The use of drug delivery systems requires an understanding of the release kinetic patterns of an encapsulated drug or a model compound. In this work, the zero-order release of the pH-sensitive nitroxide radical 5,5-dimethyl-4-dimethylamino-2-ethyl-2-(4-pyridyl)-2,5-dihydroimidazole-1-oxyl (DPI) from poly-D,L-lactide (PDLLA) films into aqueous buffer solution was studied with continuous-wave electron paramagnetic resonance spectroscopy (EPR). The EPR method allowed for quantifying the DPI release kinetics from PDLLA films and analyzing rotational mobility and the concentration of the spin probe inside the films during their swelling and degradation. The EPR data were globally analyzed within the previously proposed phenomenological diffusion model based on the processes of pores formation and overgrowth in polyester films. The interaction between the doubly protonated DPI cation, formed in acid media inside the polymer pores, and the counterions of (oligo)lactic acid is proposed. Such interaction leads to the formation of bulk DPI-containing paramagnetic aggregates which make the release kinetics diffusion-controlled. This is in contrast to the pore-formation control observed for the standard spin probe 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxide (TEMPOL). Therefore, the release rate depends on the thickness of the film and the size and the charge of the dopant. Keywords: poly-D,L-lactide films; spin probes; electron paramagnetic resonance; mechanism of drug release; mathematical model of the release kinetics; zero-order release.

Spin probe electron paramagnetic resonance spectroscopy was applied to estimate release kinetic patterns from globules formed in solutions of thermoresponsive polymers poly-N-isopropylacrylamide (PNIPAM) and graft copolymer based on N-isopropylacrylamide and oligolactide (P(NIPAM-g-PLA)) containing (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) spin probe as a drug model. It is shown that the main mechanism of TEMPO release from globules of thermoresponsive polymers in aqueous solutions above LSCT is Brownian diffusion.

Monitoring of the acidity inside the pores of aliphatic polyesters during their swelling and hydrolysis is important challenge of biomedicine. pH-sensitive nitroxyl radical 5,5-dimetyl- 4-dimetylamino-2-ethyl-2-(4-pyridyl)-2,5-dyhydroimidazole-1-oxyl (DPI) was used to control the acidity inside thin film of poly-D,L-lactide. Based on the analysis of DPI EPR spectra, it was found that the pH in liquid-filled pores formed in the polymer matrix does not exceed 2 from the very beginning. Possibly, the generation of the pores proceeds due to the catalysis of polylactide hydrolysis by terminal carboxyl groups of the polymer or by basic groups of the nitroxide probe. A sharp increase in the number of the motile paramagnetic particles is observed in the first two days which is consistent with the formation of liquid-filled pores. Within 7–9 days, the amount of motile probes in the pores accumulates, and then begins to decrease over time. In parallel, the amount of the immobilized nitroxides becomes negligible in 10–15 days. The release rate of DPI from the poly-D,L-lactide film is independent of time, which is preferable when similar systems are used as controlled drug release units.

Impregnation of the thermoresponsive graft copolymer of N -isopropylacrylamide and oligolactide, (P(NIPAM- co -PLA)), with the composition 83.8 : 16.2 wt % with a stable nitroxyl radical, 4-oxo-2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPONE), in SC-CO 2 medium using a high-pressure reactor that allows recording electron paramagnetic resonance (EPR) spectra in situ is performed for the first time. The diffusion coefficient of TEMPONE in P(NIPAM- co -PLA) swelled in SC-CO 2 is estimated.

This paper presents a brief review of the methods for creating and diagnosing materials based on aliphatic polyesters used to create temporary prostheses and dosage forms of prolonged action. After a review of polymeric materials used in biomedicine, the special role of aliphatic polyesters in achieving these goals is substantiated. The need for impregnating polymeric biomedical products with biologically active compounds and the main approaches currently used for this are described. Particular attention is paid to green supercritical fluid (SCF) technologies for the formation of porous scaffolds with simultaneous impregnation, which makes it possible to control the structure, size, connectivity of pores, and the distribution of dopants. The possibilities of EPR spectroscopy (spin probe method) are discussed, which make it possible to obtain unique data that characterize the structure of polymer matrices and the features of their degradation with the release of paramagnetic additives. Modern ideas about the mechanisms of degradation of aliphatic polyesters and the release of biologically active substances from them are presented. Mathematical approaches to modeling qualitatively different experimental curves of the release of low molecular weight substances from poly-D,L-lactide (PDLLA) films of different thicknesses are discussed.

The article compares the metaphysics of sex in the early and late philosophy of Sergei Bulgakov. At the early stage, Bulgakov perceived sex of a person as a half, which should find integrity in an androgynous marriage. He criticized a person's escaping from marriage and family, believing that in most cases it is insincere and comes from disappointment and fear. The nature of sex is fundamentally damaged by the Fall, which determines the kind of the suffering associated with it and encourages a person to avoid them. However, but for exceptional circumstances of the rarest cases of "odd spirits," the integrity of sex can only be achieved in the married life of a man and a woman. At a later stage in his philosophy, Bulgakov revises his views on human sex: it becomes a faded reflection of the transcendental Masculine and Feminine principles in the Divine. A person is tasked with purifying and sublimating these principles in oneself, which is achieved by a chaste life in virginity, which Bulgakov again opposes to life in marriage. The later Bulgakov gives preference to celibacy, arguing that marriage does not help to solve the problem of sex. In addition, in his later views, Bulgakov criticizes the ideal of the androgyne. He believes that the androgyne is only deceptively integral; in fact, it destroys the selfsufficiency of each of the sexes in itself. In both early and later views, Bulgakov goes beyond the canonical Christian views on the issues of marriage and virginity, opposing these paths to each other and valorizing one of them in comparison with the other. In his early and later philosophy, Bulgakov denies the middle way of platonic love outside of marriage, believing that it is self-deception and results in a person's inflaming their passions for nothing, and not overcoming them. The article concludes that, in the context of modern gender problems, it is useful to rethink Bulgakov's philosophy in order to return to sex its metaphysical foundations which were lost in modern discourse. Understanding of these foundations gives a modern person the possibility to realize sex not only as a limitation, but also as a capability that allows fulfilling one's inner spiritual potential. It is this possibility that is denied by gender theories, which extinguish sex of its deep essence. Returning a spiritual basis to sex allows overcoming the modern person's alienation from oneself.

Coil-to-globule transition and dynamics of inhomogeneities in aqueous solutions of graft copolymers of NIPAM with different content of oligolactide groups were studied using spin probe continuous wave EPR spectroscopy. The technique of the suppressing of TEMPO as spin probe by spin exchange with Cu2+ ions was applied. This approach allowed us to detect individual EPR spectra of the probe in collapsed globules and estimate its magnetic and dynamic parameters reliably. The formation of inhomogeneities at temperatures lower than the volume phase transition temperature measured via transmission, and differential scanning calorimetry was fixed. An increase in oligolactide content in copolymers leads to the formation of looser globules, allowing for the exchange of the probe molecules between the globules and the external solution.

Optical spectroscopy and ESR spectroscopy were used for the first time to quantitatively describe the release of a nitroxyl probe from poly-D,L-lactide (PDLLA) films into phosphate buffer. The bifunctional probe, 2,2,5,5-tetramethyl-4-phenyl-3-imidazoline-1-oxyl-3-oxide (IMNO), contains a paramagnetic nitroxyl group and has a high extinction coefficient in the UV spectrum. Polymer films were obtained from porous PDLLA-based matrices formed and doped with IMNO in supercritical CO2 (SC-CO2). The combined use of the above-mentioned methods was shown to be promising to gain a more detailed information on the release of probes from PDLLA films, the duration of which did not exceed three weeks.

A novel approach based on convolution of the electron paramagnetic resonance (EPR) spectra was used for quantitative study of the release kinetics of paramagnetic dopants from poly(d,l-lactide) films. A non-monotonic dependence of the release rate on time was reliably recorded. The release regularities were compared with the dynamics of polymer structure changes determined by EPR, SEM, and optic microscopy. The data obtained allow for the conclusion that the main factor governing dopant release is the formation of pores connected with the surface. In contrast, the contribution of the dopant diffusion through the polymer matrix is negligible. The dopant release can be divided into two phases: release through surface pores, which are partially closed with time, and release through pores initially formed inside the polymer matrix due to autocatalytic hydrolysis of the polymer and gradually connected to the surface of the sample. For some time, these processes co-occur. The mathematical model of the release kinetics based on pore formation is presented, describing the kinetics of release of various dopants from the polymer films of different thicknesses.

Методы электронного парамагнитного резонанса (ЭПР) в варианте методикиспинового зонда и оптической микроскопии были использованы для установления закономерностей формирования пористых матриксов на основе D,L-полилактида в среде сверхкритического СО2 с одновременной импрегнациейпарамагнитным биологически активным веществом 4-гидрокси-2,2,6, 6-тетраме-тилпиперидин-1-оксидом (ТЕМПОЛ). Сделаны оценки зависимости средней илокальной концентрации допанта от условий импрегнации. Показано, что полученные матриксы отвечают ряду важнейших требований, предъявляемых к пористым материалам для тканевой инженерии. Поскольку импрегнация полимерапарамагнитным соединением дает возможность изучать равномерность распределения допанта в образце на макроскопическом и микроскопическом уровнях,а также судить о структуре полимерной матрицы, спектроскопия ЭПР являетсяперспективным методом исследования пористых полимерных материалов, сформированных в сверхкритических условиях. The spin probe technique as a version of the electron paramagnetic resonance (EPR)spectroscopy was used to reveal the regularities of the formation of porous matrixesbased on D,L-polylactide in a supercritical CО medium with the simultaneousimpregnation by paramagnetic biologically active test molecule 4-Hydroxy-2,2,6,6-tetra-methylpiperidine 1-oxyl (TEMPOL). The dependences of the average and local dopantconcentration on impregnation conditions were estimated. It was concluded that EPRspectroscopy is a promising method for studying porous polymeric materials formedin supercritical conditions. Impregnation of the polymer with a paramagnetic compoundallows one to estimate the uniformity of the dopant distribution in a sample on bothmacroscopic and microscopic levels, and also to judge the structure of the polymermatrix. The data obtained by EPR and optical spectroscopy showed that the resultingmatrixes meet the important requirements for porous materials for tissue engineering.

Впервые метод электронного парамагнитного резонанса (ЭПР) использован для количественного описания процесса высвобождения парамагнитного биологически активного вещества из полимерного биодеградируемого матрикса. В качестве парамагнитного соединения выбран стандартный спиновый зонд TEMPONE, в качестве полимера - D,L-полилактид, вспененный в среде сверхкритического диоксида углерода (СК-CO). Показано, что высвобождение TEMPONE из пористого D,L-полилактида в фосфатный буфер с pH 7,4 происходит постепенно, без периодов выброса и стагнации, что свидетельствует о принципиальной возможности применения используемой технологии импрегнации и вспенивания полимера для создания материалов медицинского назначения. For the first time, the EPR-method was used to quantitatively describe the process of releasing a paramagnetic biologically active substance from a polymer biodegradable matrix. A standard TEMPONE spin probe was chosen as the paramagnetic compound, and D, L-polylactide foamed in supercritical carbon dioxide was used as the polymer. It is shown that the release of TEMPONE from porous D, L-polylactide into phosphate buffer with pH 7,4 occurs gradually, without periods of burst and stagnation, which indicates that it is possible in principle to use the used technology of impregnation and foaming of the polymer to create materials for medicalpurposes.

Abstract—The electron spin resonance method was used to quantitatively describe the release of a paramagnetic bioactive substance from a biodegradable polymer matrix. A standard spin probe TEMPONE was chosen as the paramagnetic compound and poly-D,L-lactide foamed in supercritical carbon dioxide (SC–CO2) was used as the polymer. The release of TEMPONE from a porous poly-D,L-lactide to phosphate buffer saline (pH 7.4) was shown to occur gradually (without periods of burst and stagnation), which suggests that the used process of polymer impregnation and foaming can be applied to design materials for medical purposes.

The regularities of formation of D,L-polylactide porous matrices in supercritical CO2 environment with simultaneous impregnation with paramagnetic biologically active 4-hydroxy-2,2,6,6-tetramethylpiperidine- 1-oxyl (TEMPOL) was studied using spin probe electron paramagnetic resonance (EPR) and optical microscopy. The dependence of the average and local concentration of a dopant on impregnation conditions was assessed. The resulting matrices meet important requirements for porous materials for tissue engineering. Considering that impregnation of a polymer with a paramagnetic compound makes it possible to study the uniform distribution of a dopant in a sample at macroscopic and microscopic levels and to study a structure of a polymer matrix, EPR spectroscopy is a promising method for studying porous polymeric materials formed under supercritical conditions.

The precision of measuring concentrations of nirtoxide radicals in polymeric matrixes using modern electron paramagnetic resonance spectrometer is analyzed. The contributions of the radical nature and concentration, signal-to-noise ratio, and the integration procedure are tested as factors influencing on the precision of the measurement. It has shown that recording spectra with modern EPR spectrometer with possibility of computer analysis of spectra, the contribution of the integration error to the total error strongly depends on the signal-to-noise ratio. If the ratio is < 20, its contribution increases fast with the decrease of this parameter. If this ratio is ≥ 20, the input of the integration error becomes negligible, and the main contribution to the total error of concentration measurements comes from errors of the Q-factor determination, which are usually close to 8–10%.

BackgroundThe three primary headaches, tension-type headache, migraine and cluster headache, occur in both genders, but all seem to have a sex-specific prevalence. These gender differences suggest that both male and female sex hormones could have an influence on the course of primary headaches. This review aims to summarise the most relevant and recent literature on this topic.MethodsTwo independent reviewers searched PUBMED in a systematic manner. Search strings were composed using the terms LH, FSH, progesteron*, estrogen*, DHEA*, prolactin, testosterone, androgen*, headach*, migrain*, tension type or cluster. A timeframe was set limiting the search to articles published in the last 20years, after January 1st 1997.ResultsMigraine tends to follow a classic temporal pattern throughout a woman's life corresponding to the fluctuation of estrogen in the different reproductive stages. The estrogen withdrawal hypothesis forms the basis for most of the assumptions made on this behalf. The role of other hormones as well as the importance of sex hormones in other primary headaches is far less studied.ConclusionThe available literature mainly covers the role of sex hormones in migraine in women. Detailed studies especially in the elderly of both sexes and in cluster headache and tension-type headache are warranted to fully elucidate the role of these hormones in all primary headaches.

This systematic review summarizes the existing data on headache and pregnancy with a scope on clinical headache phenotypes, treatment of headaches in pregnancy and effects of headache medications on the child during pregnancy and breastfeeding, headache related complications, and diagnostics of headache in pregnancy. Headache during pregnancy can be both primary and secondary, and in the last case can be a symptom of a life-threatening condition. The most common secondary headaches are stroke, cerebral venous thrombosis, subarachnoid hemorrhage, pituitary tumor, choriocarcinoma, eclampsia, preeclampsia, idiopathic intracranial hypertension, and reversible cerebral vasoconstriction syndrome. Migraine is a risk factor for pregnancy complications, particularly vascular events. Data regarding other primary headache conditions are still scarce. Early diagnostics of the disease manifested by headache is important for mother and fetus life. It is especially important to identify "red flag symptoms" suggesting that headache is a symptom of a serious disease. In order to exclude a secondary headache additional studies can be necessary: electroencephalography, ultrasound of the vessels of the head and neck, brain MRI and MR angiography with contrast ophthalmoscopy and lumbar puncture. During pregnancy and breastfeeding the preferred therapeutic strategy for the treatment of primary headaches should always be a non-pharmacological one. Treatment should not be postponed as an undermanaged headache can lead to stress, sleep deprivation, depression and poor nutritional intake that in turn can have negative consequences for both mother and baby. Therefore, if non-pharmacological interventions seem inadequate, a well-considered choice should be made concerning the use of medication, taking into account all the benefits and possible risks.

The sensitivities of the k{sub eff} eigenvalue to neutron cross sections have become commonly used in similarity studies and as part of the validation algorithm for criticality safety assessments. To test calculations of the sensitivity coefficients, a benchmark study (Phase III) has been established by the OECD-NEA/WPNCS/EG UACSA (Expert Group on Uncertainty Analysis for Criticality Safety Assessment). This paper presents some sensitivity results generated by the benchmark participants using various computational tools based upon different computational methods: SCALE/TSUNAMI-3D and -1D, MONK, APOLLO2-MORET 5, DRAGON-SUSD3D and MMKKENO. The study demonstrates the performance of the tools. It also illustrates how model simplifications impact the sensitivity results and demonstrates the importance of 'implicit' (self-shielding) sensitivities. This work has been a useful step towards verification of the existing and developed sensitivity analysis methods. (authors)

The sensitivities of the keff eigenvalue to neutron cross sections have become commonly used in similarity studies and as part of the validation algorithm for criticality safety assessments. To test calculations of the sensitivity coefficients, a benchmark study (Phase III) has been established by the OECD-NEA/WPNCS/EG UACSA (Expert Group on Uncertainty Analysis for Criticality Safety Assessment). This paper presents some sensitivity results generated by the benchmark participants using various computational tools based upon different computational methods: SCALE/TSUNAMI-3D and -1D, MONK, APOLLO2-MORET 5, DRAGON-SUSD3D and MMKKENO. The study demonstrates the performance of the tools. It also illustrates how model simplifications impact the sensitivity results and demonstrates the importance of 'implicit' (self-shielding) sensitivities. This work has been a useful step towards verification of the existing and developed sensitivity analysis methods.

We describe constructing solutions of the field equations of Chern-Simons and topological BF theories in terms of deformation theory of locally constant (flat) bundles. Maps of flat connections into one another (dressing transformations) are considered. A method of calculating (nonlocal) dressing symmetries in Chern-Simons and topological BF theories is formulated.