A Systematic Review of Gastric Acid-Reducing Agent-Mediated Drug-Drug Interactions with Orally Administered Medications.

BACKGROUND AND OBJECTIVE: Several review articles have been published discussing gastric acid-related drug-drug interactions (DDIs) mediated by coadministration of antacids, histamine H2 receptor antagonists, or proton pump inhibitors, but are not sufficiently comprehensive in capturing all documented DDIs with acid-reducing agents (ARAs) and tend to focus on gastric pH-dependent DDIs and/or basic drugs. Subsequently, several new drugs have been approved, and new information is available in the literature. The objective of this systematic review is to comprehensively identify oral medications that have clinically meaningful DDIs, including loss of efficacy or adverse effects, with gastric ARAs, and categorize these medications according to mechanism of interaction. METHODS: An indepth search of clinical data in the PDR3D: Reed Tech Navigator™ for Drug Labels, University of Washington Drug-Drug Interaction Database, DailyMed, Drugs@FDA.gov, and UpToDate®/Lexicomp® Drug and Drug Interaction screening tool was conducted from 1 June to 1 August 2018. The PDR3D, University of Washington Drug-Drug Interaction Database, and DailyMed were searched with terms associated with gastric acid and ARAs. Conflicting findings were further investigated using the UpToDate®/Lexicomp® screening tool. Clinical relevance was assessed on whether an intervention was needed, and prescribing information and/or literature supporting the DDI. RESULTS: Through the search strategy, 121 medications were found to clinically meaningfully interact with ARAs. For 38 medications the mechanism of interaction with ARAs was identified as gastric pH dependent, and for 83 medications the interaction was found to be not gastric pH mediated, with mechanisms involving metabolic enzymes, transporters, chelation, and urine alkalization. Additionally, 109 medications were studied and did not have a clinically meaningful interaction with ARAs. CONCLUSION: This review may provide a resource to healthcare professionals in aiding the care of patients by increasing awareness of interactions with ARAs and may also identify and potentially aid in avoiding clinically relevant DDIs and preventing risk of treatment failure and/or adverse effects. Advances in non-clinical predictions of gastric pH-mediated DDIs may guide the need for a future clinical evaluation.

Nonsteroidal anti-inflammatory drug, indomethacin improves spatial memory and NMDA receptor function in aged animals.

A redox-mediated decrease in N-methyl-D-aspartate (NMDA) receptor function contributes to psychiatric diseases and impaired cognition during aging. Inflammation provides a potential source of reactive oxygen species for inducing NMDA receptor hypofunction. The present study tested the hypothesis that the nonsteroidal anti-inflammatory drug indomethacin, which improves spatial episodic memory in aging rats, would enhance NMDA receptor function through a shift in the redox state. Male F344 young and aged rats were prescreened using a 1-day version of the water maze task. Animals were then treated with the indomethacin or vehicle, delivered in a frozen milk treat (orally, twice per day, 18 days), and retested on the water maze. Indomethacin treatment enhanced water maze performance. Hippocampal slices were prepared for examination of CA3-CA1 synaptic responses, long-term potentiation, and NMDA receptor-mediated synaptic responses. No effect of treatment was observed for the total synaptic response. Long-term potentiation magnitude and NMDA receptor input-output curves were enhanced for aged indomethacin-treated animals. To examine redox regulation of NMDA receptors, a second group of aged animals was treated with indomethacin or vehicle, and the effect of the reducing agent, dithiothreitol ([DTT], 0.5 mM) on NMDA receptor-mediated synaptic responses was evaluated. As expected, DTT increased the NMDA receptor response and the effect of DTT was reduced by indomethacin treatment. The results indicate that indomethacin acted to diminish the age-related and redox-mediated NMDA receptor hypofunction and suggest that inflammation contributes to cognitive impairment through an increase in redox stress.

Increased tumor targeted delivery using a multistage liposome system functionalized with RGD, TAT and cleavable PEG.

Though PEGylation has been widely used to enhance the accumulation of liposomes in tumor tissues through enhanced permeability and retention (EPR) effects, it still inhibits cellular uptake and affects intracellular trafficking of carriers. Active targeting molecules displayed better cell selectivity but were shadowed by the poor tumor penetration effect. Cell penetrating peptides could increase the uptake of the carriers but were limited by their non-specificity. Dual-ligand system may possess a synergistic effect and create a more ideal drug delivery effect. Based on the above factors, we designed a multistage liposome system co-modified with RGD, TAT and cleavable PEG, which combined the advantages of PEG, specific ligand and penetrating peptide. The cleavable PEG could increase the stability and circulation time of liposomes during circulation. After the passive extravasation to tumor tissues, the previously hidden dual ligands on the liposomes were exposed in a controlled manner at the tumor site through exogenous administration of a safe reducing agent L-cysteine. The RGD specifically recognized the integrins overexpressed on various malignant tumors and mediated efficient internalization in the synergistic effect of the RGD and TAT. Invitro cellular uptake and 3D tumor spheroids penetration studies demonstrated that the system could not only be selectively and efficiently taken up by cells overexpress ingintegrins but also penetrate the tumor cells to reach the depths of the avascular tumor spheroids. In vivo imaging and fluorescent images of tumor section further demonstrated that this system achieved profoundly improved distribution within tumor tissues, and the RGD and TAT ligands on C-R/T liposomes produced a strong synergistic effect that promoted the uptake of liposomes into cells after the systemic administration of L-cysteine. The results of this study demonstrated a tremendous potential of this multistage liposomes for efficient delivery to tumor tissue and selective internalization into tumor cells.

Effects of adding low levels of a disulfide reducing agent on the disulfide interactions of ß-lactoglobulin and κ-casein in skim milk.

Low concentrations of a disulfide reducing agent were added to unheated and heated (80 °C for 30 min) skim milk, with and without added whey protein. The reduction of the ß-lactoglobulin and κ-casein disulfide bonds was monitored over time using electrophoresis. The distribution of the proteins between the colloidal and serum phases was also investigated. κ-Casein disulfide bonds were reduced in preference to those of ß-lactoglobulin in both unheated and heated skim milk (with or without added whey protein). In addition, in heated skim milk, while the serum κ-casein was reduced more readily than the colloidal κ-casein, the distribution of κ-casein between the two phases was not affected.

Modulation of allergenicity of major house dust mite allergens Der f 1 and Der p 1 by interaction with an endogenous ligand.

Although many allergens bind endogenous molecules other than Abs in the human body, whether the interaction can modulate allergenicity has been unknown. Here, we investigated the effect of the interaction of recombinant major mite group 1 allergens (Der f 1 and Der p 1), which belong to the papain-like cysteine protease family, with an endogenous protease inhibitor, cystatin A, on their allergenicity. Cystatin A bound reduced forms of the allergens, in which the cysteine residue at the catalytic center of the protease activity was reduced by treatment with L-cysteine, but did not bind oxidized forms. Cystatin A partially inhibited the binding of IgE in mite-allergic volunteers' sera to the reduced forms, but unexpectedly enhanced the basophil histamine-releasing activity. A catalytic site-mutant of Der f 1 behaved in terms of histamine release, similarly to the reduced form. Molecular modeling showed that cystatin A interacts with the allergens within a narrow area. The results indicate that interaction with cystatin A reduces the limited number of IgE epitopes of the allergens but enhances their biological activity to release histamine, suggesting a new concept, that interaction between allergens and their endogenous ligands modulates the allergenicity even toward enhancement in the effector phase. On the other hand, i.p. immunization without alum of mice with cystatin A-treated reduced Der f 1 induced less serum Der f 1-specific IgE than immunization with reduced Der f 1 alone, suggesting that endogenous protease inhibitors suppress the induction of allergen-specific IgE, which is dependent on the enzymatic activity of cysteine protease-allergens, in the sensitization process.

Improving the effect of NaOCl pretreatment on bonding to caries-affected dentin using self-etch adhesives.

OBJECTIVE: To evaluate the effect of sodium hypochlorite pretreatment on adhesion to normal and caries-affected dentin using self-etch adhesives. METHODS: Forty extracted human molars with coronal carious lesions were used in this experiment. The occlusal dentin surfaces including the caries-affected dentin in each group were treated as follows: group 1, rinsed with water; group 2, treated with 6% NaOCl for 15s; group 3, treated with 6% NaOCl for 30 s; group 4, application with Accel for 30 s after NaOCl-30 s pretreatment. After rinsing with water and air-drying, the treated dentin surfaces were applied with self-etch systems (Bond Force and Clearfil Protect Bond) according to the manufacturers' instructions, and built-up with resin composite. After 37 degrees C water storage for 24 h, the bonded normal or caries-affected dentin areas were isolated to create an hourglass configuration with a cross-sectional area of approximately 1 mm(2). The specimens were subjected to tensile stress at a cross-head speed of 1.0 mm/min. RESULTS: NaOCl-15 s pretreatment significantly improved the muTBS of both self-etch adhesives to caries-affected dentin, while the 30 s pretreatment did not affect them. For normal dentin, NaOCl-30 s pretreatment significantly reduced the muTBS of both self-etch adhesives although the 15s pretreatment did not alter them. Furthermore, the application of Accel with a reducing effect increased the muTBS to normal and caries-affected dentin treated with NaOCl for 30 s. CONCLUSIONS: The effects of NaOCl pretreatment on bonding of both self-etch adhesives were dependent upon type of dentin (normal and caries-affected dentin) and the treatment time.

Regulation of inflammation and redox signaling by dietary polyphenols.

Reactive oxygen species (ROS) play a key role in enhancing the inflammation through the activation of NF-kappaB and AP-1 transcription factors, and nuclear histone acetylation and deacetylation in various inflammatory diseases. Such undesired effects of oxidative stress have been found to be controlled by the antioxidant and/or anti-inflammatory effects of dietary polyphenols such as curcumin (diferuloylmethane, a principal component of turmeric) and resveratrol (a flavonoid found in red wine). The phenolic compounds in fruits, vegetables, tea and wine are mostly derivatives, and/or isomers of flavones, isoflavones, flavonols, catechins, tocopherols, and phenolic acids. Polyphenols modulate important cellular signaling processes such as cellular growth, differentiation and host of other cellular features. In addition, they modulate NF-kappaB activation, chromatin structure, glutathione biosynthesis, nuclear redox factor (Nrf2) activation, scavenge effect of ROS directly or via glutathione peroxidase activity and as a consequence regulate inflammatory genes in macrophages and lung epithelial cells. However, recent data suggest that dietary polyphenols can work as modifiers of signal transduction pathways to elicit their beneficial effects. The effects of polyphenols however, have been reported to be more pronounced in vitro using high concentrations which are not physiological in vivo. This commentary discusses the recent data on dietary polyphenols in the control of signaling and inflammation particularly during oxidative stress, their metabolism and bioavailability.

Attenuation of half sulfur mustard gas-induced acute lung injury in rats.

Airway instillation into rats of 2-chloroethyl ethyl sulfide (CEES), the half molecule of sulfur mustard compound, results in acute lung injury, as measured by the leak of plasma albumin into the lung. Morphologically, early changes in the lung include alveolar hemorrhage and fibrin deposition and the influx of neutrophils. Following lung contact with CEES, progressive accumulation of collagen occurred in the lung, followed by parenchymal collapse. The co-instillation with CEES of liposomes containing pegylated (PEG)-catalase (CAT), PEG-superoxide dismutase (SOD), or the combination, greatly attenuated the development of lung injury. Likewise, the co-instillation of liposomes containing the reducing agents, N-acetylcysteine (NAC), glutathione (GSH), or resveratrol (RES), significantly reduced acute lung injury. The combination of complement depletion and airway instillation of liposomes containing anti-oxidant compounds maximally attenuated CEES-induced lung injury by nearly 80%. Delayed airway instillation of anti-oxidant-containing liposomes (containing NAC or GSH, or the combination) significantly diminished lung injury even when instillation was delayed as long as 1 h after lung exposure to CEES. These data indicate that CEES-induced injury of rat lungs can be substantially diminished by the presence of reducing agents or anti-oxidant enzymes delivered via liposomes.

Glutathione reductase from human cataract lenses can be revived by reducing agents and by a molecular chaperone, alpha-crystallin.

PURPOSE: The aim of this study was to investigate how glutathione reductase (GR) loses its activity during cataract formation and whether it is possible to revive it back to the normal levels. METHOD: In this study, endogenous as well as synthetic reducing systems (GSH, TTase, DTT, captopril) and alpha-crystallin at different concentrations were incubated with the soluble fraction of human cataract lens protein. The activity of glutathione reductase with or without the reducing agents and alpha-crystallin was tested, and the difference in activity gained was calculated. RESULTS: Five agents (GSH, DTT, TTase, captopril, alpha-low crystallin) were able to revive the activity of GR from human cataract lenses to different extents. CONCLUSION: This study shows that human lens GR activity was revived by different reducing agents as well as by a molecular chaperone (alpha-crystallin).

On the conformation of the COOH-terminal domain of the large mechanosensitive channel MscL.

COOH-terminal (S3) domains are conserved within the MscL family of bacterial mechanosensitive channels, but their function remains unclear. The X-ray structure of MscL from Mycobacterium tuberculosis (TbMscL) revealed cytoplasmic domains forming a pentameric bundle (Chang, G., R.H. Spencer, A.T. Lee, M.T. Barclay, and D.C. Rees. 1998. SCIENCE: 282:2220-2226). The helices, however, have an unusual orientation in which hydrophobic sidechains face outside while charged residues face inside, possibly due to specific crystallization conditions. Based on the structure of pentameric cartilage protein, we modeled the COOH-terminal region of E. coli MscL to better satisfy the hydrophobicity criteria, with sidechains of conserved aliphatic residues all inside the bundle. Molecular dynamic simulations predicted higher stability for this conformation compared with one modeled after the crystal structure of TbMscL, and suggested distances for disulfide trapping experiments. The single cysteine mutants L121C and I125C formed dimers under ambient conditions and more so in the presence of an oxidant. The double-cysteine mutants, L121C/L122C and L128C/L129C, often cross-link into tetrameric and pentameric structures, consistent with the new model. Patch-clamp examination of these double mutants under moderately oxidizing or reducing conditions indicated that the bundle cross-linking neither prevents the channel from opening nor changes thermodynamic parameters of gating. Destabilization of the bundle by replacing conservative leucines with small polar residues, or complete removal of COOH-terminal domain (Delta110-136 mutation), increased the occupancy of subconducting states but did not change gating parameters substantially. The Delta110-136 truncation mutant was functional in in vivo osmotic shock assays; however, the amount of ATP released into the shock medium was considerably larger than in controls. The data strongly suggest that in contrast to previous gating models (Sukharev, S., M. Betanzos, C.S. Chiang, and H.R. Guy. 2001a. NATURE: 409:720-724.), S3 domains are stably associated in both closed and open conformations. The bundle-like assembly of cytoplasmic helices provides stability to the open conformation, and may function as a size-exclusion filter at the cytoplasmic entrance to the MscL pore, preventing loss of essential metabolites.

Urinary oxalic acid excretion differs after oral loading of rats with various oxalate salts.

BACKGROUND: To compare urinary oxalate excretion after the oral administration of oxalic acid, disodium oxalate, or calcium oxalate in rats. METHODS: Male Wistar rats were divided into four groups of six rats each and were intravenously hydrated with normal saline, and then were administered normal saline (control group), 10 mg of oxalic acid, equimolar disodium oxalate, or equimolar calcium oxalate via a gastrostomy. Urine specimens were collected just before administration and at hourly intervals up to 5 h afterwards. The urinary oxalate, calcium, magnesium and phosphorus levels were measured. RESULTS: Urinary oxalate excretion peaked at 1-2 h after administration of oxalic acid or equimolar disodium oxalate, while administration of calcium oxalate only caused a small increase of urinary oxalate excretion. Cumulative urinary oxalate excretion during 5 h was 1.69 +/- 0.10 mg (mean +/- SD; 17%), 1.43 +/- 0.13 mg (13%), and 0.22 +/- 0.03 mg (2%) after the administration of oxalic acid, disodium oxalate, and calcium oxalate, respectively. Urinary calcium excretion showed a decrease in the oxalic acid and disodium oxalate groups, while urinary magnesium or phosphorus excretion did not change significantly. CONCLUSION: The upper gastrointestinal tract seems to be the major site of oxalic acid absorption and only free oxalate is absorbed irrespective of whether it is the sodium salt or not. After binding to calcium in the gut, oxalic acid absorption seems to be inhibited in the presence of calcium and this means that calcium oxalate is poorly absorbed (at least in the upper gastrointestinal tract).

The control of Varroa destructor using oxalic acid.

Twenty-four honeybee (Apis mellifera) colonies were used to monitor the efficacy of a solution of 2.9% oxalic acid (OA) and 31.9% sugar against the mite Varroa destructor. Mite mortality was established prior to and after OA treatments, which were conducted in August and September. The treatments resulted in 37% mite mortality as opposed to 1.11% in the controls. OA treatment conducted in September on previously untreated colonies resulted in 25% mite mortality. OA treatments in October and November resulted in approximately 97% mite mortality. These results suggest that OA is effective during the broodless period and less effective when applied to colonies with capped broods. The possible use of OA against the Varroa mite in honeybee colonies as an alternative to routine chemical treatments is discussed.

Drug targeting to hypoxic tissue using self-inactivating bioreductive delivery systems.

Hypoxia is a characteristic feature of a number of diseases including some cancers, rheumatoid arthritis and diabetes. Hypoxic tissue facilitates the use of bioreductive drug targeting systems as oxygen suppresses the release of the active drug. This review focuses on bioreductive delivery where accompanying intramolecular cyclisation negates adduct formation between the bioreductive and macromolecules such as DNA. To date, three systems have been reported. In the quinone lactonization system, reduction of the quinone facilitates through bond cyclisation and concomitant release of the drug. In the self-alkylating system, a nucleophile is built into the bioreductive structure to favour intramolecular cyclisation over nucleophilic attack from DNA moieties. The final system is based on vitamin E which undergoes redox mediated cyclisation between its oxidised (tocopherol quionone) and reduced (tocopherol) forms. Self-inactivating bioreductive delivery systems represent a powerful tool for extending bioreductive-based drug delivery to non-cancerous hypoxic tissues.

Redox manipulation of NMDA receptors in vivo: alteration of acute pain transmission and dynorphin-induced allodynia.

The redox modulatory site of the N-methyl-D-aspartate (NMDA) receptor directly regulates NMDA receptor function. Sulfhydryl reducing agents, such as dithiothreitol (DTT), potentiate NMDA receptor-evoked currents in vitro, whereas oxidizing agents, such as 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB), attenuate these currents. In this study, we examined the effect of this redox manipulations on nociceptive spinal cord signaling in mice. Intrathecal (i.t.) administration of DTT (0.1-30 nmol), presumably reducing the NMDA receptor, dose-dependently enhanced NMDA-induced nociceptive behaviors, and this enhancement was blocked by the oxidizing agent, DTNB. Pretreatment with DTT (10 nmol, i.t.) enhanced NMDA-induced tail-flick thermal hyperalgesia and intraplantar formalin-induced nociceptive behaviors. Finally, DTT pretreatment enhanced the long lasting allodynia induced by i.t. administration of dynorphin, whereas post-treatment with DTNB reduced the permanent allodynia induced by dynorphin for 5 days. Potentiation of all four of these NMDA-dependent nociceptive behaviors by DTT suggests that the reduction of the NMDA receptor by endogenous reducing agents may contribute to augmented pain transmission in response to activation by endogenous glutamate. Moreover, blockade of in vivo NMDA receptor reducing agents or oxidation of the NMDA receptor redox site may prove therapeutically useful in the treatment of chronic pain.