Interactions of the potent synthetic AT1 antagonist analog BV6 with membrane bilayers and mesoporous silicate matrices

The present work describes the drug:membrane interactions and a drug delivery system of the novel potent AT1 blocker BV6. This designed analog has most of the pharmacological segments of losartan and an additional biphenyltetrazole moiety resulting in increased lipophilicity. We found that BV6:membrane interactions lead to compact bilayers that may in part explain its higher in vitro activity compared to losartan since such environment may facilitate its approach to AT1 receptor. Its high docking score to AT1 receptor stems from more hydrophobic interactions compared to losartan. X-ray powder diffraction (XRPD) and thermogravimetric analysis (TGA) have shown that BV6 has a crystalline form that is not decomposed completely up to 600 °C. These properties are desirable for a drug molecule. BV6 can also be incorporated into a mesoporous silicate drug-delivery matrix SBA-15. The properties of the obtained drug-delivery system have been inspected by XRD, 13C CP/MAS, TGA and nitrogen sorption experiments

Exploring the interactions of irbesartan and irbesartan–2-hydroxypropyl-β-cyclodextrin complex with model membranes

The interactions of irbesartan (IRB) and irbesartan–2-hydroxypropyl-β-cyclodextrin (HP-β-CD) complex with Dipalmitoyl Phosphatidylcholine (DPPC) bilayers have been explored utilizing an array of biophysical techniques ranging from Differential Scanning Calorimetry (DSC), Small angle X-ray Scattering (SAXS), ESI Mass-Spectrometry (ESI-MS) and solid state Nuclear Magnetic Resonance (ssNMR). Molecular Dynamics (MD) calculations have been also conducted to complement the experimental results. Irbesartan was found to be embedded in the lipid membrane core and to affect the phase transition properties of the DPPC bilayers. SAXS studies revealed that irbesartan alone does not display perfect solvation since some coexisting irbesartan crystallites are present. In its complexed form IRB gets fully solvated in the membranes showing that encapsulation of IRB in HP-β-CD may have beneficial effects in the ADME properties of this drug. MD experiments revealed the topological and orientational integration of irbesartan into the phospholipid bilayer being placed at about 1 nm from the membrane centre

Investigation of multiple factors which may contribute to Vitamin D levels of bedridden pregnant women and their preterm neonates

Objective: 25-Hydroxyvitamin D (25-OH-D) is the marker, which indicates vitamin D levels. The aim of this study was to investigate the possible factors, which contribute to serum 25-OH-D levels in bedridden mothers and their preterm neonates.Methods: Twenty-six preterm neonates born during the period of 24-33 weeks of gestational age and 20 mothers (who experienced pregnancy complications) were recruited to the study.Results: Five major results were obtained. (i) The 25-OH-D serum levels for preterm neonates and their mothers were found to possess strong correlation (ii) and both differed significantly in comparison with the optimal levels. (iii) An increase of mothers 25-OH-D serum levels was associated with an increased possibility that the neonates would be measured to have normal 25-OH-D levels. (iv) Sex was not a key factor to neonates 25-OH-D levels. (v) No correlation was found between mothers 25-OH-D levels and their vitamin D3 supplement (400 IU/d during pregnancy).Conclusions: Due to insufficient exposure to sunlight and a diet not enriched with vitamin D, bedridden pregnant women suffer from vitamin D deficiency and pregnancy complications lead often to birth of preterm neonates with the same deficiency. Mothers should increase the total amount of vitamin D intake (food and supplement). © 2015 Taylor & Francis

Exploring the interactions of irbesartan-2-hydroxypropyl-β-cyclodextrin complex in micelles

Irbesartan is a beneficial drug against hypertension and other diseases. Although it is a polydynamic drug, it suffers from high lipophilicity. New formulations of the drug may increase its efficient pharmacological profile. Towards this aim, we have studied the interactions of irbesartan in simple or complexed form with 2- hydroxypropyl-cyclodextrin in micelles. The interactions of the drug in the two forms in the micelle environment are discussed. Of special interest, is the highly flexibility of the spacer phenyl rin

The dynamic properties of angiotensin II type 1 receptor inverse agonists in solution and in the receptor site

In this article, the conformational properties of olmesartan and its methylated analogue were charted using a combination of NMR spectroscopy and molecular modeling. For the molecular docking experiments three different forms of angiotensin II type 1 receptor (AT1R) have been used: (a) crystal structure; (b) homology model based on CXCR4 and (c) homology model based on rhodopsin. The aim of this study was to possibly explain the differences between the experimental findings derived from mutagenesis studies on this receptor and the crystal structure of the AT1R-olmesartan complex. Molecular Dynamics (MD) experiments were performed to illustrate the stability of the AT1R-inverse agonist complex and the most prominent interactions during the simulated trajectory. The obtained results showed that olmesartan and its methyl ether exert similar interactions with critical residues justifying their almost identical in vitro activity. However, the docking and MD experiments failed to justify the mutation findings in a satisfactory matter, indicating that the real system is more complex and crystal structure or homology models of AT1R receptors cannot simulate it sufficiently. Various conformations of olmesartan and olmesartan methyl ether were simulated to provide chemical shifts. These are compared with the experimental NMR results. Useful information regarding the putative bioactive conformations of olmesartan and its methylated analogue has been obtained. Finally, comparative data regarding the binding poses and energies of olmesartan, olmesartan methyl ether and three derivative compounds of olmesartan (R239470, R781253, and R794847) were acquired using Prime/MM-GBSA calculations. © 2016 The Author

The dynamic properties of angiotensin II type 1 receptor inverse agonists in solution and in the receptor site

In this article, the conformational properties of olmesartan and its methylated analogue were charted using a combination of NMR spectroscopy and molecular modeling. For the molecular docking experiments three different forms of angiotensin II type 1 receptor (AT1R) have been used: (a) crystal structure; (b) homology model based on CXCR4 and (c) homology model based on rhodopsin. The aim of this study was to possibly explain the differences between the experimental findings derived from mutagenesis studies on this receptor and the crystal structure of the AT1Rolmesartan complex. Molecular Dynamics (MD) experiments were performed to illustrate the stability of the AT1R-inverse agonist complex and the most prominent interactions during the simulated trajectory. The obtained results showed that olmesartan and its methyl ether exert similar interactions with critical residues justifying their almost identical in vitro activity. However, the docking and MD experiments failed to justify the mutation findings in a satisfactory matter, indicating that the real system is more complex and crystal structure or homology models of AT1R receptors cannot simulate it sufficiently. Various conformations of olmesartan and olmesartan methyl ether were simulated to provide chemical shifts. These are compared with the experimental NMR results. Useful information regarding the putative bioactive conformations of olmesartan and its methylated analogue has been obtained. Finally, comparative data regarding the binding poses and energies of olmesartan, olmesartan methyl ether and three derivative compounds of olmesartan (R239470, R781253, and R794847) were acquired using Prime/MM-GBSA calculations. 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND licens

Evaluation of Barley's Beta-glucan Food Fortification through Investigation of Intestinal Permeability in Healthy Adults

Objective: Intestinal permeability is an index of the adequate function of the intestinal barrier and its modification is associated with intestinal diseases. The aim of the study is to investigate the hypothesis that barley's beta-glucan can inhibit the alteration of intestinal permeability and maintain intestinal integrity after a period of consumption of a carbohydrate snack (cake) rich in sugars. Methods and Design: Volunteers participated in a placebo-controlled intervention study for 1 month. In this double-blind methodology, they were randomly assigned to (1) the intervention group (daily consumption of one portion of cake fortified with barley's beta-glucan) or (2) the placebo group (daily consumption of the same cake without the enrichment). Intestinal permeability was assessed using the lactulose/mannitol test. Setting: Athens, Greece. Subjects: Twenty-three healthy volunteers (age > 40 years). Results: Intestinal permeability did not differ between the 2 groups, both at the beginning and at the end of the intervention. In addition, the intestinal permeability was not significantly modified at the end of the intervention in each group. Conclusions: The results of the lactulose/mannitol test for the intervention and placebo groups were comparable. For healthy adults, the daily consumption of a simple cake (placebo) and the consumption of the cake fortified with barley's beta-glucan resulted in similar impact for intestinal permeability; thus, beta-glucans did not exert a protective role in intestinal permeability of healthy adults. © 2016, © 2015 American College of Nutrition Published by Taylor & Francis Group, LLC

Does a parenteral nutrition decision support system for total nutrients improve prescription procedure and neonatal growth?

Background and objectives: Parenteral nutrition (PN) is an integral part of the nutritional support of critically ill neonates in the intensive care units (ICU). The evaluation of a decision support system for total nutrients (DSSFTN) is of great importance for clinical practice. This study’s aim was to evaluate the impact caused by implementation of a DSSFTN on PN support and neonatal growth. This pilot work was supported by the hospital PN team (PNT) in order to assess possible benefits stemming from the use of DSSFTN. Materials and methods: DSSFTN development is based on the incorporation of pharmaceutical and therapeutic protocols. Thirty-eight neonates were recruited. Inclusion criteria included: patients should (a) be hospitalized in ICU, (b) receive PN support at least for 15 days, (c) have birth weight 550–1600 g. One exclusion criterion was applied: patients should have no inborn error of metabolism. 15 doctors prescribed PN for two groups of neonates. PN was calculated by doctors for Group 1 (19 neonates) and respectively was calculated by the DSSFTN (and checked by doctors) for Group 2 (19 neonates). A questionnaire was completed later by doctors to evaluate DSSFTN. Results: The implementation of DSSFTN led to appropriate composition and administration of PN. Growth was not significantly different between the study groups. Compliance with guidelines was observed. DSSFTN ameliorated intercommunication among doctors. Conclusions: The implementation of DSSFTN enables health professionals to facilitate the complex task of prescribing. It ensures the consistency of PN prescriptions, as it leads to appropriate dosing in all nutrients. DSSFTN provides real-time PN interventions (clinical conditions and enteral amounts are included additionally) and minimizes exposure to human errors. © 2019 Informa UK Limited, trading as Taylor & Francis Group

Differential Scanning Calorimetry (DSC) on Sartan/Cyclodextrin Delivery Formulations

Differential scanning calorimetry (DSC) is a widely utilized method for the interactions of drug molecules with drug delivery systems (DDSs). Herein is described a protocol for studying the interactions and entrapment efficiency of the prototype sartan losartan and the polydynamic, structurally similar irbesartan inside the nontoxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD). The thermal scan properties of both sartan molecules have been studied when physically mixed or complexed with the cyclodextrin. The thermograms indeed showed significant differences between the mixtures and complexes, establishing DSC as a valuable method to characterize the state of the drugs in these pharmaceutical formulations. © 2021, Springer Science+Business Media, LLC, part of Springer Nature

Charting the structural and thermodynamic determinants in phenolic acid natural product - cyclodextrin encapsulations

Cyclodextrins are pliable platforms that have served to optimize the pharmaceutic profile of numerous compounds and to enhance the stability of natural food additives. Caffeic and rosmarinic acid are natural products with proven health benefits, though their full therapeutic potential has not been exploited. To enhance their pharmaceutic profile, we developed cyclodextrin-based formulates and unveiled their thermodynamic and structural principles. The complexes' stoichiometry was determined by ESI-MS. Solid-state and liquid NMR spectroscopy revealed the interactions and the topographical location of the caffeic and rosmarinic acid inside the cyclodextrin cavity. The theoretically analyzed HP-β-CD's degree of substitution (DS) of caffeic and rosmarinic acids can explain the intensities obtained by 2D NOESY experiments. The thermodynamics and the affinity of the complexes were evaluated through isothermal titration calorimetry. In addition, the rosmarinic and caffeic acids as, also, their complexes showed considerable antimicrobial activity against common food spoilage and pathogenic bacteria. The generated data could provide the basis to understand the structural and thermodynamic determinants implicated in natural products - CD recognition and to develop platforms for the optimization of their pharmaceutical and stability profiles in order to be utilized as safe and stable natural antimicrobial food additives.Communicated by Ramaswamy H. Sarma