Lockdown Due to COVID-19 and Its Consequences on Diet, Physical Activity, Lifestyle, and Other Aspects of Daily Life Worldwide: A Narrative Review.

The novel coronavirus, termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the disease called coronavirus disease 2019 (COVID-19). Besides the important rates of mortality and morbidity directly attributed to the infection itself, many studies detected an important shift towards mostly unhealthy lifestyle patterns in previously healthy non-infected populations all around the world. Although most of the changes in lifestyle had or will have a negative impact on general population health status, some findings are encouraging. Notwithstanding that there was an obvious necessity for governments to apply national lockdowns, it is also necessary to identify and comprehend the consequences they have caused. A narrative literature review was performed, based on scientific articles and previous reviews. An accurate description of changes in eating habits and alcohol consumption, physical activity, mental health, daily routines, economic impacts, and broader effects on society is provided for each continent and different age groups through this review. The volume of selected scientific surveys encompasses approximately 400,000 persons.

Application of Neutralization and Freeze-Drying Technique for the Preparation of the Beneficial in Drug Delivery 2-Hydroxypropyl-ß-Cyclodextrin Complexes with Bioactive Molecules.

Bioavailability of active substances is of great importance for the formulation of a drug product, as it actually reflects drug absorption and achievement of the optimum pharmacological effect. A great number of chemical compounds with excellent pharmacological properties possess low solubility and permeability values, ending in low bioavailability in the human body after administration (especially after per os administration). CDs are oligosaccharides that possess biological properties similar to their linear counterparts, but some of their physicochemical properties differ. They are enhancing bioavailability and solving problems of absorption for poorly soluble lipophilic drugs by forming water-soluble inclusion complexes. For this reason, they are widely used in drug delivery systems (Carrier et al. J Control Release 123:78-99, 2007; Kurkov and Loftsson, Int J Pharm 453:167-80, 2013). The main purpose of this chapter is to show a protocol for the preparation of drug:CDcomplex delivery systems.

Molecular Dynamics Protocols for the Study of Cyclodextrin Drug Delivery Systems.

Hypertension treatment is a current therapeutic priority as there is a constantly increasing part of the population that suffers from this risk factor, which may lead to cardiovascular and encephalic episodes and eventually to death. A number of marketed medicines consist of active ingredients that may be relatively potent; however, there is plenty of room to enhance their pharmacological profile and therapeutic index by improving specific physicochemical properties. In this work, we focus on a class of blood pressure regulators, called sartans, and we present the computational scheme for the pharmacological improvement of irbesartan (IRB) as a representative example. IRB has been shown to exert increased pharmacological action compared with other sartans, but it appears to be highly lipophilic and violates Lipinski rule (MLogP >4.15). To circumvent this drawback, proper hydrophilic molecules, such as cyclodextrins, can be used as drug carriers. This chapter describes the combinatory use of computational methods, namely molecular docking, quantum mechanics, molecular dynamics, and free energy calculations, to study the interactions and the energetic contributions that govern the IRB:cyclodextrin association. We provide a detailed computational protocol, which aims to assist the improvement of the pharmacological properties of sartans. This protocol can also be applied to any other drug molecule with diminished hydrophilic character.

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-ß-cyclodextrin (2-HP-ß-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.

Applications of NMR in Drug:Cyclodextrin Complexes.

NMR spectroscopy is an effective technique, applicable for studying bioactive materials or drug delivery systems in order to obtain comprehensive details related to structural and dynamic characteristics at atomic resolution. The applications of NMR spectroscopy have been increased considerably as a result of the combination of advancement in technological NMR instrumentation and scientific knowledge. This chapter is dedicated to highlight the applications of NMR spectroscopy in drug:cyclodextrin complexes using both liquid- and solid-state NMR spectroscopy.

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.

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-ß-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.

Administration of an Intravenous Fat Emulsion Enriched with Medium-Chain Triglyceride/ω-3 Fatty Acids is Beneficial Towards Anti-Inflammatory Related Fatty Acid Profile in Preterm Neonates: A Randomized, Double-Blind Clinical Trial.

Intravenous administration of pure soybean oil emulsions high in linoleic acid may lead to inflammation and lipid peroxidation in preterm neonates. We aimed to investigate the effects of a medium-chain triglyceride (MCT)/ω-3 polyunsaturated fatty acid (PUFA)-enriched intravenous fat emulsion (IVFE) on plasma fatty acid (FA) profile and serum interleukin-6 (IL-6) in preterm neonates. In this double-blind randomized study, 92 preterm neonates (gestational age < 32 weeks, birth weight < 1500 g) were assigned to receive either MCT/ω-3 PUFA-enriched IVFE (Intervention Group) or soybean oil-based IVFE (Control Group). Levels of FAs were measured at baseline (day 0) and day 15 of parenteral nutrition with gas-chromatography mass-spectrometry. Serum IL-6 was measured with sandwich ELISA in 59 neonates. Plasma FAs changed significantly over time; the MCT/ω-3 PUFA-IVFE group showed higher ω-3 PUFAs (p = 0.031), eicosapentaenoic acid (p = 0.000), and oleic acid (p = 0.003), and lower ω-6/ω-3 PUFAs ratio (p = 0.001) and ω-6 PUFAs (p = 0.023) compared to control group. Linoleic acid was higher in the soybean oil (SO)-based IVFE arm compared to the MCT/ω-3 PUFAs-IVFE arm (p = 0.006). Both fat emulsion types decreased IL-6 compared to baseline, but changes were insignificant between groups. Administration of MCT/ω-3 PUFA-enriched IVFE in preterm neonates is beneficial in changing the FA profile consistent with attenuated inflammatory response.

Antihypertensive activity and molecular interactions of irbesartan in complex with 2-hydroxypropyl-ß-cyclodextrin.

Irbesartan (IRB) exerts beneficial effects either alone or in combination with other drugs on numerous diseases, such as cancer, diabetes, and hypertension. However, due to its high lipophilicity, IRB does not possess the optimum pharmacological efficiency. To circumvent this problem, a drug delivery system with 2-hydroxypropyl-ß-cyclodextrin (2-HP-ß-CD) was explored. The 1:1 complex between IRB and 2-HP-ß-CD was identified through ESI QTF HRMS. Dissolution studies showed a higher dissolution rate of the lyophilized IRB-2-HP-ß-CD complex than the tablet containing IRB at pH = 1.2. DSC results revealed the differences of the thermal properties between the complex and various mixtures consisting of the two components, namely IRB and 2-HP-ß-CD. Interestingly, depending on the way the mixture preparation was conducted, different association between the two components was observed. Molecular dynamics (MD) simulations predicted the favorable formation of the above complex and identified the dominant interactions between IRB and 2-HP-ß-CD. In vitro pharmacological results verified that the inclusion complex not only preserves the binding affinity of IRB for AT1R receptor, but also it slightly increases it. As the complex formulation lacks the problems of the tablet, our approach is a promising new way to improve the efficiency of IRB.

Host-Guest Interactions between Candesartan and Its Prodrug Candesartan Cilexetil in Complex with 2-Hydroxypropyl-ß-cyclodextrin: On the Biological Potency for Angiotensin II Antagonism.

Renin-angiotensin aldosterone system inhibitors are for a long time extensively used for the treatment of cardiovascular and renal diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive drugs by blocking the octapeptide hormone Angiotensin II to stimulate AT1 receptors. The antihypertensive drug candesartan (CAN) is the active metabolite of candesartan cilexetil (Atacand, CC). Complexes of candesartan and candesartan cilexetil with 2-hydroxylpropyl-ß-cyclodextrin (2-HP-ß-CD) were characterized using high-resolution electrospray ionization mass spectrometry and solid state 13C cross-polarization/magic angle spinning nuclear magnetic resonance (CP/MAS NMR) spectroscopy. The 13C CP/MAS results showed broad peaks especially in the aromatic region, thus confirming the strong interactions between cyclodextrin and drugs. This experimental evidence was in accordance with molecular dynamics simulations and quantum mechanical calculations. The synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN's complexation, CAN exerts higher antagonistic activity than CC. Therefore, a formulation of CC with 2-HP-ß-CD is not indicated, while the formulation with CAN is promising and needs further investigation. This intriguing result is justified by the binding free energy calculations, which predicted efficient CC binding to 2-HP-ß-CD, and thus, the molecule's availability for release and action on the target is diminished. In contrast, CAN binding was not favored, and this may allow easy release for the drug to exert its bioactivity.

Comparative Perturbation Effects Exerted by the Influenza A M2 WT Protein Inhibitors Amantadine and the Spiro[pyrrolidine-2,2'-adamantane] Variant AK13 to Membrane Bilayers Studied Using Biophysical Experiments and Molecular Dynamics Simulations.

Aminoadamantane drugs are lipophilic amines that block the membrane-embedded influenza A M2 WT (wild type) ion channel protein. The comparative effects of amantadine ( Amt) and its synthetic spiro[pyrrolidine-2,2'-adamantane] (AK13) analogue in dimyristoylphosphatidylcholine (DMPC) bilayers were studied using a combination of experimental biophysical methods, differential scanning calorimetry (DSC), X-ray diffraction, solid-state NMR (ssNMR) spectroscopy, and molecular dynamics (MD) simulations. All three experimental methods pointed out that the two analogues perturbed drastically the DMPC bilayers with AK13 to be more effective at high concentrations. AK13 was tolerated in lipid bilayers at very high concentrations, while Amt was crystallized. This is an important consideration in the formulations of drugs as it designates a limitation of Amt incorporation. MD simulations verify provided details about the strong interactions of the drugs in the interface region between phosphoglycerol backbone and lipophilic segments. The two drugs form hydrogen bonding with both water and sn-2 carbonyls in their amine form or water and phosphate oxygens in their ammonium form. Such localization of the drugs explains the DMPC bilayers reorientation and their strong perturbing effect evidenced by all biophysical methodologies applied.

Reactions in NMR Tubes as Key Weapon in Rational Drug Design.

NMR spectroscopy is a powerful technique suitable for obtaining detailed structural and dynamic data at atomic resolution. Progress in NMR instrumentation has led the scientific community to produce novel techniques which provide valuable information to resolve demanding and crucial questions of molecular biology and rational drug design. This chapter outlines the progress of NMR spectroscopy in the rational drug design. In addition, it offers an example of a reaction in NMR tube for achieving rational drug design.

Exploring the interactions of irbesartan and irbesartan-2-hydroxypropyl-ß-cyclodextrin complex with model membranes.

The interactions of irbesartan (IRB) and irbesartan-2-hydroxypropyl-ß-cyclodextrin (HP-ß-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-ß-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 1nm 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).

Leveraging NMR and X-ray Data of the Free Ligands to Build Better Drugs Targeting Angiotensin II Type 1 G-Protein Coupled Receptor.

The angiotensin II type 1 receptor (AT1R) has been recently crystallized. A new era has emerged for the structure-based rational drug design and the synthesis of novel AT1R antagonists. In this critical review, the X-ray crystallographic data of commercially available AT1R antagonists in free form are analyzed and compared with the conformational analysis results obtained using a combination of NMR spectroscopy and Molecular Modeling. The same AT1R antagonists are docked and compared in terms of their interactions in their binding site using homology models and the crystallized AT1R receptor. Various aspects derived from these comparisons regarding rational drug design are outlined.

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.

Rational drug design paradigms: the odyssey for designing better drugs.

Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules.

Investigation of the interactions of silibinin with 2-hydroxypropyl-ß-cyclodextrin through biophysical techniques and computational methods.

Cyclodextrins (CDs) are a well-known class of supermolecules that have been widely used to protect drugs against conjugation and metabolic inactivation as well as to enhance the aqueous solubility and hence to ameliorate the oral bioavailability of sparingly soluble drug molecules. The hepatoprotectant drug silibinin can be incorporated into CDs, and here we elucidate the interaction between the drug and the host at the molecular level. The complexation product of silibinin with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) is characterized by Differential Scanning Calorimetry, mass spectrometry, solid and liquid high-resolution NMR spectroscopy. The chemical shift changes using (13)C CP/MAS on the complexing of the guest with the host provided significant information on the molecular interactions, and they were in agreement with the 2D NOESY results. These results point out that in both solid and liquid forms, the drug is engulfed and interacts with HP-ß-CD in identical manner. Molecular dynamics calculations have been performed to examine the thermodynamic characteristics associated with the silibinin-HP-ß-CD interactions and to study the stability of the complex. To approximate the physiological conditions, the aqueous solubility and dissolution characteristics of the complex at pH states simulating those of the upper gastrointestinal tract have been applied. To evaluate the antiproliferative activity of silibinin-HP-ß-CD complex comparatively to silibinin in MCF-7 human cancer cells, MTT assays have been performed.

The application of solid-state NMR spectroscopy to study candesartan cilexetil (TCV-116) membrane interactions. Comparative study with the AT1R antagonist drug olmesartan.

ΑΤ1 receptor (AT1R) antagonists exert their antihypertensive effects by preventing the vasoconstrictive hormone AngII to bind to the AT1 receptor. It has been proposed that these biological effects are mediated through a two-step mechanism reaction. In the first step, they are incorporated in the core of the lipid bilayers and in the second step they reach the active site of the receptor through lateral diffusion. In this model, drug/membrane interactions are key elements for the drugs achieving inhibition at the AT1 receptor. In this work, the interactions of the prodrug candesartan cilexetil (TCV-116) with lipid bilayers are studied at molecular detail. Solid-state (13)C-CP/MAS, 2D (1)H-(1)H NOESY NMR spectroscopy and in silico calculations are used. TCV-116 and olmesartan, another drug which acts as an AT1R antagonist are compared for their dynamic effects in lipid bilayers using solid-state (2)H-NMR. We find a similar localization of TCV-116 compared to other AT1 antagonists in the intermediate polar region. In addition, we can identify specific local interactions. These interactions may be associated in part with the discrete pharmacological profiles observed for different antagonists.