New Alginate/PNIPAAm Matrices for Drug Delivery.

This paper deals with a comparative study on the interpolymeric complexes of alginate poly(N-isopropyl acryl amide (PNIPAAm) and corresponding graft copolymers with various compositions in respect to their toxicity, biocompatibility and in vitro and in vivo release of theophylline (THP). Loading of the various matrices with theophylline and characterization of loaded matrices was studied by near infrared spectroscopy⁻chemical imaging (NIR⁻CI) analysis, scanning electron microscopy (SEM) and thermogravimetric analysis (TGA). It was appreciated that THP loading is higher than 40% and the drug is relatively homogeneous distributed within all matrices because of some specific interactions between components of the system. All samples have been found to be non-toxic and biocompatible. It was established that graft copolymers having a good stability show a better drug carrier ability, a higher THP loading, a prolonged release (longer release duration for graft copolymers of 235.4⁻302.3 min than that for IPC 72/28 of 77.6 min, which means approximately four times slower release from the graft copolymer-based matrices than from the interpolymeric complex) and a good bioavailability. The highest values for THP loading (45%), prolonged release (302.3 min) and bioavailability (175%) were obtained for graft copolymer AgA-g-PNIPAAm 68. The drug release mechanism varies with composition and architecture of the matrix.

Inhibition of bcl-2 and cox-2 Protein Expression after Local Application of a New Carmustine-Loaded Clinoptilolite-Based Delivery System in a Chemically Induced Skin Cancer Model in Mice.

Our research has focused on in vitro and in vivo evaluations of a new Carmustine (BCNU)-loaded clinoptilolite-based delivery system. Two clinoptilolite ionic forms-hydrogen form (HCLI) and sodium form (NaCLI)-were prepared, allowing a loading degree of about 5-6 mg BCNU/g of zeolite matrix due to the dual porous feature of clinoptilolite. Clinoptilolite-based delivery systems released 35.23% of the load in 12 h for the BCNU@HCLI system and only 10.82% for the BCNU@NaCLI system. The BCNU@HCLI system was chosen to develop gel and cream semisolid dosage forms. The cream (C_BCNU@HCLI) released 29.6% of the loaded BCNU after 12 h in the Nylon synthetic membrane test and 31.6% in the collagen membrane test, higher by comparison to the gel. The new cream was evaluated in vivo in a chemically induced model of skin cancer in mice. Quantitative immunohistochemistry analysis showed stronger inhibition of B-cell lymphoma-2 (bcl-2) and cyclooxygenase 2 (cox-2) protein expression, known markers for cancer survival and aggressiveness, after the treatment with C_BCNU@HCLI by comparison to all the control treatment types, including an off-label magistral formula commercially available Carmustine cream as reference, bringing evidence that a clinoptilolite-based delivery systems could be used as a cancer drug carriers and controlled release systems (skin-targeted topical delivery systems).

Awareness about antibiotic resistance in a self-medication user group from Eastern Romania: a pilot study.

BACKGROUND: Awareness about antibiotic resistance depends on the attitudes and information about antibiotic resistance of both patients and physicians. Persons who practice self-medication are at high risk of also self-medicating with antibiotics. The purpose of the present study was to evaluate the awareness about antibiotic resistance by investigating the practice in a group of self-medication users in a sample of adults in Romania and the variables associated with such practice. MATERIAL AND METHODS: A cross-sectional self-filled questionnaire based study was conducted from December 2016 through January 2017 amongst 218 self-medication users (SMUG). The attitudes, the level of knowledge, the perceptions, about antibiotic use (ABU) and about antibiotic resistance (ABR) were compared to a reference group represented by medical residents group in their specialty training (MRG) considered to have a higher level of knowledge and awareness about ABU and ABR. RESULTS: The response rate was 87.2% in the SMUG group and 100% in the MRG group. The SMUG group reported self-medication practices for antibiotics with a high frequency at any time in life (72%), but with a very low frequency from the month previous to the date of the study (12%), comparative with the MRG group (75% and 7%, respectively). The multivariate logistic regression analysis showed that self-medication with antibiotics at any time in life in the SMUG group could be predicted by the answers to two questions regarding the practices and knowledge about ABU (Q13 and Q20). On the other hand, in the MRG group, a question about ABR perception (Q23), could be predictor for self-medication with antibiotics. Self-medication with antibiotics in the month previous to the date of the study in the SMUG group could be predicted with three questions: one about ABU practice (Q14), one about ABR perception (Q26) and one referring to ABR knowledge (Q28). On the other hand, in the MRG group, a question about ABR knowledge (Q32) could be predictor for self-medication with antibiotics. The reduced awareness about ABR in the SMUG group, is revealed by the reduced number of subjects (38%), who did not know that missing an antibiotic dose during a medical treatment contributes to ABR, comparative with the MRG group (84%). Indirectly, low ABR awareness in the SMUG group is revealed by the confusion about the appropriate use of antibiotics in bacterial or viral infections (that antibiotics are not used against viruses). CONCLUSIONS: The findings from our study on the awareness about antibiotic resistance in the SMUG group might help the policy makers and regulatory authorities to develop educational programs directed to change the perceptions and attitudes about the appropriate use of antibiotics in order to diminish self-medication practices with antibiotics.

Imbalance in the diurnal salivary testosterone/cortisol ratio in men with severe obstructive sleep apnea: an observational study / Desequilíbrio na proporção salivar diurna de testosterona/cortisol em homens com apneia obstrutiva do sono grave: um estudo observacional

ABSTRACT INTRODUCTION: The complex relationship between sleep disorders and hormones could lead to alterations in the production of cortisol and testosterone in obstructive sleep apnea (OSA) patients. OBJECTIVE: The purpose of this study was to determine the diurnal trajectories of salivary free-testosterone, free-cortisol and their ratio (T/C). METHODS: Ten subjects newly diagnosed with OSA, based on nocturnal polysomnography evaluation and excessive daytime sleepiness, and seven matched controls were consecutively recruited. Cortisol and testosterone were measured in salivary samples collected upon awakening, at noon and in the evening. The psychometric evaluation of anxiety/depression and referred sexual function disturbances was performed to evaluate the presence of neuropsychological comorbidities. RESULTS AND CONCLUSION: The main finding was that OSA subjects displayed hypocortisolism upon awakening and a significant reduction in testosterone concentration in the evening in comparison with the control group, which has maintained the physiological testosterone and cortisol diurnal fluctuation, with higher hormone concentrations in the morning and lower concentrations in the evening. The use of data from multiple diurnal measurements rather than a single point allowed the detection of T/C ratio changes of opposite signs at the beginning and end of the day: the OSA subjects had a higher T/C ratio than the controls in the morning, while their T/C ratio was significantly lower than that of the controls in the evening. The imbalances in the anabolic-catabolic diurnal equilibrium suggest that OSA is associated with a dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, potentially an underlying cause of some of the neuropsychological comorbidities observed in OSA patients.

Resumo Introdução: A relação complexa entre os distúrbios do sono e os hormônios pode levar a alterações na produção de cortisol e testosterona em pacientes com Apneia obstrutiva do sono (AOS). Objetivo: O objetivo deste estudo foi determinar as curvas diurnas de testosterona e cortisol livres na saliva e sua proporção (razão T/C). Método: Dez indivíduos recém-diagnosticados com AOS com base na avaliação por polissonografia noturna e sonolência diurna excessiva e sete controles pareados foram recrutados, consecutivamente. Cortisol e testosterona foram medidos em amostras de saliva coletadas ao acordar, ao meio-dia e à noite. A avaliação psicométrica dos distúrbios de ansiedade/depressão e função sexual mencionados foi realizada para detectar a presença de comorbidades neuropsicológicas. Resultados: O achado principal foi que os indivíduos com AOS apresentam hipocortisolismo ao acordar e uma redução significante na concentração de testosterona à noite, em comparação com o grupo controle, que manteve a variação fisiológica diurna de testosterona e cortisol com concentrações hormonais mais elevadas pela manhã e concentrações mais baixas durante a noite. O uso de dados de várias mensurações diurnas, em vez de uma única mensuração, permitiu detectar as alterações na razão T/C de sinais opostos no início e no final do dia: os indivíduos com AOS apresentaram razão T/C maior que os controles na parte da manhã, enquanto que a razão T/C foi significantemente inferior à dos controles durante a noite. Conclusão: Os desequilíbrios no balanço anabólico-catabólico diurno sugerem que a AOS está associada a uma desregulação dos eixos hipotálamo-hipófise-adrenal e hipotálamo-hipófise-gonadal, potencialmente a causa subjacente de algumas das comorbidades neuropsicológicas observadas em pacientes com AOS.

No definitive evidence for a connection between autoimmune thyroid diseases and stress in women.

The purpose of this literature review was to examine the available clinical studies performed during the last 15 years to identify if there is a causal relationship between the onset and course of autoimmune thyroid diseases (AITDs) and the hypothalamic-pituitary-adrenal (HPA) axis/sympathetic-adrenomedullary system (SAM) (dys)function in women. Using the PubMed, Web of Science and Scopus databases, a comprehensive search was performed, and 14 articles were finally identified. The majority of selected studies suggested a causal connection between Graves' Disease (GD) and stress, as well as between Hashimoto Thyroiditis (HT), with its variant postpartum thyroiditis, and stress. However, due to heterogeneity in the protocols, mainly based on the theoretical side effects of stress on the immune-neuroendocrine system, and the different modalities used to establish the impact of stress on individuals, no definitive conclusions could be reached to explain the mechanisms by which stress contributes to the onset of AITDs in women and to determine whether stress management could help in modifying the course of AITDs.

NEW CLASS OF DRUGS: THERAPEUTIC RNAi INHIBITION OF PCSK9 AS A SPECIFIC LDL-C LOWERING THERAPY.

Hyperlipidemia is a well-known risk factor for coronary heart disease, the leading cause of death for both men and women. Current lipid-lowering treatment is not always efficient, therefore new pharmacological interventions that reduce LDL cholesterol (LDL-C) have been developed. This paper presents new class of specific LDL lipid-lowering drugs under investigation in phase II or III clinical trials. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis, improve the liver's ability to clear LDL from the plasma, reducing LDL-C levels. Currently, three monoclonal antibodies PCSK9 inhibitors (alirocumab, evolocumab and bococizumab) are evaluated in clinical outcome trials. ALN-PCSsc, the new first-in- class therapeutic RNA interference (RNAi) inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) is also the first-in-class investigational medicine that acts by turning off PCSK9 synthesis in the liver. The development leadership of ALN-PCSsc has now transferred from Alnylam Pharmaceuticals to The Medicines Company, who has initiated the ORION-1 Phase II study at the beginning of 2016. ALN-PCSsc has significant potential given its highly competitive profile as compared with monoclonal antibodies anti-PCSK9 MAbs, a recently approved class of LDL-C lowering drugs.

Imbalance in the diurnal salivary testosterone/cortisol ratio in men with severe obstructive sleep apnea: an observational study.

INTRODUCTION: The complex relationship between sleep disorders and hormones could lead to alterations in the production of cortisol and testosterone in obstructive sleep apnea (OSA) patients. OBJECTIVE: The purpose of this study was to determine the diurnal trajectories of salivary free-testosterone, free-cortisol and their ratio (T/C). METHODS: Ten subjects newly diagnosed with OSA, based on nocturnal polysomnography evaluation and excessive daytime sleepiness, and seven matched controls were consecutively recruited. Cortisol and testosterone were measured in salivary samples collected upon awakening, at noon and in the evening. The psychometric evaluation of anxiety/depression and referred sexual function disturbances was performed to evaluate the presence of neuropsychological comorbidities. RESULTS AND CONCLUSION: The main finding was that OSA subjects displayed hypocortisolism upon awakening and a significant reduction in testosterone concentration in the evening in comparison with the control group, which has maintained the physiological testosterone and cortisol diurnal fluctuation, with higher hormone concentrations in the morning and lower concentrations in the evening. The use of data from multiple diurnal measurements rather than a single point allowed the detection of T/C ratio changes of opposite signs at the beginning and end of the day: the OSA subjects had a higher T/C ratio than the controls in the morning, while their T/C ratio was significantly lower than that of the controls in the evening. The imbalances in the anabolic-catabolic diurnal equilibrium suggest that OSA is associated with a dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, potentially an underlying cause of some of the neuropsychological comorbidities observed in OSA patients.

New Nitric Oxide Donors With Therapeutic Potential.

Nitric oxide (NO), formerly known as the endothelium-derived relaxing factor, is a mediator with a key role in the body, both in the central nervous system and in periphery. NO is synthesized by several cell types, where it acts as an autocrine and paracrine signaling molecule. Harnessing the impressive therapeutic potential of nitric oxide (NO) remains an ongoing challenge. In order to overcome the limitations linked with the use of nitric oxide and specially to increase the release of the radical in the targeted area, promising therapeutic strategies have been implemented, based on specific technologies which create releasing agents and vehicles for nitric oxide. Organic nitrites are the most known NO donor drugs, used especially in the treatment of cardiovascular diseases. In recent years, technological advances have allowed obtaining variations synthetic derivatives (such as diazeniumdiolates, S-nitrosothiols), which can generate NO in a controlled mode in the body and to chemically stabilize it; these compounds were studied with promising results in various animal models of vasospasm and pulmonary hypertension. Another high value therapeutic path is represented by the development of hybrid drugs (new nonsteroidal anti-inflammatory NO donor agents), with practical applications in inflammatory disorders accompanied by pain. Also, there is increasing evidence of the existence of NO donors with important antioxidant and hepatoprotective effects.

Development, optimization and biological evaluation of chitosan scaffold formulations of new xanthine derivatives for treatment of type-2 diabetes mellitus.

New xanthine derivatives as antidiabetic agents were synthesized and new chitosan formulations have been developed in order to improve their biological and pharmacokinetic profile. Their physicochemical properties in terms of particle size, morphology, swelling degree, crystalline state, the loading efficiency as well as in vitro release and biodegradation rate were evaluated. According to the results the optimized formulations have a high drug loading efficiency (more than 70%), small particle size, a good release profile in the simulated biological fluids (the percentage of cumulative release being more than 55%) and improved biodegradation rate in reference with chitosan microparticles. The presence of xanthine derivatives (6, 7) in chitosan microparticles was demonstrated by means of FTIR analysis. The X-ray diffraction (XRD) proved that xanthine derivatives present a crystalline state. The biological evaluation assays confirmed the antioxidant and antidiabetic effects of the xanthine derivatives (6, 7) and their chitosan formulations (CS-6, CS-7). Xanthine derivative 6 showed a high antiradical scavenging effect (DPPH remaining=41.78%). It also reduced the glucose blood level with 59.30% and recorded level of glycosylated hemoglobin was 4.53%. The effect of its chitosan formulation (CS-6) on the level of blood glucose (114.5mg/dl) was even more intense than the one recorded by pioglitazone (148.5mg/dl) when used as standard antidiabetic drug. These results demonstrated the potential application of xanthine derivative 6 and its chitosan formulation (CS-6) in the treatment of the diabetes mellitus syndrome.

Imidazoline receptor antagonists idazoxan and efaroxan enhance locomotor functions in rats.

UNLABELLED: Discovered in 1984, imidazoline receptors (I1, I2, I3) are located centrally and peripherally being involved in various physiologic and pathophysiologic processes in the body. Experimental and clinical investigations have suggested the interrelations between imidazoline, adrenergic, dopaminergic, glutamatergic and opioid systems, which may explain the influence of different substances acting on imidazoline receptors in cognitive disorders, behavioral disturbances and motor diseases pathways. AIM: To investigate the effects of two imidazoline receptor antagonists on locomotor activity and endurance capacity in rats. MATERIAL AND METHODS: The experiment was carried out with white male Wistar rats (200-250 g) divided into 3 groups of 7 animals each, treated intraperitonealy with the same volume of solution as follows: Group I (Control): distilled water 0.3 ml/100 g body weight; Group II (IDZ): idazoxan 3 mg/kbw; Group III (EFR): efaroxan 1 mg/kbw. Exercise capacity was evaluated using a locomotor PanLAB treadmill test. The data were presented as mean +/- standard deviation and significance was tested by SPSS Statistics for Windows version 17.0 and ANOVA method. Experimental protocol was implemented according to recommendations of the Gr.T. Popa" University Committee for Research and Ethical Issues. RESULTS: Intraperitoneal administration of idazoxan and efarox- an resulted in a significant increase in running distance compared with the control group (p < 0.05). At the same time a reduction in the number and time of electric shocks delivered to motivate the animal to keep running was observed. In this experimental behavioral model the effects of idazoxan on the evaluated parameters were more intense than those of efaroxan. CONCLUSIONS: In our experimental conditions we demonstrated the ability of imidazoline receptor antagonists idazoxan and efaroxan to improve fatigue resistance during forced running in rats.

The effects of magnesium nanovesicle formulations on spatial memory performance in mice.

AIM: The study investigates the effects of magnesium nanovesicles on the memory processes performance in mice. MATERIALS AND METHODS: L-a-phosphatidylcholine was used to obtain nano formulations as lipid vesicles systems stabilized thereafter with chitosan. The experiment was carried out on white Swiss mice, divided into 3 groups of 7 animals each, treated orally 7 consecutive days: Group I (Control): 0.1 mL/10g distilled water; Group II (Mg): 1 mmol/kbw magnesium chloride; Group III (Mg-vesicles): 1 mmol/kbw magnesium nanovesicles. The spatial memory performance was assessed by recording spontaneous alternation behavior in Y-maze test. Each animal was placed at the end of one arm and allowed to move freely through the maze during a single 8 min session. Alternation was defined as a consecutive entry in three different arms. The alternation percentage was computed according to the formula: (number of alternations/total number of arm visits--2) x 100. Data were analyzed using SPSS 17.0 software. Experimental protocols were implemented according to the recommendations of the University Committee for Research and Ethical Issues. RESULTS: New carrier formulations entrapping magnesium chloride were designed: their mean size was 129.56 nm and the mean Zeta potential was +36.1 mV, indicating a moderate stability of the solution. Oral administration of magnesium vesicles resulted in a significant increase of spontaneous alternation percent in Y-maze test (p < 0.01), which suggests an improvement of short-term memory. CONCLUSIONS: Using magnesium chloride entrapped in lipid vesicles induced an enhancement of cognitive functions in mice especially by facilitation of learning extinction.

Effects of two serotoninergic agents on the behavioral manifestations in rats.

AIM: To investigate the effects of two serotonin receptor antagonists on spontaneous behavior in rats. MATERIAL AND METHOD: The experiment was carried out on white male Wistar rats (150-200g) divided into 3 groups of 6 animals each, treated intraperitoneally with the same volume of solution as follows: Group I (Control): saline solution 0.1 ml/10 g weight; Group II (SB-269970): SB-269970 1 mg/kbw; Group III (NAN-190): NAN-190 1 mg/kbw. The effects of serotonin receptor antagonists on the spontaneous psychomotor skills of rats were tested in Actimeter LE-8811 (PanLab). The data were presented as mean +/- standard deviation and significance was tested by SPSS Statistics for Windows version 17.0 and ANOVA method. The experimental protocol was implemented according to the guidelines for handling and use of experimental animals of the Research Ethics Committee of the Iasi "Grigore T. Popa" University and ethical standards of the European Community. RESULTS: The 5HT1 serotonin receptor antagonist NAN-190 determined a statistically significant reduction (p < 0.01) in both horizontal and vertical movements as compared with the control group, whereas the 5HT7 serotonin receptor antagonist SB269970 had no influence on rat behavioral manifestations. CONCLUSIONS: In our experimental conditions 1 mg/kbw NAN-190 decreased the total escape attempts, corresponding to a significant diminution of exploratory and self-maintenance spontaneous behavior in this experimental animal model. These manifestations may be correlated with the anxiolytic effect of 5HT1 serotonin receptor antagonist NAN-190 in rats. The administration of 5HT7 serotonin receptor antagonist SB-269970 did not alter the spontaneous activity in this behavioral experimental model in rats.

Synergic effects of pregabalin-acetaminophen combination in somatic and visceral nociceptive reactivity.

BACKGROUND/AIMS: The present study investigates the effects of pregabalin (PGB), acetaminophen (ACET) and tenoxicam (TNX) administration in somatic and visceral nociception, using the tail flick test and the writhing test in mice. METHODS: In the tail flick test, the substances were administered orally and the latency time response was recorded 15, 30, 60, 90 and 120 min after administration. In the writhing test, pain responses were scored every 5 min during a 30-min period after intraperitoneal injection of diluted acetic acid. RESULTS: Our study demonstrated that oral administration of the combination PGB-ACET resulted in a stronger increase of latency reaction - statistically significant after 15 min compared to TNX and after 30 min compared to PGB in tail flick test. In the writhing test, the combination PGB-ACET, but also PGB-TNX, resulted in a stronger decrease of writhe numbers - statistically significant compared to the effects of the separate administration of each substance. This decrease was more intense in animals treated with the combination PGB-ACET than with PGB-TNX. CONCLUSION: These results suggest an antinociceptive activity which may be a consequence of the synergic action of the substances.

The effects of two polymeric matrices for indomethacin in cutaneous nociceptive reactivity in mice.

AIM: This paper is focused on the investigation the effects of two polymeric matrices for indomethacin in cutaneous pain models in mice. There were used two different co-polymers polyhydroxyethyl methacrylate and undecan, polymerization reactions being conducted under nitrogen, at 80 degrees C. MATERIAL AND METHODS: The experiments were carried out on white Swiss mice (20-25 g), divided into 6 groups of 7 animals each, treated orally. Biocompatibility properties of indomethacin-loaded copolymeric matrices ware evaluated by assessing the effects on the blood parameters, the serum biochemical tests of animals treated. The nociceptive somatic testing was performed using hot plate assay and tail immersion test. The latency (second) response to paw, respectively tail thermal noxious stimulation, was measured before the experiment and 15, 30, 60, 90, 120 minutes, 4, 6, 8, 10, 12 hours after the substances administration. RESULTS: Laboratory analysis did not show significant differences of blood parameters, serum biochemical tests between control mice group (IND) and groups treated with 1 M, 1 IND, 3 M, 3 IND. In our experimental conditions IND determined a significant increasing of the latency period response, in hot plate and also in tail immersion tests. Using two different co-polymers for indomethacin incorporation we obtained an increasing of the latency time pain reaction in hot plate assay, respectively in tail immersion test, statistically significant (*p < 0.05) compared with the simple copolymers administration. CONCLUSIONS: We demonstrated that indomethacin co-polymeric matrices 1 IND and 3 IND determined similar immune responses with indomethacin and simple co-polymers after oral administration in mice, indicative of good in vivo biocompatibility. Oral administration of both 1 IND and 3 IND resulted in prolonged antinociceptive effects in hot plate assay and also in tail immersion test in mice.

Self-medication with antimicrobial drugs among university students in a Northeast region of Romania.

UNLABELLED: Self-medication with antimicrobial drugs is an important problem in the world and may lead to serious consequences for healthcare systems. OBJECTIVE: To evaluate the prevalence and patterns of self-medication with antimicrobial drugs among university students in a Northeast region of Romania. MATERIAL AND METHODS: A cross-sectional questionnaire-based study was conducted to collect data from medical and non-medical students who lived in residence halls. Data were analyzed using descriptive statistics and the chi-square test, when applicable. RESULTS: Out of the 320 questionnaires distributed, a total of 281 students completed and returned the questionnaires. Among these, 115 (41%) respondents admitted to have used at least one antibiotic in the six months prior to the survey, 44% of whom did not seek medical advice (irrational self-medication). The most common antimicrobial drugs used for self-medication were amoxicillin (37%), amoxicillin-clavulanate (33%), ciprofloxacin and penicillin (14%) and the most frequently reported reasons for self-medication were respiratory and oral infections (31%), common cold (25%), and genitourinary infections (20%). Some students mentioned the use of more than one antimicrobial drug, for more than one disease. CONCLUSIONS: self-medication with antimicrobial drugs is a relatively common practice among students in Romania. This suggests the need for interventions to prevent the irrational use of antimicrobial drugs, such as the implementation of national programs for public education regarding the risks and consequences for the health of irrational use of antimicrobials.

Restoring the salivary cortisol awakening response through nasal continuous positive airway pressure therapy in obstructive sleep apnea.

Partial and largely conflicting data are currently available on the interplay between obstructive sleep apnea (OSA) and hypothalamus-pituitary-adrenal axis (HPA) activity in adult obese men. This study was performed to evaluate the daily trajectories of salivary cortisol, specifically with respect to the salivary cortisol awakening response (CAR), a common method used to assess HPA axis activity. The main findings of this study were that adult male obese subjects who were newly diagnosed with severe OSA showed the following: (1) a flattening of the CAR; (2) levels of cortisol at awakening that were lower than those of the controls; and (3) maintenance of the physiological circadian activity of the HPA axis, with the highest hormone concentrations produced in the morning and the lowest in the evening. This study was also designed to investigate the effects of 3 and 6 mos of treatment with continuous airways positive pressure (CPAP). CPAP use resulted in a significant recovery of the sleep patterns disrupted by OSA; moreover, mild neuropsychological signs of depression and anxiety in severe OSA patients were concomitantly progressively improved by CPAP treatment. Furthermore, this study reports that 3 and 6 mos of CPAP therapy restored the presence of CAR and was able to significantly reduce the difference in the morning cortisol levels between the OSA and control groups. In conclusion, we report here that compared with obese nonapneic matched controls, OSA patients present a dysregulation of HPA axis activity, as shown by the flattening of the diurnal pattern of cortisol production in response to repeated challenge due to hypoxia and sleep fragmentation. This dysregulation was especially detectable in the first hour after awakening and restored after 3 and 6 mos of treatment with CPAP.

Effects of some dopamine agents on modulation of memory processes performance in rats.

UNLABELLED: Apomorphine is a potent dopamine receptor agonist which has been used as a neuro-protective agent in the treatment of Parkinson's disease. SCH-23390 is a synthetic compound that presents selective D1 dopamine receptors antagonist activity and possesses pharmacologic effects similar to standard antipsychotics. AIM: Experimental researches on the effects of two substances acting on dopamine receptors on the cognitive processes in rats. MATERIAL AND METHODS: The experiment was carried out on white male Wistar rats (150-200 g) divided into 3 groups of 6 animals each, treated intraperitonealy with the same volume of solution as follows: Group I (Control): saline solution 0.3 ml; Group II (coded APO): apomorphine 2 mg/kbw; Group III (coded SCH): SCH-23390 0.3 mg/kbw. Working memory was assessed using the radial-arm maze. The following measures were recorded: the number of entering an arm containing food, but previously entered (working memory errors); the number of entering an arm that was not baited (reference memory errors); time taken to consume all five baits and the number of arms entered until a repeat entry was made (entries to repeat). The data were presented as mean +/- standard deviation and significance was tested by SPSS Statistics for Windows version 17.0 and ANOVA method. Experimental protocol was implemented according to the recommendations of the "Grigore T. Popa" University Committee for Research and Ethical Issues. RESULTS: In our experimental conditions dopamine agonist apomorphine produced significantly (p < 0.05) more novel choices in the first eight-arm entries than the saline vehicle. The animals treated with apomorphine entered significantly (P < 0.05) more arms compared to the control group. D1 receptor antagonist SCH-23390 induced a significant decrease (p < 0.05) in the number of working memory errors (elements relevant for short-time memory quantification) and average time taken to consume all five baits (p < 0.05), but did not modify the number of reference memory errors (for long-time memory quantification) compared to the control group, suggesting a short-time memory retention enhancement and an improvement of discriminative spatial learning. SCH-23390 administration resulted in a not quite significant increase in the number of entries to repeat compared to control rats. CONCLUSIONS: The administration of apomorphine also increased the search efficiency in total arm entries, suggesting that it facilitates the response in the test session of secondary reinforcement, more than rewarding, effect combined with a lack of discrimination. Our research revealed that D1 receptor antagonist SCH-23390 influenced short-time memory, without affecting long-time memory of experimented animals.

The relevance of circadian rhythms disruption on pulmonary SOD expression in rat.

The light-dark cycle represents a significant component of the circadian system in most mammals. Any disturbance of this cycle is reflected in a large number of changes in the physiological and also behavioral status of the organism, together with considerable alterations of the redox balance. Increasing evidence suggests that reactive oxygen species (ROS) have their own function in the circadian system. Superoxide dismutases (SOD) family represents the first prompt antioxidant enzymatic system, identified in all aerobic organisms and able to counteract ROS toxicity; there are three distinct isoenzymes: CuZn-SOD (SOD1), Mn-SOD (SOD2), and extracellular EC-SOD (SOD3). In the case of circadian disruption, when ROS production is enhanced, the impact of the oxidative aggression on superoxide dismutases (SOD) rhythmicity and distribution is still unclear. To estimate the influence of circadian rhythms disruption on pulmonary SOD, we exposed male Wistar rats to continuous light stimuli for four weeks and then investigated the SOD immunohistochemical expression in lungs, which are among the most sensitive organs to oxygen. CuZn-SOD, Mn-SOD and EC-SOD presented a particular immunoreactivity in the investigated pulmonary tissues. These findings support our viewpoint that there is a direct correlation between the rhythmicity of circadian cycles and pulmonary SOD expression.

Synthesis and characterization of some cellulose/chondroitin sulphate hydrogels and their evaluation as carriers for drug delivery.

Mixed hydrogels based on natural, biodegradable and biocompatible polysaccharides, such as cellulose (C) and chondroitin sulphate (CS) in various mixing ratios were prepared by a crosslinking technique and characterized by swelling behaviour, FTIR spectroscopy, scanning electron microscopy, toxicity and biocompatibility tests. The mixed cellulose/chondroitin sulphate hydrogels have been loaded with 7-[2-nitroxiacetyl-oxy-3-(4-acetyl-amino-phenoxy)-propyl]-8-morpholino-1,3-dimethyl-xanthine, a novel nitric oxide donor compound with a lower toxicity and a higher anti-inflammatory activity than its parent molecules, paracetamol and theophylline. Swelling and release kinetics have been also studied. It has been established that an increase of CS content in hydrogels composition leads to a higher swelling ratio for all formulations and to a decreased released amount of nitric oxide donor compound. It has been found that the swelling occurs by an anomalous swelling mechanism, while the release of nitric oxide donor compound follows a diffusion controlled mechanism.

In vitro and in vivo theophylline release from cellulose/chondroitin sulfate hydrogels.

In vitro and in vivo release of the theophylline, loaded in mixed polysaccharidic cellulose/chondroitin sulfate (C/CS) hydrogels has been evaluated. The C/CS hydrogels in various mixing ratios obtained by a crosslinking technique were supplementary characterized by swelling studies in a pH 2.2 acidic solution at 37 °C, simulating the gastrointestinal medium, as in vivo theophylline delivery was done by oral administration. The hydrogels loading degree with theophylline was evaluated by near infrared chemical imaging (NIR-CI) technique and confirmed also by FT-IR spectroscopy. Based on PLS-DA (partial least squares-discriminate analysis) prediction, the drug loading was found up to 92.5%. The in vitro release profiles of theophylline from C/CS hydrogels showed that an increase of chondroitin sulfate leads to a decreased theophylline percent released, increased half release time and time to reach maximum percent released. During in vivo test, the raw theophylline was rapidly, absorbed, distributed, and eliminated. Comparatively with raw drug administration, the t1/2 and AUC0-72 value were 4 times higher for theophylline loaded into 50/50 C/CS hydrogel. A good in vitro-in vivo correlation was found. A retarded release, controlled by CS content can be achieved by using mixed hydrogels as carriers.