Electrochemical and Spectroscopic Studies Performed for Indomethacin and 1-Naphthol Incorporated in 1-Butyl-3-methyl-imidazolium Bis(2-ethylhexyl) Sulfosuccinate Vesicles to Investigate Them as a Potentially pH-Sensitive Nanocarrier.

Characterization studies of 1-butyl-3-methyl-imidazolium bis(2-ethylhexyl) sulfosuccinate vesicles at different pH values have been carried out by using liquid surface tension, transmission electron microscopy, and dynamic light scattering. The results show that there are no vesicle changes in its size and negative Z potential at pH 3, 6, and 10. Furthermore, indomethacin and 1-naphthol, both pH-dependent, electroactive, and fluorescence probes, were used to further characterize the bilayer employing electrochemical and emission techniques. The partition of indomethacin and 1-naphthol between the water and bilayer pseudophases only occurs for the neutral species and does not happen for the anionic species because the highly negative Z bilayer potential prevents incorporation due to negative repulsion. For the neutral species, the partition constant values were evaluated by square wave voltammetry and emission spectroscopy. Finally, for the indomethacin incorporated into the vesicle bilayer at pH 3, the release profile was monitored over time at pH 6. It was found that a change in the pH values causes the complete release of indomethacin after 25 min, which led us to think that the vesicles presented in this work can be used as a pH-sensitive nanocarrier for neutral pH-sensitive drugs.

PRODAN Photophysics as a Tool to Determine the Bilayer Properties of Different Unilamellar Vesicles Composed of Phospholipids.

Vesicles formed by phospholipids are promising candidates for drug delivery. It is known that the lipid composition affects properties such as the rigidity-fluidity of the membrane and that it influences the bilayer permeability, but sometimes sophisticated techniques are selected to monitor them. In this work, we study the bilayer of different unilamellar vesicles composed of different lipids (1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC, and lecithin) and diverse techniques such as extruder and electrospun templates and using 6-propionyl-2-(N,N-dimethyl) aminonaphthalene (PRODAN) and its photophysics. Moreover, we were able to monitor the influence of cholesterol on the bilayers. We demonstrate that the bilayer properties can be evaluated using the emission feature of the molecular probe PRODAN. This fluorescent probe gives relevant information on the polarity and fluidity of the microenvironment for unilamellar vesicles formed by two different methods. The PRODAN emission at 434 nm suggests that the bilayer properties significantly change if DOPC or lecithin is used in the vesicle preparation especially in their fluidity. Moreover, cholesterol induces alterations in the bilayer's structural and microenvironmental properties to a greater or lesser degree in both vesicles. Thus, we propose an easy and elegant way to evaluate physicochemical properties, which is fundamental for manufacturing vesicles as a drug delivery system, simply by monitoring the molecular probe emission band centered at 434 nm, which corresponds to the PRODAN species deep inside the bilayer.

Amphiphilic Ionic Liquids Capable to Formulate Organized Systems in an Aqueous Solution, Designed by a Combination of Traditional Surfactants and Commercial Drugs.

The present review describes the state of the art in the conversion of pharmaceutically active ingredients (API) in amphiphilic Ionic Liquids (ILs) as alternative drug delivery systems. In particular, we focus our attention on the compounds generated by ionic exchange and without original counterions which generate different systems in comparison with the simple mixtures. In water, these new amphiphiles show similar or even better properties as surfactants in comparison with their precursors. Cations such as 1-alkyl-3-methyl-imidazolium and anions such as dioctyl sulfosuccinate or sodium dodecyl sulfate appear as the amphiphilic components most studied. In conclusion, this work shows interesting information on several promissory compounds and they appear as an interesting challenge to extend the application of ILs in the medical field.

Trends in maternal mortality in India over two decades in nationally representative surveys.

OBJECTIVE: To assess national and regional trends and causes-specific distribution of maternal mortality in India. DESIGN: Nationally representative cross-sectional surveys. SETTING: All of India from 1997 to 2020. SAMPLE: About 10 000 maternal deaths among 4.3 million live births over two decades. METHODS: We analysed trends in the maternal mortality ratio (MMR) from 1997 through 2020, estimated absolute maternal deaths and examined the causes of maternal death using nationally representative data sources. We partitioned female deaths (aged 15-49 years) and live birth totals, based on the 2001-2014 Million Death Study to United Nations (UN) demographic totals for the country. MAIN OUTCOME MEASURES: Maternal mortality burden and distribution of causes. RESULTS: The MMR declined in India by about 70% from 398/100 000 live births (95% CI 378-417) in 1997-98 to 99/100 000 (90-108) in 2020. About 1.30 million (95% CI 1.26-1.35 million) maternal deaths occurred between 1997 and 2020, with about 23 800 (95% CI 21 700-26 000) in 2020, with most occurring in poorer states (63%) and among women aged 20-29 years (58%). The MMRs for Assam (215), Uttar Pradesh/Uttarakhand (192) and Madhya Pradesh/Chhattisgarh (170) were highest, surpassing India's 2016-2018 estimate of 113 (95% CI 103-123). After adjustment for education and other variables, the risks of maternal death were highest in rural and tribal areas of north-eastern and northern states. The leading causes of maternal death were obstetric haemorrhage (47%; higher in poorer states), pregnancy-related infection (12%) and hypertensive disorders of pregnancy (7%). CONCLUSIONS: India could achieve the UN 2030 MMR goals if the average rate of reduction is maintained. However, without further intervention, the poorer states will not. TWEETABLE ABSTRACT: We estimated that 1.3 million Indian women died from maternal causes over the last two decades. Although maternal mortality rates have fallen by 70% overall, the poorer states lag behind.

Effect of a 2-step probiotic program on digestive health and performance of Holstein heifer calves.

Managing the composition of the bacterial communities in the digestive tract with the use of probiotics that enhance protective microflora could result in positive effects on health and performance of calves. The objective of this study was to evaluate a 2-step probiotic program (added to colostrum and milk) on the digestive health and growth of preweaning Holstein heifers. A randomized clinical trial was conducted from July to October 2020 in a calf rearing facility in Colorado. Calves were housed in pairs sharing the same treatment in 2 polyethylene hutches within a common area of 4.50 m2. A total of 232 calves were enrolled at birth and randomly allocated into 2 treatment groups [control (CTR) = 116; treatment (PB) = 116] and followed until weaning (64 ± 3 d). Treatment consisted of 2 formulations of a multistrain bacterial-based probiotic added in colostrum (PBF1) and milk (PBF2). Treatment calves received 2 g of PBF1 added to each colostrum feeding, and 1 g of PBF2 added to the milk at the morning feeding 3 times per week up to weaning. Calf weight was collected at birth, at 30 d of age, and at weaning. Serum total protein was determined at age 3 ± 1 d and a health assessment was completed 3 times per week. Statistical analyses were performed using SAS, with calf considered the experimental unit clustered by housing pair. Cox proportional hazard analysis and time to event analysis were used to compare time to the first diarrhea event and time to recovery between treatment groups. The total number of diarrhea events and culling were assessed by Poisson regression and logistic regression analysis, respectively. Linear regression was performed to evaluate differences in average daily gain by treatment group. Overall, the mean (± standard error) temperature humidity index (THI) was 75 (± 0.44) units during the study period, which resulted in continuous exposure to heat stress in the day hours. No difference between treatment groups was observed in serum total protein. The overall incidence of diarrhea was 96.6% (CTR = 99%, PB = 95%); no differences were determined in the hazard of a first diarrhea episode or in the median time to the first diarrhea event (11 d in both groups). Similarly, no differences were found in the likelihood of recovery or in the median time to recovery from diarrhea (7 d in both groups). Likewise, treatment group was not associated with the number of diarrhea events, mean (± standard error, g/d) average daily gain from birth to weaning [CTR = 562.5 (13.9); PB = 570.8 (13.5)], or with the odds of culling. The most prevalent pathogen isolated from feces was Clostridium, which tended to be more frequent in CTR calves than PB calves. In conclusion, the probiotic program did not affect the incidence of enteric disease or the growth of preweaning heifer calves.

Is it Necessary for the Use of Fluorinated Compounds to Formulate Reverse Micelles in a Supercritical Fluid? Searching the Best Cosurfactant to Create "Green" AOT Reverse Micelle Media.

Herein, we report the effect of employing two different alcohols, such as n-pentanol and 2,2,3,3,4,4,5,5-octafluoro pentanol (from now on F-pentanol), into 1,4-bis-2-ethylhexylsulfosuccinate (AOT) reverse micelles (RMs), to determine the interfacial activity and establish the best candidate to act as a cosurfactant in supercritical RMs. Dynamic light scattering (DLS), Fourier transform infrared (FT-IR), and fluorescence emission spectroscopy allowed us to determine and understand the behavior of alkanols in RMs. As a result, we found interesting displacements of alkanol molecules within the RMs, suggesting that the electrostatic interaction between SO3- and Na+ weakens because of new interactions of n-pentanol with SO3- through H-bonds, changing the curvature of the micellar interface. According to FT-IR and DLS studies, F-pentanol forms a RM polar core interacting through intermolecular H-bonds, suggesting no perturbations of the AOT RM interface. Hence, n-pentanol was selected as a cosurfactant to form supercritical RMs, which is confirmed by red edge excitation shift studies, using C343 as a molecular probe. Herein, we were able to create RMs under supercritical conditions without the presence of modified surfactants, fluorinated or multitailed compounds, which, to the best of our knowledge, was not shown before.

How the external solvent in biocompatible reverse micelles can improve the alkaline phosphatase behavior.

In the last decade, the nature of the nonpolar solvents that can be part of reverse micelles (RMs) has been the topic of several investigations to improve their applications. In this sense, the hydrolysis of 1-naphthyl phosphate catalyzed by the enzyme alkaline phosphatase (AP) was used as a probe to investigate the effect of the change of the external solvent on RMs formulated with the anionic surfactant sodium diethylhexyl sulfosuccinate (AOT). As external nonpolar solvents, two biocompatible lipophilic esters, isopropyl myristate and methyl laurate, and the traditional nonpolar solvents, n-heptane and benzene, were used. The results were compared among the RMs investigated and with the reaction in homogeneous media. Thus, the effect of the nanoconfinement as well as the impact of the replacement of a conventional external nonpolar solvent by biocompatible solvents were analyzed. The results indicate that the catalytic efficiency in the AOT RMs is larger than that in homogeneous media, denoting a different hydration level over the AP enzyme, which is directly related to the different degrees of nonpolar solvent penetration to the RM interface. Our findings demonstrated that toxic solvents such as n-heptane and benzene can be replaced by nontoxic ones (isopropyl myristate or methyl laurate) in AOT RMs without affecting the performance of micellar systems as nanoreactors, making them a green and promising alternative toward efficient and sustainable chemistry.

Influence of the AOT Counterion Chemical Structure on the Generation of Organized Systems.

The impact of the imidazolium counterion structure on the organized systems formed by the surfactant 1,4-bis-2-ethylhexylsulfosuccinate, AOT, both in aqueous solutions and in nonpolar solvents is investigated. With this in mind, we investigated if the ionic liquid-like (IL-like) surfactant 1-ethyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate, emim-AOT, forms direct micelles or vesicles in water. Dynamic light scattering, zeta potential, conductivity, fluorescence spectroscopy, and UV-visible spectroscopy measurements were performed to characterize the organized systems in aqueous solutions. We also studied the self-aggregation of emim-AOT, 1-butyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate, bmim-AOT, and of 1-hexyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate, hmim-AOT, in nonpolar solvents. The results obtained showed that the IL-like surfactant emim-AOT forms direct micelles in water, as sodium 1,4-bis-2-ethylhexylsulfosuccinate (Na-AOT) does. However, emim-AOT aggregates are larger, have a lower surface charge, are more stable, and have a more polar and less fluid micellar interface than Na-AOT micelles. It was also observed that emim-AOT and hmim-AOT form reverse micelles in nonpolar solvents. The size of the imidazolium cations dramatically influences the size of the reverse micelles and their ability to solubilize water.

Interfacial Dynamics and Its Relations with ?Negative? Surface Viscosities Measured at Water?Air Interfaces Covered with a Cationic Surfactant.

We studied the dynamics of a cationic surfactant monolayer, Gemini 12-2-12, at the air?water interface for surfactant aqueous solutions at concentrations below the critical micelle concentration. We present surface rheology experiments performed in a Langmuir trough by the oscillatory barrier technique. From these, we found negative surface viscosities at certain frequencies. We demonstrate that this unphysical result is a consequence of an unconsidered surfactant dynamics within the interfacial region. By surface pressure relaxation experiments, after a sudden modification of the interfacial area and by dynamic surface tension and surface potential measurements, several relaxation phenomena and relaxation times were identified. We found that surfactant adsorption and desorption processes are asymmetric: the characteristic times and the number of processes involved in the mechanisms of adsorption and desorption are different. This asymmetry invalidates the usual data analysis procedure that leads to the negative viscosities. Similar mechanisms could be at the origin of the negative viscosities reported in other systems, a possibility that remains to be explored.

Use of Ionic Liquids-like Surfactants for the Generation of Unilamellar Vesicles with Potential Applications in Biomedicine.

The goal of this work is to understand the influence of the counterion nature on the organized systems formed by 1,4-bis-2-ethylhexylsulfosuccinate surfactants in aqueous solutions and how these aggregates will influence the deoxyribonucleic acid (DNA)-surfactant interactions. With this in mind, two ionic liquid-like surfactants were investigated: 1-butyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate (bmim-AOT) and 1-hexyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate (hmim-AOT). Measurements of dynamic light scattering, ζ-potential, transmission electron microscopy, and fluorescence and UV-visible spectroscopy were performed to study the characteristics of the vesicles formed by bmim-AOT and hmim-AOT. Regarding the determination of the interaction of the surfactants with DNA, circular dichroism was used. The results obtained showed that bmim-AOT and hmim-AOT ionic liquid-like surfactants spontaneously form unilamellar vesicles in water at very low surfactant concentrations. The characteristics of these aggregates are dependent on the length of the tail of the counterions. The length of the hydrophobic chains of the counterions also influences the DNA-surfactant interactions through hydrophobic effects.