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.

Determinación de acrilamida y furosina en harinas y papillas infantiles / Determination of acrylamide and furosine in flour and infant formulas

Una de las modificaciones más importantes inducidas en el alimento durante el calentamiento es la reacción de Maillard, donde participan aminoácidos y azúcares reductores, pudiendo producirse mejora de las características organolépticas del alimento pero también pérdida del valor nutritivo y aparición de compuestos tóxicos. Los cereales infantiles son hidrolizados durante el procesado, aumentando los niveles de azúcares reductores, por lo que en el tostado o desecado de estas muestras puede favorecerse el desarrollo de la reacción de Maillard. Los niños son especialmente susceptibles ala disminución del valor nutritivo y al consumo de compuestos potencialmente tóxicos, de ahí la importancia de conocer el grado de desarrollo de esta reacción en dichos productos. En este estudio se determinó el contenido de acrilamida y furosina en harinas crudas y tostadas y en papillas infantiles, con el fin de evaluar la extensión de la reacción de Maillard. El contenido de furosina osciló entre11,5-34,6 mg/100 g de proteínas en las muestras de harinas y entre 122-1193 mg/100 g de proteínas en las muestras de papillas. No se detectó acrilamida en las muestras de harinas y osciló entre 0,22 y 9,6Cg/kg en las papillas. Las pérdidas de lisina pueden considerarse altas en algunas muestras, pero no suponen riesgo de déficit nutricional al consumirse estos productos con leche. La acrilamida sólo se encontró en niveles cuantificables en cuatro muestras y en concentraciones muy bajas; éstas se encuentran lejos de la dosis máxima permitida y por lo tanto no deberían representar problemas adversos tras su consumo(AU)

One of the most important modifications originated in foods during thermal treatment is Maillard reaction, in which amino acids and reducing sugars are participants. This reaction can improve the organoleptic characteristics of foods but, moreover, can lead to nutritional value losses and apparition of toxicological compounds. Infant cereals are hydrolyzed during processing, increasing reducing sugar levels thereby Maillard reaction can be favored in toasted or dried samples. Infants are especially susceptible to the decreased nutritional value and to the toxicological compounds consumption. Thus it is important to know the development rate of this reaction in these products. In this study acrylamide and furosine content in raw and toasted flour and in infant formulas were determined, in order to evaluate Maillard reaction evolution. Furosine content ranged from 11.5 to34.6 mg/100 g of proteins in toasted flour samples and from 122 to 1193 mg/100 g of proteins in formula samples. Acrylamide was not detected in flour samples ranging from 0.22 and 9.6 Cg/kg in formula samples. Lysine losses can be considered to be high in several samples, but it does not suppose a nutritional deficiency risk because these products are consumed together with milk. Acrylamide only was found in quantified levels in four samples and in very low concentrations. These values are lower than the maximum dose allowed and, therefore, they should not represent adverse problems after their consumption(AU)

Development of gene vectors for pinpoint targeting to human hepatocytes by cationically modified polymer complexes.

We developed a vector that might enable gene therapy of metabolic liver disease or hepatoma. Here we demonstrate the use of cationically modified biocompatible phospholipid polymer conjugated with hepatitis B surface (HBs) antigen for the specific transfer of genes into human hepatocytes. Poly(2-methacryloyloxyethyl phosphorylcholine (MPC)- co-N,N-dimethylaminoethyl methacrylate (DMAEMA)-co- p-nitrophenylcarbonyloxyethyl methacrylate(NPMA))(polyMDN) was prepared as a frame of vector. The specific expression of sFlt-1 or GFP by polyMDN conjugated with HBs containing plasmid (plasmid/polyMDN-HBs), polyMDN containing plasmid (plasmid/polyMDN), plasmid only and PBS were assessed in tumor cells (HepG2 or WiDr) in vitro and in vivo. The histological findings, organ weight changes, and degree of liver dysfunction were examined in the mice administered by several reagents. The sFlt-1 and GFP expression was observed only in the HepG2 cells transfected with sFlt-1 or GFP/polyMDN-HBs. None of the side effects mentioned above was observed. In conclusion, these results suggest that polyMDN-HBs is a human hepatocyte-specific gene delivery vector that might not have serious side effects.

Single-dose pharmacokinetics of the DNA-binding bioreductive agent NLCQ-1 (NSC 709257) in CD2F1 mice.

NLCQ-1 (NSC 709257) is a weak DNA-binding bioreductive antiproliferative agent, with potent in vitro antiproliferative activity against rodent and human tumor cell lines under aerobic and anaerobic conditions. Interest in this quinoline analog is based in part on its in vivo synergistic antitumor effect with radiotherapy or chemotherapy against mouse tumors and human xenografts. A sensitive, specific HPLC method was developed to measure NLCQ-1 in biological fluids. Calibration curves were linear in the range 10.4-667 ng/ml and the lower limit of quantitation was 10.4 ng/ml in plasma. NLCQ-1 was stable in organic solvents, buffered solutions and human plasma for 24 h at 37 degrees C. NLCQ-1 was unstable in rodent and dog plasma when incubated for longer than 10 h. NLCQ-1 human plasma protein binding was high (about 99%), and included binding to both alpha(1)-acid glycoprotein and serum albumin. The plasma elimination of NLCQ-1 in mice after a 10-mg/kg intravenous bolus dose was described by a two-compartment open model with t(1/2beta), V(ss), and Cl(TB) values of 41.3 min, 2.04 l/kg and 69.9 ml/min per kg, respectively. NLCQ-1 had high (85%) intraperitoneal and modest (28%) oral relative bioavailability. Little of the administered NLCQ-1 dose (6.4%) was excreted in 24-h urine. The mouse pharmacokinetic data suggested that oral administration may achieve plasma concentration and systemic exposure similar to those observed after intravenous administration of NLCQ-1.

Reduction of [VO2(ma)2]- and [VO2(ema)2]- by ascorbic acid and glutathione: kinetic studies of pro-drugs for the enhancement of insulin action.

To shed light on the role of V(V) complexes as pro-drugs for their V(IV) analogues, the kinetics of the reduction reactions of [VO2(ma)2]- or [VO2(ema)2]- (Hma = maltol, Hema = ethylmaltol), with ascorbic acid or glutathione, have been studied in aqueous solution by spectrophotometric and magnetic resonance methods. EPR and 51V NMR studies suggested that the vanadium(V) in each complex was reduced to vanadium(IV) during the reactions. All the reactions studied showed first-order kinetics when the concentration of ascorbic acid or glutathione was in large excess and the observed first-order rate constants have a linear relationship with the concentrations of reductant (ascorbic acid or glutathione). Potentiometric results revealed that the most important species in the neutral pH range is [VO2(L)2]- for the V(V) system where L is either ma- or ema-. An acid dependence mechanism was proposed from kinetic studies with varying pH and varying maltol concentration. The good fits of the second order rate constant versus pH or the total concentration of maltol, and the good agreement of the constants obtained between fittings, strongly supported the mechanism. Under the same conditions, the reaction rate of [VO2(ma)2]- with glutathione is about 2000 times slower than that of [VO2(ma)2]- with ascorbic acid, but an acid dependence mechanism can also be used to explain the results for the reduction with glutathione. Replacing the methyl group in maltol with an ethyl group has little influence on the reduction rate with ascorbic acid, and the kinetics are the same no matter whether [VO2(ma)2]- or [VO2(ema)2]- is reduced.

Reduction-mediated 99mTc-labeling of antitumor monoclonal antibodies: effect of increasing specific activity on antibody binding kinetics.

Reduction-mediated 99mTc-labeling of antibodies has gained widespread acceptance in preparation of tumor imaging agents. Increased specific activity to enhance detection signals has raised the question of whether such an attempt would cause change in antibody binding kinetics. To answer this question, two antitumor monoclonal antibodies, i.e. IOR-CEA (IgG1) and EMD (IgG2a) were labeled with 99mTc to yield specific activities ranging from 549-4414 MBq/mg. Regression analysis of the binding data revealed that the binding kinetics of IOR-CEA were shifted from monovalent to bivalent binding upon increasing the specific activities. This phenomenon of affinity enhancement was confirmed by the dissociation study where we found soluble CEA had greater difficulty in extracting the cell-bound IOR-CEA labeled at higher specific activity. The bivalent bindings was further supported by the finding that IOR-CEA with higher specific activities delivered less than expected radioactivity to tumor targets despite their immunoreactivities being well preserved. For EMD, the kinetics seemed to be shifted from bivalent to monovalent interaction. At higher specific activities, adverse changes in immunoreactivity were recognized. Breakage of EMD into 99mTc-Fab fragments was likely to occur and was supported by the observation that EMD delivered more than expected radioactivities to target cells upon increasing specific activity. Precaution should be taken when one deals with high specific activity labeling since this might alter the antibody binding kinetics either favorably or unfavorably.