Improved in vitro bioavailability of a newly developed functionalized calcium carbonate salt as a food ingredient and its comparison with available commercial calcium salts.

The bioaccessibility and bioavailability of a functionalized Calcium (Ca) salt as food ingredient, based on modified Ca carbonate and hydroxyapatite (FCC), was determined and compared with frequently used Ca sources (Ca citrate tetrahydrate (CCT), tri-Ca phosphate (triCP) and Ca carbonate (CC). Results showed a similar Ca bioaccessibility for CCT (76.44 ± 9.73%), CC (73.7 ± 8.18%) and FCC (74.4 ± 1.87%) and a lower value for tri-CP (46.07 ± 8.68%). FCC showed the highest bioavailability, 5.68 ± 0.26%, compared to CC, CCT and tri-CP (3.93 ± 0.99%, 3.41 ± 0.33%, 1.85 ± 0.34%, respectively). The innovative chemical composition and structure of FCC based on amorphous hydroxyapatite combined with Ca carbonate, a greater porosity, lower agglomerates and particle size, improve the Ca solubility in the intestinal media, explaining the similar bioaccessibility but higher bioavailability of FCC compared to CCT, tri-CP and CC.

Comparative Pharmacokinetics/Pharmacodynamics of Fixed-Dose Combination of Esomeprazole and Calcium Carbonate (AD-206) to the Conventional Esomeprazole.

PURPOSE: Proton pump inhibitors (PPIs) are used for the treatment of acid-related disorders. Demands for enhanced stability and faster onset led to the development of AD-206, a fixed-dose combination of a PPI (esomeprazole) with an antacid salt (calcium carbonate). This study compared the pharmacokinetics (PKs) and pharmacodynamics (PDs) of AD-206 (Addpharma) with conventional esomeprazole (Nexium®, AstraZeneca). MATERIALS AND METHODS: A randomized, open-label, two-treatment, two-sequence crossover study was conducted with 2 different doses of esomeprazole at 20 and 40 mg with a fixed calcium carbonate dose of 600 mg in AD-206. Forty-four subjects were included in each dose group and randomly received either AD-206 or the conventional esomeprazole for 7 consecutive days in each period. After a single- and multiple-dose, blood samples for the PK analysis were analyzed, and 24-hour intragastric pH monitoring was conducted. RESULTS: The systemic exposure of esomeprazole after a multiple-dose of AD-206 was similar to that of the conventional esomeprazole in both doses, but the time to reach the peak concentration was faster in AD-206. The percentage decrease from baseline in the integrated gastric acidity for a 24-hour interval after the dose was not significantly different between the AD-206 and the conventional esomeprazole after a single- and multiple-dose for both doses, and the time to reach pH 4 was faster for AD-206. CONCLUSION: AD-206 showed a similar systemic exposure and suppression of gastric acid secretion after a multiple-dose compared to the conventional esomeprazole.

Functionalised calcium carbonate as a coformer to stabilize amorphous drugs by mechanochemical activation.

The aim of this study was to investigate the amorphization, physical stability and drug release of a model drug, carvedilol (CAR), when loaded onto functionalised calcium carbonate (FCC) using mechanochemical activation (vibrational ball milling). The solid-state characteristics and physical stability of CAR-FCC samples, prepared at different weight ratios and for different milling times, were determined using differential scanning calorimetry and X-ray powder diffraction. Upon milling CAR-FCC samples containing 50% CAR, amorphization of CAR was observed after 10 min. For CAR-FCC samples milled for either 30 or 90 min, it was found that CAR was amorphised at all ratios (10-90% CAR), but FCC remained crystalline. The glass transition temperature (Tgα) of the various CAR-FCC samples milled for 90 min was found to be similar (38 °C) for all ratios containing 20% CAR and above. The similar Tgαs for the different drug ratios indicate deposition of amorphous CAR onto the surface of FCC. For CAR-FCC samples containing 10% CAR, a Tgα of 49 °C was found, which is 11 °C higher compared with other CAR-FCC samples. This may indicate restricted molecular mobility resulting from CAR molecules that are in close contact with the FCC surface. The physical stability, under both stress (100 °C) and non-stress conditions (25 °C at dry conditions), showed that drug concentrations up to 30% CAR can be stabilized in the amorphous form for at least 19 weeks under non-stress conditions when deposited onto FCC, compared to less than a week physical stability of neat amorphous CAR. In vitro drug release showed that CAR-FCC samples containing 60% CAR and below can improve the drug release and generate supersaturated systems compared to neat amorphous and crystalline CAR. Samples with lower drug concentrations (40% CAR and below) can maintain supersaturation during 360 min of dissolution testing. This study indicates that the crystalline inorganic material, FCC, can facilitate amorphization of drugs, provide stabilization against drug crystallization, and improve dissolution properties of amorphous drugs upon mechanochemical activation.

Relative bioavailability and pharmacokinetic comparison of calcium glucoheptonate with calcium carbonate.

Adequate calcium intake is important for the prevention of bone loss and osteoporosis. For some populations such as those of Southeast Asia where calcium intake is very low, supplements represent a suitable dietary source of calcium. The objective of this study was to compare the relative oral bioavailability of calcium from calcium glucoheptonate, a highly soluble calcium salt containing 8.2% of elemental calcium, to that of calcium carbonate. A single-dose, randomized-sequence, open-label, two-period crossover study, with a 7-day washout period, was conducted in 24 Indonesian healthy adult volunteers. After a 12-hour (overnight) fast, subjects received either two oral ampoules of 250 mg/10 mL of calcium glucoheptonate each or one effervescent tablet of calcium carbonate containing 500 mg of elemental calcium. The relative oral bioavailability of calcium from calcium glucoheptonate as compared to calcium carbonate was 92% within 6 hours and 89% within 12 hours after study drug administration. The 90% confidence intervals for the mean test/reference ratios of the maximum plasma concentration and the area under the concentration-time curve at 12 hours post-administration were 77.09%-120.31% and 60.58%-122.30%, respectively. Five subjects experienced a total of eight adverse events which were all mild and transient; no serious adverse events or deaths were reported. These results indicate that calcium glucoheptonate is associated with a high relative bioavailability of calcium compared to calcium carbonate, and is well-tolerated. Calcium glucoheptonate might thus be a potential choice for calcium supplementation in Southeast Asian populations.

Development and characterization of novel ambroxol sustained-release oral suspensions based on drug-polymeric complexation and polymeric raft formation.

The aim was to develop sustained-release aqueous suspensions of ambroxol utilizing drug-polymer complexation and raft-forming formulations. Ambroxol-carrageenan (ABX-CRG) complexation was studied for the optimum binding capacity, which was used to prepare the complex by kneading and coprecipitation. The prepared complex was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffractometry. The complex was formulated as suspensions in aqueous raft-forming vehicle of sodium alginate (NA) and calcium carbonate (CC). The suspensions differed in the molecular weight and concentration of NA, in addition to CC level and inclusion of CRG in excess of drug-polymer complexation. In 0.1 M HCl as simulated gastric fluid, the suspensions were observed for their ability to form rafts and studied for drug-release. The optimum sustained-release, raft forming and pourable formulation using high molecular weight NA, NA concentration of 18 mg/ml and CC concentration of 9 mg/ml was reached. Another optimum suspension was obtained by replacement of CC with excess CRG. However, pH dissolution profiles of the optimum suspensions revealed less pH sensitivity of the release consequent to this replacement as well as more stable ABX release upon aging. Relative to Gaviscon liquid, the optimum suspensions formed rafts of similar strength and higher resilience.

In vivo evaluation of anticancer efficacy of drug loaded cockle shell-derived aragonite nanoparticles.

Doxorubicin (DOX) is an effective and commonly used anthracycline anticancer drug for the treatment of osteosarcoma (OS). However, its antitumor effect is hampered by the nonspecific distribution and significant adverse effects. Nanoparticles based drug delivery systems are promising approaches to maximize the anticancer efficacy while decrease the side effects. In this study, biogenic aragonite nanoparticles (ANPs) were developed from cockle shells and loaded with DOX. An orthotopic rat OS model was induced by UMR-106 cells tibia cavity injection. The anticancer efficacy study included five groups: normal control group, OS model group, free DOX group (2 mg/kg), DOX-ANPs 1 group (2 mg of equivalent DOX/kg) and DOX-ANPs 2 group (1.5 mg of equivalent DOX/kg). This study demonstrates that the DOX-ANPs treatment groups can significantly reduce the tumor volume and increase the surviving ratio as compared to the OS model group. In addition, these two DOX-ANPs groups showed less toxicity to the normal organs compared to the free DOX group. Furthermore, DOX-ANPs 2 group showed the similar anticancer efficacy as DOX-ANPs 1 group, which suggested that DOX loaded onto the ANPs may allow the reduction of chemotherapy doses. These results highlight the promising application of ANPs derived from cockle shells as an effective drug delivery system for a successful chemotherapy against OS. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1898-1907, 2019.

Formulation, optimization, and evaluation of raft-forming formulations containing Nizatidine.

OBJECTIVE: The main objective of this research is to formulate, optimize, and evaluate raft-forming chewable tablets of Nizatidine. Various raft-forming agents were used in preliminary screening. Sodium alginate showed maximum raft strength, so tablets were prepared using sodium alginate as the raft forming agent, along with calcium carbonate (CaCO3) as antacid and raft strengthening agent, and sodium bicarbonate (NaHCO3) as a gas generating agent. RESEARCH DESIGN AND METHODS: Raft forming chewable tablets containing Nizatidine were prepared by direct compression and wet granulation methods, and evaluated for drug content, acid neutralization capacity, raft strength, and in-vitro drug release in 0.1 N HCl. Box-Behnken design was used for optimization. RESULTS: Two optimized formulations were predicted from the design space. The first optimized recommended concentrations of the independent variables were predicted to be X1 = 275.92 mg, X2 = 28.60 mg, and X3 = 202.14 mg for direct compression technique and the second optimized recommended concentrations were predicted to be X1 = 253.62 mg, X2 = 24.60 mg, and X3 = 201.77 mg for wet granulation technique. Optimized formulations were stable at accelerated environmental testing for six months at 35 °C and 45 °C with 75% relative humidity. X-Ray showed that the raft floated immediately after ingestion and remained intact for ∼3 h. CONCLUSION: Raft was successfully formed and optimized. Upon chewing tablets, a raft is formed on stomach content. That results in rapid relief of acid burning symptoms and delivering the drug into systemic circulation with enhanced bioavailability.

Calcium-carbonate packaging magnetic polydopamine nanoparticles loaded with indocyanine green for near-infrared induced photothermal/photodynamic therapy.

Indocyanine green (ICG) is an efficient photosensitizer that can facilitate producing cytotoxic reactive oxygen species (ROS). At the same time, ICG also has characteristic absorption of near-infrared light and thus can induce a strong photothermal effect. Both of these important features of ICG may be applied for noninvasive light-induced tumor ablation. On the other hand, ICG is lack of stability in blood circulation and susceptible to aggregation or premature clearance from the body. These issues need to be effectively addressed before antitumor application of ICG becomes possible. Herein, a nanocomposite consisting of calcium carbonate modified magnetic polydopamine (PDA) nanoparticles and loaded with ICG, namely Fe3O4@PDA@CaCO3/ICG (FPCI) NPs, was developed to integrate the photothermal capability of PDA with the photodynamic capability of ICG. Particularly, calcium carbonate not only entrapped ICG in the form of stable aggregate to evade blood clearance, but also facilitated controlled release of ICG in response to acidic tumor microenvironment via self-decomposition. With the aid of magnetic guidance, this multifunctional therapeutic agent makes it possible to achieve the combination of photothermal (PTT) and photodynamic therapies (PDT) against tumors, which was demonstrated by this proof-of-concept study based on in vitro and in vivo tumor models. STATEMENT OF SIGNIFICANCE: Currently, there is an ongoing trend of realizing precise and targeted tumor therapy using functional nanocomplexes. Magnetic particles, which can be manipulated by a magnetic field, have attracted increasing attention for tumor therapy. This submitted work demonstrated that calcium carbonate nanoshell was precipitated onto magnetic nanocores mediated by polydopamine. Moreover, indocyanine green (ICG), as a potent photosensitizer, was embedded in this nanocomplex and protected by the calcium carbonate nanoshell, resulting in high drug loading efficiency and enhanced drug stability on the carrier. This new nanocomposite was demonstrated to achieve controlled and pH-responsive release of ICG in tumor environment. This work explored the relationship between the physiochemical properties of the nanocomplex and their potential biomedical applications, aiming to inspire the development of analogous nanoplatforms featured with calcium carbonate blocks.

Estudio comparativo de la absorción neta de calcio de dos formulaciones distintas de carbonato de calcio en mujeres posmenopáusicas / Comparative study of net calcium absorption of two different pharma¬ceutical formulations of calcium carbonate in posmenopausal women

La suplementación con calcio reduciría, sola o asociada a otra medicación para osteoporosis, la pérdida de masa ósea y el riesgo de fracturas. Sin embargo, su tasa de adherencia es baja debido a la poca tolerancia. Objetivo: comparar la tasa de absorción neta de calcio entre dos formulaciones distintas de carbonato de calcio (500 mg): comprimidos vs. mousse. Material y métodos: 11 pruebas fueron realizadas en mujeres posmenopáusicas de 58,9±3 años. El diseño fue exploratorio abierto, aleatorizado, prospectivo cruzado de fase 4. Intervención: las participantes fueron aleatorizadas en dos grupos para recibir las dos formulaciones previa suplementación con vitamina D3. La tasa de absorción neta de calcio fue estudiada por la prueba de inhibición de hormona paratiroidea (PTH). Se obtuvieron muestras de sangre: basal y en la 1a, 2a y 3a hora posadministración del calcio asignado, y de orina de 2 horas basal y al final de la prueba. Determinaciones bioquímicas: calcio, fósforo, albúmina, 25-hidroxivitamina D y hormona paratiroidea intacta y calciuria. Análisis estadístico: método de los trapecios para calcular el área bajo la curva (AUC) de la concentración de calcio en el tiempo (R Development Core Team (2008). http://www.Rp-project.org) y Anova con dos términos de error para evaluar el efecto secuencia, período y formulación. Resultados: la mayor inhibición de PTH se observó a dos horas de la toma de ambas formulaciones (comprimidos -39,2% vs. mousse -38,0%; p=ns), con similar AUC0-3 h (comprimidos 3,35; IC 95%: 3,32; 3,37 vs. mousse 3,36; IC 95%: 3,33; 3,38). Cuando analizamos tolerancia y preferencias no se observaron diferencias estadísticamente significativas entre ambas formulaciones. Conclusión: el carbonato de calcio en mousse mostró similar tasa de absorción intestinal, preferencia y tolerancia gastrointestinal que en comprimido. (AU)

Calcium supplementation, administered alone or in combination with a specific medication for osteoporosis, would reduce bone mass loss and fracture risk in postmenopausal women. However, the adherence rate to calcium supplements is low, mainly due to low tolerance. Objective: comparisson of net calcium absorption rate between two different pharmaceutical formulations of calcium carbonate (PFCa) in postmenopausal women. Materials and Methods: 11 tests were performed in postmenopausal women aged 58.9±3 yrs. Design: Comparative, randomized, prospective, open-label exploratory crossover study of calcium mousse versus calcium pills. Intervention: Participants were randomized in 2 groups to receive the 2 different PFCa (500mg): pills vs. mousse, with previous vitamin D3 supplementation. The parathyroid hormone (PTH) inhibition test and the area-under-thecurve (AUC) of calcium were analyzed. Blood samples were taken at baseline and 1, 2 and 3 hrs after intake of the assigned PFCa. Urine samples (2hs) were obtained at -baseline, after 2hs of PFCa intake and at the end of the test. Biochemical Determinations: Serum: calcium, phosphorus, albumin, 25-hydroxyvitamin D, and intact PTH. In urine: calcium. Statistical Analysis: The trapezoid rule was applied to assess AUC in time (R Development Core Team (2008). http://www.Rp-project.org). An ANOVA model with 2 error terms was used to assess the effect of sequence, period, and formulation. Results: The highest inhibition PTH rates were observed after 2 hrs of PFCa (pills -39.2% vs. mousse -38.0%; p=ns). The AUC0-3hrs for both PFCa was similar (pills 3.35; 95%CI: 3.32; 3.37 vs. mousse 3.36; 95%CI: 3.33; 3.38). No statistically significant differences were observed when we analyze tolerance and predilection. Conclusion: The calcium carbonate in mousse showed an adequate rate of intestinal absorption, similarly predilection and gastrointestinal tolerance than the pill presentation. (AU)

Enhancing anti-tumor efficiency in hepatocellular carcinoma through the autophagy inhibition by miR-375/sorafenib in lipid-coated calcium carbonate nanoparticles.

Sorafenib is a first-line drug for hepatocellular carcinoma (HCC). Autophagy has been shown to facilitate sorafenib resistance. miR-375 has been shown to be an inhibitor of autophagy. In this study, miR-375 and sorafenib were co-loaded into calcium carbonate nanoparticles with lipid coating (miR-375/Sf-LCC NPs). The nanoparticles had high loading efficiency and were ∼50 nm in diameter. Besides, the NPs could increase the stability and residence time of both drugs. Moreover, we demonstrated that autophagy was activated in HCC cells by sorafenib but not by miR-375/Sf-LCC NPs. In vitro, miR-375/Sf-LCC NPs exhibited pH-dependent drug release and potent cytotoxicity. In vivo, miR-375/Sf-LCC NPs increased miR-375 and sorafenib uptake in tumor (2 folds compared with Lipofectamine 2000-miR-375 and 2-5 folds compared with free sorafenib). Furthermore, miR-375/Sf-LCC NPs showed greatly enhanced therapeutic efficacy in an HCC xenograft model. These findings suggest that miR-375/Sf-LCC NPs may be a promising agent for the HCC therapy. STATEMENT OF SIGNIFICANCE: Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third leading cause of cancer mortality globally. In this manuscript, miR-375 and sorafenib were co-loaded into calcium carbonate nanoparticles with lipid coating (miR-375/Sf-LCC NPs) to treat HCC. We demonstrated that miR-375/Sf-LCC NPs can deliver sorafenib and miR-375 into HCC cells and tumor tissues, increase drug retention time in tumor, significantly inhibit autophagy and produce enhanced anti-tumor effect.

A Pilot Study of OkKidney, a Phosphate Counting Application in Patients on Peritoneal Dialysis.

BACKGROUND: Hyperphosphatemia is associated with adverse outcomes in patients treated with peritoneal dialysis (PD). We have shown that a fixed meal phosphate binder dosing schedule is not appropriate. The purpose of this study was to evaluate the beta version of OkKidney, a phosphate counting app that matches meal phosphate content with binder dose. METHODS: A convenience sample of adult patients treated with PD completed a pre-survey that included the technology readiness index (TRI 2.0). After a short information session, patients used OkKidney for 30 days. Pre- and post-intervention serum calcium, serum phosphate, and calcium carbonate binder intake were collected and compared using a paired t-test. A post-intervention survey using a 5-point Likert scale was used to gather patient feedback. RESULTS: Ten patients (5M, 5F) completed the study protocol. Participants were 55 ± 17 years old, predominately Caucasian, retired (60%), and owned a smartphone (70%). The median TRI score was 3.66 (max 5), indicating a moderate level of readiness. The post-survey results indicated a favorable rating for ease of use (µ = 4.4 ± 0.84) and usefulness (µ = 4.3 ± 0.68) of OkKidney. The average serum phosphate (p = 0.99) and calcium (p = 0.68) were not different pre-/post-intervention, but calcium carbonate intake tended to decrease (p = 0.12). CONCLUSION: Patients reported a positive experience with OkKidney. Further patient-specific adjustments of the binder dose to meal phosphate content may be required to demonstrate a statistically significant decrease in phosphate levels. We believe a larger trial is warranted to investigate the clinical implications of this app.

Highly bioavailable nanocalcium from oyster shell for preventing osteoporosis in rats.

Oyster shell is one of the foremost natural sources of calcium and is used as an alternative treatment for osteoporosis. In this study, we demonstrated that zinc-activated nanopowdered oyster shell (Zn-NPOS) effectively reduced bone loss compared with powdered oyster shell (POS) in an ovariectomized rat (OVX) model. As a result of nanosizing, the solubility and bioavailability of the oyster shell were greatly improved, and its effectiveness was further enhanced by zinc activation. Bone analysis indicated greater recovery from ovariectomy-induced bone loss following Zn-NPOS treatment. Moreover, Zn-NPOS treatment resulted in higher bone strength and superior trabecular architecture compared with NPOS and POS treatments. Furthermore, Zn-NPOS showed greater efficiency in increasing bone formation and reducing bone resorption markers. Therefore, nanosizing with zinc activation could be a viable strategy for improving the efficiency of oyster shells used for osteoporosis prevention.

Eggshell fractions containing different particle sized affect mineral absorption but not bone mineral retention in growing rats.

The purpose of this study was to compare the calcium (Ca) bioavailability from eggshell fractions containing different particle size to purified CaCO3 in male growing rats. Mineral absorption, bone mineral concentration, and biomechanical properties were evaluated. Mean Ca absorption of rats fed with eggshell diets amounted to 56.2% of the ingested Ca, which is considered high. However, we observed lower Ca absorption in large-sized particle eggshell fraction (ES L) and small-sized particle eggshell fraction groups but similar Ca absorption in intermediate-sized particle eggshell fraction (ES M) compared with the CaCO3 group. Rats that received ES M and ES L had higher P and Mg absorption than the CaCO3 group. No changes were observed in the bone mineral deposition, weight or mechanical resistance. We conclude that eggshell Ca is well absorbed by the intestine and retained in bones of growing rats, being a low cost alternative to achieve adequate Ca ingestion.

Antibacterial Activity of Ciprofloxacin-Encapsulated Cockle Shells Calcium Carbonate (Aragonite) Nanoparticles and Its Biocompatability in Macrophage J774A.1.

The use of nanoparticle delivery systems to enhance intracellular penetration of antibiotics and their retention time is becoming popular. The challenge, however, is that the interaction of nanoparticles with biological systems at the cellular level must be established prior to biomedical applications. Ciprofloxacin-cockle shells-derived calcium carbonate (aragonite) nanoparticles (C-CSCCAN) were developed and characterized. Antibacterial activity was determined using a modified disc diffusion protocol on Salmonella Typhimurium (S. Typhimurium). Biocompatibilittes with macrophage were evaluated using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-Bromo-2'-deoxyuridine (BrdU) assays. Transcriptional regulation of interleukin 1 beta (IL-1ß) was determined using reverse transcriptase-polymerase chain reaction (RT-PCR). C-CSCCAN were spherical in shape, with particle sizes ranging from 11.93 to 22.12 nm. Encapsulation efficiency (EE) and loading content (LC) were 99.5% and 5.9%, respectively, with negative ζ potential. X-ray diffraction patterns revealed strong crystallizations and purity in the formulations. The mean diameter of inhibition zone was 18.6 ± 0.5 mm, which was better than ciprofloxacin alone (11.7 ± 0.9 mm). Study of biocompatability established the cytocompatability of the delivery system without upregulation of IL-1ß. The results indicated that ciprofloxacin-nanoparticles enhanced the antibacterial efficacy of the antibiotic, and could act as a suitable delivery system against intracellular infections.

Cellular uptake of poly(allylamine hydrochloride) microcapsules with different deformability and its influence on cell functions.

It is important to understand the safety issue and cell interaction pattern of polyelectrolyte microcapsules with different deformability before their use in biomedical applications. In this study, SiO2, poly(sodium-p-styrenesulfonate) (PSS) doped CaCO3 and porous CaCO3 spheres, all about 4µm in diameter, were used as templates to prepare microcapsules with different inner structure and subsequent deformability. As a result, three kinds of covalently assembled poly(allylaminehydrochloride)/glutaraldehyde (PAH/GA) microcapsules with similar size but different deformability under external osmotic pressure were prepared. The impact of different microcapsules on cell viability and functions are studied using smooth muscle cells (SMCs), endothelial cells (ECs) and HepG2 cells. The results demonstrated that viabilities of SMCs, ECs and HepG2 cells were not significantly influenced by either of the three kinds of microcapsules. However, the adhesion ability of SMCs and ECs as well as the mobility of SMCs, ECs and HepG2 cells were significantly impaired after treatment with microcapsules in a deformability dependent manner, especially the microcapsules with lower deformability caused higher impairment on cell functions. The cellular uptake kinetics, uptake pathways, intracellular distribution of microcapsules are further investigated in SMCs to reveal the potential mechanism. The SMCs showed faster uptake rate and exocytosis rate of microcapsules with lower deformability (Cap@CaCO3/PSS and Cap@CaCO3), leading to higher intracellular accumulation of microcapsules with lower deformability and possibly larger retardation of cell functions. The results pointed out that the deformability of microcapsules is an important factor governing the biological performance of microcapsules, which requires careful adjustment for further biomedical applications.

Effect of High-Calcium Diet on Coronary Artery Disease in Ossabaw Miniature Swine With Metabolic Syndrome.

BACKGROUND: Calcium is a shortfall essential nutrient that has been a mainstay of osteoporosis management. Recent and limited findings have prompted concern about the contribution of calcium supplementation to cardiovascular risk. A proposed mechanism is through the acceleration of coronary artery calcification. Determining causality between calcium intake and coronary artery calcification has been hindered by a lack of sensitive methodology to monitor early vascular calcium accumulation. The primary study aim was to assess the impact of high calcium intake on coronary artery calcification using innovative calcium tracer kinetic modeling in Ossabaw swine with diet-induced metabolic syndrome. Secondary end points (in vitro wire myography, histopathology, intravascular ultrasound) assessed coronary disease. METHODS AND RESULTS: Pigs (n=24; aged ≈15 months) were fed an atherogenic diet with adequate calcium (0.33% by weight) or high calcium (1.90% from calcium carbonate or dairy) for 6 months. Following 5 months of feeding, all pigs were dosed intravenously with (41)Ca, a rare isotope that can be measured in serum and tissues at a sensitivity of 10(-18) mol/L by accelerator mass spectrometry. Kinetic modeling evaluated early coronary artery calcification using (41)Ca values measured in serial blood samples (collected over 27 days) and coronary artery samples obtained at sacrifice. Serum disappearance of (41)Ca and total coronary artery (41)Ca accumulation did not differ among groups. Secondary end points demonstrated no treatment differences in coronary artery disease or function. CONCLUSION: There was no detectable effect of high calcium diets (from dairy or calcium carbonate) on coronary artery calcium deposition in metabolic syndrome swine.

The fate of calcium carbonate nanoparticles administered by oral route: absorption and their interaction with biological matrices.

BACKGROUND: Orally administered particles rapidly interact with biological fluids containing proteins, enzymes, electrolytes, and other biomolecules to eventually form particles covered by a corona, and this corona potentially affects particle uptake, fate, absorption, distribution, and elimination in vivo. This study explored relationships between the biological interactions of calcium carbonate particles and their biokinetics. METHODS: We examined the effects of food grade calcium carbonates of different particle size (nano [N-Cal] and bulk [B-Cal]: specific surface areas of 15.8 and 0.83 m(2)/g, respectively) on biological interactions in in vitro simulated physiological fluids, ex vivo biofluids, and in vivo in gastrointestinal fluid. Moreover, absorption and tissue distribution of calcium carbonates were evaluated following a single dose oral administration to rats. RESULTS: N-Cal interacted more with biomatrices than bulk materials in vitro and ex vivo, as evidenced by high fluorescence quenching ratios, but it did not interact more actively with biomatrices in vivo. Analysis of coronas revealed that immunoglobulin, apolipoprotein, thrombin, and fibrinogen, were the major corona proteins, regardless of particle size. A biokinetic study revealed that orally delivered N-Cal was more rapidly absorbed into the blood stream than B-Cal, but no significant differences were observed between the two in terms of absorption efficiencies or tissue distributions. Both calcium carbonates were primarily present as particulate forms in gastrointestinal fluids but enter the circulatory system in dissolved Ca(2+), although both types showed partial phase transformation to dicalcium phosphate dihydrate. Relatively low dissolution (about 4%), no remarkable protein-particle interaction, and the major particulate fate of calcium carbonate in vivo gastrointestinal fluids can explain its low oral absorption (about 4%) regardless of particle size. CONCLUSION: We conclude that calcium carbonate nanoparticles can act more actively with biological matrices in vitro and ex vivo, but that in vivo, their biological interactions and biokinetics are not affected by particle size.

Arginine promotes fluoride uptake into artificial carious lesions in vitro.

BACKGROUND: This study focused on the interaction of arginine and fluoride on the remineralization of artificial enamel carious lesions in vitro. METHODS: Human enamel blocks with artificial carious lesions were prepared and randomly divided into six treatment groups (n=30 for each group): deionized water, arginine solution, NaF solution, arginine/NaF solution, arginine-free fluoride toothpaste slurry and arginine-containing fluoride toothpaste slurry. After a pH-cycling regimen for 10 days, subsets of specimens from each group were subjected to independent analysis, including surface microhardness (n=8/30), cross-sectional microhardness (n=8/30), enamel fluoride uptake (n=8/30) and polarized light microscopy (n=6/30). The samples tested for surface microhardness were further subjected to simulated plaque acid challenge before surface microhardness was remeasured. RESULTS: Arginine solution promoted remineralization compared with deionized water control (p<0.05). When used in combination with fluoride, arginine significantly increased fluoride uptake compared with fluoride alone (p<0.05). In addition, lesions treated with arginine-containing toothpaste also showed superior fluoride uptake compared with those treated with conventional fluoride toothpaste (p<0.05). CONCLUSIONS: Arginine promoted enamel fluoride uptake when used in combination with fluoride, thereby contributing to resistance of enamel to carious demineralization.

Physicochemical analysis and repeated-dose 90-days oral toxicity study of nanocalcium carbonate in Sprague-Dawley rats.

In our previous studies of nanocalcium carbonate, in which we performed physicochemical analysis, genotoxicity, acute single-dose and repeated-dose 14-day oral toxicity testings in Sprague-Dawley (SD) rats, nanocalcium carbonate did not show a difference in toxicity compared to vehicle control. Here, we provide the first report of a repeated-dose 90-day oral toxicity test of nanocalcium carbonate in Sprague-Dawley rats, with physicochemical comparison of micro and nanocalcium carbonate. We find that the two particles differ in size, hydrodynamic size, and specific surface area, with no differences in components, crystalline structure and radical production. In terms of ionization ability, nanocalcium carbonate was slightly more ionized within 1% than microcalcium carbonate at pH 5 and pH 7. In the repeated-dose 90-day oral toxicity test of nanocalcium carbonate, there was no significant toxicity, and similar blood concentrations of Ca(2+) compared to the vehicle control group. Based on our results, although nanocalcium carbonate has different physicochemical properties, nanocalcium carbonate does not differ from microcalcium carbonate in terms of toxicity. Based on the results, we suggest that the no-observed-adverse-effect level (NOAEL) of nanocalcium carbonate is 1000 mg kg(-1) day(-1) in SD rats according to the maximum dose (OECD guideline 408). However, the NOAEL might be higher than 1000 mg kg(-1) day(-1) because there were no adverse effects revealed by consistent pathological findings or biochemical parameter changes. To justify a safe concentration of nanocalcium carbonate, which is a low toxicity chemical, more data is required on dose levels above 1000 mg kg(-1). Our findings may be useful for creating safety guidelines for the use nanocalcium carbonate.

Effects of calcium carbonate, sevelamer hydrochloride or pantoprazole on the pharmacokinetics of cinacalcet.

BACKGROUND AND OBJECTIVES: Secondary hyperparathyroidism is a common consequence of chronic kidney disease. Cinacalcet (Sensipar(®)) is often prescribed in combination to reduce elevated levels of parathyroid hormone, calcium and phosphorus. The objective of this study was to assess the effects of concomitantly administered therapies of calcium carbonate (CaCO(3); TUMS(®)), sevelamer hydrochloride (HCl; Renagel(®)) and pantoprazole sodium (Protonix(®)) on the pharmacokinetics and safety of cinacalcet in healthy subjects. METHODS: Three randomized, open-label, two-way crossover pharmacokinetic studies were conducted in healthy subjects. Participants received single doses of cinacalcet alone or in combination with either CaCO(3), sevelamer HCl or pantoprazole. The pharmacokinetic profile of cinacalcet was characterized. Safety assessments including adverse event reporting, changes in vital signs and clinical laboratory measurements were conducted throughout the studies. RESULTS: The 90 % confidence intervals for the area under the concentration-time curve from time zero to the last quantifiable concentration (AUC(last)), area under the concentration-time curve from time zero to infinity (AUC(0-∞)) and maximum plasma concentration (C(max)) of cinacalcet were within the accepted range of 80-125 % for both CaCO(3) and sevelamer HCl co-administration with cinacalcet. No severe or serious adverse events or clinically relevant changes in physical or laboratory findings occurred during the studies. CONCLUSION: The pharmacokinetic parameters of cinacalcet were not affected by co-administration of CaCO(3), sevelamer HCl or pantoprazole. Co-administration of these agents with cinacalcet does not require an adjustment of the dose of cinacalcet.