Screening of water distilled Rosa damascena Mill. flowers as hematopoietic agent in an animal model.

Pancytopenia is classified as low blood cell count. Low levels of hemoglobin, red blood cells, white blood cells and platelets are indicative of pancytopenic state. This pancytopenic state can be treatment (drug) or disease induced. Conventional approaches available to treat pancytopenia are usually associated with many undesirable adverse effects, are costly and parenterally administered. Interest in natural products has significantly increased due to their ability to stimulate cellular components of immune system. This study is designed to investigate the hematopoietic i.e. erythropoeitic, leucopoietic and thrombopoeitic potential of water distilled flowers of Rosa damascena Mill.

Spectrum-effect relationship between fingerprints and hemopoietic effects of small molecular fraction of Polygoni Multiflori radix praeparata.

Polygoni multiflori Radix Praeparata (PMRP) is a traditional medicine used for nourishing essence and blood in China. However, it is unclear which PMRP compounds are responsible for its hematopoietic effect. In this study, spectrum-effect relationship was used to discovery potential hematopoietic compounds. The fingerprints of 20 PMRP batches were established by HPLC and the hematopoietic effect was determined using red blood cell, hemoglobin, hematocrit, and platelet indexes in aplastic anemia model mice. The spectrum-effect relationship between common peaks and hematopoietic efficacy values was established using gray relational analysis and partial least squares analysis. Spectrum-effect relationship results showed that peaks 21 (emodin-8-O-(6´-O-acetyl)-ß-D-glucoside), 15 (2, 3, 5, 4'-tetrahydroxystilbene-2-O-di-glucoside), 16 (cis-2,3,5,4'-tetrahydroxy-stilbene-2-O-ß-D-glucoside), 11 (unknown), 20(unknown, 12 (epicatechin), 29 (carboxyl emodin), and 31 (emodin) in the fingerprints were closely related to the hematopoietic effect. This work successfully established the spectrum-effect relationship between PMRP hematopoietic effect and its fingerprints, which can be used to explain the material basis for the PMRP hematopoietic effect.

Comparisons of antithrombosis, hematopoietic effects and chemical profiles of dried and rice wine-processed Rehmanniae Radix extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM), Rehmanniae Radix (RR, derived from the root of Rehmannia glutinosa (Gaertn.) DC.) is commonly used as natural medicine for thousands of years, two types including the dried and rice-wine processed RR were used for different clinical purposes respectively, which were the typical case that pharmaceutical effect changed by processing in TCM. AIM OF STUDY: The goal of this study was to investigate the differences in the antithrombosis and hematopoietic effects of extracts of dried and processed RR (DRR and PRR) in vivo, and to explore the chemical basis underlying changes of medicinal properties caused by processing. MATERIALS AND METHODS: The aqueous extracts of DRR and PRR were prepared. Protective effect of varying doses of different extracts were investigated in type-I carrageenan induced mice tail thrombosis and cyclophosphamide induced myelosuppression model. The chemical composition of DRR and PRR extracts were determined by High Performance Liquid Chromatography coupled with tandem quadrupole time-of-flight Mass Spectrometry (HPLC/Q-TOF-MS). RESULTS: In antithrombosis activity tests, PRR possessed less ameliorated effects than DRR in the model mouse on body temperature, tail thrombus length and blood flow. Both DRR and PRR had no significant influence on prothrombin time (PT) and activated partial thromboplastin time (APTT), only high dose DRR could decrease the content of fibrinogen (FIB) in plasma. Histological examination of lung tissue suggested that thrombosis was significantly improved in DRR-H group. For myelosuppression model, only PRR could improve peripheral hemogram, both DRR and PRR had hematopoietic effects as demonstrated by their abilities to ameliorate the bone marrow nucleated cells (BMNC) and pathology of bone marrow tissue. The hematopoietic effects of PRR were significantly more potent than that of DRR at the concentration of 9 g/kg. By comparing the chemical composition, we found that iridoid glycosides were decreased and furfural derivatives increased in DRR after processing which may be the chemical mechanism contribute to the differences in efficacy. CONCLUSIONS: According to the results of this research, processing with rice wine for nine cycles significantly reduced antithrombotic effects and enhanced the hematopoietic effects of DRR as demonstrated in model mice. It can scientifically explain the different effect among two types of RR in clinical through the diverse method of processing and usage. Meanwhile, the predicted activity compounds from two types of RR can be potential candidates for the treatment of thrombosis and anemia.

Particle Size, Surface Area, and Amorphous Content as Predictors of Solubility and Bioavailability for Five Commercial Sources of Ferric Orthophosphate in Ready-To-Eat Cereal.

Ferric orthophosphate (FePO4) has had limited use as an iron fortificant in ready-to-eat (RTE) cereal because of its variable bioavailability, the mechanism of which is poorly understood. Even though FePO4 has desirable sensory properties as compared to other affordable iron fortificants, few published studies have well-characterized its physicochemical properties. Semi-crystalline materials such as FePO4 have varying degrees of molecular disorder, referred to as amorphous content, which is hypothesized to be an important factor in bioavailability. The objective of this study was to systematically measure the physicochemical factors of particle size, surface area, amorphous content, and solubility underlying the variation in FePO4 bioavailability. Five commercial FePO4 sources and ferrous sulfate were added to individual batches of RTE cereal. The relative bioavailability value (RBV) of each iron source, determined using the AOAC Rat Hemoglobin Repletion Bioassay, ranged from 51% to 99% (p < 0.05), which is higher than typically reported. Solubility in dilute HCl accurately predicted RBV (R² = 0.93, p = 0.008). Amorphous content measured by Dynamic Vapor Sorption ranged from 1.7% to 23.8% and was a better determinant of solubility (R² = 0.91; p = 0.0002) than surface area (R² = 0.83; p = 0.002) and median particle size (R² = 0.59; p = 0.12). The results indicate that while solubility of FePO4 is highly predictive of RBV, solubility, in turn, is strongly linked to amorphous content and surface area. This information may prove useful for the production of FePO4 with the desired RBV.

Solid lipid nanoparticles loaded with iron to overcome barriers for treatment of iron deficiency anemia.

According to the World Health Organization, 46% of the world's children suffer from anemia, which is usually treated with iron supplements such as ferrous sulfate. The aim of this study was to prepare iron as solid lipid nanoparticles, in order to find an innovative way for alleviating the disadvantages associated with commercially available tablets. These limitations include adverse effects on the digestive system resulting in constipation and blood in the stool. The second drawback is the high variability in the absorption of iron and thus in its bioavailability. Iron solid lipid nanoparticles (Fe-SLNs) were prepared by hot homogenization/ultrasonication. Solubility of ferrous sulfate in different solid lipids was measured, and effects of process variables such as the surfactant type and concentration, homogenization and ultrasonication times, and charge-inducing agent on the particle size, zeta potential, and encapsulation efficiency were determined. Furthermore, in vitro drug release and in vivo pharmacokinetics were studied in rabbits. Results indicated that Fe-SLNs consisted of 3% Compritol 888 ATO, 1% Lecithin, 3% Poloxamer 188, and 0.2% dicetylphosphate, with an average particle size of 25 nm with 92.3% entrapment efficiency. In vivo pharmacokinetic study revealed more than fourfold enhanced bioavailability. In conclusion, Fe-SLNs could be a promising carrier for iron with enhanced oral bioavailability.

Comparative metabolomics analysis on hematopoietic functions of herb pair Gui-Xiong by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry and pattern recognition approach.

The compatibility of Angelicae Sinensis Radix (Danggui, DG) and Chuanxiong Rhizoma (Chuanxiong, CX), a famous herb pair Gui-Xiong (GX), can produce synergistic and complementary hematopoiesis. In present study, global metabolic profiling with ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) combined with pattern recognition method was performed to discover the underlying hematopoietic regulation mechanisms of DG, CX and GX on hemolytic and aplastic anemia rats (HAA) induced by acetyl phenylhydrazine (APH) and cyclophosphamide (CP). Thirteen endogenous metabolites contributing to the separation of model group and control group were tentatively identified. The levels of LPCs including lysoPC (18:0), lysoPC (20:4), lysoPC (16:0) and lysoPC (18:2), sphinganine, nicotinic acid, thiamine pyrophosphate, phytosphingosine, and glycerophosphocholine increased significantly (p<0.05) in HAA, while the levels of oleic acid, 8,11,14-eicosatrienoic acid, ceramides (d18:1/14:0), and 17a-hydroxypregnenolone decreased significantly (p<0.05) in comparison with control rats. Those endogenous metabolites were chiefly involved in thiamine metabolism and sphingolipid metabolism. The metabolic deviations could be regulated closer to normal level after DG, CX and GX intervention. In term of hematopoietic function, GX was the most effective as shown by the relative distance in PLS-DA score plots and relative intensity of metabolomic strategy, reflecting the synergic action between DG and CX. The relative distance calculation was firstly used in metabolomics for semi-quantization.

Anti-anaemia efficacy of ß-lactoglobulin hydrolysate-iron complex on iron-deficient anaemic rats.

PURPOSE: The effects of orally administered ß-lactoglobulin hydrolysate-iron complex (ß-LGH-Fe) on haematological and biochemical parameters in anaemic rats were evaluated. Female weaning Sprague-Dawley rats were fed with iron-deficient diet to induce iron deficiency anaemia. After 6 weeks, the obtained anaemic rats were divided into five groups: iron deficiency control group (iron-deficient diet without ß-LGH-Fe complex supplementation, IDC); three groups supplemented with different dosages of ß-LGH-Fe complex (0.5 mg Fe/kg BW, iron-deficient diet with low ß-LGH-Fe, IDLFe; 2.0 mg Fe/kg BW, iron-deficient diet with medium ß-LGH-Fe, IDMF; 4.0 mg Fe/kg BW, iron-deficient diet with high ß-LGH-Fe, IDHFe); and ferrous sulphate-supplemented group at a dosage of 2.0 mg Fe/kg BW. RESULTS: ß-LGH-Fe complex could significantly improve hematocrit and haemoglobin decrease, and normalise the serum iron level, total iron-binding capacity and transferrin saturation of anaemic rats in a dose-dependent manner. Serum ferritin content and hepatic nonheme iron level were also increased. In addition, the antioxidant enzyme activities of superoxidase dismutase, catalase and glutathione peroxidase in both plasma and liver homogenate were improved. The production of malondialdehyde and pro-inflammatory cytokines (TNF-α and IL-6) decreased. CONCLUSIONS: It suggests that ß-LGH-Fe complex can ameliorate iron deficiency anaemia, which might make it a potential ingredient with anti-anaemia activity.

Erythropoietic agents from natural sources.

Anemia occurs frequently in individuals who suffer from chronic kidney disease (CKD) or gynecologic disease or who receive anticancer therapy. Since 1988, medical practitioners have treated patients with anemia successfully with recombinant human erythropoietin (EPO), which is currently the largest therapeutic protein class in the world. It has some disadvantages, however, such as high cost, parenteral administration, and immunogenicity. A novel, economical, orally administrable, and nonimmunogenic hematopoietic agent would be valuable as an alternative or supportive therapy for EPO. Considering the long history of usage of natural products and the recent progress in identification of their active constituents, especially of herbal medicines, researchers and clinicians should find natural products to be useful sources of hematopoietic drugs. In this review, the authors have described EPO therapy and traditional medicines for anemia, including their mechanisms of action for erythropoiesis.

Effect of iron liposomes on anemia of inflammation.

Supplementation with iron-fortified foods is an effective method for treating iron deficiency diseases. However, traditional iron agents used to treat anemia of inflammation (AI) have little effect. In this study, two types of iron liposomes, heme liposomes (HEME-LIP) and ferric citrate liposomes (FAC-LIP), were prepared by the rotary-evaporated film-ultrasonication method, and the encapsulation efficiencies, microstructures, size distributions and zeta potentials were assessed. Both types of iron liposomes showed stable physical characteristics. When used to treat rat models of AI, FAC-LIP and HEME-LIP could increase serum iron levels by 119% and 54% higher than did ferric citrate (FAC) and heme, respectively. Furthermore, the hepcidin, a key regulator of iron homeostasis was up-regulated by these iron liposomes, especially by HEME-LIP. These results indicate that the absorption of iron liposomes was improved over that of unencapsulated iron agents. Thus, iron liposomes may be used to fortify food in treating iron deficiency diseases, especially AI.

Short-term stability of a new generic sodium ferric gluconate in complex with sucrose.

BACKGROUND: Sodium ferric gluconate in complex (SFG) is used to treat iron deficiency anemia in patients aged ≥6 years undergoing chronic hemodialysis and receiving supplemental epoetin therapy. Both the branded product (Ferrlecit, branded SFG) and a new generic version of sodium ferric gluconate in complex (Nulecit; generic SFG) are provided in 5 mL vials. SFG may be administered by slow intravenous (IV) injection of the undiluted product or by 1 h IV infusion after dilution in 100 mL 0.9% sodium chloride. This study evaluated the short-term stability of undiluted and diluted generic SFG at room temperature and under refrigeration. METHODS: Samples of generic SFG undiluted in 10 mL syringes or diluted in IV infusion bags containing 0.9% sodium chloride solution were stored at room temperature or under refrigerated conditions (2-8°C). Samples at room temperature were stored for ≤48 h if undiluted and for ≤24 h if diluted. All refrigerated samples were stored for ≤7 days. Parameters evaluated were elemental iron (Fe) concentration and SFG apparent molecular weight. All tests were performed on two lots of the generic product. RESULTS: Fe concentrations were identical in both lots and did not vary substantially over time under different conditions of storage or dilution. SFG apparent molecular weight varied across all samples from 306,000 to 354,000 Daltons, well within the range of 289,000 to 440,000 Daltons specified as the molecular weight in the FDA-approved prescribing information. CONCLUSION: Iron content and SFG apparent molecular weight were stable under all experimental conditions. Undiluted generic SFG was stable for ≥2 days at room temperature and ≥7 days under refrigerated conditions, and generic SFG diluted in IV infusion bags containing 0.9% sodium chloride solution was stable for ≥1 day at room temperature and ≥7 days under refrigerated conditions.

CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools.

Anemia as associated with numerous clinical conditions can be debilitating, but frequently can be treated via administration of epoetin-alfa, darbepoietin-alfa, or methoxy-PEG epoetin-beta. Despite the complexity of EPO-EPO receptor interactions, the development of interesting EPO mimetic peptides (EMPs) also has been possible. CNTO 530 is one such novel MIMETIBODY Fc-domain dimeric EMP fusion protein. In a mouse model, single-dose CNTO 530 (unlike epoetin-alfa or darbepoietin-alfa) bolstered red cell production for up to 1 month. In 5-fluorouracil and carboplatin-paclitaxel models, CNTO 530 also protected against anemia with unique efficiency. These actions were not fully accounted for by half-life estimates, and CNTO 530 signaling events therefore were studied. Within primary bone marrow erythroblasts, kinetics of STAT5, ERK, and AKT activation were similar for CNTO 530 and epoetin-alfa. p70S6K activation by CNTO 530, however, was selectively sustained. In vivo, CNTO 530 uniquely stimulated the enhanced formation of PODXL(high)CD71(high) (pro)erythroblasts at frequencies multifold above epoetin-alfa or darbepoietin-alfa. CNTO 530 moreover supported the sustained expansion of a bone marrow-resident Kit(neg)CD71(high)Ter119(neg) progenitor pool. Based on these distinct erythropoietic and EPOR signaling properties, CNTO 530 holds excellent promise as a new EPO mimetic.

Erythropoietin: new approaches to improved molecular designs and therapeutic alternatives.

Erythropoietin (Epo) is a glycoprotein hormone that is the prime regulator of erythropoiesis. Recombinant Epo is a highly effective pharmaceutical used to correct anemias associated with renal insufficiency, cancer and other diseases. Efforts to increase its efficacy in vivo by manipulating the protein's structure have met with some success, and novel Epo-like agents are in development. Additionally, efforts to create Epo mimetic agents are underway, as is the design of agents to increase endogenous production. Because Epo has tissue protective actions outside of erythropoiesis, other designs have focused on producing erythropoietically inactive molecules that still retain extra-hematopoietic activity. The demonstration that Epo can trigger signaling in some cancer cells with, potentially, adverse effects on patient health has raised warning signs in the medical community and has gained the attention of regulatory authorities.

Comparison of polysaccharide iron complexes used as iron supplements.

An oral hematinic marketed as "water soluble polysaccharide iron complex" (Vitaline Formulas) has been characterized using x-ray powder diffraction and Mössbauer spectroscopy. Another polysaccharide iron complex marketed as Niferex (Central Pharmaceuticals) has been previously studied by us and found to have a core similar to ferrihydrite, but with some long-range order of the mineral akaganéite, beta-FeOOH. The latter is seen in other ferric carbohydrate complexes synthesized by the hydrolysis of FeCl3. This commercial product, however, is very different and has a mixture of iron components including hematite (alpha-Fe2O3) magnetite (Fe3O4), goethite (alpha-FeOOH), iron metal, and a ferrous salt.