Evolution of the Pseudomonas aeruginosa aminoglycoside mutational resistome in vitro and in the cystic fibrosis setting.

Antimicrob Agents Chemother. 2018 Feb 05;:

Authors: López-Causapé C, Rubio R, Cabot G, Oliver A

Abstract
Inhaled administration of high doses of aminoglycosides is a key maintenance treatment of Pseudomonas aeruginosa chronic respiratory infections in cystic fibrosis (CF). We analyzed the dynamics and mechanisms of step-wise high-level tobramycin resistance development in vitro and compared the results with those of isogenic pairs of susceptible-resistant clinical isolates. Resistance development correlated with fusA1 mutations in vitro and in vivopmrB mutations, conferring polymyxin resistance, were also frequently selected in vitro In contrast, mutational overexpression of MexXY, a hallmark of aminoglycoside resistance in CF, was not observed in in vitro evolution experiments.

PMID: 29437613 [PubMed - as supplied by publisher]

Optimization of a meropenem plus tobramycin combination dosage regimen against hypermutable and non-hypermutable Pseudomonas aeruginosa via mechanism-based modeling and the hollow-fiber infection model.

Antimicrob Agents Chemother. 2018 Feb 05;:

Authors: Landersdorfer CB, Rees VE, Yadav R, Rogers KE, Kim TH, Bergen PJ, Cheah SE, Boyce JD, Peleg AY, Oliver A, Shin BS, Nation RL, Bulitta JB

Abstract
Objectives: Hypermutable Pseudomonas aeruginosa are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM).Methods: The PAO1 wild-type strain and its isogenic hypermutable PAOΔmutS strain (MICmeropenem 1.0 mg/liter, MICtobramycin 0.5 mg/liter, for both) were assessed using 96-h static concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum ∼108.4 CFU/ml). MBM of SCTK data was performed to predict expected HFIM outcomes. Regimens studied in the HFIM were: meropenem 1 g 8-hourly (0.5h infusion), meropenem 3 g/day continuous infusion, tobramycin 10 mg/kg 24-hourly (1h infusion) and both combinations; meropenem regimens delivered the same total daily dose. Time-courses of total and less-susceptible populations and MICs were determined.Results: For PAOΔmutS in the HFIM, all monotherapies resulted in rapid regrowth to >108.7 CFU/ml with near complete replacement by less-susceptible bacteria by day 3. Meropenem 8-hourly with tobramycin caused >7-log10 bacterial killing followed by regrowth to >6-log10 CFU/ml by day 5 and high-level resistance (MICmeropenem 32 mg/liter, MICtobramycin 8 mg/liter). Continuous infusion meropenem with tobramycin achieved >8-log10 bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4-log10 over 7-9 days, with both combination regimens achieving near eradication.Conclusions: A MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.

PMID: 29437610 [PubMed - as supplied by publisher]

Enhancing the Spreading Behavior on Pulmonary Mucus Mimicking Subphase via Catanionic Surfactant Solutions: Towards Effective Drug Delivery through the Lungs.

Mol Pharm. 2018 Feb 13;:

Authors: Alp G, Aydogan N

Abstract
Effective and efficient spreading of drug formulations on the pulmonary mucosal layer is key to successful delivery of therapeutics through the lungs. Pulmonary mucus layer, which covers the airway surface, acts as a barrier against therapeutic agents, especially in the case of chronic lung diseases due to increased thickness and viscosity of mucus. Therefore, spreading of the drug formulations on the airways gets harder. Although spreading experiments have been conducted with different types of formulations on mucus-mimicking subphases, a highly effective formulation is yet to be discovered. Adding surfactant to such formulations decreases the surface tension and triggers the Marangoni forces to enhance the spreading behavior. In this study, catanionic (cationic+anionic) surfactant mixtures composed of Dodecyltrimethyl ammonium bromide (DTAB) and Dioctyl sulfosuccinate sodium salt (AOT) mixed at various mole ratios are prepared and their spreading behavior on both mucin and cystic fibrosis (CF) mucus models are investigated for the first time in the literature. Synergistic interaction is obtained between the components of the DTAB/AOT mixtures and this interaction has enhanced the spreading of the formulation drop on both the mucin and CF mucus models when compared with the spreading performances of selected conventional surfactants. It is proposed that the catanionic surfactant mixtures, especially when mixed at the molar ratios of 8/2 and 7/3 (DTAB/AOT) improves the spreading even on the cystic fibrosis sputum model. As it is vital to transport the sufficient amount of drug to the targeted region for the treatment of diseases, this study presents an important application of fundamentals of colloidal science to pharmaceutical nanotechnology.

PMID: 29436839 [PubMed - as supplied by publisher]

Advances in the Diagnosis and Management of Cystic Fibrosis in the Genomic Era.

Clin Chem. 2018 Feb 07;:

Authors: Wiencek JR, Lo SF

Abstract
BACKGROUND: Cystic fibrosis (CF) is a complex autosomal recessive disease that continues to present unique diagnostic challenges. Because CF was first described in 1938, there has been a substantial growth of genetic and phenotypic information about the disorder. During the past few years, as more evidence has become available, a consortium of international experts determined that the 2008 guidelines from the CF Foundation needed to be reviewed and updated.
CONTENT: The goal of this review is to highlight the latest advances in CF multidisciplinary care, together with the recent updates to the 2017 CF Foundation diagnostic guidelines.
SUMMARY: Data from newborn screening programs, patient registries, clinical databases, and functional research have led to a better understanding of the CF transmembrane conductance regulator (CFTR) gene. Recent consensus guidelines have provided recommendations for clinicians and laboratorians to better assist with interpretation of disease status and related CF mutations. The highly recommended Clinical and Functional Translation of CFTR project should be the first resource in the evaluation of disease severity for CF mutations. Screen-positive newborns and patients with high clinical suspicion for CF are always recommended to undergo confirmatory sweat chloride testing with interpretations based on updated reference intervals. Every patient diagnosed with CF should receive genotyping, as novel molecular therapies are becoming standard of practice. The future of CF management must consider healthcare system disparities as CF transitions from a historically childhood disease to a predominantly adult epidemic.

PMID: 29436379 [PubMed - as supplied by publisher]

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Aspergillus fumigatus responds to natural killer (NK) cells with upregulation of stress related genes and inhibits the immunoregulatory function of NK cells.

Oncotarget. 2016 11 01;7(44):71062-71071

Authors: Schneider A, Blatzer M, Posch W, Schubert R, Lass-Flörl C, Schmidt S, Lehrnbecher T

Abstract
Natural Killer (NK) cells are active against Aspergillus fumigatus, which in turn is able to impair the host defense. Unfortunately, little is known on the mutual interaction of NK cells and A. fumigatus. We coincubated human NK cells with A. fumigatus hyphae and assessed the gene expression and protein concentration of selected molecules. We found that A. fumigatus up-regulates the gene expression of pro-inflammatory molecules in NK cells, but inhibited the release of these molecules resulting in intracellular accumulation and limited extracellular availability. A. fumigatus down-regulatedmRNA levels of perforin in NK cells, but increased its intra- and extracellular protein concentration. The gene expression of stress related molecules of A. fumigatus such as heat shock protein hsp90 was up-regulated by human NK cells. Our data characterize for the first time the immunosuppressive effect of A. fumigatus on NK cells and may help to develop new therapeutic antifungal strategies.

PMID: 27738337 [PubMed - indexed for MEDLINE]

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Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia.

Blood Cancer J. 2017 Apr 28;7(4):e559

Authors: Togasaki E, Takeda J, Yoshida K, Shiozawa Y, Takeuchi M, Oshima M, Saraya A, Iwama A, Yokote K, Sakaida E, Hirase C, Takeshita A, Imai K, Okumura H, Morishita Y, Usui N, Takahashi N, Fujisawa S, Shiraishi Y, Chiba K, Tanaka H, Kiyoi H, Ohnishi K, Ohtake S, Asou N, Kobayashi Y, Miyazaki Y, Miyano S, Ogawa S, Matsumura I, Nakaseko C, Naoe T

Abstract
Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ⩾6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.

PMID: 28452984 [PubMed - indexed for MEDLINE]

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Meta-dimensional data integration identifies critical pathways for susceptibility, tumorigenesis and progression of endometrial cancer.

Oncotarget. 2016 Aug 23;7(34):55249-55263

Authors: Wei R, De Vivo I, Huang S, Zhu X, Risch H, Moore JH, Yu H, Garmire LX

Abstract
Endometrial Cancer (EC) is one of the most common female cancers. Genome-wide association studies (GWAS) have been investigated to identify genetic polymorphisms that are predictive of EC risks. Here we utilized a meta-dimensional integrative approach to seek genetically susceptible pathways that may be associated with tumorigenesis and progression of EC. We analyzed GWAS data obtained from Connecticut Endometrial Cancer Study (CECS) and identified the top 20 EC susceptible pathways. To further verify the significance of top 20 EC susceptible pathways, we conducted pathway-level multi-omics analyses using EC exome-Seq, RNA-Seq and survival data, all based on The Cancer Genome Atlas (TCGA) samples. We measured the overall consistent rankings of these pathways in all four data types. Some well-studied pathways, such as p53 signaling and cell cycle pathways, show consistently high rankings across different analyses. Additionally, other cell signaling pathways (e.g. IGF-1/mTOR, rac-1 and IL-5 pathway), genetic information processing pathway (e.g. homologous recombination) and metabolism pathway (e.g. sphingolipid metabolism) are also highly associated with EC risks, diagnosis and prognosis. In conclusion, the meta-dimensional integration of EC cohorts has suggested some common pathways that may be associated from predisposition, tumorigenesis to progression.

PMID: 27409342 [PubMed - indexed for MEDLINE]

α1-Antitrypsin Infusion for treatment of Steroid Resistant Acute Graft-versus-Host Disease.

Blood. 2018 Feb 02;:

Authors: Magenau JM, Goldstein SC, Peltier D, Soiffer RJ, Braun T, Pawarode A, Riwes MM, Kennel M, Antin JH, Cutler CS, Ho VT, Alyea EP, Parkin BL, Yanik GA, Choi SW, Lewis EC, Dinarello CA, Koreth J, Reddy P

Abstract
Corticosteroid resistance following acute GVHD (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness due to poor response or excessive toxicity, primarily from infection. Alpha-1 antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by down-modulation of inflammation and increasing ratios of regulatory to effector T cells. In this prospective multicenter clinical study we sought to determine the safety and response rate of AAT administration in SR-aGVHD (NCT01700036). Forty patients at a median age of 59 years received intravenous AAT twice weekly for four weeks as first line treatment for SR-aGVHD. The primary endpoint was overall response rate (ORR), the proportion of SR-aGVHD in CR+PR by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rate by day 28 was 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious-mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with pre-clinical data, correlative samples showed an increase in ratio of activated Tregs to effector T cells after AAT treatment. These data suggest that AAT is safe, and may be potentially efficacious in treating SR-aGVHD.

PMID: 29437593 [PubMed - as supplied by publisher]

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[Safety data of the new, reduced-dose influenza vaccine FluArt after its first season on the market].

Orv Hetil. 2017 Dec;158(49):1953-1959

Authors: Vajó P, Gyurján O, Szabó ÁM, Kalabay L, Vajó Z, Torzsa P

Abstract
INTRODUCTION: The currently licensed seasonal influenza vaccines contain split, subunit or whole virions, typically in amounts of 15 µg hemagglutinin per virus strain for adult and up to 60 µg in elderly patients.
AIM: The present study reports safety data of the newly licensed, reduced dose vaccine with 6 µg of hemagglutinin per strain produced by Fluart (Hungary) after its first season on the market. The main objective of enhanced safety surveillance was to detect a potential increase in reactogenicity and allergic events that is intrinsic to the product in near real-time in the earliest vaccinated cohorts.
METHOD: The study methods were based on the Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU by the European Medicines Agency.
STATISTICS: We used the Fisher exact test with 95% confidence intervals.
RESULTS: We studied 587 patients and detected a total 24 adverse events, all of which have already been known during the licensing studies of the present vaccine. The frequencies of the adverse events were not different from what had been seen with the previously licensed 15 µg vaccine.
CONCLUSIONS: Based on the results, the authors conclude that the new, reduced dose vaccine FluArt is safe and tolerable. Orv Hetil. 2017; 158(49): 1953-1959.

PMID: 29199437 [PubMed - indexed for MEDLINE]

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Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects.

BMC Pharmacol Toxicol. 2017 Apr 28;18(1):18

Authors: Chartier M, Morency LP, Zylber MI, Najmanovich RJ

Abstract
BACKGROUND: Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects.
METHODS: We perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects.
RESULTS: We observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases.
CONCLUSIONS: The detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects.

PMID: 28449705 [PubMed - indexed for MEDLINE]

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Consumption of antihistamines in Serbia in the period 2011-2015 and the correlation with adverse drug reaction reports.

Vojnosanit Pregl. 2016 Nov;73(11):1076-7

Authors: Radonjić V, Jović I, Kalaba M, Godman B, Košutić J

PMID: 29341563 [PubMed - indexed for MEDLINE]

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A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia.

Clin Cancer Res. 2017 Feb 15;23(4):899-907

Authors: Pratz KW, Rudek MA, Gojo I, Litzow MR, McDevitt MA, Ji J, Karnitz LM, Herman JG, Kinders RJ, Smith BD, Gore SD, Carraway HE, Showel MM, Gladstone DE, Levis MJ, Tsai HL, Rosner G, Chen A, Kaufmann SH, Karp JE

Abstract
Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone.Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML).Results: A total of 99 patients received veliparib 10-100 mg orally twice daily on days 1-8, 1-14, or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m2/d + carboplatin 120-150 mg/m2/d on days 3-7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27-0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders.Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899-907. ©2016 AACR.

PMID: 27551000 [PubMed - indexed for MEDLINE]

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Performance of toxicity probability interval based designs in contrast to the continual reassessment method.

Stat Med. 2017 Jan 30;36(2):291-300

Authors: Horton BJ, Wages NA, Conaway MR

Abstract
Toxicity probability interval designs have received increasing attention as a dose-finding method in recent years. In this study, we compared the two-stage, likelihood-based continual reassessment method (CRM), modified toxicity probability interval (mTPI), and the Bayesian optimal interval design (BOIN) in order to evaluate each method's performance in dose selection for phase I trials. We use several summary measures to compare the performance of these methods, including percentage of correct selection (PCS) of the true maximum tolerable dose (MTD), allocation of patients to doses at and around the true MTD, and an accuracy index. This index is an efficiency measure that describes the entire distribution of MTD selection and patient allocation by taking into account the distance between the true probability of toxicity at each dose level and the target toxicity rate. The simulation study considered a broad range of toxicity curves and various sample sizes. When considering PCS, we found that CRM outperformed the two competing methods in most scenarios, followed by BOIN, then mTPI. We observed a similar trend when considering the accuracy index for dose allocation, where CRM most often outperformed both mTPI and BOIN. These trends were more pronounced with increasing number of dose levels. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 27435150 [PubMed - indexed for MEDLINE]

Related Articles

Implementation of adaptive methods in early-phase clinical trials.

Stat Med. 2017 Jan 30;36(2):215-224

Authors: Petroni GR, Wages NA, Paux G, Dubois F

Abstract
There has been constant development of novel statistical methods in the design of early-phase clinical trials since the introduction of model-based designs, yet the traditional or modified 3+3 algorithmic design remains the most widely used approach in dose-finding studies. Research has shown the limitations of this traditional design compared with more innovative approaches yet the use of these model-based designs remains infrequent. This can be attributed to several causes including a poor understanding from clinicians and reviewers into how the designs work, and how best to evaluate the appropriateness of a proposed design. These barriers are likely to be enhanced in the coming years as the recent paradigm of drug development involves a shift to more complex dose-finding problems. This article reviews relevant information that should be included in clinical trial protocols to aid in the acceptance and approval of novel methods. We provide practical guidance for implementing these efficient designs with the aim of augmenting a broader transition from algorithmic to adaptive model-guided designs. In addition we highlight issues to consider in the actual implementation of a trial once approval is obtained. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 26928191 [PubMed - indexed for MEDLINE]

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Effects of gender on capecitabine toxicity in colorectal cancer.

J Oncol Pharm Pract. 2016 Jun;22(3):454-60

Authors: Ilich AI, Danilak M, Kim CA, Mulder KE, Spratlin JL, Ghosh S, Chambers CR, Sawyer MB

Abstract
BACKGROUND: Capecitabine is a highly water soluble prodrug of 5-fluorouracil that is dosed by patient body surface area. Body surface area dosing makes no allowances for differences in body composition. There is mounting evidence that lean body mass is a better predictor of toxicity than body surface area for drugs which distribute into the lean compartment. Because women, on average, have lower lean body mass than men, we expect that women would experience a higher incidence of toxicity than men when body surface area dosing is used.
OBJECTIVE: To determine whether female colorectal cancer patients experienced a higher incidence of dose-limiting toxicity than men when treated with adjuvant capecitabine.
METHODS: We conducted a retrospective chart review of colorectal cancer patients treated with adjuvant capecitabine at our institute between 2008 and 2012. Patients receiving capecitabine were identified from the pharmacy dispensing database and then screened for inclusion. Dosing and toxicity information were gathered and dose-limiting toxicity incidence (defined as a composite endpoint of dose delay, dose reduction, or discontinuation of therapy) was compared between males and females using the chi-square test. Binary logistic regression analysis was then performed to account for differences between male and female populations.
RESULTS: A total of 299 patients (163 males, 136 females) met inclusion criteria. Females had a significantly higher dose-limiting toxicity incidence than males (67.7 vs. 52.2%, p = 0.007). Relationships between gender and dose-limiting toxicity incidence remained significant after logistic regression analysis (OR: 2.04; 95% CI: 1.23-3.36).
CONCLUSION: Female colorectal cancer patients experience a higher dose-limiting toxicity incidence than male patients when given adjuvant capecitabine dosed according to body surface area.

PMID: 26002954 [PubMed - indexed for MEDLINE]

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The role of netupitant and palonosetron in chemotherapy-induced nausea and vomiting.

J Oncol Pharm Pract. 2016 Jun;22(3):477-84

Authors: Abramovitz RB, Gaertner KM

Abstract
The combination of netupitant and palonosetron was approved by the Food and Drug Administration in October 2014 for the prevention of acute and delayed chemotherapy-induced nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic chemotherapy. Netupitant and palonosetron is available as a single capsule to be administered prior to each cycle of chemotherapy. The approval was based on phase II and III data in patients undergoing treatment with moderately and highly emetogenic chemotherapy. Netupitant and palonosetron's benefits include a convenient dosage form, dual-targeted mechanism, and favorable side effect profile, while its main limitations are cost and potential logistical issues surrounding administration. More studies are needed to adequately determine its role in therapy as well as which patients will derive the most benefit from its use.

PMID: 25914408 [PubMed - indexed for MEDLINE]

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Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice.

J Oncol Pharm Pract. 2016 Jun;22(3):511-6

Authors: Holle LM, Puri S, Clement JM

Abstract
BACKGROUND: Oral chemotherapy is being routinely used in metastatic castrate-resistant prostate and renal cell cancer. Although convenient, these drugs require monitoring for adherence, toxicity, and drug interactions to maximize outcomes. Oncology pharmacists have the training and expertise that place them in an optimal position to collaboratively provide medication therapy management.
METHODS: A board-certified oncology pharmacist, working in collaboration with a medical oncologist, initiated an oral chemotherapy-monitoring program. The pharmacist provided education, completed medication therapy management; monitored for adherence and toxicity; and recommended treatment of toxicity and supportive care issues. Patient encounters included one of the following: collaboration with medical oncologist visit, pharmacist visit, or telephone or email follow-up between visits.
RESULTS: From December 2012 to May 2014, the pharmacist had 123 encounters with 20 patients with either metastatic prostate (n = 17) or renal cell cancer (n = 3). All patients were males (median age 80 years). Most encounters were clinic visits, in collaboration with physician visit or alone (52%); 36% were telephone encounters, and 11.3% were email follow-ups. Medication-related problems were identified in 25% of the 315 assessments made. Problems included: adverse drug reactions, 40%; inappropriate therapy, 20%; and noncompliance, 18%. Recommendations included: modification of laboratory monitoring, 25%; cancer or non-cancer therapy modification, 12%; drug discontinuation, 6.9%. Non-cancer therapy-related drug information and coordination of care accounted for 30% of recommendations.
CONCLUSION: Our program led to identification of a number of potentially clinically significant issues for patients on oral chemotherapy and demonstrated the benefit of the pharmacist in the multidisciplinary team to assist in addressing them.

PMID: 25900102 [PubMed - indexed for MEDLINE]

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Funding Opportunity PAR-18-664 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support rigorous clinical validation of a candidate biomarker using retrospective and/or prospective methods in a manner that is consistent with the purpose of the biomarker. This FOA assumes that: 1) a candidate biomarker has already been identified, 2) an analytical method has been developed and validated that is consistent with the purpose of the biomarker and 3) a working hypothesis regarding context of use is in place. The goal of this FOA is to facilitate the advancement of robust and reliable biomarkers of neurological disease for use in multi-site clinical trials and clinical practice.

Funding Opportunity RFA-DE-19-003 from the NIH Guide for Grants and Contracts. The NIDCR-funded FaceBase data repository and knowledgebase (www.facebase.org) was established to advance craniofacial research by creating comprehensive datasets on craniofacial development and dysmorphologies and disseminating them to the wider craniofacial research community. Since FaceBases inception, the data management and integration hub has been charged with the critical functions of collecting datasets and analytic tools developed by dataset-generating spoke projects, curating and integrating those resources, and disseminating them to the wider research community through the FaceBase website. This Request for Applications (RFA) solicits renewal applications for the role of the Data Management and Integration Hub. As in the past, the FaceBase 3 hub will continue to be responsible for integration and presentation of existing FaceBase datasets, development or adoption of new approaches for data search and visualization, and outreach to the wider craniofacial research community. In addition, the hub will assume an important new mission, that of working with investigators within the craniofacial research community to make their datasets compatible with FaceBases data models, curating and integrating these new datasets with those already held by FaceBase.