Acute Administration of Bioavailable Curcumin Alongside Ferrous Sulphate Supplements Does Not Impair Iron Absorption in Healthy Adults in a Randomised Trial.

Ferrous sulphate (FS) is a cost effective, readily available iron supplement for iron deficiency (ID). The pro-oxidant effect of oral ferrous iron is known to induce inflammation, causing gastric side-effects and resulting in poor compliance. Curcumin is a potent antioxidant and has also been shown to exhibit iron chelation in-vitro, although it is not established whether these effects are retained in-vivo. The aim of this study was therefore to assess the influence of a formulated bioavailable form of curcumin (HydroCurcTM; 500 mg) on acute iron absorption and status in a double blind, placebo-controlled randomized trial recruiting 155 healthy participants (79 males; 26.42 years ± 0.55 and 76 females; 25.82 years ± 0.54). Participants were randomly allocated to five different treatment groups: iron and curcumin placebo (FS0_Plac), low dose (18 mg) iron and curcumin placebo (FS18_Plac), low dose iron and curcumin (FS18_Curc), high dose (65 mg) iron and curcumin placebo (FS65_Plac), and high dose iron and curcumin (FS65_Curc). Participants were provided with the supplements according to their relevant treatment groups at baseline (0 min), and blood collection was carried out at 0 min and at 180 min following supplementation. In the treatment groups, significant difference was observed in mean serum iron between baseline (0 min) and at end-point (180 min) (F (1, 144) = 331.9, p < 0.0001) with statistically significant intra-group increases after 180 min (p < 0.0001) in the FS18_Plac (8.79 µmol/L), FS18_Curc (11.41 µmol/L), FS65_Plac (19.09 µmol/L), and FS65_Curc (16.39 µmol/L) groups. A significant difference was also observed between the two time points in serum TIBC levels and in whole blood haemoglobin (HGB) in the treatment groups, with a significant increase (1.55%/2.04 g/L) in HGB levels from baseline to end-point observed in the FS65_Curc group (p < 0.05). All groups receiving iron demonstrated an increase in transferrin saturation (TS%) in a dose-related manner, demonstrating that increases in serum iron are translated into increases in physiological iron transportation. This study demonstrates, for the first time, that regardless of ferrous dose, formulated curcumin in the form of HydroCurc™ does not negatively influence acute iron absorption in healthy humans.

Acute and Subacute Toxicity and Cytotoxicity of Opuntia Dillenii (Ker-Gawl) Haw. Seed Oil and Its Impact on the Isolated Rat Diaphragm Glucose Absorption.

This study aims to assess the safety of the Opuntia dillenii (Ker-Gawl) haw. seed oil (ODSO) and its effect on the glucose absorption activity of the isolated rat hemidiaphragm. This oil's safety was studied by exploring its acute (doses 1, 3, 5, and 7 mL/kg) and subacute (doses 1 and 2 mL/kg) toxicities in albino mice and Wistar rats, respectively. The safety of the ODSO was also assessed by studying its effect on the HepG2 cell viability in vitro. The effect of ODSO, or combined with the insulin, on the glucose absorption activity of isolated rat hemidiaphragm was evaluated at the dose 1 g/L in vitro. The results demonstrated the safety of ODSO. Indeed, this study showed that this oil does not produce any mortality or signs of toxicity after the single-dose administration in mice. Additionally, the daily intake of the ODSO during four weeks does not induce a significant variation in the biochemical parameters and body weight of rats compared with the control group. Besides, the cell viability of HepG2 did not change in the presence of ODSO. On the other hand, the ODSO increased the glucose absorption activity of the isolated rat hemidiaphragm, and this activity was significantly enhanced when combined with insulin. This study confirms, on one side, the safety of this oil and its efficacy and, on the other side, encourages its potential use as a complement to treat diabetes.

A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.

BACKGROUND: Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. METHODS: A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. RESULTS: Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1ß, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment. CONCLUSIONS: The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy. LAY SUMMARY: Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.

Engineering biocompatible benzodithiophene-based polymer dots with tunable absorptions as high-efficiency theranostic agents for multiscale photoacoustic imaging-guided photothermal therapy.

To date, photoacoustic imaging (PAI) and PAI-guided photothermal therapy (PTT) have been performed for noninvasive cancer diagnosis and precise ablation of tumors. To conduct concurrent PAI and PTT, it is essential to develop theranostic agents with strong optical absorption and high photothermal transfer efficiency. In this study, we have engineered theranostic agents with tunable absorptions based on conjugated polymer dots (Pdots) with different structures via the simple precipitation method. The as-synthesized Pdots exhibit strong absorption, high biocompatibility, and superior stability. In addition, the Pdots demonstrate that they can serve as contrast agents for multiscale PAI in vitro and in vivo. More importantly, a high photothermal conversion efficiency up to 40% is reached under irradiation with LED light, resulting in effective cancer treatment with extremely low light dose. Consequently, they show the potential as imaging-guided therapeutic agents for clinical cancer treatment and various biomedical applications.

Superior Glycemic Control With a Glucose-Responsive Insulin Analog: Hepatic and Nonhepatic Impacts.

We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3-3H]glucose began at -120 min. Basal sampling (-30 to 0 min) was followed by two study periods (150 min each), clamp period 1 (P1) and clamp period 2 (P2). At 0 min, somatostatin and GRI (36 ± 3 pmol/kg/min) or HI (1.8 pmol/kg/min) were infused intravenously; basal glucagon was replaced intraportally. Glucose was infused intravenously to clamp plasma glucose at 80 mg/dL (P1) and 240 mg/dL (P2). Whole-body insulin clearance and insulin concentrations were not different in P1 versus P2 with HI, but whole-body insulin clearance was 23% higher and arterial insulin 16% lower in P1 versus P2 with GRI. Net hepatic glucose output was similar between treatments in P1. In P2, both treatments induced net hepatic glucose uptake (HGU) (HI mean ± SEM 2.1 ± 0.5 vs. 3.3 ± 0.4 GRI mg/kg/min). Nonhepatic glucose uptake in P1 and P2, respectively, differed between treatments (2.6 ± 0.3 and 7.4 ± 0.6 mg/kg/min with HI vs. 2.0 ± 0.2 and 8.1 ± 0.8 mg/kg/min with GRI). Thus, glycemia affected GRI but not HI clearance, with resultant differential effects on HGU and nonHGU. GRI holds promise for decreasing hypoglycemia risk while enhancing glucose uptake under hyperglycemic conditions.

Cucurbitane Triterpenoids from the Fruits of Momordica Charantia Improve Insulin Sensitivity and Glucose Homeostasis in Streptozotocin-Induced Diabetic Mice.

SCOPE: Momordica charantia (M. charantia) has antidiabetic effects, and cucurbitane-type triterpenoid is one of the compounds of M. charantia. This study aims to investigate whether the new cucurbitane-type triterpenoids affect insulin sensitivity both in vitro and in vivo, and the underlying mechanisms. METHODS AND RESULTS: Four compounds (C1-C4) isolated from the ethanol extract of M. charantia enhance glucose uptake in C2C12 myotubes via insulin receptor substrate-1 (IRS-1) rather than via adenosine monophosphate-activated protein kinase. The most potent, compound 2 (C2), significantly increases the activation of IRS-1 and downstream signaling pathways, resulting in glucose transporter 4 translocation. Furthermore, these C2-induced in vitro effects are blocked by specific signal inhibitors. We further evaluate the antidiabetic effect of C2 using a streptozotocin (STZ)-induced diabetic mouse model. Consistent with in vitro data, treatment with C2 (1.68 mg kg-1 ) significantly decreases blood glucose level and enhances glycogen storage in STZ-injected mice. These effects appear to be mediated by the IRS-1 signaling pathway in skeletal muscle, not in adipose and liver tissues, suggesting that C2 improves hyperglycemia by increasing glucose uptake into skeletal muscle. CONCLUSION: Our findings demonstrate that the new cucurbitane-type triterpenoids have potential for prevention and management of diabetes by improving insulin sensitivity and glucose homeostasis.

Behaviour of aluminium in forest soils with different lithology and herb vegetation cover.

The aim of this study was to determine the content, distribution and behaviour of Al in soils under beech forest with different parent rock, and to assess the role of herbaceous vegetation on soil Al behaviour. We hypothesize that the contents of elements in the soil sorption complex (Al etc.) are strongly influenced by vegetation cover. Also, low molecular mass organic acids (LMMOA) can be considered as an indicator of soil organic matter (SOM) decomposition and vegetation litter turnover. Speciation of LMMOA, nutrition content (PO43-, Ca2+, K+) and element composition in aqueous extracts were determined by means of ion chromatography and inductively coupled plasma - optical emission spectrometry (ICP-OES) respectively. Active and exchangeable pH, sorption characteristics and exchangeable Al (Alex) were determined in BaCl2 extracts by ICP-OES. Elemental composition of parent rocks was assessed by means of X-ray fluorescence spectroscopy. Herb-poor localities showed lower pH, less nutrients (PO43-, Ca2+, K+), less LMMOA, a larger stock of SOM and greater cation exchange capacity. There was also lower mobilisation of Al in organic horizons, which explains the larger pools of Al. Generally, we can conclude that LMMOA, and thus soil vegetation cover, play an important role in the Al soil cycle.

Conjugated linoleic acid does not affect digestion and absorption of fat and starch-a randomized, double-blinded, placebo-controlled parallel study.

OBJECTIVE: Conjugated linoleic acid (CLA) is known as a potent agent for altering body weight and composition. However, its effect on the process of digestion is still unknown. The aim of this study has been to elucidate the effect of a 3-month supplementation with CLA on starch and fat digestion and absorption in humans. APPROACH: The study included 74 obese and overweight adults who were randomized to receive 3.0 g of CLA or sunflower oil as placebo daily for 3 months. Digestion and absorption of fat and starch was assessed using non-invasive breath tests with a stable 13C isotope (cumulative percentage dose recovery, CPDR) before and after the supplementation period. To exclude the effect of oxidation, in addition total energy expenditure (TTE) was measured by a 13C bicarbonate breath test. RESULTS: The changes in CPDR values (∆CPDR median 〈interquartile range〉) were no different between subjects from the CLA group and the placebo group (fat: -0.2 〈-9.1-4.1〉 versus 0.6 〈-7.0-8.0〉, p < 0.4796; starch: -1.3 〈-9.5-2.4〉 versus -1.0 〈-5.1-1.7〉, p < 0.5520, respectively). The incidence of negative and positive values of ∆CPDR was no different between groups [for fat: 53.1% versus 46.7%, RR 1.138, (95% CI 0.689-1.882) and for starch: 67.7% versus 56.7%, RR 1.195, (95% CI 0.804-1.777)]. The changes in TTE did not differ between the CLA and the placebo group (respectively 1 〈48; 267〉 versus -8 〈-120;93〉 kcal; p < 0.2728). CONCLUSION: Supplementation with CLA for 3 months did not affect fat and starch digestion assessed by 13C mixed triglyceride breath test and 13C starch breath test.

Seropharmacological study on osteogenic effects of post-absorption ingredients of an osteoprotective herbal formula.

OBJECTIVE: To further investigate the {ptin vitro} effects of an osteoprotective herbal formula "ELP" (Herba Epimedii, Fructus Ligustri Lucidi and Fructus Psoraleae) using seropharmacological approach. METHODS: Rats were fed with ELP or its individual component herbs for 2 days. The serum containing the postabsorbed ingredients of the herbal items were collected for cell culture using UMR106 cell, RAW264.7 cell and mesenchymal stem cell (MSC) isolated from the bone marrow of the rats. The effects of the herbal-containing serum on cell toxicity were detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay; bromodeoxyuridine assay was conducted to measure the cell proliferation of UMR106 cell and MSC; cell activity was measured using colorimetric method, and mRNA expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteopontin (OPN) of UMR106 and MSC as well as matrix metalloproteinase 9 (MMP-9), tartrate-resistant acid phosphatase (TRAP) and cathepsin K of RAW264.7 were analyzed using real-time reverse-transcription polymerase chain reaction. RESULTS: ELP and its component serum exhibited no cytotoxic effects on the cells. The ELP-containing serum increased the proliferation of UMR106 cell and MSC by 25.7% and 14.4 %, respectively and the alkaline phosphatase activity of MSC was increased by 42.6%. On the contrary, it inhibited the RAW264.7 cell differentiation by 29.2 %. ELP serum upregulated the Runx2 expression of UMR and MSC by 1.18 fold and 1.27 fold, respectively. It also upregulated ALP and OPN expression in MSC by 1.69- and 2.12-fold, respectively. On the other hand, ELP serum down-regulated MMP-9 and cathepsin K expression of RAW264.7 cell by 0.46- and 0.36-fold, respectively. CONCLUSIONS: The serum of the animals fed with ELP contains active ingredients which are effective in promoting osteogenesis and inhibiting osteoclastogenesis.

Combination treatment with Rhizoma Paridis and Rhizoma Curcuma longa extracts and 10-hydroxycamptothecin enhances the antitumor effect in H22 tumor model by increasing the plasma concentration.

The combination of Western medicine and Chinese prescription is the most effective tumor therapy in China market. In our previous report, a new prescription composed by Rhizoma Paridis and Rhizoma Curcuma longa called LouHuang preparation (LH) shows good antitumor activity. 10-Hydroxycamptothecin (HCPT) as a chemotherapy agent is used for treatment of solid tumors in clinical. In this study, we investigated the combination effect of LH and HCPT on H22 tumor cells in vitro and in vivo. In vitro test, combination of LH and HCPT presented a synergistic effect on H22 cancer cells. Because of the toxicity of HCPT in normal dosage with intraperitoneal injection, we chose a low dose in the study. LH increased the tumor inhibition rate of HCPT in H22 tumor model from 39% to 55% and showed additive effect by the q value method. The concentration of HCPT in plasma was detected by HPLC-FLD method and increased from 60 to 75ng/mL when combined with LH. For the absorption research, LH significantly enhanced the absorption transport of HCPT from 7019.04 to 11569.02ng/cm2, while improved the permeation flux (F) and apparent permeability (Papp) of HCPT from 10.62 to 21.47 (ng/cm2min) and 9.92-20.07 (10-6cm/s), respectively. The study indicates that LH could boost the efficacy of HCPT by increasing the plasma concentration regardless of the formulation and combined administration of HCPT and LH might be used as an adjuvant drug for treatment of liver cancer.

Iron absorption after introducing and discontinuation of iron and zinc supplementation in rats.

The aim of this study was to investigate the changes in iron apparent absorption (IAA%) during and after iron and zinc supplementation in rats. The study was conducted on 6-week old male Wistar rats in 3 stages: 4-week period of adaptation to the control (C) and iron deficient (D) diets (stage I); 4-week period of supplementation with 10-time more iron (CSFe, DSFe), zinc (CSZn, DSZn) or both iron and zinc (CSFeZn, DSFeZn) compared to C diet (stage II); 2-week of post-supplementation period (rats were fed the same diets as in the adaptation period, stage III). IAA% was measured in five consecutive days directly after introducing and discontinuation of iron and zinc supplementation as well as in the end of stage II (days: 22-24th) and stage III (days: 8-10th). Overall in the second day after introducing and in the fifth day after discontinuation of iron or iron and zinc supplementation, the IAA% had undergone to the level compatible with the values in the end of each stage. At the end of stage II, IAA% in CSFeZn (54.1 ± 2.7%) rats was not different from the IAA% in CSFe rats (53.9 ± 1.9%), but in DSFeZn group IAA% (49.4 ± 2.1%) was significantly lower than in DSFe (57.4 ± 2.3%) group. Moreover, IAA% after stage II and stage III in DSZn group was significantly lower (39.2 ± 2.8% and 38.6 ± 2.6%, respectively) than in group D (60.7 ± 1.9% and 54.3 ± 3.0%, respectively). In conclusion, zinc administered simultaneously with iron (Zn:Fe weight ratio=1:1) decreased IAA% in adult rats fed on iron deficient diet, but not in rats fed on control diet. IAA% reduction by zinc supplementation has been extended to 10 days after discontinuation of the treatment. Adaptation of the rats to high doses of iron or iron and zinc and also to the cessation of these treatments was relatively fast. However, IAA% was stabilized faster after introducing the supplementation than it's discontinuation.

Acute Copper and Ascorbic Acid Supplementation Inhibits Non-heme Iron Absorption in Humans.

The objective of the study is to determine the effect of copper (Cu) plus the reducing agent ascorbic acid (AA) on the absorption of non-heme iron (Fe). Experimental study with block design in which each subject was his own control. After signing an informed consent, 14 adult women using an effective method of contraception and negative pregnancy test received 0.5 mg Fe, as ferrous sulfate, alone or with Cu, as copper sulfate, plus ascorbic acid (AA/Cu 2/1 molar ratio) at 4/1; 6/1 and 8/1 Cu/Fe molar ratios as an aqueous solution on days 1, 2, 14, and 15 of the study. Fe absorption was assessed by erythrocyte incorporation of iron radioisotopes (55)Fe and (59)Fe. Geometric mean (range ± SD) absorption of Fe at 4/1 and 6/1 Cu/Fe molar ratios (and AA/Cu 2/1 molar ratio) and Fe alone was 57.4 % (35.7-92.1 %), 64.2 % (45.8-89.9 %), and 38.8 % (20.4-73.8 %), respectively (ANOVA for repeated measures p < 0.001; post hoc test Scheffé, p < 0.05). This is attributable to the enhancing effect of AA on non-heme Fe absorption; however, Fe absorption at Cu/Fe 8/1 molar ratio was 47.3 % (27.7-80.8) (p = NS compared with Fe alone). It was expected that Fe absorption would have been equal or greater than at 4/1 and 6/1 molar ratios. Copper in the presence of ascorbic acid inhibits non-heme Fe absorption at Cu/Fe 8/1 molar ratio.

Quantification of Drug-Induced Inhibition of Canalicular Cholyl-l-Lysyl-Fluorescein Excretion From Hepatocytes by High Content Cell Imaging.

We describe the use of a commercially available high content cell imaging algorithm (Cellomics Arrayscan Spot Detector) to quantify biliary excretion of the fluorescent probe substrate cholyl-l-lysyl-fluorescein (CLF) from rat hepatocytes cultured in collagen/matrigel sandwich configuration and to explore inhibition of this process by a variety of test compounds. The method provided robust, reproducible data. Twenty-nine pharmaceuticals inhibited biliary CLF efflux from hepatocytes and a broad range of potencies of inhibition were observed (IC50 values ranged between <1 and 794 µM). Thirteen drugs that inhibited CLF efflux also inhibited hepatocellular uptake of the probe substrate [(3)H]-taurocholate. Although no clear correlation between the potencies of inhibition of the 2 processes was evident, these data highlight the need to consider possible uptake transporter inhibition when interpreting hepatocyte CLF inhibition data. It has been reported that CLF is transported by MRP2. The CLF efflux inhibition data correlated closely with published data on inhibition by the drugs of the bile salt export pump (Bsep), which suggests that the tested drugs inhibit both Bsep and Mrp2. Calculation of the ratios between the maximum human plasma concentrations of the drugs and their CLF efflux inhibition IC50 values raised the possibility that for many, but not all, of them the in vitro effects may be functionally significant in vivo and that Mrp2 inhibition might be a drug-induced liver injury (DILI) risk factor. These data indicate that imaging hepatocyte CLF inhibition is a promising new method for quantification of biliary efflux inhibition by drugs, which could aid assessment of compound-related DILI risk.

Protocatechuic acid activates key components of insulin signaling pathway mimicking insulin activity.

SCOPE: Insulin resistance represents an independent risk factor for metabolic and cardiovascular diseases. Researchers have been interested in identifying active harmless compounds, as many insulin-sensitizing drugs have shown unwanted side-effects. It has been demonstrated that anthocyanins and one of their representative metabolites, protocatechuic acid (PCA), ameliorate hyperglycemia, and insulin sensitivity. This study investigated the mechanism of action of PCA responsible for the glucose uptake upregulation. METHODS AND RESULTS: In human visceral adipocytes, PCA stimulated insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (+40% with respect to untreated cells) and the downstream events, i.e. phosphoinositide 3-kinase binding to IRS-1 and Akt phosphorylation (+100%, +180%, respectively, with respect to untreated cells). The insulin-like activity of PCA seemed to be mediated by insulin receptor since by inhibiting its autophosphorylation, the PCA effects were completely abolished. Furthermore, PCA was able to activate adenosine monophosphate-activated protein kinase, a serine/threonine kinase whose activation elicits insulin-sensitizing effects. CONCLUSION: This study showed that PCA stimulates the insulin signaling pathway in human adipocytes increasing GLUT4 translocation and glucose uptake. Decreasing insulin resistance is a most desirable aim to be reached for an effective therapeutic/preventive action against metabolic syndrome and type 2 diabetes. Identifying specific food/food components able to improve glucose metabolism can offer an attractive, novel, and economical strategy.

Application of the extended clearance concept classification system (ECCCS) to predict the victim drug-drug interaction potential of statins.

BACKGROUND: During drug development, it is an important safety factor to identify the potential of new molecular entities to become a victim of drug-drug interactions (DDIs). In preclinical development, however, anticipation of clinical DDIs remains challenging due to the lack of in vivo human pharmacokinetic data. METHODS: We applied a recently developed in vitro-in vivo extrapolation method, including hepatic metabolism and transport processes, herein referred to as the Extended Clearance Concept Classification System (ECCCS). The human hepatic clearances and the victim DDI potentials were predicted for atorvastatin, cerivastatin, fluvastatin, lovastatin acid, pitavastatin, pravastatin, rosuvastatin, and simvastatin acid. RESULTS: Hepatic statin clearances were well-predicted by the ECCCS with six out of eight clearances projected within a two-fold deviation to reported values. In addition, worst-case DDI predictions were projected for each statin. Based on the ECCCS class assignment (4 classes), the mechanistic interplay of metabolic and transport processes, resulting in different DDI risks, was well-reflected by our model. Furthermore, predictions of clinically observed statins DDIs in combination with relevant perpetrator drugs showed good quantitative correlations with clinical observations. CONCLUSIONS: The ECCCS represents a powerful tool to anticipate the DDI potential of victim drugs based on in vitro drug metabolism and transport data.

Nano-carrier systems: Strategies to overcome the mucus gel barrier.

The present review provides an overview of nanotechnology-based strategies to overcome various mucus gel barriers including the intestinal, nasal, ocular, vaginal, buccal and pulmonary mucus layer without destroying them. It focuses on the one hand on strategies to improve the mucus permeation behavior of particles and on the other hand on systems avoiding the back-diffusion of particles out of the mucus gel layer. Nanocarriers with improved mucus permeation behavior either exhibit a high density of positive and negative charges, bearing mucolytic enzymes such as papain and bromelain on their surface or display a slippery surface due to PEG-ylation. Furthermore, self-nanoemulsifying-drug-delivery-systems (SNEDDS) turned out to exhibit comparatively high mucus permeating properties. Strategies in order to avoid back-diffusion are based on thiolated polymers reacting to a higher extent with cysteine subunits of the mucus at pH 7 in deeper mucus regions than at pH 5 being prevalent in luminal mucus regions of the intestinal and vaginal mucosa. Furthermore, particles changing their zeta potential from negative to positive once they have reached the epithelium seem to be promising carriers. The summarized knowledge should provide a good starting point for further developments in this field.

Prevention of osteoporosis by oral administration of phytate-removed and deamidated soybean ß-conglycinin.

Phytate-removed and deamidated soybean ß-conglycinin (PrDS) prepared by ion-exchange resins was supplemented to be 4% in the diet administered to ovariectomized rats to investigate its preventive effect on osteoporosis. The apparent calcium absorption rate decreased following ovariectomy and was not replenished by oral administration of phytate-removed soybean ß-conglycinin (PrS) or casein. On the other hand, administration of PrDS restored the calcium absorption rate to the same level as the sham group. Markers of bone resorption, such as serum parathyroid hormone (PTH) and urinary deoxypyridinoline (DPD), increased, and the bone mineral density and breaking stress decreased following ovariectomy. However, PrDS supplementation suppressed the changes caused by the decrease in calcium absorption from the small intestine. Therefore, PrDS supplementation shows promise for the prevention of postmenopausal osteoporosis.

Orally supplemented L-arginine impairs amino acid absorption depending on dose in horses.

The beneficial effect of L-arginine (L-Arg) supplementation, on the physiology of several species, has generated an interest in the use of L-Arg as a nutraceutical in horses, but dosage and absorption of orally supplemented L-Arg must be inferred from other species. The study objective was to determine the effect of 2 oral L-Arg doses on plasma arginine concentrations and the effect on absorption of other amino acids in mares. In Experiment 1, mares were blocked by age and breed and were fed L-Arg supplemented (supplemented with 0.025% BW L-Arg; n=6) or control (no supplement; n=6) concentrate on a single day with blood samples taken at 0, 0.5, 1, 2, 3, 4, and 5 h relative to feeding. In Experiment 2, mares (n=6) were used in a 3×3 Latin square design with L-Arg (0.0125% of BW), urea (0.0087% of BW), and control (no supplement) fed mixed into a grain concentrate as single meal with blood samples taken at 0, 1,2, 4, 6, 8,10, and 12 h relative to feeding. In Experiment 1, L-Arg supplementation increased (P<0.05) plasma L-Arg and ornthine concentrations and decreased (P<0.05) lysine and methionine concentrations compared with the control group. At 1 h post feeding, L-Arg mares had lower (P<0.05) plasma concentrations of histidine, glutamic acid, proline, isoleucine, threonine, phenylalanine, leucine, valine, alanine, and taurine. In Experiment 2, L-Arg supplementation increased (P<0.05) arginine and ornithine concentrations compared with urea and control; there was no difference among other amino acids. These experiments indicate that L-Argis absorbed and, dependent on the dose, alters the absorption of other amino acids in mares.

Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations.

INTRODUCTION: Malaria is a major health concern and affects over 300million people a year. Accordingly, there is an urgent need for new efficacious anti-malarial drugs. A major challenge in developing new anti-malarial drugs is to design active molecules that have preferable drug-like characteristics. These "drug-like" characteristics include physiochemical properties that affect drug absorption, distribution, metabolism, and excretion (ADME). Compounds with poor ADME profiles will likely fail in vivo due to poor pharmacokinetics and/or other drug delivery related issues. There have been numerous assays developed in order to pre-screen compounds that would likely fail in further development due to poor absorption properties including PAMPA, Caco-2, and MDCK permeability assays. METHODS: The use of cell-based permeability assays such as Caco-2 and MDCK serve as surrogate indicators of drug absorption and transport, with the two approaches often used interchangeably. We sought to evaluate both approaches in support of anti-malarial drug development. Accordingly, a comparison of both assays was conducted utilizing apparent permeability coefficient (Papp) values determined from liquid chromatography/tandem mass spectrometry (LC-MS) analyses. RESULTS: Both Caco-2 and MDCK permeability assays produced similar Papp results for potential anti-malarial compounds with low and medium permeability. Differences were observed for compounds with high permeability and compounds that were P-gp substrates. Additionally, the utility of MDCK-MDR1 permeability measurements was demonstrated in probing the role of P-glycoprotein transport in Primaquine-Chloroquine drug-drug interactions in comparison with in vivo pharmacokinetic changes. DISCUSSION: This study provides an in-depth comparison of the Caco-2 and MDCK-MDR1 cell based permeability assays and illustrates the utility of cell-based permeability assays in anti-malarial drug screening/development in regard to understanding transporter mediated changes in drug absorption/distribution.

Small increases in dietary calcium above normal requirements exacerbate magnesium deficiency in rats fed a low magnesium diet.

In North America, the calcium (Ca):magnesium (Mg) intake ratio has increased over the last several decades raising concerns about possible adverse effects of Ca intakes on Mg status. The primary objective of this study was to investigate whether small decreases or increases in dietary Ca from normal requirements worsen Mg status in rats fed a low Mg diet. Weanling male Sprague-Dawley rats were fed 1 of 8 diets for 6 weeks. The 7 test diets were supplemented with low Mg (0.18 g/kg diet) and either 1 (1Ca), 3 (3Ca), 5 (5Ca), 7.5 (7.5Ca), 10 (10Ca), 15 (15Ca) or 20 (20Ca) g Ca/kg diet. The control diet was supplemented with normal Mg (0.5 g/kg) and Ca (5 g/kg). Rats fed higher Ca gained less weight and had lower fat mass and energy efficiency. Compared to rats fed normal Ca (5Ca), Mg concentrations in serum and femur were lower in rats fed the higher Ca diets. Haemoglobin and haematocrit were also lower in rats fed the 15Ca and 20Ca diets. Rats fed the 10Ca, 15Ca and 20Ca diets had higher urine Ca compared to rats fed the 5Ca diet. Increase in urine Ca was associated with a rise in urine Mg. The higher Ca diets increased the Ca:Mg molar ratio in serum, femur, heart and kidney. These results suggest that small increases in dietary Ca exacerbate Mg deficiency in rats fed an inadequate Mg diet by reducing intestinal Mg absorption and also by impairing renal Mg reabsorption at higher Ca intakes.