Analysis of iron status after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis.

BACKGROUND: Iron deficiency is highly prevalent in people with cystic fibrosis (PwCF). While elexacaftor/tezacaftor/ivacaftor (ETI) has shown remarkable improvements in respiratory symptoms in PwCF, the effect of ETI on iron status remains unknown. This study aims to identify the effect of ETI on iron status in PwCF. METHODS: A single-center retrospective cohort study of 127 adult PwCF was conducted to assess the impact of ETI on iron, ferritin, transferrin levels, and percent saturation of transferrin (PSAT). Data were collected from the electronic medical record from January 2017 to September 2022, encompassing 2 years before and after ETI initiation. The primary outcome was serum iron parameters: iron, ferritin, transferrin, and PSAT levels following ETI treatment. Secondary outcomes analyzed iron supplementation. Univariate and multivariate mixed-effects models were used for the analysis of ETI. RESULTS: After adjusting for covariates, following ETI initiation, the mean iron level increased by 20.24 µg/dL (p < .001), ferritin levels were 31.4% (p < .001) higher, PSAT showed a 5.09 percentage point increase (p < .001), and transferrin levels increased by 2.71 mg/dL (p = .439). Patients with and without iron supplementation experienced a significant increase in iron after ETI (p < .001). CONCLUSIONS: ETI is associated with a significant increase in iron, ferritin, and PSAT levels. Patients with and without iron supplementation demonstrated a significant increase in iron. This study shows the benefits of ETI on iron status in PwCF. However, further translational studies are required to understand the impact of ETI on iron absorption and metabolism in PwCF.

Changes in nutrition and growth status in young children in the first 12 weeks of ivacaftor therapy.

BACKGROUND: Highly effective CFTR modulators improve nutritional status and are of particular importance among younger children experiencing rapid growth. This study was designed to examine CFTR modulator associated changes in nutritional and other extrapulmonary outcomes in children 4-24 months of age with ivacaftor treatment over 12 weeks. METHODS: Children 4-24 months were recruited from US and Canadian CF Centers. Eligible children were ivacaftor naïve and approved to start therapy. Anthropometrics, diet, sleeping energy expenditure (SEE), nutrition biomarkers, pancreatic status, serum and fecal calprotectin, serum bile acids, plasma fatty acids were measured. Changes from baseline at 6 and 12 weeks were examined using mixed effects linear regression modeling. RESULTS: Fifteen participants enrolled (40% male). Weight-for-age z-scores increased at 6 (p = 0.03) and 12 weeks ivacaftor therapy (p<0.001) compared to baseline. Plasma docosatetraenoic acid (DTA), total saturated fatty acids increased at 6 weeks (p = 0.02) and 12 weeks (p = 0.009). At 12 weeks, serum CO2 concentration decreased (p = 0.002), serum urea nitrogen increased (p = 0.01) and fecal elastase increased (p = 0.02) compared to baseline. Bile acids, deoxycholic acid increased (p = 0.03) and ursodeoxycholic acid decreased (p = 0.02) after 12 weeks. Plasma total fatty acids, palmitic acid, mead, and docosatetraenoic acid (DTA) increased after 12 weeks (p = 0.02, p = 0.002 and p = 0.04, respectively). Plasma total saturated fatty acids increased at 6 weeks (p = 0.02) and 12 weeks (p = 0.009). Dietary intake (p = 0.04) and percent kcal from protein (p = 0.04) increased after 12 weeks compared to baseline. CONCLUSIONS: Overall, younger children experienced favorable changes in nutritional and growth status in the first 12 weeks of ivacaftor therapy.

Body mass index and nutritional intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults with cystic fibrosis.

BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy in adults with CF. METHODS: Dietary intake, measured with myfood24®, and BMI were collected from adults with CF at baseline and follow-up as part of an observational study. Changes in BMI and nutritional intake in participants who commenced ETI therapy between time points were assessed. To contextualize findings, we also assessed changes in BMI and nutritional intake between study points in a group on no modulators. RESULTS: In the pre and post ETI threapy group (n = 40), BMI significantly increased from 23.0 kg/m2 (IQR 21.4, 25.3) at baseline to 24.6 kg/m2 (IQR 23.0, 26.7) at follow-up (p<0.001), with a median of 68 weeks between time points (range 20-94 weeks) and median duration of ETI therapy was 23 weeks (range 7-72 weeks). There was a significant decrease in energy intake from 2551 kcal/day (IQR 2107, 3115) to 2153 kcal/day (IQR 1648, 2606), p<0.001. In the no modulator group (n = 10), BMI and energy intake did not significantly change between time points (p>0.05), a median of 28 weeks apart (range 20-76 weeks). CONCLUSIONS: These findings tentatively suggest that the increase in BMI with ETI therapy may not simply be attributable to an increase in oral intake. Further exploration into the underlying aetiology of weight gain with ETI therapy is needed.

Deciphering mechanistic implications of antimicrobial and antioxidant potentials of certain new dibutyltin(IV) formulations as possible therapeutic options based on DFT and hybrid materials paradigm.

Mechanistic implications of antimicrobial and in vitro antioxidant potentials of a set of newly generated nonbridged mononuclear N,O-orthometallated and carboxylate bridged binuclear nonorthometallated dibutyltin(IV) formulations have been investigated. Some of these formulations were screened for their antibacterial and antifungal activities against Escherichia coli and Candida albicans, respectively whereas in vitro antioxidant potential was examined by Ferric reducing antioxidant power (FRAP) assay. Nonbridged mononuclear N,O-orthometallated dibutyltin(IV) formulations were generated by the reactions of Bu2 SnCl2 with sodium salts of 2-aminophenol/substituted 2-aminophenol and flexible N-protected amino acids in 1:1:1 molar ratio in refluxing dry THF. Plausible structures of these nonbridged mononuclear N,O-orthometallated dibutyltin(IV) formulations containing flexible N-protected amino acids have been suggested on the basis of spectroscopic and mass studies of some representative formulations. Plausible structures suggested on the basis of spectroscopic studies are corroborated by density functional theory (DFT/B3LYP method) (SPARTAN-20) investigation of a representative dibutyltin(IV) complex and the ligands involved in it. The presence of two different classes of organic ligands in this complex provides an opportunity to study optimized topologies, bonding, distortions, optimized energy, and stability of the complex.

Impact of pharmacy services on time to elexacaftor-tezacaftor-ivacaftor initiation.

BACKGROUND: The approval of elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) expanded highly effective cystic fibrosis transmembrane receptor modulator therapy to approximately 90% of persons aged 12 years and older with cystic fibrosis. Clinical pharmacists and pharmacy technicians played a key role in planning for ELX/TEZ/IVA initiation prior to US Food and Drug Administration approval as well as initiating therapy after approval. OBJECTIVE: To evaluate the impact of pharmacy services on time to ELX/TEZ/IVA initiation. METHODS: A retrospective chart review evaluated 146 patients aged at least 12 years with cystic fibrosis qualifying for ELX/TEZ/IVA at a single health system between October 21, 2019, and April 1, 2020. RESULTS: Patients filling ELX/TEZ/IVA at an integrated health system specialty pharmacy (HSSP) vs an outside specialty pharmacy (SP) started on therapy an average of 10.8 days sooner (10.8 days ± 14.0 vs 21.6 days ± 18.8, respectively; P = 0.006). More patients filling at an HSSP received ELX/TEZ/IVA within 14 days of the prescription being written compared with outside SPs (82.0% vs 41.4%, respectively; P = 0.001). Before ELX/TEZ/IVA initiation, patients were hospitalized for a cystic fibrosis-related complication for an average of 6.26 days (range = 0-183) compared with 1.16 days (range = 0-91) after ELX/TEZ/IVA initiation. Lastly, an estimated $134,810 was saved in hospitalization dollars in the 105 patients that were able to fill ELX/TEZ/IVA at an HSSP by initiating the drug an average of 10.8 days sooner than outside SPs. CONCLUSIONS: The results of this study demonstrate the value of an integrated HSSP model. The ability to fill specialty medications at an integrated HSSP may optimize medication access, control costs, and improve patient outcomes for patients receiving care within a health system. DISCLOSURES: Dr Loucks has accepted payment for reviewing content of Lexicomp through Wolters Kluwer Consulting and for presenting and attending the American Society of Health System Pharmacists (ASHP) Summer Meeting in June 2022. Dr Loucks is also a Workgroup Chair for the ASHP Pharmacist Section of Specialty Pharmacy Practitioners - Section Advisory Group on Outcomes and Value. Dr Simonsen was a participant in the Vertex Pharmaceuticals Advisory Board in April 2019 and accepted payment for travel and expenses. The remaining authors have no conflicts of interest or financial interests to disclose. This work is in part supported by the Statistical Expertise and Network (StatNet) Award of Cystic Fibrosis Foundation.

Impact of highly effective CFTR modulator therapy on digital clubbing in patients with cystic fibrosis.

BACKGROUND: The association of certain disease processes with digital clubbing is well documented. Digital clubbing is often reversible after successful treatment of the underlying pathology, for example, after lung transplantation in patients with cystic fibrosis (CF). We examined the effect of highly effective Cystic Fibrosis Transmembrane Regulator (CFTR) modulators, defined for the purposes of this study as ivacaftor or the combination of ivacaftor, tezacaftor, and elexacaftor (ETI), on digital clubbing. MATERIALS AND METHODS: Clubbing index was measured on plaster of Paris casts of right index fingers obtained from 15 patients with cystic fibrosis, before and after initiation of CFTR modulator therapy. Similar measurements were made on casts for 9 cystic fibrosis patients who underwent lung transplantation. Measurements were made on the most recent casts available before treatment and the first cast available at least 3 months after initiation of treatment. The Wilcoxon signed-rank text was used to detect any significant difference in the pre- and post-treatment casts for each individual. RESULTS: A significant decrease in the clubbing index was found after both lung transplantation and treatment with highly effective CFTR modulator therapy. CONCLUSIONS: These results add to the body of evidence demonstrating the efficacy of highly effective CFTR modulator therapy, the first agents that act directly at the dysfunctional chloride channel responsible for CF. By demonstrating that CFTR modulator therapy is capable of reversing digital clubbing, this study suggests a beneficial effect on lung pathology aside from air flow and gas transfer.

Impact of elexacaftor/tezacaftor/ivacaftor on vitamin D absorption in cystic fibrosis patients.

BACKGROUND: Cystic fibrosis (CF) is a multisystem disorder that results in the buildup of mucus in various organs. Ninety percent of CF patients are classified as pancreatic insufficient, leading to malabsorption of nutrients and fat-soluble vitamins without the assistance of exogenous pancreatic enzymes. This study was designed to determine if serum 25-hydroxyvitamin D concentrations were impacted by initiation of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA). METHODS: Serum 25-hydroxyvitamin D concentrations were measured before and 1 year post-ELX/TEZ/IVA initiation. A Wilcoxon signed-rank test was used to compare values. RESULTS: Seventy-six patients were included in the final analysis. The average age of our population was 25.8 years (SD = 13.2 years) with a majority being male, homozygous F508del, pancreatic insufficient, and not modulator-naive. The median increase of serum vitamin D concentration after initiating ELX/TEZ/IVA was 5 ng/ml (interquartile range = -4, 13; p = .0035). CONCLUSIONS: We suggest that ELX/TEZ/IVA may improve fat-soluble vitamin absorption, specifically serum 25-hydroxyvitamin D. These results may lead to adjustments in vitamin supplementation in patients receiving cystic fibrosis transmembrane conductance regulator modulator therapy.

Emerging preclinical modulators developed for F508del-CFTR have the potential to be effective for ORKAMBI resistant processing mutants.

BACKGROUND: F508del is prototypical of Class 2 CFTR mutations associated with protein misprocessing and reduced function. Corrector compounds like lumacaftor partially rescue the processing defect of F508del-CFTR whereas potentiators like ivacaftor, enhance its channel activity once trafficked to the cell surface. We asked if emerging modulators developed for F508del-CFTR can rescue Class 2 mutations previously shown to be poorly responsive to lumacaftor and ivacaftor. METHODS: Rescue of mutant CFTRs by the correctors: AC1, AC2-1 or AC2-2 and the potentiator, AP2, was studied in HEK-293 cells and in primary human nasal epithelial (HNE) cultures, using a membrane potential assay and Ussing chamber, respectively. RESULTS: In HEK-293 cells, we found that a particular combination of corrector molecules (AC1 plus AC2-1) and a potentiator (AP2) was effective in rescuing both the misprocessing and reduced function of M1101K and G85E respectively. These findings were recapitulated in patient-derived nasal cultures, although another corrector combination, AC1 plus AC2-2 also improved misprocessing in these primary tissues. Interestingly, while this corrector combination only led to a modest increase in the abundance of mature N1303K-CFTR it did enable its functional expression in the presence of the potentiator, AP2, in part, because the nominal corrector, AC2-2 also exhibits potentiator activity. CONCLUSIONS: Strategic combinations of novel modulators can potentially rescue Class 2 mutants thought to be relatively unresponsive to lumacaftor and ivacaftor.

Biogenic Synthesis of Silver Nanoparticles with High Antimicrobial and Catalytic Activities using Sheng Di Huang (Rehmannia glutinosa).

Silver nanoparticles (AgNPs) are widely sought after for a variety of biomedical and environmental applications due to their antimicrobial and catalytic properties. We present here a green and simple synthesis of AgNPs utilizing traditional Chinese medicinal herbs. The screening of 20 aqueous herb extracts shows that Sheng Di Huang (Rehmannia glutinosa) had the most promising potential in producing AgNPs of 30±6 nm, with narrow size distribution and high crystallinity. The antimicrobial activities of these AgNPs conducted on E. coli cells were found to be superior in comparison to poly(vinylpyrrolidone)-capped AgNPs synthesized using common chemical method. Additionally, the AgNPs obtained possess excellent catalytic performance in the reduction of 4-nitrophenol to 4-aminophenol. We compared the phytochemical and FTIR spectral analyses of the herb extract before and after synthesis, in order to elucidate the phytochemicals responsible for the reduction of Ag+ ions and the capping of the AgNPs produced.

Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR.

Rationale: Animal models have been highly informative for understanding the characteristics, onset, and progression of cystic fibrosis (CF) lung disease. In particular, the CFTR-/- rat has revealed insights into the airway mucus defect characteristic of CF but does not replicate a human-relevant CFTR (cystic fibrosis transmembrane conductance regulator) variant.Objectives: We hypothesized that a rat expressing a humanized version of CFTR and harboring the ivacaftor-sensitive variant G551D could be used to test the impact of CFTR modulators on pathophysiologic development and correction.Methods: In this study, we describe a humanized-CFTR rat expressing the G551D variant obtained by zinc finger nuclease editing of a human complementary DNA superexon, spanning exon 2-27, with a 5' insertion site into the rat gene just beyond intron 1. This targeted insertion takes advantage of the endogenous rat promoter, resulting in appropriate expression compared with wild-type animals.Measurements and Main Results: The bioelectric phenotype of the epithelia recapitulates the expected absence of CFTR activity, which was restored with ivacaftor. Large airway defects, including depleted airway surface liquid and periciliary layers, delayed mucus transport rates, and increased mucus viscosity, were normalized after the administration of ivacaftor.Conclusions: This model is useful to understand the mechanisms of disease and the extent of pathology reversal with CFTR modulators.

Facile synthesis of Fe-p-aminophenol nanoparticles for photothermal therapy.

Fe-p-aminophenol (Fe-PAP) nanoparticles, a newly developed photothermal agent (PTA), were successfully synthesized via a one-pot method at room temperature. The resultant product exhibited good photothermal effect with a photothermal conversion efficiency of 36%. In vitro and in vivo evaluation demonstrated that Fe-PAP was an effective PTA for photothermal therapy (PTT).

ORKAMBI-Mediated Rescue of Mucociliary Clearance in Cystic Fibrosis Primary Respiratory Cultures Is Enhanced by Arginine Uptake, Arginase Inhibition, and Promotion of Nitric Oxide Signaling to the Cystic Fibrosis Transmembrane Conductance Regulator Channel.

ORKAMBI, a combination of the corrector, lumacaftor, and the potentiator, ivacaftor, partially rescues the defective processing and anion channel activity conferred by the major cystic fibrosis-causing mutation, F508del, in in vitro studies. Clinically, the improvement in lung function after ORKAMBI treatment is modest and variable, prompting the search for complementary interventions. As our previous work identified a positive effect of arginine-dependent nitric oxide signaling on residual F508del-Cftr function in murine intestinal epithelium, we were prompted to determine whether strategies aimed at increasing arginine would enhance F508del-cystic fibrosis transmembrane conductance regulator (CFTR) channel activity in patient-derived airway epithelia. Now, we show that the addition of arginine together with inhibition of intracellular arginase activity increased cytosolic nitric oxide and enhanced the rescue effect of ORKAMBI on F508del-CFTR-mediated chloride conductance at the cell surface of patient-derived bronchial and nasal epithelial cultures. Interestingly, arginine addition plus arginase inhibition also enhanced ORKAMBI-mediated increases in ciliary beat frequency and mucociliary movement, two in vitro CF phenotypes that are downstream of the channel defect. This work suggests that strategies to manipulate the arginine-nitric oxide pathway in combination with CFTR modulators may lead to improved clinical outcomes. SIGNIFICANCE STATEMENT: These proof-of-concept studies highlight the potential to boost the response to cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, lumacaftor and ivacaftor, in patient-derived airway tissues expressing the major CF-causing mutant, F508del-CFTR, by enhancing other regulatory pathways. In this case, we observed enhancement of pharmacologically rescued F508del-CFTR by arginine-dependent, nitric oxide signaling through inhibition of endogenous arginase activity.

High-Throughput Screening for Modulators of CFTR Activity Based on Genetically Engineered Cystic Fibrosis Disease-Specific iPSCs.

Organotypic culture systems from disease-specific induced pluripotent stem cells (iPSCs) exhibit obvious advantages compared with immortalized cell lines and primary cell cultures, but implementation of iPSC-based high-throughput (HT) assays is still technically challenging. Here, we demonstrate the development and conduction of an organotypic HT Cl-/I- exchange assay using cystic fibrosis (CF) disease-specific iPSCs. The introduction of a halide-sensitive YFP variant enabled automated quantitative measurement of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function in iPSC-derived intestinal epithelia. CFTR function was partially rescued by treatment with VX-770 and VX-809, and seamless gene correction of the p.Phe508del mutation resulted in full restoration of CFTR function. The identification of a series of validated primary hits that improve the function of p.Phe508del CFTR from a library of ∼42,500 chemical compounds demonstrates that the advantages of complex iPSC-derived culture systems for disease modeling can also be utilized for drug screening in a true HT format.

Antioxidants and selenocompounds inhibit 3,5-dimethylaminophenol toxicity to human urothelial cells.

Exposure to alkyl anilines may lead to bladder cancer, which is the second most frequent cancer of the urogenital tract. 3,5-dimethylaniline is highly used in industry. Studies on its primary metabolite 3,5-dimethylaminophenol (3,5-DMAP) showed that this compound causes oxidative stress, changes antioxidant enzyme activities, and leads to death of different mammalian cells. However, there is no in vitro study to show the direct effects of 3,5-DMAP on human bladder and urothelial cells. Selenocompounds are suggested to decrease oxidative stress caused by some chemicals, and selenium supplementation was shown to reduce the risk of bladder cancer. The main aim of this study was to investigate whether selenocompounds organic selenomethionine (SM, 10 µmol/L) or inorganic sodium selenite (SS, 30 nmol/L) could reduce oxidative stress, DNA damage, and apoptosis in UROtsa cells exposed to 3,5-DMAP. 3,5-DMAP caused a dose-dependent increase in intracellular generation of reactive oxygen species, and its dose of 50 µmol/L caused lipid peroxidation, protein oxidation, and changes in antioxidant enzyme activities in different cellular fractions. The comet assay also showed single-strand DNA breaks induced by the 3,5-DMAP dose of 50 µmol/L, but no changes in double-strand DNA breaks. Apoptosis was also triggered. Both selenocompounds provided partial protection against the cellular toxicity of 3,5-DMAP. Low selenium status along with exposure to alkyl anilines can be a major factor in the development of bladder cancer. More mechanistic studies are needed to specify the role of selenium in bladder cancer.

Italian and North American dietary intake after ivacaftor treatment for Cystic Fibrosis Gating Mutations.

BACKGROUND: In patients with cystic fibrosis (CF), ivacaftor treatment results in significant weight gain and the impact on diet has not been explored. METHODS: A study in 22 subjects (6.1-61.6 years) compared diet, energy balance, weight gain, and body composition, before and after three months of treatment in Italians and North Americans with CFTR gating mutations. RESULTS: With no differences between groups in energy or macronutrient intake at baseline, fat intake increased in all subjects, and both fat and energy intake increased in Italians. Height, weight, BMI, lean and fat mass, and % body fat increased and resting energy expenditure decreased after treatment. Weight gain was associated with energy and fat intake. CONCLUSIONS: Fat intake increased with treatment, possibly due to the recommendation to take ivacaftor with high fat meals. Increased energy and fat intake correlated with weight gain. Regional dietary patterns differed.

Cost-Effectiveness and Budget Impact of Lumacaftor/Ivacaftor in the Treatment of Cystic Fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a chronic, progressive, genetic disease affecting more than 30,000 people in the United States and 70,000 people globally. The goals of treatment are to slow disease progression, reduce pulmonary exacerbations, relieve chronic symptoms, and improve the patient's quality of life. Lumacaftor/ivacaftor is a new therapy for CF that has demonstrated good clinical outcomes, including improved absolute percentage predicted forced expiratory volume in 1 second (FEV1%). However, given the high cost of therapy, there is a need to evaluate the overall value of lumacaftor/ivacaftor in CF management. OBJECTIVES: To (a) conduct a cost-effectiveness analysis (CEA) of lumacaftor/ivacaftor to understand the overall effectiveness of the drug compared with its costs and (b) conduct a budget impact analysis (BIA) to understand the potential financial effect of introducing a new drug in a health plan. METHODS: Two static decision models were developed using Microsoft Excel to evaluate the cost-effectiveness and budget impact of lumacaftor/ivacaftor over a 1-year time frame from a payer perspective. Model inputs included drug costs (wholesale acquisition costs), drug monitoring schedules (package inserts), drug monitoring costs (Centers for Medicare & Medicaid physician fee schedule and published literature), FEV1% predicted and pulmonary exacerbation values (clinical trials), and cost to treat pulmonary exacerbations (published literature). The outcomes in the CEA included total cost of therapy; average cost-effectiveness ratio (ACER), defined as cost per FEV1% predicted; and incremental cost-effectiveness ratio (ICER), defined as the difference in the ratio of cost per FEV1% predicted of lumacaftor/ivacaftor and placebo. Outcomes in the BIA included total budget impact; cost per member per month (PMPM), defined as total budget impact per hypothetical plan population; and cost per treated member per month (PTMPM), defined as total budget impact per target CF population. All costs were adjusted to 2016 dollars, and one-way sensitivity analyses were conducted to test the model robustness given uncertainty in model inputs and study assumptions. RESULTS: The annual cost of therapy per patient for lumacaftor/ivacaftor was $379,780. The ACER for lumacaftor/ivacaftor was $151,912, while the ICER for lumacaftor/ivacaftor compared with placebo was $95,016 per FEV1% predicted. The annual total budget impact due to the inclusion of lumacaftor/ivacaftor on the health plan formulary was $266,046. The PMPM cost was $0.02 and the PTMPM cost was $6.21. CONCLUSIONS: In patients with CF, lumacaftor/ivacaftor has demonstrated better clinical effectiveness compared with placebo alongside an increased drug acquisition cost. However, the therapy may be a viable alternative to existing standard therapy over a short time horizon. Health care payers, both private and public, need to evaluate the cost-effectiveness and the financial effect when considering expansion of new drug coverage in CF management. DISCLOSURES: No outside funding supported this study. Covvey and Kamal have received research funding from Novartis Pharmaceuticals. Covvey, Giannetti, and Kamal have received research funding from the College of Psychiatric and Neurologic Pharmacists. Kamal serves as a consultant to the Lynx Group (Cranbury, NJ) and Manticore Consulting Group (Scottsdale, AZ). Mukherjee has nothing to disclose. A related poster abstract was presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting; March 27-30, 2017; Denver, CO.

Green synthesis of gold nanoparticles using Artemisia dracunculus extract: control of the shape and size by varying synthesis conditions.

In this study, selective green synthesis of gold nanoparticles (nAu) with the use of Tarragon extract (Artemisia dracunculus) was investigated. Characterization of the synthetized nAu was carried out using several techniques including: UV-Vis, SEM, zeta potential analysis, DLS, and ATR-FTIR. Based on measurements of Tarragon extract by HPLC-MS, significant chemical substances participating as reducing and stabilizing agents were identified. FTIR confirmed typical functional groups that could be found in these acids on the nAu surface, such as O-H, C=O and C-O. The effects of various parameters (concentration of Tarragon extract, Au precursor, and initial pH of the synthesis) on the shape and size of the nanoparticles have been investigated. UV-Vis and SEM confirmed the formation of nAu at various concentrations of the extract and Au precursor and showed correlation between the added extract concentration and shift in maximal absorbance towards higher frequencies, indicating the formation of smaller nanoplates. Zeta potential determined at various pH levels revealed that its value decreased with pH, but for all experiments in the pH range of 2.8 to 5.0, the value is below - 30 mV, an absolute value high enough for long-term nAu stability. In order to evaluate nAu catalytic activity, the reduction of 4-nitrophenol to 4-aminophenol by sodium borohydride was used as a model system. The reaction takes place 1.5 times faster on Au-triangles than on Au-spherical NPs.

Impact of a cystic fibrosis transmembrane conductance regulator (CFTR) modulator on high-dose ibuprofen therapy in pediatric cystic fibrosis patients.

BACKGROUND: This study was undertaken to determine if a clinically relevant drug-drug interaction occurred between ibuprofen and lumacaftor/ivacaftor. METHODS: Peak ibuprofen plasma concentrations were measured prior to and after lumacaftor/ivacaftor initiation. A Wilcoxon signed rank sum test was used to compare the values. RESULTS: Nine patients were included in the final analysis. Peak ibuprofen plasma concentrations decreased an average of 36.4 mcg/mL after initiation of lumacaftor/ivacaftor with a relative reduction of 41.7%. The average peak plasma concentration was 84.2 mcg/mL (SD = 10.9) prior to lumacaftor/ivacaftor initiation and 47.9 mcg/mL (SD = 16.4) following initiation (P = 0.0039). Peak concentrations occurred at an average of 100 min (SD = 30) and 107 min (SD = 40) prior to and following lumacaftor/ivacaftor initiation, respectively. CONCLUSIONS: We suggest a clinically relevant drug-drug interaction exists between ibuprofen and lumacaftor/ivacaftor. Lumacaftor may cause subtherapeutic ibuprofen plasma concentrations due to the induction of CYP enzymes and increased metabolism of ibuprofen. Based on this analysis, we have modified our use of ibuprofen in several patients after evaluation of this drug-drug interaction.

Biogenic gold nanoparticles for reduction of 4-nitrophenol to 4-aminophenol: an eco-friendly bioremediation.

The present study investigated the synthesis of gold nanoparticles (AuNPs) using mangrove plant extract from Avicennia marina as bioreductant for eco-friendly bioremediation of 4-nitrophenol (4-NP). The AuNPs synthesised were confirmed by UV spectrum, transmission electron microscopy (TEM), X-ray diffraction, Fourier transmission infrared spectroscopy (FTIR), dynamic light scattering (DLS), and zeta potential. The AuNPs were found to be spherical in shape with size ranging from 4 to 13 nm, as evident by TEM and DLS. Further, the AuNPs were encapsulated with sodium alginate in the form of gold nano beads and used as heterogeneous catalyst and degrading agent to reduce 4-NP. This reduction in 4-NP into 4-aminophenol was confirmed by UV and FTIR. The aqueous solution of 4-NP peaked its absorbance at 320 nm, and shifted to 400 nm, with an intense yellow colour, appeared due to formation of 4-nitrophenolate ion. After the addition of AuNps, the 4-NP solution became colourless and peaked at 400 nm and reduced to 290 nm corresponding to the formation of 4-aminophenol. Hence, the present work suggested the AuNPs as the potent, eco-friendly bionanocomposite catalyst for bioremediation of 4-NP.

CFTR rescue with VX-809 and VX-770 favors the repair of primary airway epithelial cell cultures from patients with class II mutations in the presence of Pseudomonas aeruginosa exoproducts.

BACKGROUND: Progressive airway damage due to bacterial infections, especially with Pseudomonas aeruginosa remains the first cause of morbidity and mortality in CF patients. Our previous work revealed a repair delay in CF airway epithelia compared to non-CF. This delay was partially prevented after CFTR correction (with VRT-325) in the absence of infection. Our goals were now to evaluate the effect of the Orkambi combination (CFTR VX-809 corrector + VX-770 potentiator) on the repair of CF primary airway epithelia, in infectious conditions. METHODS: Primary airway epithelial cell cultures from patients with class II mutations were mechanically injured and wound healing rates and transepithelial resistances were monitored after CFTR rescue, in the absence and presence of P. aeruginosa exoproducts. RESULTS: Our data revealed that combined treatment with VX-809 and VX-770 elicited a greater beneficial impact on airway epithelial repair than VX-809 alone, in the absence of infection. The treatment with Orkambi was effective not only in airway epithelial cell cultures from patients homozygous for the F508del mutation but also from heterozygous patients carrying F508del and another class II mutation (N1303 K, I507del). The stimulatory effect of the Orkambi treatment was prevented by CFTR inhibition with GlyH101. Finally, Orkambi combination elicited a slight but significant improvement in airway epithelial repair and transepithelial resistance, despite the presence of P. aeruginosa exoproducts. CONCLUSIONS: Our findings indicate that Orkambi may favor airway epithelial integrity in CF patients with class II mutations. Complementary approaches would however be needed to further improve CFTR rescue and airway epithelial repair.