Dual pH Research Articles

Rethinking the laryngopharyngeal reflux treatment algorithm: Evaluating an alternate empiric dosing regimen and considering up‐front, pH‐impedance, and manometry testing to minimize cost in treating suspect laryngopharyngeal reflux disease

Empiric proton pump inhibitor (PPI) trials for laryngopharyngeal reflux (LPR) are common. A majority of the patients respond to acid suppression. This work intends to evaluate once-daily, 40 mg omeprazole and once-nightly, 300 mg ranitidine (QD/QHS) dosing as an alternative regimen, and use this study's cohort to evaluate empiric regimens prescribed for LPR as compared to up-front testing with pH impedance multichannel intraluminal impedance (MII) with dual pH probes and high-resolution manometry (HRM) for potential cost minimization. Retrospective cohort review and cost minimization study. A chart review identified patients diagnosed with LPR. All subjects were treated sequentially and outcomes recorded. Initial QD/QHS dosing increased after 3 months to BID if no improvement and ultimately prescribed MII and HRM if they failed BID dosing. Decision tree diagrams were constructed to determine costs of two empiric regimens and up-front MII and HRM. Ninety-seven subjects met the criteria. Responders and nonresponders to empiric therapy were identified. Seventy-two subjects (74%) responded. Forty-eight (67% of responders and 49% of all) improved with QD/QHS dosing. Forty-nine (51%) subjects escalated to BID dosing. Twenty-four subjects (33% of responders and 25% of all) improved on BID therapy. Twenty-five subjects (26%) did not respond to acid suppression. Average weighted cost was $1,897.00 per patient for up-front testing, $3,033.00 for initial BID, and $3,366.00 for initial QD/QHS. An alternate QD/QHS regimen improved the majority who presented with presumed LPR. Cost estimates demonstrate that the QD/QHS regimen was more expensive than the initial BID high-dose PPI for 6 months. Overall per-patient cost appears less with up-front MII and HRM. 4. Laryngoscope, 127:S1-S13, 2017.

Dual pH-/temperature-responsive and fluorescent hydrogel for controlled drug delivery

Abstract The purpose of this investigation is to develop a dual pH-/temperature-responsive and fluorescent hydrogel based on piperazine and Pluronic F127 (PF127). Firstly, polyurethane was synthesized using 1,6-hexamethylene diisocyanate, 1,4-bis(hydroxyethyl) piperazine, and PF127 by a step polymerization process. Erythrosine B (EB) is then incorporated into copolymers to offer a fluorescence property. The polyurethane-PF127-EB copolymer can spontaneously self-assemble into hydrogels with a great number of closely packed micelles, and the hydrogels also have the ability to undergo thermo-sensitive sol-gel phase transition above the critical gelation concentration. The gelation temperature can be adjusted near the physiological condition by modulating the concentration of the copolymer in an aqueous medium. The acid-titration curves indicate a good pH-responsive property, and the UV-vis and fluorescence spectra exhibit strong self-fluorescence signals for hydrogels. As a result, the hydrogels not only can serve as drug carriers but can also be utilized as fluorescence imaging probes in biomedical applications.

Abstract 316: Adap1 Prevents Cardiomyocyte Hypertrophy by Interfering with Integrin Signaling

The Arf GTPase activating protein with dual PH domains 1 (Adap1), a putative regulator of the small G protein ADP-ribosylation factor 6 (Arf6), might be expressed to some extent in the heart. Although Arf6 roles in cardiomyocytes are not well defined, this small G protein was shown to alter surface expression of integrins in other cell types. Considering the importance of integrins on cellular mechanisms of adhesion and spreading, we hypothesized that Adap1 might impact cardiomyocyte hypertrophy by regulating integrin signaling . In order to determine the role of Adap1 in cardiomyocytes, we analyzed its cardiac expression in Sprague Dawley rats. Comparatively to its high mRNA expression in the brain, we showed that Adap1 transcript is expressed at relatively low levels in the heart of adult and neonatal rats. However, Western blot detection of Adap1 showed that it is well expressed in the whole heart of adult and neonatal rats at levels reaching 13% and 17% relative to the brain, respectively. Moreover, Adap1 was 3-fold more abundant in isolated rat neonatal ventricular cardiomyocyte (RNVC) comparatively to partially enriched non-cardiomyocyte cells. Adenoviral-mediated overexpression of ADAP1 partially prevented the increase in cell surface area of cultured RNVCs in response to increasing serum concentrations. Interestingly, ADAP1 overexpression completely blocked constitutively active mutant Mek1- and phenylephrine-induced hypertrophy of RNVCs. In these conditions, ADAP1 did not impair the Mek1ca-induced fetal gene program in RNVCs, suggesting that its anti-hypertrophic effect was not mediated by transcriptional regulation. In fact, cell surface biotin labeling indicated that ADAP1 significantly reduced the localization of integrin β1 at the membrane of RNVCs without changing its total expression. Strikingly, integrin β1 was almost completely absent from the surface of RNVCs overexpressing both ADAP1 and Mek1ca. These findings demonstrate for the first time that Adap1 expressed in cardiomyocytes interferes with the surface expression of integrin β1, thereby slowing the development of hypertrophy in vitro. Further in vivo studies are needed to characterize the anti-hypertrophic function of Adap1 in response to pathological stresses.

P(NIPAM-co-AA)@BMMs with mesoporous silica core and controlled copolymer shell and its fractal characteristics for dual pH- and temperature-responsive performance of ibuprofen release

ABSTRACTA kind of core–shell hybrid composite (P@BMMs) as a drug carrier was prepared through seed polymerization method, in which, biomodal mesoporous materials (BMMs) as core and copolymer poly(N-isopropylacryl-acrylamide)-co-poly(acrylicacid) [P(NIPAM-co-AA)] with pH- and temperature-responsive characteristics as shell. Its structural features and textural parameters were characterized using various techniques. The kinetic and thermodynamic evaluation demonstrated the existence of hydrogen bond interaction between IBU and P(NIPAM-co-AA)-coated surfaces. Meanwhile, the smart thermo/pH-responsive properties of ibuprofen (IBU) release could be regulated through adjusting coated amount of copolymer. Specially, the responsive properties of P@BMMs were traced by small-angle X-ray scattering technique, suggesting the surface roughness and structural irregularities.

Thermally induced reversible and reprogrammable actuation of tough hydrogels utilising ionoprinting and iron coordination chemistry

Ionoprinting has proven itself as a technique capable of enabling repeated post-synthesis programming of hydrogels into a variety of different shapes, achieved through a variety of different actuation pathways. To date, the technique of ionoprinting has been limited to conventional brittle hydrogels, with reversible actuation requiring a change in submersion solution. In this study, ionoprinting has been combined for the first time with a tougher interpenetrating network polymer (IPN) hydrogel with dual pH and temperature responsiveness. This new methodology eliminates the brittle material failure typically occurring during shape change programming and actuation in hydrogels, thus allowing for the realisation of more highly strained and complex shape formation than previously demonstrated. Critically, the temperature responsiveness of this system enables actuation between an unfolded (2D) and a folded (3D) shape through an external stimuli; enabling reversible actuation without a change in submersion solution. Here, the reversible thermally induced actuation is demonstrated for the first time through the formation of complex multi-folded architectures, including an origami crane bird and Miura folds, from flat hydrogel sheets. The robustness of the IPN hydrogel is demonstrated through multiple reprogramming cycles and repeated actuation of a single hydrogel sheet formed into 3D shapes (hexagon, helix and zig-zag). These advancements vastly improve the applicability of ionoprinting extending its application into areas of soft robotics, biomedical engineering and enviro intelligent sensors.

Abstract 1858: Theranostic nanoparticles for detection and treatment of pancreatic cancer

Abstract Background: Despite continued efforts to improve early detection and treatment of pancreatic adenocarcinoma, the disease still carries a poor prognosis. The combination of multispectral optoacoustic tomography (MSOT) and theranostic nanoparticles offers a possible solution by providing tumor targeting using fluorescent dyes and treatment through drug delivery. We describe a 40 nm colloidal mesoporous silica nanoparticle (CMS) with vermiform pores and a chitosan coating and tagged with the V7 peptide to provide pH-specific dual targeting to deliver a contrast agent in a tumor-specific fashion. Methods: CMSs were synthesized using a modified Stober method, coated with chitosan, and conjugated with a V7 peptide, resulting in a dual acidic pH targeting system. Particle characterization was performed using transmission electron microscopy (TEM), UV-vis spectrophotometry, Zeta potential, and dynamic light scattering . To determine acidic pH specificity of V7-CMS, Panc1 and S2VP10 cell lines were incubated in cell culture medium at either pH 7.4 or 6.6 followed by treatment with V7-CMS. Particle uptake was determined using near infrared (NIR) fluorescence and tissue phantoms. Finally, for in vivo testing, the same CMSNs were injected into mice bearing S2VP10 pancreatic tumors. MSOT imaging was performed 8 hours after CMS injection. Results: TEM images demonstrated successful synthesis of approximately 40 nm V7-CMSs with vermiform pores. On NIR imaging, V7-CMS demonstrated acidic pH specificity in both S2VP10 and Panc 1 cells at pH 6.6, with particle localization and signal intensity 8-fold and 5-fold higher, respectively, than that observed at pH 7.4. In tissue phantoms, increased pH specificity was also observed in both S2VP10 and Panc 1 cells at pH 6.6. Particle location and signal intensity on MSOT was 20-fold and 4-fold higher, respectively, than that observed at pH 7.4. In the murine orthotopic S2VP10 pancreatic tumor model, MSOT imaging 8 hours after IV CMS injection demonstrated V7-CMS accumulation specifically within pancreatic tumors. Conclusion: The acidic pH specific dual targeting system using chitosan-coated and pHLIP V7-tagged CMSs results in tumor specificity. Preferential binding and dye release was increased as much as 20-fold at pH 6.6 as compared to pH 7.4 in tissue phantoms. MSOT was able to detect tumor specific accumulation of V7-CMS in vivo. These small, pH specific particles hold significant promise for effectively identifying pancreatic tumors with high sensitivity and specificity and for targeted drug delivery. Note: This abstract was not presented at the meeting. Citation Format: Phillip Chuong, Neal Bhutiani, Lacey R. McNally. Theranostic nanoparticles for detection and treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1858. doi:10.1158/1538-7445.AM2017-1858

Curcumin-loaded dual pH- and thermo-responsive magnetic microcarriers based on pectin maleate for drug delivery

Magnetic microgels with pH- and thermo-responsive properties were developed from the pectin maleate, N-isopropyl acrylamide, and Fe3O4 nanoparticles. The hybrid materials were characterized by infrared spectroscopy, scanning electron microscope coupled with X–ray energy dispersive spectroscopy, wide angle X–ray scattering, Zeta potential, and magnetization hysteresis measurements. Curcumin (CUR) was loaded into the microgels, and release assays were carried out in simulated environments (SGF and SIF) at different conditions of temperature (25 or 37°C). A slow and sustainability CUR release was achieved under external magnetic field influence. Loaded CUR displayed stability, bioavailability and greater solubility regarding free CUR. Besides, the cytotoxicity assays showed that magnetic microgels without CUR could suppress the Caco-2 cells growth. So, the pectin maleate, N-isopropyl acrylamide, and Fe3O4 could be tailored to elicit hybrid-based materials with satisfactory application in the medical arena.

Dual pH- and ammonia-vapor-responsive electrospun nanofibrous membranes for oil-water separations

In the last few years, the amount of industrial oily wastewater discharge and number of oil spill accidents have increased exponentially, spurring the development of highly efficient, cost-effective oil-water separation technologies. In this study, a dual pH- and ammonia-vapor-responsive polyimide (PI)-based nanofibrous membrane with high permeate flux and stability was developed for oil-water separations. The membrane was prepared by successively dip-coating electrospun PI in decanoic acid (DA)-TiO2 and silica nanoparticles (SNPs). The novel SNP/DA-TiO2/PI membrane exhibits superhydrophobicity in air and superoleophilicity in neutral aqueous environments (e.g., at pH 6.5). However, the membrane becomes hydrophilic and superoleophobic in basic aqueous environments (e.g., at pH 12), resulting in only water permeation during oil-water separations. The oil-water separation potential of this innovative dual-responsive membrane was investigated using several model oil-water mixtures. The membrane has extremely high flux (6500±100Lm−2h−1) and separation efficiency (>99%) and is reusable. In addition, thermal stability and abrasion resistance tests show that the membrane is highly stable under extreme conditions. This dual-responsive electrospun nanofibrous membrane has potential for use in industrial oil-polluted water and oil spill treatment and in systems that require selective oil-water permeation. Furthermore, changes in the surface wettability can also be induced by exposure to ammonia vapor, which might facilitate remote-controlled oil-water separations.

Dual (pH- and temperature-) stimuli responsive nanocarrier with bimodal mesoporous silica nanoparticles core and copolymer shell for controlled ibuprofen-releasing: Fractal feature and diffusion mechanism

A kind of organic-inorganic hybrid composite with core-shell structure was successfully prepared via seed polymerization method using environmental stimuli (pH/temperature) copolymer poly(N-isopropylacryl-acrylamide)-co-poly(acrylic acid) (P(NIPAM-co-AA)) as a shell and bimodal mesoporous silica nanoparticles (BMMs) with small size of 20–50 nm as a core. The capacity of loading ibuprofen (IBU) and the subsequent release performance from resultant P(NIPAM-co-AA)@BMMs (denoted as P@BMMs) under different external conditions were investigated in detail. Meanwhile, its structural features and textural parameters were characterized using XRD, N2 adsorption-desorption isotherms, SEM and TEM, SAXS, FT-IR, solid-state Si29 NMR, TGA and elemental analysis techniques. The results demonstrated that P(NIPAM-co-AA) as a shell coating on the external surface of BMMs acted as temperature-pH gate valve to control release behaviors, while mesoporous BMMs as reservoir provided enough space to encapsulate IBU molecules with high loading. SAXS patterns evidently presented that P@BMMs before IBU-loading and after releasing possessed the fractal feature, suggesting their surface roughness and structural irregularities, in which the mass fractal was increased from 2.36 for BMMs to 2.41 for BMMs-MPS to 2.51 for P@BMMs, and even the transformation from the mass fractal to surface fractal for I/P@BMMs was about 2.80. In addition, three types of kinetic models (first-order, Higuchi and Korsmeyer-Peppas power law) were employed to evaluate the release profiles, indicating that the drug-release kinetic of P@BMMs was suitable to Korsmeyer-Peppas power law model with non-Fickian diffusion mechanism.

Preparation of dual responsive low-molecular-weight hydrogel for long-lasting drug delivery

A novel low-molecular-weight hydrogel (LMWG) was fabricated by oligopeptide and phenylboronic acid to obtain a smart molecular hydrogel with dual glucose and pH response for long-term drug delivery in this study. Dual glucose and pH responsiveness of the blank molecular hydrogel was first evaluated by on-line tracking the dynamics curves using UV spectroscopy. Model drugs of phenformin for antidiabetes and doxorubicin for anticancer were selected to evaluate the drug carry and glucose/pH responsive drug release of the molecular hydrogel. The results showed the drug-loaded LMWG had good sustaining and long-lasting drug delivery in physiological or pathological environment.

Mo1015 - The Diagnostic Yield of Gastric pH-Metry During Ambulatory Gastro-Oesophageal Reflux Monitoring

Introduction Catheter-based ambulatory monitoring to study gastro-oesophageal reflux (GER) is conventionally performed using a single pH sensor to detect intra-oesophageal acid. A less-often used system is a dual pH catheter, allowing simultaneous measurement of oesophageal and gastric pH. In our tertiary referral GI Physiology Unit, we routinely perform pHmetry or impedance-pHmetry using dual-pH sensor probes for concurrent oesophageal and gastric pH monitoring. Aim: To evaluate the additional diagnostic yield associated with using gastric pHmetry analysis during gastro-oesophageal reflux pH monitoring. Method We retrospectively evaluated 2916 dual pH reflux studies done in our unit between 2009 and 2016 (pH-only or combined pH-impedance). In patients having ‘off’ PPI studies we looked for evidence of prolonged gastric pH buffering by meals that provoked further investigation with gastric emptying study, and for evidence of gastric achlorhydria. In patients having ‘on’ PPI studies (for investigation of reflux refractory to PPI therapy) we evaluated whether inadequate gastric acid suppression (defined as gastric pH >4 for>50% of study period1) could be seen on gastric pH monitoring. Results 271 patients (9.4%) had studies performed ‘on’ the patient’s current proton pump inhibitor therapy (PPI) to investigate refractory GORD symptoms. 150/271 patients (55% of ‘on PPI’ studies) were shown to require escalation of treatment, due to inadequacy of gastric acid suppression (defined as gastric pH >4 for>50% of 1) The gastric pH profile further contributed to the diagnostic workup in 135 patients studied ‘off’ acid suppressive therapy (5% of ‘off PPI’ cohort). 111 patients with overlapping symptoms of reflux and dyspepsia had prolonged postprandial elevation of gastric pH period study2, prompting suspicion of gastroparesis. 72/111 underwent formal gastric emptying testing on 13C-octanoic acid breath test or scintigraphy, and 59/72 were confirmed to have delayed gastric emptying. Finally, latent gastric achlorhydria (gastric pH >4 for the entire study period) was discovered in 24 patients, thus explaining PPI failure and obviating the need to continue PPI for presumed acid reflux. Conclusion For small extra cost (£5 per study in the UK) and no additional labour (automated gastric pH analysis), intragastric pH profiling in routine GER monitoring contributes to diagnostic yield and subsequent clinical management in three ways: 1) assessing adequacy of gastric acid suppression ‘on PPI’ in the event of persistent symptoms; 2) suggesting underlying gastroparesis in reflux-dyspepsia overlap syndromes; 3) revealing latent gastric achlorhydria. References . Bonapace ES, et al. Dig Dis Sci. 2000Jan;45(1):34–9. . Ooi & Glasinovic, et al. UEG Journal 2016;4(5S):A157–A720.A497.[P0991] Disclosure of Interest J. Ooi: None Declared, P Woodland Conflict with: Reckitt Benckiser (Hull, UK), E Glasinovic: None Declared, K Nikaki: None Declared, S Sonmez: None Declared, E Yazaki: None Declared, D Sifrim Conflict with: Reckitt Benckiser (Hull, UK); Sandhill Scientific (CO, USA)

Mo1018 - Dual Sensor pH Monitoring Using an Upper Esophageal Sphincter Sensor Accurately Identifies Clinically Relevant Artifactual Acidic Swallows Better than Multichannel Intraluminal Impedance Recording

Mo1018 - Dual Sensor pH Monitoring Using an Upper Esophageal Sphincter Sensor Accurately Identifies Clinically Relevant Artifactual Acidic Swallows Better than Multichannel Intraluminal Impedance Recording

Dual emission and pH based naphthalimide derivative fluorescent sensor for the detection of Bi3+

This paper describes a novel dual emission N-hydroxy 1,8-naphthalimide (NHN) sensor for selective determination of Bi3+ ion and pH. This chemosensor displayed a red shift in absorption spectra and fluorescence enhancement towards highly selective Bi3+ ion in neutral aqueous solution. The binding stoichiometry of NHN with Bi3+ have been determined to be 1:1 by the job’s plot and the binding constant is calculated by Benesi-Hildebrand relation. The effect of β-cyclodextrin (β-CD) on NHN is also studied at pH∼7. The binding mode of NHN with Bi3+ through carbonyl and the hydroxyl group of NHN is confirmed by FT-IR spectra. The influence of hydroxyl group in naphthalimide as a function of pH and metal ions was studied by UV–vis and fluorescence spectroscopy. Fluorescence emission of naphthalimide varied in a narrow range of pH (5–9) and was only slightly influenced by the addition of metal ions in aqueous solution.

Poly(N-isopropylacrylamide)-coated β-cyclodextrin–capped magnetic mesoporous silica nanoparticles exhibiting thermal and pH dual response for triggered anticancer drug delivery

ABSTRACTIn this research a novel controlled anticancer drug delivery system with dual pH and thermal responses was designed based on magnetic mesoporous silica nanoparticles that were anchored by β-cyclodextrin and coated by poly(N-isopropylacrylamide) (PNIPAM). Results demonstrated that the behavior of doxorubicin (anticancer drug) release depended on pH and temperature conditions. At endosomal pH (pH 5.5) the amount of drug release enhanced because the cap was removed from the pores. Furthermore, PNIPAM shell collapsed above the lower critical solution temperature and the releasing of drug increased. Thus, this nanocarrier would have the potential to be applied in the tumor therapy.

Core-shell drug carrier from folate conjugated chitosan obtained from prawn shell for targeted doxorubicin delivery.

A multifunctional drug carrier with dual targeting (magnetic and folate-receptor) and pH sensitive core-shell hybrid nanomaterial has been developed to carry an anticancer drug doxorubicin.Superparamagnetic iron oxide nanoparticles (IONPs) were used as core of the carrier and cross-linked folate conjugated chitosan (FA-CS) was acted as shell in which doxorubicin was physically entrapped. Transmission electron microscopy (TEM) analysis confirmed the average particle size of IONPs and FA-CS coated IONPs 8.2 and 15.4 nm respectively. Magnetic measurement indicated that both the IONPs and FA-CS coated IONPs were superparamagnetic at room temperature with a magnetization value 57.72 and 37.44 emu/g respectively.At pH 5.8 (malignant tissue) showed a burst release of 30.05% of the doxorubicin in the first 4 h followed by a sustained release of 88.26% of drug over 72 h.From these results it is expected that doxorubicin loaded nanoparticles can be a promising drug carrier for the treatment of solid tumors with the ability to reduce toxic side effects of drugs by selective targeting and sustained release.

Fundoplication for laryngopharyngeal reflux despite preoperative dysphagia.

INTRODUCTION Fundoplication for laryngopharyngeal disease with oesophageal dysmotility has led to mixed outcomes. In the presence of preoperative dysphagia and oesophageal dysmotility, this procedure has engendered concern in certain regards. METHODS This paper describes a consecutive series of laryngopharyngeal reflux (LPR) patients with a high frequency of dysmotility. Patients were selected for surgery with 24-hour dual channel pH monitoring, oesophageal manometry and standardised reflux scintigraphy. RESULTS Following careful patient selection, 33 patients underwent fundoplication by laparoscopy. Surgery had high efficacy in symptom control and there was no adverse dysphagia. CONCLUSIONS Evidence of proximal reflux can select a group of patients for good results of fundoplication for atypical symptoms.

Synthesis and investigation of dual pH‐ and temperature‐responsive behaviour of poly[2‐(dimethylamino)ethyl methacrylate]‐grafted gold nanoparticles

Gold nanoparticles (AuNPs) were synthesized by reduction of chloroauric acid (HAuCl4) aqueous solution with hydrazine monohydrate. The AuNPs were immediately treated with cysteamine to obtain amine‐functionalized nanoparticles (Au‐NH2). The reaction of Au‐NH2 with epichlorohydrin and subsequent treatment with sodium hydroxide gave epoxidized AuNPs (Au‐EP). Then, thiol‐capped AuNPs (Au‐SH) were synthesized by reaction of Au‐EP with cysteamine. A ‘grafting to’ approach was utilized to graft bromine‐terminated poly(N,N′‐dimethylaminoethyl methacrylate), synthesized via aqueous atom transfer radical polymerization, with various molecular weights (6280, 25 800, 64 200 and 87 600 g mol−1) onto Au‐SH to obtain Au‐P1, Au‐P2, Au‐P3 and Au‐P4 samples, respectively. All samples were exposed to temperature and pH variations, and Z‐average diameter was monitored using dynamic light scattering. According to the results, polymer‐grafted nanoparticles collapsed at lower temperatures with increasing solution pH for all molecular weight ranges due to deprotonation of tertiary amine groups. However, higher molecular weight polymers were more sensitive to pH variation especially in alkaline media. Also, a high degree of agglomeration was observed for Au‐P4 nanoparticles in alkaline media on increasing the temperature to 55 and 65 °C.

A dual pH- and reduction-responsive anticancer drug delivery system based on PEG–SS–poly(amino acid) block copolymer

A dual pH- and reduction-responsive anticancer drug delivery system was developed by conjugating mPEG with a poly(amino acid) derivative using a disulfide linker.

Dual pH and ultrasound responsive nanoparticles with pH triggered surface charge-conversional properties

A novel ultrasound responsive nanoparticle system with tunable surface charge-conversional properties is presented.

Synthesis of an injectable, self-healable and dual responsive hydrogel for drug delivery and 3D cell cultivation

An injectable, self-healable and dual pH and temperature responsive hydrogel was facilely prepared and applied as a potential carrier for drug delivery and cell cultivation.