Poor Intestinal Absorption Research Articles

Methodology to nanoencapsulate hepatoprotective components from Picrorhiza kurroa as food supplement

Abstract Picrorhiza kurroa root and rhizome powder of extract is well-recognized neutraceutical for healthy liver functioning. The major hepatoprotective components (picrosides I and II) of P. kurroa extract shows poor intestinal absorption and poor bioavailability due to sparingly aqueous solubility. To improve bioavailability of these biomolecules, a nanoformulation of this extract has been developed with pluronic-F-68 copolymer based biodegradable PLA nanoparticles by nanoprecipitation method. This method showed high encapsulation efficiency as 60.1±2.8% (for picroside I) and 67.2±7.4% (for picroside II). The hydrodynamic (by zeta size) and actual size (by TEM) revealed homogenously rounded nanoparticles of size 174±34 nm and 154±12 nm respectively. This formulation showed an initial burst and half release up to 27±3 h, followed by a sustained release (up to 210±10 h). Nanoformulation of this traditional herbal extract provides neutraceutical with value addition property for better hepato-protection by enhancing intestinal absorption and bioavailability.

Soluble prodrugs for efficient instestinal delivery of resveratrol

Colitis is a widespread pathology; chronic inflammation is often involved in the process of tumorigenesis leading to colon cancer. Natural compounds such as flavonoids and stilbenes have been shown to have interesting anti-inflammatory and chemopreventive properties; their therapeutic potential is great, but low bioavailability and rapid metabolism hinder their full pharmacological exploitation. We are working on the development of prodrugs of natural polyphenols, with the aim of potentiating their effectiveness in specific pathophysiological contexts. The goal is to increase the levels of the intact natural compound at the site of action, improving its absorption and/or decreasing its metabolism, thanks to temporary protection of the phenolic hydroxyls in the molecule. We present here a series of resveratrol prodrugs functionalized with galactosyl moieties through N-monosubstituted carbamate linkages. These compounds turned out to be very soluble in water compared to resveratrol itself, greatly improving handling of the compound. Highly-soluble derivatives were not able to reach the systemic circulation after oral administration; however, poor intestinal absorption may be expected to allow their presence at high levels in the lumen of the lower intestinal tract, making them useful for the treatment of intestinal diseases. After chronic administration, a striking difference was observed in the intestinal fate of resveratrol compared to its tri-substituted galactosyl derivative: in colon and caecum the former was present mainly as its bacterial metabolite dihydroresveratrol, while the latter was mainly present as partially hydrolyzed derivatives. This points to protracted release of intact resveratrol, which is then inevitably reduced to dihydroresveratrol by bacterial enzymes. These findings suggest a possible use of glycosyl-resveratrol derivatives for the treatment of colitis and prevention of colon cancer.

Polymeric Nanoparticle Technologies for Oral Drug Delivery

Biologics increasingly are being used for the treatment of many diseases. These treatments typically require repeated doses administered by injection. Alternate routes of administration, particularly oral, are considered favorable because of improved convenience and compliance by patients, but physiological barriers such as extreme pH level, enzyme degradation, and poor intestinal epithelium permeability limit absorption. Encapsulating biologics in drug delivery systems such as polymeric nanoparticles prevents inactivation and degradation caused by low pH and enzymes of the gastrointestinal tract. However, transport across the intestinal epithelium remains the most critical barrier to overcome for efficient oral delivery. This review focuses on recent advances in polymeric nanoparticles being developed to overcome transport barriers and their potential for translation into clinical use.

A single ascending dose, initial clinical pharmacokinetic and safety study of ursolic acid in healthy adult volunteers (1044.6)

Objective: To assess the safety and pK parameters after administration of a single ascending oral dose of ursolic acid.Methods: 14 subjects were administered a single oral ascending dose of ursolic acid 100mg, 500mg and 1000mg. pK assessements were conducted at pre‐dose, 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, 24 hr and 48 hr.Safety assessments were also conducted.Results: Statistical analysis was conducted for 11 subjects who had completed the trial with no serious adverse events reported. For the 100mg dose: 4 subjects‐ ursolic content was noted at 5 timepoints at 0.5hr‐8hr with 4 timepoints‐ levels were lower than LLOQ (lower limit of quantification‐10.5ng/ml) and in 7 subjects, ursolic acid content was not observed. For the 500mg dose: ursolic acid content was observed in 6 subjects at 12 timepoints at 1‐12hr with 10 timepoints‐the levels were lower than LLOQ and in 5 subjects, ursolic acid content was not observed. For the 1000mg dose: ursolic acid content was observed in 9 subjects at 21 timepoints at 1‐12 hr with 12 timepoints‐the levels were lower than LLOQ and in 2 subjects, ursolic acid content was not observed.Conclusion: These results revealed low and variable bioavailability for oral ursolic acid in human subjects. Possible reasons could include: Poor water solubility with decreased absorption and rapid elimination, metabolism by the gut wall and liver with poor intestinal absorption. Metabolism of ursolic acid by the human gut microbiome may yield variability in the peak plasma levels. Human peak level results differ remarkably from the peak levels observed in the preclinical animal research.

Biopharmaceutics classification of puerarin and comparison of perfusion approaches in rats

The present study was conducted to characterize the biopharmaceutics classification system (BCS) category of puerarin in terms of intrinsic dissolution rate (IDR) and rat intestinal permeability and to investigate the poor intestinal absorption probably related to the drug metabolism in the gut wall of rats. Equilibrium solubility of puerarin was determined in various phosphate buffers and water, and IDR was estimated by measuring the dissolution of a non-disintegrating compact. Intestinal permeability (Peff and Pblood) of puerarin was determined using the technology of in situ single-pass intestinal perfusion (SPIP) and intestinal perfusion with venous sampling (IPVS) in fasted rats. Metabolism of puerarin in intestinal tissue was tested by S9 incubation in vitro. The aqueous solubility of puerarin in phosphate buffers and water was good with a maximum solubility of 7.56 mg/mL at pH 7.4. Obtained IDR values of puerarin were in the range of 0.360-1.088 mg/min/cm(2), with maximum and minimum IDR value of pH 7.4 and pH 4.0, respectively. The Peff was 1.252 × 10(-5)cm/s determined by SPIP and the Pblood was 0.068×10(-5)cm/s by IPVS in jejunum at puerarin 80 μg/mL. The metabolism rate of puerarin determined by the intestinal S9 fraction indicated that the gut wall metabolism of puerarin is one cause of poor absorption. According to the proposed classification of drugs and the results obtained from equilibrium solubility, IDR, Peff and Pblood, it is concluded that puerarin could be categorized IV drug of the BCS based on its low solubility and low intestinal permeability values.

Biological Activities and Possible Dental Application of Three Major Groups of Polyphenols

The present article reviewed the biological activities and possible dental application of three major polyphenols, i.e., lignin-carbohydrate complexes, tannins, and flavonoids, citing mostly our in vitro studies together with those from other groups. All these polyphenols showed much lower tumor-selective cytotoxicity against oral squamous cell carcinoma cells vs. normal oral cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast), in comparison to popular chemotherapeutic antitumor drugs. Several compounds showing higher tumor-selectivity did not induce internucleosomal DNA fragmentation, a biochemical hallmark of apoptosis, in oral carcinoma cell lines. Lignin-carbohydrate complex protected the cells from the cytopathic effects of HIV infection and UV irradiation more efficiently than other polyphenols. Limited digestion of lignin-carbohydrate complex suggests that the lignin moiety is involved in the prominent anti-HIV activity, whereas the carbohydrate moiety may function in immunopotentiating activity through a cell surface receptor. Alkaline extract of plant leaf, which contains higher amounts of lignin-carbohydrate complex, showed potent anti-inflammatory action against IL-1β-stimulated human gingival fibroblasts. Local application of lignin-carbohydrate complex through oral mucosa is recommended, considering its poor intestinal absorption.

Pharmacokinetics of streptomycin sulfate in Staphylococcus aureus-infected Clarias gariepinus (Burchell 1822)

Most bacteria causing fish diseases in Nigeria have been observed to be susceptible to aminoglycosides like streptomycin. However, route of administration for effective therapy has been a challenge due to the reported poor intestinal absorption, hence a need to study its kinetics.Clarias gariepinus were divided into four groups of 14 fish each. Fish in A were Staphylococcus aureus-infected while those in B were uninfected and both received streptomycin by bath at 70mg/l, while it was 70mg/kg via gastric gavage for groups C which were Staphylococcus aureus-infected and D which were uninfected. Blood and tissue collection was done between 1 and 120h post exposure to streptomycin. Samples were analyzed by ELISA, while some portions of tissues of infected fish were fixed for histopathology.Sum of area under curve values for serum and kidney (AUC0–8h) were 5876.5μgh/l and 399,287μgh/kg; 4519.3μgh/l and 183,474μgh/kg; 27,771.2μgh/l and 82,539μgh/kg; as well as 18,768.4μgh/l and 33,252.5μgh/kg respectively for groups A, B, C and D. Microscopically the lesions were localized and extensive hepatic coagulative necrosis with diffuse tubular necrosis.Possible systemic therapeutic value is suggested, depending on increased distribution of streptomycin and levels of streptomycin in kidneys of diseased fish at corresponding times being higher than in sera.

Drug-Delivery Systems of Green Tea Catechins for Improved Stability and Bioavailability

Numerous studies in humans, animal models and cell lines have suggested the potential benefits from the consumption of green tea polyphenols, including prevention of cancer and heart diseases. However these potential effects have been strongly limited by green tea catechins low bioavailability, which hinders the development of therapeutic applications. In this review formulations that are being proposed for delivery of green tea catechins are discussed. New delivery systems are presented as valid alternatives to overcome the limitations such as green tea catechins poor stability or intestinal absorption.

P-glycoprotein is responsible for the poor intestinal absorption and low toxicity of oral aconitine: In vitro, in situ, in vivo and in silico studies

Aconitine (AC) is a highly toxic alkaloid from bioactive plants of the genus Aconitum, some of which have been widely used as medicinal herbs for thousands of years. In this study, we systematically evaluated the potential role of P-glycoprotein (P-gp) in the mechanisms underlying the low and variable bioavailability of oral AC. First, the bidirectional transport of AC across Caco-2 and MDCKII-MDR1 cells was investigated. The efflux of AC across monolayers of these two cell lines was greater than its influx. Additionally, the P-gp inhibitors, verapamil and cyclosporin A, significantly decreased the efflux of AC. An in situ intestinal perfusion study in rats showed that verapamil co-perfusion caused a significant increase in the intestinal permeability of AC, from 0.22×10−5 to 2.85×10−5cm/s. Then, the pharmacokinetic profile of orally administered AC with or without pre-treatment with verapamil was determined in rats. With pre-treatment of verapamil, the maximum plasma concentration (Cmax) of AC increased sharply, from 39.43 to 1490.7ng/ml. Accordingly, a 6.7-fold increase in the area under the plasma concentration–time curve (AUC0–12h) of AC was observed when co-administered with verapamil. In silico docking analyses suggested that AC and verapamil possess similar P-gp recognition mechanisms. This work demonstrated that P-gp is involved in limiting the intestinal absorption of AC and attenuating its toxicity to humans. Our data indicate that potential P-gp-mediated drug–drug interactions should be considered carefully in the clinical application of aconite and formulations containing AC.

Evaluation of treatment efficacy of doxycycline and albendazole against scuticociliatosis in olive flounder (Paralichthys olivaceus)

Scuticociliatosis is a leading cause of mass mortality in cultured olive flounder (Paralichthys olivaceus) in Korea. However, still no effective treatment measures have been developed. In the present study, we selected two drugs, doxycycline and albendazole, that were demonstrated to have high in vitro scuticocidal activity and possess ability to cross blood–brain barrier (BBB), and evaluated their treatment efficacy against scuticociliatosis caused by Miamiensis avidus in olive flounder. In both oral and bath treatment experiments, groups of fish fed a diet containing doxycycline or bathed with freshwater containing doxycycline showed clearly higher survival rates than control groups. Although the groups of fish fed a diet containing albendazole or bathed with freshwater containing albendazole showed higher survival rates than the control group, the rates were greatly lower than those of the groups treated with doxycycline. Poor intestinal absorption, low solubility in water, and low lipophilicity of albendazole were considered as the possible cause of the low efficacy. In conclusion, the present results suggest that doxycycline can be used to treat systemic scuticociliatosis in olive flounder through oral administration and bath.

A Description on Study of Intestinal Barrier, Drug Permeability and Permeation Enhancers

is considered to be small, since this pathway occupies less than 0.1% of the total surface area of the intestinal epithelium, and the presence of tight junctions (TJ) between the epithelial cells limits drug absorption. These drugs have low intrinsic membrane permeability, probably because of their low lipophilicity and zwit- terion character at physiological pH or act as a substrate to drug efflux pumps like p-glycoprotein, ionic charge and high molecular weight. WHO listed out the BCS class III drugs, they are shown in below Table-1 Abstract Penetration enhancers are present in a large number of transdermal, dermatological, and cosmetic products to aid dermal absorption of curatives and aesthetics. Delivery of hydrophilic drug by per oral route has always fascinated the researchers. Hydrophilic drugs show low bioavailability through oral administration because of their poor intestinal permeation & absorption. In the last few years there has been great interest focused on search of different intestinal permeation enhancers for the oral delivery of BCS class III drugs, small polar molecules, vaccines, hormones, peptides and proteins, which are well suitable for the delivery of the above products to give enhanced bio- availability by increasing intestinal permeability. This review targets to discuss functioning, anatomy and physiology of the intestinal barrier, drug absorption from intestinal tract, mechanism of intestinal drug permeability, detail information about intestinal permeation enhancers and its mechanism of action, invitro methods for studying drug permeability, and importantly the advantages and applications of newer permeation enhancers

Curcumin and analog 2a inhibit â‐catenin pathway and ADPKD cyst growth

Inhibition of signaling pathways is actively pursued for ADPKD treatment. Since cyst growth involves many proliferative pathways, multiple‐pathway inhibition could be advantageous. Curcumin inhibits cell‐proliferation pathways activated both in cancer and in ADPKD cyst cells, yet no therapeutic levels are achieved by oral (PO) administration due to poor intestinal absorption and liver inactivation. We studied (a) the effects of Curcumin and Analog 2a (which lacks glucuronidation sites, hence increasing absorption) on proliferation and cyst formation by ADPKD cyst cells in primary cultures and in a telomerase immortalized cell line and on active β‐catenin levels in both primary and cell line cultures; (b) the effects of PO administration of curcumin on cyst development in nude‐mouse implants; (c) the blood and kidney levels of both drugs after PO administration to mice. We found that: 1. Curcumin and Analog 2a were more cytotoxic to cyst cells than to normal kidney cells. 2. Curcumin and Analog 2a inhibited active β‐catenin in cyst cells. 3. Curcumin, undetectable in mouse blood after PO administration, decreased cyst volume in the implants, but not cyst number. 4. Analog 2a was detectable in mouse blood and concentrated in the kidney after PO administration. We conclude that Analog 2a increased effectiveness, decreased toxicity to normal cells and improved bioavailability support the use of new curcumin analogs for ADPKD treatment.

Iron replacement options: oral and intravenous formulations

SUMMARYLack of iron is one of the main causes of anemia in the general population and iron deficiency anemia (IDA) is associated with increased morbidity and mortality. Treatment of iron deficiency with oral iron supplements is a simple and inexpensive, but oral iron is a less‐than‐ideal treatment because of gastrointestinal side‐effects and long treatment times needed to resolve anemia and replenish body iron stores. Nonadherence is common, and even in compliant patients poor intestinal absorption fails to compensate for the iron need in the presence of ongoing blood losses or inflammatory conditions. Modern intravenous (IV) iron formulations have emerged as safe and effective alternatives to oral iron for the treatment of IDA. Given their demonstrated effectiveness and favorable safety profile in a broad spectrum of diseases associated with IDA, the current paradigm that oral iron is first‐line therapy should be reconsidered. In the past few years, three new IV iron compounds (ferric carboxymaltose, ferumoxytol and iron isomaltoside 1000) have been released for clinical use in patients with IDA. These new preparations with more favorable administration regimens have the potential to improve the convenience and cost‐effectiveness of IV iron therapy.

Design and Characterization of Atenolol Transdermal Therapeutic Systems: Enhancement of Permeability via Iontophoresis

The aim of the present investigation was to improve the permeation of Atenolol by preparing a transdermal patch and using the method of iontophoresis. Influence of chemical penetration enhancers was also studied. Combination of iontophoresis and chemical penetration enhancer d-limonene and oleic acid produced satisfactory permeation and flux. The electrically driven penetration enhancement provided by this method has succeeded in overcoming the formidable barrier presented by the stratum corneum, and has shown to be a promising technique for the transport of hydrophilic drug Atenolol from polymeric films. Atenolol is a water-soluble, ionizable drug and suffers from poor bioavailability when given by oral route due to its incomplete intestinal absorption and first-pass metabolism. Being a BCS class III drug, Atenolol has low log P (0.23) value, which also may be the reason for its poor intestinal absorption. Iontophoretic delivery using Ag/AgCl electrodes with current density of 0.35 mA/cm(2) enhances its delivery rate and thereby overcomes the problem of incomplete absorption. The prepared transdermal patches were subjected to ex vivo drug permeation studies using rat skin in phosphate buffer pH 7.4 for 24 h (passive and iontophoresis), and samples collected were analyzed by gradient high-pressure liquid chromatography. The column used was chiral alpha-glycoprotein (AGP) column (10 cm, particle size 5μ) and UV-detection at 225 nm was used. The effectiveness of permeation enhancers (d-Limonene and oleic acid) was determined by comparing drug flux in the presence and absence of each enhancer. Combination strategies of iontophoresis with chemical enhancers like oleic acid led to the significantly higher flux levels compared with passive transdermal delivery.

Absorption, Disposition, and Pharmacokinetics of Saponins from Chinese Medicinal Herbs: What Do We Know and What Do We Need to Know More?

Saponins are a group of amphiphilic glycosides containing one or more sugar chains linked to a nonpolar triterpene or steroid aglycone skeleton, which are believed to be responsible for the pharmacological activities of many Chinese medicinal herbs. The purpose of this paper is to summarize the contemporary knowledge of the absorption, disposition, and pharmacokinetics of some important saponins, including ginsenosides, licorice saponins, dioscorea saponins, astragalosides, and saikosaponins. Poor intestinal absorption of saponins is mainly due to their unfavorable physicochemical traits, such as large molecular mass ( > 500 Da), high hydrogen-bonding capacity ( > 12), and high molecular flexibility ( > 10), that underlie poor membrane permeability. Rapid and extensive biliary excretion is another primary factor that limits the oral bioavailability of most saponins. However, several saponins, including ginsenosides Ra3, Rb1, Rc, and Rd, and dioscin, are excreted slowly into the bile and in turn have significantly long elimination half lives (7-25 h in rats). These longcirculating saponins may be used as pharmacokinetic markers to substantiate systemic exposure to the ingested herb extracts. In addition to biliary excretion for elimination of most saponins unchanged, renal excretion may also be important for certain saponins. Saponins can be hydrolyzed by the colonic microflora. After absorption, the deglycosylated aglycones undergo phase I and/or II metabolism by the host. In line with the poor permeability, saponin concentrations in most rat tissues are lower than the concurrent plasma level and the brain level is usually very low. However, the liver concentrations of many saponins, as well as the kidney levels of certain saponins, can be quite high, which involves transporter-mediated uptake mechanisms. Repeated p.o. ingestion of glycyrrhizin appears to be able to induce CYP3A in rodents and humans, while several deglycosylated products of ginsenosides can moderately inhibit CYP activities in vitro with IC50 values of 10-50 μM. More research is required for elucidation of the absorption, disposition, and pharmacokinetics of multiple saponins to enhance understanding which saponins are most likely to exert pharmacological effects in vivo, as well as influence of complex herb matrix. In addition, research is also needed to characterize the microbiotal deglycosylation and the subsequent aglycone metabolism by the host for a broader range of saponins, as well as the hepatobiliary transporter phenotyping for and the interaction with saponins. Furthermore, in vitro and in vivo studies of saponin-based herb-drug interactions are also warranted.

The effect of P‐Glycoprotein on methadone hydrochloride flux in equine intestinal mucosa

Methadone is an effective analgesic opioid that may have a place for the treatment of pain in horses. However, its absorption seems to be impaired by the presence of a transmembrane protein, P-glycoprotein, present in different tissues including the small intestine in other species. This study aims to determine the effect of the P-glycoprotein on methadone flux in the equine intestinal mucosa, as an indicator of in vivo drug absorption. Jejunum tissues from five horses were placed into the Ussing chambers and exposed to methadone solution in the presence or absence of Rhodamine 123 or verapamil. Electrical measurements demonstrated tissue viability for 120 min, and the flux of methadone across the jejunal membrane (mucosal to submucosal direction) was calculated based on the relative drug concentration measured by ELISA. The flux of methadone was significantly higher only in the presence of verapamil. P-glycoprotein was immunolocalized in the apical membrane of the jejunal epithelial cells (enterocytes), mainly located in the tip of the villi compared to cells of the crypts. P-glycoprotein is present in the equine jejunum and may possibly mediate the intestinal transport of methadone. This study suggests that P-glycoprotein may play a role in the poor intestinal absorption of methadone in vivo.

Bioavailabilty Studies of Curcuminoids: Lessons Learned and the Need for Labeled Reference Materials

Turmeric, the rhizome of the plant Curcuma longa L., has been used for centuries in Ayurvedic medicine for the treatment of different diseases. Curcuminoids – curcumin, demethoxy-curcumin, and bisdemethoxy-curcumin – represent the major active constituents of turmeric. It is essential to determine the bioavailability of curcuminoids, the ability to deliver the active ingredient to the bloodstream. However, since curcuminoids have high hydrolytic instability at physiological pH and poor intestinal absorption, their presence in blood/plasma is very low. Radiolabeled materials are excellent tools to assess the difference between the amount of compound absorbed and metabolized during first pass through the intestine and liver. But, synthesis of radiolabeled analogues is costly and the analysis requires special facility and equipment, therefore the use of labeled compounds in botanical research is very limited. Without available labeled compounds, the bioavailability of curcuminoids is measured using various analytical techniques such as gas chromatography, capillary electrophoresis with amperometric detection, liquid chromatography (LC) with UV or photodiode array detection, LC-tandem mass spectrometry and matrix assisted laser desorption/ionization. Human colon carcinoma-derived cell line Caco-2 can also be used to estimate bioavailability. The apparent permeability coefficient P app is generally acknowledged as predictive for in vivo bioavailability: P app <1 indicates less than 20%, absorption. Our experiments showed that when differentiated Caco-2 cells were exposed to curcumin, the major basolateral products were hexahydro-curcumin sulfate, small amounts of curcumin-glucuronide and octahydro-curcumin sulfate; confirming the rapid reduction of curcumin. For curcumin, a P app of 0.03–0.07 was calculated, indicating virtually no bioavailability of the non-metabolized compound. For metabolites, P app was 0.5–1.3 suggesting low bioavailability of the metabolites.

An enhanced bioavailable formulation of curcumin using fenugreek-derived soluble dietary fibre

Poor intestinal absorption has been regarded as a major limiting factor for the therapeutic use of curcumin, the primary active constituent of turmeric. Herein, we investigated the bioavailability of a novel formulation of curcumin-impregnated soluble dietary fibre dispersions (BR213 curcumagalactomannosides) comprising an extensive gel forming and non-digestible soluble galactomannan fibre derived from the spice fenugreek. The dispersions were prepared as microgranulates of mean particle size 150±20μm by an ultrasound mediated gel-phase dispersion technique. In vitro release studies at pH 1.2 and 6.8 showed slow and prolonged release of colloidal curcumin from the amorphous microgranulates of curcumin-impregnated soluble fibre. Enhanced bioavailability of the new formulation was further demonstrated in animals (Wistar rats) and human volunteers in comparison with unformulated curcumin. It was observed that the relative absorption of curcumin from the novel fibre formulation, as evident from the area under curve calculations, was 20 times higher in animals and 15.8 times higher in humans when supplemented orally. Maximum absorption was also found to be prolonged as compared to the unformulated curcumin.

Transient zinc deficiency syndrome in a breast-fed infant due to decreased zinc in breast milk (type II hypozincemia of infancy): A case report and review of the literature

Abstract Type II hypozincemia of infancy is a rare, hereditary zinc deficiency occurring in infants while exclusively on breast feeding. It is caused by defective transfer of zinc into breast milk. Only a few dozen cases have been reported. A 6-month-old, full-term, breast-fed female infant presented with a 3-week history of erythematous to dusky red papules and annular plaques over the perioral and diaper area as well as the digits. The eruption was accompanied by poor appetite and irritable crying. Serum zinc was low (4.896 μmol/L, normal = 10.71−18.36 μmol/L) in the patient but was normal in the mother. Interestingly, the zinc level in the breast milk was very low (2.142 μmol/L; normal postpartum zinc = 18.36 μmol/L at 6 months). Histopathology of a skin biopsy specimen showed spongiotic psoriasiform dermatitis with pallor of superficial keratinocytes, consistent with deficiency disease. With oral zinc sulfate supplement, her skin lesions improved significantly within 4 days. Type II hypozincemia needs to be differentiated from the classical hereditary acrodermatitis enteropathica, which typically develops symptoms after weaning because of poor intestinal absorption of zinc in the affected infants. Mutations in zinc transporter genes have been detected in SLC39A4 (Zip4) and SLC30A2 (ZnT2), respectively, in classical acrodermatitis enteropathica and type II hypozincemia. No mutation was found in these two genes in the present pedigree. Therefore, the genetic defect in our patient might involve other zinc transporter genes.

Red grape skin and seeds polyphenols: Evidence of their protective effects on endothelial progenitor cells and improvement of their intestinal absorption

Scope To evaluate the ability of grape skin and seeds to protect endothelial progenitor cells (EPC) from oxidative stress induced by hyperglycemia (HG) compared to red wine (RW) and prepare innovative pharmaceutical systems for the oral administration of red grape extract allowing the overcoming of its poor intestinal absorption. Methods and results Human EPC were characterized by expression of cell surface markers. Cells were incubated with different concentrations of total polyphenols from grape components or RW in the presence or absence of HG. Cell viability, migration, adhesion, and reactive oxygen species (ROS) production were assayed. Intestinal permeation of polyphenols was studied in the absence or presence of a quaternary ammonium-chitosan conjugate (N +(60)-Ch). Grape components and RW increased EPC viability, adhesion and migration, and prevented the HG effect ( P < 0.01). ROS production induced by HG was significantly reduced only by grape seed extract and RW ( P < 0.01). N +(60)-Ch acted as an effective enhancer of polyphenol permeability across the excised rat intestine. Conclusions Red grape components are a source of antioxidant compounds that ameliorate EPC viability and function, while preventing endothelial dysfunction. The use of polycationic chitosan derivatives can promote the absorption of polyphenols across intestinal epithelium, thus increasing their bioavailability and potential therapeutic value in atherosclerosis.