical and experimental studies. The goal of personalized medicine is to determine the right drug, for the right patient, at the right time. Whole-genome examinations may help to change the approach to the disease and the patient resulting in the creation of "personalized medicine" with new diagnostic and treatment strategies designed on the basis of genetic background of each individual. The identification of high-risk patients in pharmacogenomics analyses will help to avoid many unwarranted side effects while optimizing treatment efficacy for individual patients. Personalized therapies for kidney diseases are still at the preliminary stage mainly due to high costs of such analyses and the complex nature of human genome. This review will focus on several areas of interest: renal disease pathogenesis, diagnosis, treatment, rate of progression and the prediction of prognosis.

PMID: 28604601 [PubMed - indexed for MEDLINE]