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Herein, broadband dielectric (BDS) and Fourier transform infrared spectroscopy (FTIR), together with differential scanning calorimetry (DSC) and X-ray diffraction (XRD), were applied to study the molecular dynamics, molecular interactions as well as physical stability of an amorphous Active Pharmaceutical Ingredient (API)-probucol (PRO)-infiltrated into anodic aluminum oxide (AAO) membranes of pore size, d ~ 10-160 nm. Interestingly, the behavior of examined substance strongly depends on the applied thermal protocol. Remarkably, for the first time, we observed that the structural dynamics of the slowly cooled PRO under confinement is significantly enhanced when compared to thatofthe quenched material. This unusual behavior was interpreted as a result of surface-induced effects (including the formation of well-resolved interfacial H-bonded layer and adsorption-desorption processes near the interface) that are magnified by the extremely high sensitivity to density fluctuation of studied PRO, reflected in the enormous pressure coefficient of the glass transition temperature dTg/dp = 427 K/GPa. In fact, FTIR investigations revealed that PRO tends to self-associate under confinement and forms a strongly bonded interfacial layer, which controls the variation in the structural dynamics of core molecules. Finally, we observed that the tendency to crystallize of confined API is reduced with respect to the bulk, even though the critical size of PRO nuclei (rc ~ 3 nm) is significantly lower than the smallest examined pore size. Nevertheless, after few weeks of storage, the investigated substance crystallized in larger pores, while it remained stable in the nanochannels of d = 10 nm. A combination of XRD and DSC measurements indicated that the infiltrated PRO forms two polymorphs, the stable form I (dominating in bulk) and unstable form II (prevailing under confinement). That means that porous matrices might be used to obtain and maintain prolonged stability of unstable polymorphic forms of API.

The impact of the chain length or dispersity of polymers in controlling the crystallization of amorphous active pharmaceutical ingredients (APIs) has been discussed for a long time. However, because of the weak control of these parameters in the majority of macromolecules used in pharmaceutical formulations, the abovementioned topic is poorly understood. Herein, four acetylated oligosaccharides, maltose (acMAL), raffinose (acRAF), stachyose (acSTA), and α-cyclodextrin (ac-α-CD) of growing chain lengths and different topologies (linear vs cyclic), mimicking the growing backbone of the polymer, were selected to probe the influence of these structural factors on the crystallization of naproxen (NAP)an API that does not vitrify regardless of the cooling rate applied in our experiment. It was found that in equimolar systems composed of NAP and linear acetylated oligosaccharides, the progress and activation barrier for crystallization are dependent on the molecular weight of the excipient despite the fact that results of Fourier transform infrared studies indicated that there is no difference in the interaction pattern between measured samples. On the other hand, complementary dielectric, calorimetric, and X-ray diffraction data clearly demonstrated that NAP mixed with ac-α-CD (cyclic saccharide) does not tend to crystallize even in the system with a much higher content of APIs. To explain this interesting finding, we have carried out further density functional theory computations, which revealed that incorporation of NAP into the cavity of ac- α-CD is hardly possible because this state is of much higher energy (up to 80 kJ/mol) with respect to the one where the API is located outside of the saccharide torus. Hence, although at the moment, it is very difficult to explain the much stronger impact of the cyclic saccharide on the suppression of crystallization and enhanced stability of NAP with respect to the linear carbohydrates, our studies clearly showed that the chain length and the topology of the excipient play a significant role in controlling the crystallization of this API.

Background: Human milk, in addition to nutrients, contains many biologically active substances including immunoglobulins, growth factors, cytokines, and a diverse population of somatic cells. Breast milk involves no risk of allergy, contains antibodies, and contains factors such as epidermal growth factor (EGF) and erythropoietin, which may promote the growth and repair of skin cells. The discovery of stem cells and the HAMLET complex in breast milk has led to increased interest in human milk as a natural medicine. Aim of the study: The aim of the study was to identify the effect of topical application of breast milk on the separation time of the umbilical cord stump in newborns. Case report: This paper presents the case of a patient who decided to treat her child’s umbilical cord stump with colostrum/breast milk because her two older children had experienced long umbilical stump separation times. As a result of this treatment, separation of the stump occurred 90 hours after labor. There were no abnormalities in the construction of the navel, complications, or separation disorders of the umbilical cord stump. Conclusion: This research demonstrates that colostrum/mother’s milk was used as an easy, cheap, effective, and natural method of umbilical cord care.

Objectives The aim of the study was assessment of the quality of life of patients infected with HIV. A short version of the WHOQOL-BREF questionnaire, developed by the World Health Organization, was used, which allows simultaneous evaluation of the quality of life in somatic, social, environmental and psychological spheres, and an author-constructed questionnaire. Material and methods The study group included 105 patients (x males, y females) infected with HIV. The quality of life was assessed using the short version of the WHOQOL-BREF questionnaire supplemented with an author-constructed questionnaire, which consisted of 21 closed questions. Results The WHOQOL-BREF questionnaire and authorconstructed questionnaire are reliable tools for the assessment of the quality of life in adults. The results obtained show the good quality of life of patients infected with HIV. Acceptance of own illness and permanent employment are the basic factors affecting the quality of life of HIV infected patients. Conclusions 1. The perceived state of the quality of life strongly depends on many factors, such as physical and family conditions and the attitude towards the patient. 2. Positive attitude and acceptance of one’s own illness has a great impact on further treatment and quality of life. 3. Support and assistance from the loved ones increases the sense of security of infected people and improves their quality of life. 4. The problem of discrimination and stigmatization still affects patients infected with HIV, resulting from insufficient knowledge in Polish society.

10-Alkylthiocolchicines have been obtained and characterized by spectroscopic methods and their biological activities as: cytotoxic, anti-inflammatory and analgesic activities have been tested. Cytotoxic activity against SKOV-3 ovarian cell line for 10-alkylthiocolchicine analogues was reported and tested compounds showed to be more active than commonly used doxorubicin. Some of tested C-10 alkylthiolated colchicines have been found to exhibit cytotoxicity at levels comparable to that of the natural product—colchicine. 10-Methylthiocolchicine has IC50 = 8 nM and 10-ethylthiocolchicine has IC50 = 47 nM in comparison to colchicine IC50 = 37 nM. Moreover for 10-alkylthioderivatives apoptosis test, cyclin B1 and cell cycle tests were performed. 10-n-Butylthiocolchicine was tested for anti-inflammatory and analgesic activities it showed to produce analgesic rather than anti-inflammatory effect.

In this paper, the molecular dynamics as well as inter- and intramolecular interactions in the homogenous solid dispersions (SDs) of active pharmaceutical ingredient - probucol (PRO) with acetylated glucose (acGLU), acetylated sucrose (acSUC), and sucrose acetoisobutyrate (aibSUC), prepared in 5:1 molar ratio, have been investigated using broadband dielectric (BD) and Fourier transform infrared (FTIR) spectroscopy. Importantly, high pressure dielectric measurements revealed that as for neat PRO, a breakdown of the isochronal structural (α) and JG-β exact superpositioning, due to increasing separation between both processes under compression, can also be detected in its mixtures with acetylated saccharides (acSACCHs). Furthermore, the analysis of temperature dependences of JG-β-relaxation times for PRO and PRO-acSACCH SDs at selected isobaric conditions indicated the increase in the cooperativity of the secondary process (reflected in the value of the activation entropy, ΔSβ) at elevated pressure in all systems. The mere addition of the small amount of excipient to neat PRO (p = 0.1 MPa) resulted in a greater value of ΔSβ (it was the most noticeable in the case of aibSUC). Further FTIR studies carried out on the pressure densified glasses of PRO, and binary mixtures suggested that the observed changes in the cooperativity of the JG-β-process, as well as the failure of the exact isochronal superpositioning of α- and JG-β relaxation times, are due to varying H-bond pattern in the examined single- and two-component systems at high compression/in the presence of saccharide.

The aim of this study was to assess the activity of extracts from Platycodon grandiflorum A. DC (PG) in a model of chronic bronchitis in rats. The research was carried out on three water extracts: E1 &ndash, from roots of field cultivated PG, E2 &ndash, from biotransformed roots of PG, E3 &ndash, from callus of PG. The extracts differed in saponins and inulin levels&mdash, the highest was measured in E3 and the lowest in E1. Identification of secondary metabolites was performed using two complementary LC-MS systems. Chronic bronchitis was induced by sodium metabisulfite (a source of SO2). Animals were treated with extracts for three weeks (100 mg/kg, intragastrically) and endothelial growth factor (VEGF), transforming growth factors (TGF-&beta, 1, -&beta, 2, -&beta, 3), and mucin 5AC (MUC5AC) levels were determined in bronchoalveolar lavage fluid, whereas C reactive protein (CRP) level was measured in serum. Moreover, mRNA expression were assessed in bronchi and lungs. In SO2-exposed rats, an elevation of the CRP, TGF-&beta, 1, TGF-&beta, 2, VEGF, and mucin was found, but the extracts&rsquo, administration mostly reversed this phenomenon, leading to control values. The results showed a strong anti-inflammatory effect of the extracts from PG.

Herein, we tested the validity of the thermodynamic scaling of two (α and δ) relaxation processes observed in the isotropic and nematic phases of itraconazole, that is classified as a liquid crysta...

Adolescent forms of idiopathic scoliosis are commonly encountered deformities of the thoracic and lumbar spine. They affect a significant number of adolescents, yet their cause is still unknown. The presented research is a cross-sectional analysis of 3933 volunteers (2131 girls and 1802 boys). The participants were primary school students aged 9 to 13 years old. This study determined a relationship between predictors such as: body mass, body height and body mass index (BMI) (independent variables) and angle of trunk rotation (ATR) value (dependent variable). Moreover, a stepwise multiple regression with backward selection was conducted to determine to what extent the dependent variable is explained by body mass, body height and BMI. In the group of 11,12,13-year-old girls, the analyzed results of multiple stepwise regression were statistically significant. Among the all studied predictors, it has been shown that body mass in the 11-year-old girls and body height in 12- and 13-year-old girls are major correlates of a 1-year ATR increase in proximal and main thoracic spine levels.

Summary Introduction: Rhodiola rosea (RR) and Rhodiola kirilowii (RK) are well known for their influence on central nervous system, however their impact on the development of alcohol tolerance has not yet been proven. Objective: The aim of this study was to determine the ability of RR and RK roots extracts to inhibit the development of alcohol tolerance in vivo, both, peripheral (metabolic) and central ones. Methods: Male Wistar rats were treated with RR and RK extracts (p.o.) and ethanol (i.p.) for ten consecutive days. On the first, third, fifth and eighth days the hypothermic action of ethanol was measured, while on the ninth day the loss of righting reflex was examined. On the tenth day rats were treated with assigned extract and sacrificed 1 h after the ethanol injection. Results: Both extracts inhibited development of tolerance to the hypothermic action of ethanol. The observed effect seems to be specific since none of the extracts affected body temperature in water-treated animals. RK extract also prolonged the hypnotic action of ethanol. RR-treated rats had higher blood-ethanol concentrations, in contrast to RK ones. Conclusions: RR and RK extracts inhibited the development of tolerance to the hypothermic action of ethanol. Prolongation of the hypnotic action of ethanol by RK extract may be associated with influence on the central nervous system, while the RR one also inhibited the development of metabolic tolerance.

In this article, thermal properties, molecular dynamics, crystallization kinetics, and intermolecular interactions in pure naproxen (NAP), its amide (NH2–NAP), and four esters (methyl, Met-NAP; iso...

Summary Introduction: In recent years, the search for potential neuroprotective properties of salidroside and its ability to influence the activity of nervous system become the subject of intense studies of many research groups. None of these studies, however, include an attempt to determine the effect of salidroside on the course of alcohol tolerance in vivo. Objective: The aim of this study was to investigate the ability of salidroside to inhibit the development of alcohol tolerance in rats, determining whether the effect of its action may occur in a dose-dependent manner, reducing both metabolic and central tolerance without affecting body temperature in control rats. Methods: Male Wistar rats were injected daily with ethanol at a dose of 3 g/kg for 9 consecutive days to produce ethanol tolerance. Salidroside in two doses (4.5 mg/kg and 45 mg/kg b.w.) or vehiculum was administered orally. On the 1st, 3rd, 5th and 8th day a hypothermic effect of ethanol was measured, while the loss of righting reflex procedure was performed on the 2nd, 4th, 6th and 7th day. On the 9th day rats were treated with salidroside, sacrificed 1 h after ethanol injections and blood was collected for blood-ethanol concentration measurement. Results: Salidroside at a dose of 45 mg/kg inhibited the development of tolerance to hypothermic and sedative effects of ethanol, whereas insignificant elevation of blood-ethanol concentration was observed. The dose of 4.5 mg/kg b.w. had minimal effect, only small inhibition of tolerance to hypothermic action was observed. Salidroside affected neither body mass growth nor body temperature in non-alcoholic (control) rats. Conclusions: Results of the study indicate that salidroside at a dose of 45 mg/kg inhibited the development of tolerance to the hypothermic effect of ethanol. Observed inhibition of tolerance to the sedative effect of ethanol seems to be associated with salidroside influence on the central nervous system. A comprehensive explanation of the abovementioned observations requires further pharmacological and pharmacodynamic studies.

University of Medical Sciences participates in the realization of the project titled: „Development of the technology of producing cannabinoids from low THC hemp for use as preparations supporting treatment in oncological patients” awarded by the National Centre for Research and Development under project number: INNOMED/I/11/NCBR/2014. The duration of the grant is 36 months, and the total value of the grant is 28011845 PLN. The project is run by University of Life Sciences in Poznan. Laboratory of Experimental Pharmacogenetics at the Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences (PUMS) is realizing the task number 4 titled “Evaluation of efficacy and mechanisms of action of Cannabis sativa extracts with analgesic, anti-inflammatory and antiemetic properties in an in vivo model.” The aim of this project is the development of cannabinoid extract with reduced psychoactive component (THC), which due to its high content of cannabidiol (CBD) is meant to provide analgesic properties, and at the same time to reduce the risk of addiction and overdose. University of Medical Sciences is evaluating the analgesic, anti-inflammatory and antiemetic properties of the extract of Cannabis sativa in animal models coupled with neuropathic pain. Pharmacodynamic effects of plant extracts will be later assessed taking into account the level of selected genes and proteins expression.

Cardiac resynchronization therapy (CRT) represents one of the treatment used in congestive heart failure. Current guidelines for this therapy include: widening of the QRS complex, left bundle branch block, NYHA functional class, ejection fraction. However, CRT is not effective for everyone. Unfortunately, there are some patients with heart failure who do not benefit from CRT therapy. For these reasons, a large number of studies have evaluated clinical utility of two-dimensional speckle tracking echocardiography (2D STE). Mechanical dyssynchrony assessed by imaging methods, such as STE, might be able to lead to a better selection of patients who are candidates to CRT and can predict response to it. However it is not known, which potential dyssynchrony parameter is a most promising for predicting benefits from cardiac resynchronization therapy.

The aim of this work was to analyze postural stability of girls having progressive form of idiopathic scoliosis and undergoing specific period of the adolescent growth spurt. Twenty-seven girls, aged 13.4 ± 1.2 years, presenting structural idiopathic scoliosis, thoracic or thoracolumbar pattern, radiological Cobb angle 41.7 ± 17.4° (study group) and 37 healthy girls (control group) were included. The groups were sex, age, height, weight, and BMI matched. Postural stability examination was performed using two stabilometric platforms with visual control (eyes open) at three stages: (1) both legs’ stance, (2) left leg stance, and (3) right leg stance. The Center of Pressure (COP) sway path length, the area and the displacement amplitude were compared. For the double stance, no difference in postural stability parameters between the groups was found. However, for the right leg stance, the total sway path length was longer (p=0.04) and the mean amplitude of the lateral COP displacement was increased (p=0.03) in the scoliotic group. In conclusion, for double stance, the adolescent girls with progressive form of idiopathic scoliosis revealed fair postural stability compared to control group. An impaired postural control was observed during right leg stance.

Background: Human breast milk provides a child with complete nutrition but is also a popular therapeutic remedy that has been used in traditional, natural pharmacopeia, and ethnomedicine for many years. The aim of this current review is to summarize studies of non-nutritional uses of mothers’ milk. Methods: Two databases (PubMed and Google Scholar) were searched with a combination of twelve search terms. We selected articles that were published between 1 January 2010, and 1 January 2019. The language of publication was limited to English. Results: Fifteen studies were included in the systematic review. Ten of these were randomized controlled trials, one was a quasi-experimental study, two were in vitro studies, and four employed an animal research model. Conclusions: Many human milk components have shown promise in preclinical studies and are undergoing active clinical evaluation. The protective and treatment role of fresh breast milk is particularly important in areas where mothers and infants do not have ready access to medicine.

In this work, broadband dielectric spectroscopy (BDS) has been applied to investigate the aging kinetics in a low-molecular weight pharmaceutical - probucol (PRO) at various pressure (p) conditions. Unexpectedly, we found that isostructural relaxation times (τiso, i.e., τα in the glass), as well as the stretch exponent (βag) calculated using the Casalini and Roland (CR) approach at 115 and 160 MPa, vary from the respective τiso and βag determined at 0.1 MPa. These results were different in regard to the data reported earlier for polymethylmethacrylate (PMMA). Further Fourier transform infrared (FTIR) measurements on the glass recovered from high-p experiments (pressure densified glass, PDG) allowed us to certify that most likely the change in the specific intermolecular interactions, namely the formation of weak, rarely observed O H⋯S hydrogen bonds might be responsible for that. Moreover, taking into account the values of βag (free parameter) obtained from the analysis of aging data using the CR approach, we estimated primitive relaxation times (τ0) from the Coupling Model, which were close to experimental Johari-Goldstein (JG) β-relaxation times (τJG-β). Findings reported herein may contribute to a better understanding of the aging phenomenon occurring in the pressurized H-bonded systems.

In this paper, thermal and structural properties, as well as molecular dynamics of co-amorphous binary mixtures composed of itraconazole (ITZ) and four other active pharmaceutical ingredients (APIs) with antifungal activity (posaconazole (POS), ketoconazole (KET), fluconazole (FLU), and voriconazole (VOR)), have been investigated. Calorimetric measurements indicated that with increasing concentration of each excipient (EXC), the glass transition temperature and phase transition temperatures, related to the formation of nematic and smectic order, are affected in the binary systems. Comprehensive analysis of the enthalpy of isotropic-nematic transition and the temperature dependence of the order parameter, calculated from infrared data for selected mixtures, supported by the results of X-ray diffraction , enabled us to confirm the suppression of liquid crystalline (LC) ordering in ITZ by KET, FLU, and VOR. On the other hand, ITZ enforced the nematic-like molecular arrangement of POS. Further dielectric measurements revealed that the type of EXC and its content in the mixture have no impact on the ratio of α- and δ-relaxation times (τα and τδ, respectively) in ITZ. Moreover, it was shown that δ-process is more sensitive to the isotropic-nematic phase transition than the α-one, and the formation of the nematic phase in this API occurs at different τα and τδ, dependently on the type of EXC and its concentration in the mixture. Summarizing, the results of our studies are much different with respect to those reported previously by Kozyra et al. [Mol. Pharm. 15 (2018) 5192–5206] and by some of us [Kaminska et al. Eur. J. Pharm. Biopharm. 88 (2014) 1094–1104] for ITZ mixed with various polymers and acetylated maltose, respectively. This finding clearly indicates that there is a different impact of the low and high molecular weight excipients on the ability in the formation of LC phases in ITZ, which may have important implications for the further development of the formulations of this pharmaceutical.

Context:The extent of knee extensor and flexor weakness after disruption of knee ligaments affects a rehabilitation output and functional recovery and may give prognostic information on a possible risk of development of knee osteoarthritis.Objective:The hypothesis tested was whether patients with a multiple-ligament tear would have larger abnormalities in strength of the knee extensors and flexors than patients with an isolated-ligament rupture.Design:Cross-sectional study, level III.Setting:Outpatient orthopedic clinic.Participants:3 groups of recreationally active men: noninjured control (CON, n = 12), with an anterior cruciate ligament injury (ACLI, n = 10), and with combined anterior and posterior cruciate ligament injury (APCLI, n = 9), matched according to age, body mass, and height.Intervention:All patients received conservative treatment and rehabilitation and awaited ligament reconstruction surgery.Main Outcome Measures:Isokinetic maximum-repetition peak torque per body mass (PT/BM) and total work (TW), PT and TW limb-symmetry index (LSI), and flexor-to-extensor PT ratio were evaluated during concentric knee extension-flexion movements at lower (60°/s) and higher (240°/s) isokinetic velocities.Results:The main finding was that compared with the individuals with ACLI, patients with APCLI produced in their injured limbs lower mean TW (extension: 30.3%, flexion: 28.2%) and had lower mean TW LSI (extension 74% in APCLI vs 91.6% in ACLI; flexion 61.3% in APCLI vs 90.8% in ACLI) at the higher but not lower speed of isokinetic testing. However, at the lower velocity the quantified size of reduction in PT/BM and TW was greater in subjects with APCLI than ACLI as compared with the CON individuals.Conclusions:After bi-cruciate-ligament injury the capacity to produce torque by concentric muscle contractions throughout knee-extension and-flexion movements performed with high speed is lower in injured limbs than after isolated anterior cruciate ligament tear.

The presented work describes the formulation and characterization of modified release glassy solid dosage forms (GSDFs) containing an amorphous nifedipine, as a model BCS (Biopharmaceutical Classification System) class II drug. The GSDFs were prepared by melting nifedipine together with octaacetyl sucrose. Dissolution profiles, measured under standard and biorelevant conditions, were compared to those obtained from commercially available formulations containing nifedipine such as modified release (MR) tablets and osmotic release oral system (OROS). The results indicate that the dissolution profiles of the GSDFs with nifedipine are neither affected by the pH of the dissolution media, type and concentration of surfactants, nor by simulated mechanical stress of biorelevant intensity. Furthermore, it was found that the dissolution profiles of the novel dosage forms were similar to the profiles obtained from the nifedipine OROS. The formulation of GSDFs is relatively simple, and the dosage forms were found to have favorable dissolution characteristics.

Objective Opioids are often combined with adjuvants to treat symptoms that accompany pain and with adjuvant analgesics to treat neuropathic pain. Herein, we aim to investigate the analgesic and anti–inflammatory effects of oxycodone and selected adjuvants in rats. Methods Analgesic and anti–inflammatory effects of oxycodone were assessed after single subcutaneous (SC) (0.56 mg/kg) injections in rats, with the following drugs: midazolam (0.3 mg/kg), haloperidol (0.45 mg/kg), ketamine (0.3 mg/kg), hyoscine butylbromide (1.7 mg/kg), levomepromazine (0.35 mg/kg), and metoclopramide (1.0 mg/kg). Analgesia was assessed by the tail flick test. Anti–inflammatory activity was evaluated using a plethysmometer after carrageenan–induced edema. For neuropathic pain, analgesia was explored using the tail flick and von Frey tests. Neuropathic pain was induced by vincristine (0.1 mg/kg, i.p.) in male Wistar rats. Results All tested combinations of oxycodone with particular adjuvants showed increased analgesia in comparison to oxycodone alone. Compared to oxycodone alone, combinations with midazolam, haloperidol, hyoscine butylbromide, and levomepromazine prolonged analgesia. Anti–inflammatory activities were observed after co– administration of oxycodone paired with haloperidol and ketamine, which is a new aspect of the pharmacological profile of oxycodone. In the neuropathic pain model, vincristine lowered pain threshold in rats and inhibited growth of normal rat body weight. Oxycodone in combination with adjuvant analgesics showed more potent analgesia than oxycodone alone, especially in the tail–flick test. In most cases, the maximum effects were observed for 15–30 min since combined SC administration. Conclusions Analgesic and anti–inflammatory effects were observed in oxycodone combined with selected adjuvants in rats; although the mechanism of these interactions is not yet well understood. Further studies should test these combinations after chronic administration and assess the benefits and risks associated with the use of the tested combinations in humans.

In this paper, we studied the impact of saccharides having a similar backbone but differing in the degree of freedom, local molecular mobility, flexibility of the ring and intermolecular interactions on the glass-forming ability (GFA) of naproxen (NAP) in binary mixtures. For this purpose, a series of methyl and acetyl derivatives of glucose (GLS) and anhydroglucose (anhGLS), as well as neat anhGLS have been used to produce homogeneous solid dispersions (SDs) of varying molar concentration of examined active pharmaceutical ingredient (API). Systematic measurements with the use of Differential Scanning Calorimetry (DSC) and Broadband Dielectric Spectroscopy (BDS) enabled us to determine the phase transitions, homogeneity and molecular mobility of the investigated binary mixtures as well as the impact of excipient on the crystallization tendency of NAP. It turned out that acetylated glucose (acGLS), one of the most mobile and flexible saccharides of all examined herein materials, is the best excipient enhancing the GFA of studied API. Although, it should be noted that upon storage at room temperature, we observed the recrystallization of NAP from binary mixtures. Interestingly, API always crystallized to the initial polymorphic form, as shown by X-ray diffraction (XRD) investigations. Finally, since additional measurements with the use of Fourier Transform Infrared (FTIR) Spectroscopy clearly indicated that there are no significant differences in the intermolecular interactions in the systems composed of NAP and all examined saccharides, one can postulate that the mobility and ring flexibility of the matrix have, , the most important impact on the crystallization tendency of NAP upon cooling. Consequently, it seems that in some cases, more mobile/flexible matrices can be a much better choice to enhance the glass-forming ability of studied pharmaceutical.

Background: Morphine is co-administered with adjuvant drugs to treat pain, nausea, vomiting, dyspnoea and delirium in cancer patients. Aim of the Study: To investigate analgesic effects of morphine when co-administered with adjuvant drugs. Material and Methods: Two-month-old male Wistar rats received single morphine doses alone (0.45 and 0.9 mg/kg) or with midazolam (0.3 mg/kg), haloperidol (0.15 and 0.45 mg/kg), levomepromazine (0.35 mg/kg), metoclopramide (1.0 mg/kg), and hyoscine butylbromide (1.7 mg/kg) as single subcutaneous injections. Analgesia was measured by the tail-flick test after 15, 30, 45, 60, and 90 min of drug administration. In the case of significant analgesia enhancement, analgesic and sedative effects were explored in 3-, 5-, 6-, 8-, and 11-month-old rats. Results: Significant morphine (0.9 mg/kg) analgesia enhancement was observed 60 min after haloperidol (0.15 and 0.45 mg/kg) and hyoscine butylbromide co-administration. The addition of haloperidol to morphine significantly increased analgesia in 6-, 8- and 11-month-old rats while in the case of hyoscine butylbromide co-administration this effect was observed only in 11-month-old rats. Conclusions: Haloperidol and hyoscine butylbromide enhanced morphine analgesia. Future studies may explore the repeated administration of these drug combinations in rats and humans. i 2014 S. Karger AG, Basel

W artykule przedstawiono przypadek chorej, u której złamanie kości krzyżowej prowokowało ból uniemożliwiający wykonywanie podstawowych codziennych czynności. Z tego powodu chora była leczona zachowawczo ambulatoryjnie, a następnie hospitalizowana. Stosowane u pacjentki leczenie farmakologiczne bólu, zgodnie z zaleceniami przedstawionymi w schemacie drabiny analgetycznej Światowej Organizacji Zdrowia, nie przyniosło efektów terapeutycznych. W związku z utrzymującym się bólem zaproponowano leczenie chirurgiczne. Choroby współistniejące uniemożliwiały przeprowadzenie zabiegu w znieczuleniu ogólnym. U chorej wykonano zabieg stabilizacji z użyciem cementu kostnego (sakroplastykę), stosując jedynie leki nasenne i przeciwbólowe. W wyniku zabiegu dolegliwości bólowe zmniejszyły się o ponad 70%, zwiększyła się również aktywność ruchowa pacjentki.

Background: Tramadol is often coadministered subcutaneously with adjuvants to treat pain, nausea/vomiting, dyspnea and delirium in cancer patients. The aim of the study was to investigate analgesia of tramadol coadministered with adjuvants in rats. Materials and Methods: Male rats (Wistar race) received a single tramadol dose separately (0.45 mg/kg) or tramadol with haloperidol (0.45 mg/kg), midazolam (0.3 mg/kg), levomepromazine (0.35 mg/kg), metoclopramide (1.0 mg/kg), hyoscine butylbromide (1.7 mg/kg) or ketamine (0.3 mg/kg) as a single subcutaneous injection. Analgesia was measured by a tail flick test after 15, 30, 60 and 90 min of drug administration. Results: Tramadol analgesia was enhanced with haloperidol (30, 60 and 90 min) and with midazolam (60 and 90 min). Tramadol with levomepromazine (30, 60 and 90 min) and tramadol with metoclopramide (30 and 90 min) attenuated tramadol analgesia. Tramadol with hyoscine butylbromide and tramadol with ketamine did not change tramadol analgesia. Conclusions: Significant changes in tramadol analgesia after the administration of different adjuvants could be demonstrated in this experimental single-dose study. Future clinical trials have to further explore the benefits of these drug combinations.

Salvia miltiorrhiza (Lamiaceae), one of the most important and popular plants of traditional medicine of Asia, is used for the prevention and treatment of cardiovascular diseases and in central nervous system disturbances. The main aim of this study was to assess the influence of subchronic (28-fold) administration of Salvia miltiorrhiza root extract (SE, 200mg/kg, p.o.) on behavioural activity and memory of rats and to evaluate the activities of cholinesterases (AChE and BuChE) and gene expression levels of AChE and BuChE as well as of beta-secretase (BACE1) in the hippocampus and frontal cortex in vivo. Huperzine A (HU, 0.5mg/kg b.w., p.o.) served as a positive control substance, whereas scopolamine (0.5mg/kg, i.p.) injection was used as a well-known model of memory impairment. The results showed that subchronic administration of SE led to an improvement of long-term memory of rats. Strong inhibition of AChE and BuChE mRNA transcription in the frontal cortex of rats treated with SE or HU was observed. The BACE1 transcript level was significantly decreased. AChE activity was statistically significantly inhibited in the frontal cortex and the hippocampus by SE (47% and 55%, respectively). Similar effects were observed in the case of HU. In summary, activity of SE provides evidence that the plant can be a source of drugs used in the treatment of Alzheimer disease.

Broadband dielectric spectroscopy (BDS) and differential scanning calorimetry (DSC) were applied to investigate the molecular dynamics and phase transitions in binary mixtures composed of naproxen (NAP) and acetylated saccharides: maltose (acMAL) and sucrose (acSUC). Moreover, the application of BDS method and optical microscopy enabled us to study both crystallization kinetics and crystal growth of naproxen from the solid dispersions with the highest content of modified carbohydrates (1:5wt ratio). It was found that the activation barriers of crystallization estimated from dielectric measurements are completely different for both studied herein mixtures. Much higher Ea (=205kJ/mol) was obtained for NAP-acMAL solid dispersion. It is probably due to simultaneous crystallization of both components of the mixture. On the other hand, lower value of Ea in the case of NAP-acSUC solid dispersion (81kJ/mol) indicated, that naproxen is the only crystallizing compound. This hypothesis was confirmed by X-ray diffraction studies. We also suggested that specific intermolecular dipole-dipole interactions between active substance and excipient may be an alternative explanation for the difference between activation barrier obtained for NAP-acMAL and NAP-acSUC binary mixtures. Furthermore, optical measurements showed that the activation energy for crystal growth of naproxen increases in binary mixtures. They also revealed that both excipients: acMAL and acSUC move the temperature of the maximum of crystal growth towards lower temperatures. Interestingly, this maximum occurs for nearly the same structural relaxation time, which is a good approximation of viscosity, for all samples. Finally, it was also noticed that although naproxen crystallizes to the same polymorphic form in both systems, there are some differences in morphology of obtained crystals. Thus, the observed behavior may have a significant impact on the bioavailability and dissolution rate of API produced in that way.

Melissa officinalis(MO, English: lemon balm, Lamiaceae), one of the oldest and still most popular aromatic medicinal plants, is used in phytomedicine for the prevention and treatment of nervous disturbances. The aim of our study was to assess the effect of subchronic (28-fold) administration of a 50% ethanol extract ofMOleaves (200 mg/kg, p.o.) compared with rosmarinic acid (RA, 10 mg/kg, p.o.) and huperzine A (HU, 0.5 mg/kg, p.o.) on behavioral and cognitive responses in scopolamine-induced rats. The results were linked with acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase (BACE-1) mRNA levels and AChE and BuChE activities in the hippocampus and frontal cortex of rats. In our study,MOand HU, but not RA, showed an improvement in long-term memory. The results were in line with mRNA levels, sinceMOproduced a decrease of AChE mRNA level by 52% in the cortex and caused a strong significant inhibition of BACE1 mRNA transcription (64% in the frontal cortex; 50% in the hippocampus). However, the extract produced only an insignificant inhibition of AChE activity in the frontal cortex. The mechanisms ofMOaction are probably more complicated, since its role as a modulator of beta-secretase activity should be taken into consideration.

Eryngium planumL. (EP) is as a rare medicinal plant with a lot of potentials as pharmaceutical crops. The aim of our study was to assess the effect of subchronic (28-fold) administration of a 70% ethanol extract of EP roots (200 mg/kg, p.o.) on behavioral and cognitive responses in Wistar rats linked with acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase (BACE-1) mRNA levels and AChE and BuChE activities in the hippocampus and frontal cortex. On the last day of experiment, 30 min after the last dose of EP or Huperzine A (HU), scopolamine (SC) was given at a dose of 0.5 mg/kg b.w. intraperitoneally. The results of a passive avoidance test showed an improvement in long-term memory produced by the EP extract in both scopolamine-induced rats and control group. EP caused an insignificant inhibition of AChE and BuChE activities in the frontal cortex and the hippocampus. EP decreased mRNA AChE, BuChE, and BACE-1 levels, especially in the cortex. Our results suggest that the EP extract led to the improvement of the long-term memory in rats coupled with total saponin content. The mechanism of EP action is probably complicated, since HPLC-MS analysis showed 64 chemical compounds (phenolics, saponins) in the extract of EP roots.

[Purpose] To assess the effect of 12-weeks Nordic walking training on gait parameters and some elements of postural control. [Subjects and Methods] Sixty-seven women aged 65 to 74 years were enrolled in this study. The subjects were divided into a Nordic Walking group (12 weeks of Nordic walking training, 3 times a week for 75 minutes) and a control group. In both study groups, a set of functional tests were conducted at the beginning and at the end of the study: the Forward Reach Test (FRT) and the Upward Reach Test (URT) on a stabilometric platform, and the analysis of gait parameters on a treadmill. [Results] The NW group showed improvements in: the range of reach in the FRT test and the URT test in compared to the control group. The length of the gait cycle and gait cycle frequency also showed changes in the NW group compared to the control group. [Conclusion] A 12-week NW training program had a positive impact on selected gait parameters and may improve the postural control of women aged over 65 according to the results selected functional tests.

Molecular dynamics of pure nifedipine and its solid dispersions with modified carbohydrates as well as the crystallization kinetics of active pharmaceutical ingredient (API) above and below the glass transition temperature were studied in detail by means of broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction method. It was found that the activation barrier of crystallization increases in molecular dispersions composed of acetylated disaccharides, whereas it slightly decreases in those consisting of modified monocarbohydrates for the experiments carried out above the glass transition temperature. As shown by molecular dynamics simulations it can be related to the strength, character, and structure of intermolecular interactions between API and saccharides, which vary dependently on the excipient. Long-term physical stability studies showed that, in solid dispersions consisting of acetylated maltose and acetylated sucrose, the crystallization of nifedipine is dramatically slowed down, although it is still observable for a low concentration of excipients. With increasing content of modified carbohydrates, the crystallization of API becomes completely suppressed. This is most likely due to additional barriers relating to the intermolecular interactions and diffusion of nifedipine that must be overcome to trigger the crystallization process.

Aims: The purpose of this study was to evaluate the effect of naltrexone treatment for 21 consecutive days on short-term memory in ethanol-preferring and non-preferring outbred rats. Methods: Ethanol preferring, non-preferring and control Wistar rats were treated with naltrexone (0.1 mg/kg intraperitoneally (i.p.)) for 21 consecutive days. Short-term memory was assessed by using an olfactory social recognition test. Results: A single administration of naltrexone (0.1 mg/kg i.p.) to non-ethanol-treated animals facilitated social memory, whereas the drug did not affect short-term memory in either group of chronically ethanol-treated rats. Multiple naltrexone treatment also lowered alcohol intake in ethanol-preferring rats. Conclusion: Naltrexone-ethanol interaction does not seem to produce any negative effect on the short-term memory in outbred rats.

The aim of this study was to evaluate the effect of multiple acamprosate (500.0 mg/kg, p.o.) administration on short-term memory, using the social recognition test in rats. Ifenprodil (1.0 mg/kg, i.p.), arcaine (5.0 mg/kg, i.p.) and spermidine (20.0 mg/kg, i.p.) were chosen as polyamine ligands and their action or interaction with acamprosate was also studied. The doses used did not show any sedative activity, which was assessed by measuring locomotor activity and the hypnotic effect of ethanol. The findings suggest that acute acamprosate treatment did not impair short-term memory. Multiple acamprosate and a single spermidine or arcaine administration led to better performance in the memory test, whereas no significant difference was observed in ifenprodil-treated rats. Co-administration of a single arcaine or spermidine dose with multiple acamprosate produced worse results. This means that the effect of repeated acamprosate administration can be changed by the co-administration of other polyamine ligands, so that care should be taken in interpreting.

This work aims at increasing solubility and dissolution rate of ziprasidone free base—Biopharmaceutics Classifaction System (BCS) class II compound. The authors describe a practical approach to amorphization and highlight problems that may occur during the development of formulations containing amorphous ziprasidone, which was obtained by grinding in high-energy planetary ball mills or cryogenic mills. The release of ziprasidone free base from the developed formulations was compared to the reference drug product containing crystalline ziprasidone hydrochloride—Zeldox® hard gelatin capsules. All preparations were investigated using compendial tests (USP apparatuses II and IV) as well as novel, biorelevant dissolution tests. The novel test methods simulate additional elements of mechanical and hydrodynamic stresses, which have an impact on solid oral dosage forms, especially during gastric emptying. This step may prove to be particularly important for many formulations of BCS class II drugs that are often characterized by narrow absorption window, such as ziprasidone. The dissolution rate of the developed ziprasidone free base preparations was found to be comparable or even higher than in the case of the reference formulation containing ziprasidone hydrochloride, whose water solubility is about 400 times higher than its free base.

The new derivative of well-known triterpene, oleanolic acid: methyl 3-octanoyloxyiminoolean-12-en-28-oate 5, was synthesized by the action of caprylic acid on methyl oleanolate 3-oxime in the presence of dicyclohexylcarbodiimide in dioxane. The molecular structure of the obtained product 5 was confirmed by spectral methods. The acute toxicity, locomotor activity, and the dose-dependent analgesic activity were studied. In addition, the effect of compound 5 on morphine-induced analgesic activity, the dose-dependent anti-inflammatory activity and the effect of the compound on diclofenac anti-inflammatory activity study were performed. The results proved a low toxicity (LD₅₀ > 2 g/kg) of the tested product 5, which affected neither vertical nor horizontal locomotor activity in the given range of doses. The triterpene 5 also produced centrally mediated (morphine-like) analgesic action; however, only in the highest dose. The synergistic analgesic activity of 5 and morphine in the doses of 30.0 and 300.0mg/kg was found. Compound 5 expressed the anti-inflammatory action which did not affect the anti-inflammatory activity of diclofenac after their combined administration.

Acamprosate (AC) is used as a drug for treating alcoholism. We evaluated the effect of AC on serum triacylglycerol hydrolysis (GEH, glycerol ester hydrolysis), triacylglycerol transacylation with cholesterol (GECAT, glycerol ester:cholesterol acyltransferase), and acylcholesterol hydrolysis (Cease, cholesterol ester hydrolysis) in an experimental model of alcoholism. Ethanol-preferring (PRF), non-preferring (NPF), and control (CR) male Wistar rats were treated with AC (500 mg/kg, p.o.) for 21 consecutive days. The beneficial effect of AC on lipid parameters of PRF rats included decreased triacylglycerol, total cholesterol, and LDL-cholesterol, and increased HDL-cholesterol levels. Acamprosate-compensated changes associated with ethanol consumption were observed. Acamprosate treatment decreased GECAT and increased Cease control rats, but increased GECAT and decreased CEase in PRF animals. In all groups of rats, AC treatment did not influence GEH. In conclusion, our results suggest that AC can influence triacylglycerol metabolism by its action on the balance between hydrolysis and transacylation in rats.

Aims: The purpose of this study was to assess the anxiolytic activity of ifenprodil in Warsaw high-preferring (WHP) and low-preferring (WLP) rats after chronic ethanol treatment. Methods: WHP and WLP animals, their paired-ethanol-naive groups and control Wistar rats were treated with ifenprodil (1.0 mg/kg, intraperitoneally) for 21 consecutive days. Anxiolytic activity was evaluated by using the two-compartment exploratory test. In addition, the locomotor activity paradigm was also assessed. Results: Ifenprodil did not affect this paradigm in all investigated groups. The ethanol treatment led to lowering of anxiolytic scores in WHP rats. Multiple ifenprodil administration showed an anxiogenic-like activity in both WHP- and WLP-ethanol-treated groups. Conclusions: Our results suggest that, under some conditions, the role of ifenprodil in the treatment of alcoholism may be insufficient to support its use.

The aim of this study was to evaluate the effect of treatment with single (1x) and multiple (10x) doses of the anti-craving compound acamprosate (AC, calcium acetyl homotaurinate) on working memory in rats, using in a three-panel runway test. We measured tasks after the animals were treated with AC (500 mg/kg/d, i.p.); scopolamine (SC, 0.5 mg/kg/d, i.p.), a cholinergic muscarinic receptor antagonist; or both drugs concomitantly (ACSC), either for 1 day (1x) or daily for 10 consecutive days (10x). Neither 1x not 10x AC alone had a significant effect on working memory task performance, whereas treatment with SC alone had a significantly negative effect on the ability of the rats to complete the tasks. Rats receiving ACSC performed better than those receiving SC alone, making fewer errors and displaying shorter latency, similar to the performance of the control group. These observations support the hypothesis of an indirect involvement of AC in the cholinergic system.