Hormonal reactivity during martial arts practice among high-risk youths.

Martial arts have become a popular afterschool activity for youths across the globe. Accumulating data suggest that these activities may confer substantial cognitive and psychological benefits, and recent efforts have been made to introduce martial arts training into educational and rehabilitation settings. However, few studies have examined the potential mechanisms that may underlie these benefits. The current study evaluated the reactivity of two hormones, oxytocin (OT) and cortisol (CT), thought to be respectively involved in regulating mammalian social behaviors and responsivity to stress, to a session of intensive martial arts training in samples of at high-risk and low-risk (in regular educational establishments) youths. OT and CT were measured at baseline, during peak training, and following a cool down period. Analyses revealed that high-risk youths had lower OT but similar CT baseline levels, compared to low-risk youths, prior to the martial arts session. A significant group by time interaction indicated that whereas the OT levels among low-risk youths returned to baseline levels following training, OT levels among high-risk youths remained elevated. Finally, unlike low-risk youths for whom CT levels continued to increase throughout the training session, high-risk youths showed no significant CT reactivity. This study suggests that some of the beneficial effects of martial arts may be related to hormonal processes, especially increases in OT levels, and highlights the differing effects that training may have in different populations.

Y-site physical compatibility of hydrocortisone continuous infusions with admixtures used in critically ill patients.

PURPOSE: Critically ill patients with septic shock often receive multiple intravenous medications, necessitating either the placement of separate lines for medication administration or administration of medications concurrently through a Y-site connector only where compatibility has been demonstrated. The purpose of this study was to examine the physical compatibility of hydrocortisone infusions and select intravenous medications through a simulated Y site. METHODS: The medications tested for simulated Y-site physical compatibility with hydrocortisone included acetaminophen, albumin, cefepime, ciprofloxacin, cisatracurium, doripenem, epinephrine, esomeprazole, ibuprofen, levofloxacin, levothyroxine, meropenem, and norepinephrine. Hydrocortisone in solution with 0.9% sodium chloride injection was combined with an equivalent volume of solutions of each test drug at maximum or commercially available concentrations used clinically in intensive care units, as appropriate. The samples were evaluated using turbidimetric measurements and examined visually against light and dark backgrounds to determine physical compatibility. Observations and analyses were completed over a one-hour period at 15-minute intervals beginning immediately after mixing. Each test was performed in triplicate. RESULTS: All study medications demonstrated visual and/or turbidimetric physical compatibility when combined with hydrocortisone in a simulated Y-site infusion. No medications demonstrated a visual physical incompatibility when combined with hydrocortisone. CONCLUSION: Acetaminophen, albumin, cefepime, ciprofloxacin, cisatracurium, doripenem, epinephrine, esomeprazole, ibuprofen, levofloxacin, levothyroxine, meropenem, and norepinephrine exhibited physical compatibility with hydrocortisone via Y-site infusion.

Mindfulness-based program for stress reduction in infertile women: Randomized controlled trial.

Infertile women often experience chronic stress, which may have a negative impact on general well-being and may increase the burden of infertility. In this open-label, parallel, randomized controlled trial, infertile women aged 18-50 years (median 37 years) were assigned to an 8-week mindfulness-based program (MBP) or no intervention. The primary outcome was stress severity measured by the Lipp's Stress Symptoms Inventory (ISSL). Data were analyzed by modified intent-to-treat principle, which included all cases available to follow-up regardless of adherence to the intervention (62 participants from the MBP group and 37 from the control group). The median number of symptoms of chronic stress recorded in the past month decreased from six (interquartile range 2 to 9) before the MBP to two (interquartile range 1 to 4) after the intervention (p < 0.001, repeated measures analysis of variance with Time × Group interaction). Depressive symptoms also decreased after MBP, whereas general well-being improved (p < 0.01 for both outcomes). Hair cortisol and serum brain-derived neurotrophic factor (BDNF) did not change significantly between preintervention and postintervention. None of the outcomes changed significantly in the control group. MBP was effective in reducing stress and depressive symptoms while increasing general well-being in infertile women.

Impact of Two Forms of Daily Preventive Zinc or Therapeutic Zinc Supplementation for Diarrhea on Hair Cortisol Concentrations Among Rural Laotian Children: A Randomized Controlled Trial.

Zinc supplementation has been shown to reduce the morbidity burden among young children, and may reduce chronic stress. Hair cortisol has been promoted as an indicator of chronic stress. We assessed the impact of different strategies for delivering supplementary zinc on hair cortisol concentrations (HCC) in young Laotian children and examined risk factors associated with HCC. In a randomized double-blind controlled trial (NCT02428647), children aged 6⁻23 mo were randomized to one of four intervention groups and followed for ~36 weeks: daily preventive zinc (PZ) tablets (7 mg/day), daily multiple micronutrient powder (MNP) sachets (containing 10 mg zinc and 14 other micronutrients), therapeutic zinc (TZ) supplements for diarrhea treatment (20 mg/day for 10 days) or daily placebo powder. HCC of 512 children was assessed at baseline and endline. ANCOVA and linear regression models were used to assess group differences in HCC and to examine the risk factors associated with HCC, respectively. At enrollment, mean HCC was 28.8 ± 43.9 pg/mg. In models adjusted for age at enrollment, health district, and baseline HCC there was no overall effect of the interventions on endline HCC and change in HCC. When controlling for additional predetermined covariates, there was a marginally significant effect on change in HCC (p = 0.075) with a slightly lower reduction of HCC in TZ compared to PZ (mean change (95% CI): -4.6 (-7.0; -2.3) vs. -9.4 (-11.7; -7.0) pg/mg; p = 0.053). At baseline, consumption of iron rich foods was negatively associated with HCC, whereas AGP (α1-acid glycoprotein) levels, elevated AGP and C-reactive protein and high soluble transferrin receptor were positively associated with HCC. In young Laotian children, MNP, PZ and TZ had no impact on HCC. The marginal difference in change in HCC between the PZ and TZ groups was too small to be considered of health significance.

The physiological response to cold-water immersion following a mixed martial arts training session.

Combative sport is one of the most physically intense forms of exercise, yet the effect of recovery interventions has been largely unexplored. We investigated the effect of cold-water immersion on structural, inflammatory, and physiological stress biomarkers following a mixed martial arts (MMA) contest preparation training session in comparison with passive recovery. Semiprofessional MMA competitors (n = 15) were randomly assigned to a cold-water immersion (15 min at 10 °C) or passive recovery protocol (ambient air) completed immediately following a contest preparation training session. Markers of muscle damage (urinary myoglobin), inflammation/oxidative stress (urinary neopterin + total neopterin (neopterin + 7,8-dihydroneopterin)), and hypothalamic-pituitary axis (HPA) activation (saliva cortisol) were determined before, immediately after, and 1, 2, and 24 h postsession. Ratings of perceived soreness and fatigue, counter movement jump, and gastrointestinal temperature were also measured. Concentrations of all biomarkers increased significantly (p < 0.05) postsession. Cold water immersion attenuated increases in urinary neopterin (p < 0.05, d = 0.58), total neopterin (p < 0.05, d = 0.89), and saliva cortisol after 2 h (p < 0.05, d = 0.68) and urinary neopterin again at 24 h (p < 0.01, d = 0.57) in comparison with passive recovery. Perceived soreness, fatigue, and gastrointestinal temperatures were also lower for the cold-water immersion group at several time points postsession whilst counter movement jump did not differ. Combative sport athletes who are subjected to impact-induced stress may benefit from immediate cold-water immersion as a simple recovery intervention that reduces delayed onset muscle soreness as well as macrophage and HPA activation whilst not impairing functional performance.

Microfluidic immunosensor for rapid and highly-sensitive salivary cortisol quantification.

This paper presents a novel poly(dimethylsiloxane) (PDMS) microfluidic immunosensor that integrates a complementary metal-oxide-semiconductor (CMOS) optical detection system for a rapid and highly-sensitive quantification of salivary cortisol. The simple and non-invasive method of saliva sampling provides an interesting alternative to the blood, allowing a fast sampling at short intervals, relevant for many clinical diagnostic applications. The developed approach is based on the covalent immobilization of a coating antibody (Ab), a polyclonal anti-IgG, onto a treated PDMS surface. The coating Ab binds the capture Ab, an IgG specific for cortisol, allowing its correct orientation. Horseradish peroxidase (HRP)-labelled cortisol is added to compete with the cortisol in the sample, for the capture Ab binding sites. The HRP-labelled cortisol, bonded to the capture Ab, is measured through the HRP enzyme and the tetramethylbenzidine (TMB) substrate reaction. The cortisol quantification is performed by colorimetric detection of HRP-labelled cortisol, through optical absorption at 450nm, using a CMOS silicon photodiode as the photodetector. Under the developed optimized conditions presented here, e.g., microfluidic channels geometry, immobilization method and immunoassay conditions, the immunosensor shows a linear range of detection between 0.01-20ng/mL, a limit of detection (LOD) of 18pg/mL and an analysis time of 35min, featuring a great potential for point-of-care applications requiring continuous monitoring of the salivary cortisol levels during a circadian cycle.

An acute, double-blind, placebo-controlled cross-over study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood.

Little research exists in humans concerning the anxiolytic, antidepressant, sedative, and adaptogenic actions the traditional Ayurvedic medicine Bacopa monnieri (BM) possesses in addition to its documented cognitive-enhancing effects. Preclinical work has identified a number of acute anxiolytic, nootropic, and adaptogenic effects of BM that may also co-occur in humans. The current double-blind, placebo-controlled cross-over study assessed the acute effects of a specific extract of BM (KeenMind® - CDRI 08) in normal healthy participants during completion of a multitasking framework (MTF). Seventeen healthy volunteers completed the MTF, at baseline, then 1 h and 2 h after consuming a placebo, 320 mg BM and 640 mg of BM. Treatments were separated by a 7-day washout with order determined by Latin Square. Outcome measures included cognitive outcomes from the MTF, with mood and salivary cortisol measured before and after each completion of the MTF. Change from baseline scores indicated positive cognitive effects, notably at both 1 h post and 2 h post BM consumption on the Letter Search and Stroop tasks, suggesting an earlier nootropic effect of BM than previously investigated. There were also some positive mood effects and reduction in cortisol levels, pointing to a physiological mechanism for stress reduction associated with BM consumption. It was concluded that acute BM supplementation produced some adaptogenic and nootropic effects that need to be replicated in a larger sample and in isolation from stressful cognitive tests in order to quantify the magnitude of these effects. The study was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612000834853).

Cotton-made cellulose support for anti-allergic pajamas.

The cotton used to produce an interlock knitted fabric is alkaline boiled, bleached and after drying, it is grafted with monochlorotriazinyl-beta-cyclodextrin (MCT-ß-CD) as a support of an inclusion compound (IC) with natural anti-allergic active principles, in order to improve the curative properties and the comfort. Are used: extract of Viola tricolor Herb (VtH), solution of propolis (P) and of menthol (M), as well as the pharmacologic products: advantan (AD), hydrocortisone (HYD) and pimechrolimus (PI). The dimensions of the active compound molecules were established with software. The textile material grafted with MCT-ß-CD and with active principles absorbed in the cyclodextrin cavity is investigated by EDX. The anti-microbial activity of VtH, P and M was tested. Tactile determinations of softness were performed with human appraisers. By assembling the anti-allergic knitted fabric with untreated fabric, therapeutic pajamas were obtained. The manner to process and manufacture the pajamas for patients with contact and atopic (DA) dermatitis (DC) is presented.

Immune dysregulation and glucocorticoid resistance in minority and low income pregnant women.

Chronic prenatal stress contributes to poor birth outcomes for women and infants. Importantly, poor birth outcomes are most common among minority and low income women. To investigate underlying mechanisms, we tested the hypothesis that chronic stress related to minority or low income status is associated with glucocorticoid resistance as indicated by disruption in the cytokine-glucocorticoid feedback circuit. Home visits were conducted during which 3rd trimester pregnant women completed stress and depression surveys and provided blood for pro- and anti-inflammatory cytokines. Saliva was collected 5 times the preceding day for diurnal cortisol levels. For statistical analyses, women were grouped 3 ways, by race, income, and the presence or absence of either of those risk factors; this last group was labeled high or low general risk. Immune regulation was evaluated by evidence of a functioning negative feedback relationship between cytokines and cortisol. Of 96 participants, 18 were minority, 22 of low income, and 29 either minority or low income (high general risk). Pearson partial correlation identified a significant negative relationship between cortisol area under the curve (AUC) and pro- to anti-inflammatory cytokine ratios in the low general risk women (i.e., Caucasian, higher income) including IFNγ/IL10 (r=-0.73, p<0.0001), IL6/IL10 (r=-0.38, p=0.01), IL1ß/IL10 (r=-0.44, p=0.004) and TNFα/IL10 (r=-0.41; p=0.005); no such correlations existed in the high general risk women (i.e., minority, low income) for (IFNγ/IL10: r=-0.25, p=0.43; IL6/IL10: r=0.12, p=0.70; IL1 ß/IL10: r=0.05, p=0.87; TNFα/IL10: r=0.10; p=0.75), suggestive of glucocorticoid resistance. Cortisol levels throughout the day also were higher in minority and high general risk groups (p<0.05). Without cytokine glucocorticoid feedback, a pregnant woman's ability to regulate inflammation is limited, potentially contributing to adverse maternal and infant outcomes.

Oral administration of Cimicifuga racemosa extract attenuates psychological and physiological stress responses.

Dried rhizomes of Cimicifuga racemosa (CR), which are known as black cohosh, have been widely used as herbal dietary supplements to treat menopausal symptoms. The present study examined the effect of CR extracts on human psychological and physiological responses to acute stress induced by mental arithmetic tests, by measuring the subjective stress intensity, the brain-wave patterns according to electroencephalography, and the concentrations of salivary chromogranin-A and cortisol. The experiments were performed double-blind and their order was counterbalanced. Treatment with CR significantly attenuated the elevated subjective perception of stress and the increased salivary chromogranin-A levels compared with placebo treatment. CR extract also rapidly recovered the decrease in alpha waveband induced by performing the mental arithmetic task. We therefore propose that CR extracts might be suitable for the prevention and treatment of stress-related disorders.

Dietary L-tryptophan supplementation with reduced large neutral amino acids enhances feed efficiency and decreases stress hormone secretion in nursery pigs under social-mixing stress.

Tryptophan (Trp), the rate-limiting substrate of serotonin [5-hydroxytryptoamine (5-HT)] synthesis in the brain, competes with large neutral amino acids (LNAA) to cross the blood-brain barrier. This study was designed to evaluate the effect of L-Trp supplementation on nursery pigs experiencing social-mixing stress and fed diets varying in LNAA concentrations. Forty-eight individually housed barrows at 6 wk of age were randomly allotted to 4 dietary treatments based on a 2 × 2 factorial arrangement, with L-Trp supplementation (0 or 0.6%) and LNAA concentrations (4.5 or 3.8%) as the 2 main factors. Pigs were fed the diets for 7 d. On d 4, pigs within a treatment were paired in a new pen to create social-mixing stress and behavior was recorded for 24 h. Body weight was measured on d 0, 4, 5, and 7. Saliva and blood were collected on d 4 and 7. On d 7, pigs were killed to obtain hypothalami. During the entire period excluding the mixing day (d 5), L-Trp supplementation improved (P < 0.01) feed efficiency of pigs and lowering the LNAA further enhanced (P < 0.05) the effects of L-Trp. Supplementation of 0.6% L-Trp increased (P < 0.001) hypothalamic 5-HT and 5-hydroxyindoleacetic acid. The salivary cortisol concentration was reduced (P < 0.05) by lowering the LNAA. Collectively, lowering the LNAA further enhanced the improvement of feed efficiency by L-Trp supplementation of nursery pigs under social-mixing stress in association with reduced stress hormones, indicating that reducing LNAA in the diet can facilitate the effect of L-Trp on the stress response of pigs.

Effects of increasing tryptophan intake on growth and physiological changes in nursery pigs.

Tryptophan (Trp) as a precursor of serotonin (5-hydroxytryptamine, 5-HT) has long been used to extenuate aggressive behavior and control stress of humans as well as several farm animals. This study was conducted to determine the effect of supplemental L-Tryptophan (L-Trp) on growth, cerebral 5-HT concentration, stress hormone concentration, oxidative stress status, and behavior response of pigs under social stress, and also to determine an optimal daily total Trp intake that would benefit nursery pigs under social stress. Seventy two individually housed barrows at 6 wk of age were randomly allotted to 6 treatments with supplementation of 0, 2, 4, 6, 8, or 10 g L-Trp/kg to corn and soybean meal-based feedstuffs. Pigs were fed assigned feedstuffs for 15 d. Body weight was measured on d 0, 5, 10, and 15. Saliva and blood were collected on d 5, 10, and 15. On d 5 and 10, all 12 pigs in each treatment were paired in 6 new pens to record behavior for a 2-d period and returned to original individual pens. On d 15, pigs were euthanized to obtain hypothalamus. During the first 5 d, ADG and G:F increased (linear, P < 0.01) with increasing supplemental L-Trp. During the entire 15 d, ADG and G:F increased (linear, P = 0.01 and P < 0.01, respectively) with increasing supplemental L-Trp. Estimates of the daily total Trp intake based on ADG on d 15 were 10.8 g/d (P < 0.01; R(2) = 0.16) using a 1-slope broken-line analysis. Hypothalamic 5-HT and 5-hydroxyindoleacetic acid increased (linear, P < 0.01 and P = 0.03, respectively) with increasing supplemental L-Trp. Malonedialdehyde in plasma and hypothalamus, as well as salivary cortisol, on d 15 decreased (linear, P = 0.01, P < 0.01, and P < 0.01, respectively) with increasing supplemental L-Trp. Plasma urea nitrogen decreased (linear, P < 0.01) with increasing supplemental L-Trp. Increasing supplemental L-Trp affected pig behaviors during the first 2-d observation period by decreasing (quadratic, P = 0.04) lying, decreasing (linear, P = 0.04) sitting, and increasing (linear, P = 0.02) drinking. Overall, supplementation of L-Trp improved growth performance of 6 wk-old nursery pigs under social stress in association with increasing hypothalamic 5-HT production, reducing stress hormone concentrations, decreasing lipid peroxidation, increasing drinking, and reducing sitting and lying. Increase in BW gain of nursery pigs under social stress was maximal when daily total Trp intake was 10.8 g.

Bile salt composition is secondary to bile salt concentration in determining hydrocortisone and progesterone solubility in intestinal mimetic fluids.

Simulated intestinal fluids (SIFs) used to assay the solubility of orally administered drugs are typically based on a single bile salt; sodium taurocholate (STC). The aim of this study was to develop mimetic intestinal fluids with a closer similarity to physiological fluids than those reported to date by developing a mixed bile salt (MBS) system (STC, sodium glycodeoxycholate, sodium deoxycholate; 60:39:1) with different concentrations of lecithin, the preponderant intestinal phospholipid. Hydrocortisone and progesterone were used as model drugs to evaluate systematically the influence of SIF composition on solubility. Increasing total bile salt concentration from 0 to 30 mM increased hydrocortisone and progesterone solubility by 2- and ∼25-fold, respectively. Accordingly, higher solubilities were measured in the fed-state compared to the fasted-state SIFs. Progesterone showed the greatest increases in solubility in STC and MBS systems (2-7-fold) compared to hydrocortisone (no significant change; P>0.05) as lecithin concentration was increased. Overall, MBS systems gave similar solubility profiles to STC. In conclusion, the addenda of MBS and lecithin were found to be secondary to the influence of BS concentration. These data provide a foundation for the design of more bio-similar media for pivotal decision-guiding assays in drug development and quality control settings.

Physiological and psychological evaluation of the wrapped warm footbath as a complementary nursing therapy to induce relaxation in hospitalized patients with incurable cancer: a pilot study.

BACKGROUND: The wrapped warm footbath (WW-footbath) was originally designed as a means to promote relaxation, positive emotion, comfort, pleasure, and enjoyment in hospitalized patients with incurable stomach cancer during palliative care. OBJECTIVES: This study examined the physiological and psychological effects of the WW-footbath as complementary nursing intervention to induce relaxation in hospitalized patients with incurable cancer. METHODS: Eighteen subjects were divided into a footbath group (n=9) and a control group (n=9). Heart rate variability analysis (per second) with wavelet transformation was used for evaluation of autonomic, sympathetic, and parasympathetic activities. Salivary secretory immunoglobulin A and salivary cortisol levels were used as neuroimmunological parameters. Pain and psychological conditions were measured using a visual analog scale and Face Scale (FS). RESULTS: The high-frequency component of heart rate variability was not significantly increased in either group. However, the low-frequency component versus high-frequency ratio was significantly decreased in the footbath group at periods after footbath (P=.017, P=.000, P=.000, P=.003). In the footbath group, the salivary secretory immunoglobulin A level was significantly increased (P=.019), and the cortisol level tended to be reduced. Changes in visual analog scale and FS scores showed that the footbath group experienced significant pain relief and relaxation (pain, P=.047; relaxation, P=.042; comfortability, P=.008; FS, P=.013). CONCLUSIONS: The WW-footbath significantly decreased sympathetic activity in hospitalized patients with incurable cancer and may have secondary benefit for pain relief. IMPLICATIONS FOR PRACTICE: The WW-footbath can promote relaxation in hospitalized patients with incurable cancer. Moreover, the WW-footbath appears to afford pain relief associated with enhanced overall comfort.

Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist.

High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.

Effects of rib raising on the autonomic nervous system: a pilot study using noninvasive biomarkers.

CONTEXT: Rib raising is an osteopathic manipulative treatment technique used to address restricted excursion of the rib cage and modulate sympathetic nervous system (SNS) activity. However, the physiologic effects of this technique have not been well documented. OBJECTIVE: To investigate the effects of rib raising on the autonomic nervous system and the hypothalamic-pituitary-adrenal axis using noninvasive biomarkers. METHODS: Changes in salivary biomarkers after rib raising were investigated using a pretest-posttest, placebo-controlled design. Healthy adult participants were recruited and randomly assigned to rib raising or placebo (light touch) groups. All participants provided baseline saliva samples and samples immediately and 10 minutes after receiving the rib raising or placebo procedure. Salivary flow rate, alpha-amylase activity, and cortisol levels were measured for each sample. RESULTS: Twenty-three participants were recruited, of whom 14 completed the study (7 in each group). Subjects who received rib raising had a statistically significant decrease in alpha-amylase activity both immediately after (P=.014) and 10 minutes after (P=.008) the procedure. A statistically significant change in alpha-amylase activity was not seen in the placebo group at either time point. Changes in salivary cortisol levels and flow rate were not statistically significant in either group. CONCLUSIONS: The results of the present pilot study suggest that SNS activity may decrease immediately after rib raising, but the hypothalamic-pituitary-adrenal axis and parasympathetic activity are not altered by this technique. Salivary alpha-amylase may be a useful biomarker for investigating manipulative treatments targeting the SNS. Additional studies with a greater number of subjects are needed to expand on these results.

Stationary cuvette: a new approach to obtaining analytical curves by UV-VIS spectrophotometry.

BACKGROUND: Investigations in the field of pharmaceutical analysis and quality control of medicines require analytical procedures that achieve suitable performance. An analytical curve is one of the most important steps in the chemical analysis presenting a direct relationship to features such as linearity. OBJECTIVE: This study has the aim of developing a new methodology, the stationary cuvette, to derive analytical curves by spectroscopy for drug analysis. METHODOLOGY: The method consists basically of the use of a cuvette with a path length of 10 cm, containing a constant volume of solvent in which increasing amounts of a stock solution of the sample are added, droplet by droplet. After each addition, the cuvette is stirred and the absorbance is measured. This procedure was compared with the currently used methodology, which requires a labour-intensive dilution process, and possible sources of variation between them were evaluated. RESULTS: The results demonstrated that the proposed technique presented high sensitivity and similar reproducibility compared with the conventional methodology. In addition, a number of advantages were observed, such as user-friendliness, cost-effectiveness, accuracy, precision and robustness. CONCLUSION: The stationary cuvette approach may be considered to be an appropriate alternative to derive analytical curves for analysing drug content in raw materials and medicines through UV-VIS spectrophotometry.

Oxazolones as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.

2,5,5-Trisubstituted oxazolones were identified as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The synthesis, structure-activity relationship and metabolic stability of these compounds are presented.

Drug release and permeation studies of nanosuspensions based on solidified reverse micellar solutions (SRMS).

Solidified reverse micellar solutions (SRMS), i.e. mixtures of lecithin and triglycerides, offer high solubilisation capacities for different types of drugs in contrast to simple triglyceride systems [Friedrich, I., Müller-Goymann, C.C., 2003. Characterisation of SRMS and production development of SRMS-based nanosuspensions. Eur. J. Pharm. Biopharm. 56, 111-119]. Nanosuspensions based on SRMS were prepared by homogenisation close to the melting point of the SRMS matrix. In a first step the SRMS matrices of 1:1 (w/w) ratios of lecithin and triglycerides were loaded with 17beta-estradiol-hemihydrate (EST), hydrocortisone (HC) or pilocarpine base (PB), respectively, and subsequently ground in liquid nitrogen to minimise drug diffusion later on. The powder was then dispersed in a polysorbate 80 solution using high pressure homogenisation. The drug loading capacities of the nanosuspensions were very high in the case of poorly water-soluble EST (99% of total 0.1%, w/w, EST) and HC (97% of total 0.5%, w/w, HC) but not sufficient with the more hydrophilic PB (37-40% of total 1.0%, w/w, PB). These findings suggest SRMS-based nanosuspensions to be promising aqueous drug carrier systems for poorly soluble drugs like EST and HC. Furthermore, in vitro drug permeation from the different drug-loaded nanosuspensions was performed across human cornea construct (HCC) as an organotypical cell culture model. PB permeation did not differ from the nanosuspension and an aqueous solution whereas the permeation coefficients of HC-loaded nanosuspensions were reduced in comparison to aqueous and oily solutions of HC. However, the permeated amount was higher from the nanosuspensions due to a much lower HC concentration in the solution than that in the nanosuspension (solution 0.02%, w/w, versus nanosuspension 0.5%, w/w). The high drug load of the nanoparticles provides prolonged HC release. Permeated amounts of EST were reduced in comparison to HC and only detectable with an ELISA technique. The EST release from nanosuspensions and different EST-loaded systems revealed a prolonged EST release from the nanoparticulate systems in contrast to a faster release of an oily solution of an equal EST concentration. With regard to an aqueous EST suspension of similar concentration which represents a depot system the release rate from the nanosuspensions revealed the same order of magnitude which points again to a prolonged release potential of the nanosuspensions.