Study on the ocular pharmacokinetics of ion-activated in situ gelling ophthalmic delivery system for gatifloxacin by microdialysis

The poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid precorneal elimination of the drug may be overcome by the use of gel system. The present work was conducted to evaluate the relative bioavailability of ion-activated in situ ophthalmic gel of gatifloxacin by microdialysis. The conventional ophthalmic solution of gatifloxacin was used as reference. The AUC of test group is 3.8-fold vs. the reference group (1.4316 +/- 0.1327 microg.mL(-1).h vs. 0.3756 +/- 0.0380 microg.mL(-1).hr) (P < 0.05), and the C(max) of test group vs. the control group is 3.0-fold (0.3363 +/- 0.0634 microg.mL(-1) vs. 0.1112 +/- 0.0151 microg.mL(-1)) (P < 0.05). The T(max) of test group is longer than that of reference group (2.0 +/- 0.67 hr vs. 0.667 +/- 0.17 hr) (P < 0.1), and K(e) of test group is lower than that of reference group. The developed formulation has a higher bioavailability and longer residence time in aqueous humor than conventional ophthalmic solutions. The developed system is a viable alternative to conventional eye drops.     

Topical Oleo-Hydrogel Preparation of Ketoprofen with Enhanced Skin Permeability

In an attempt to improve the skin penetration of ketoprofen, various transdermal formulations were prepared, and their in vitro skin permeability and in vivo percutaneous absorption were evaluated. In vitro permeation studies were performed using a modified Franz cell diffusion system in which permeation parameters such as cumulative amount at 8 hr Q_8hr, steady-state flux J_ss, or lag time t_L were determined. In the in vivo percutaneous absorption study using the hairless mouse, maximum concentration C_max and area under the curve at 24 hr AUC_24h were measured. The optimal transdermal formulation (oleo-hydrogel formulation) of ketoprofen showed a Q_8hr value of 227.20 μg/cm², a J_ss value of 29.61 μg/cm²/hr, and a t_L value of 0.46 hr. The Q_8hr and J_ss values were about 10-fold (p <. 01) higher than those (Q_8hr = 19.61 μg/cm²; J_ss = 2.66 μg/cm²/hr) from the K-gel and about 3.5-fold (p <. 01) than those (Q_8hr = 60.00 μg/cm²; J_ss = 7.99 μg/cm²/hr) of the K-plaster. In the in vivo percutaneous absorption, the C_max (6.82 μg/ml) and AUC_24h (55.74 μg·hr/ml) values of the optimal formulation were significantly (p <. 01) higher than those of K-gel and K-plaster. The relative bioavailability of the oleo-hydrogel following transdermal administration in reference to oral administration was about 37%, and the C_max value (4.73 μg/cm²) in the hypodermis following topical administration was much higher than those from the conventional products (C_max of K-gel and K-plaster were 0.92 ± 0.19 μg/cm² and 1.27 ± 0.37 μg/cm², respectively). These data demonstrate that the oleo-hydrogel formulation of ketoprofen was more beneficial than conventional products (K-gel and K-plaster) in enhancing transdermal permeation and skin absorption of ketoprofen. Furthermore, there was a good correlation between in vitro permeation parameters and in vivo percutaneous absorption parameters.     

The efficacy of anti-VEGF antibody-modified liposomes loaded with paeonol in the prevention and treatment of hypertrophic scars

The aim of this study was to investigate the efficacy of anti-VEGF antibody-modified Paeonol liposome gels (PAE-BEV-lip gels) in the prevention and treatment of hypertrophic scars (HS). Systematic optimization of the encapsulation process of anti-VEGF antibody-modified Paeonol liposomes (PAE-BEV-lips) was performed using Box–Behnken design with the optimized parameters as follows: SPC concentration of 7.36?mg mL^?1; SPC-Chol-PAE:pNP-PEG₃₀₀₀-DOPE:BVE-PEG₃₀₀₀-DOPE ratio of 14:5:4:0.28:0.05, w/w; the hydration temperature of 41?°C; stripping using pH 7.5 sodium dihydrogen phosphate buffer; and ultrasound for 3?min (ultrasound time 2?s, interval 3?s, power 300?W). Using these conditions, the encapsulation efficiency of PAE reached the peak level, i.e. 73.61?±?2.36%. The PAE-BEV-lips displayed unimodal size-distribution with a mean diameter of (235.7?±?4.67) nm and a zeta potential of –(5.13?±?0.25) mV. The investigation of the retention effect PAE-BEV-lip gels revealed a slower transdermal delivery rate, a remarkable dermal retention effect, and superior bioavailability compared to PAE gels and PAE conventional liposome gels (PAE-lip gels). Meanwhile, PAE-BEV-lip gels exhibited definite effects on the prevention and treatment of HS of the rabbit ears. The PAE-BEV-lip gels group showed a lower scar proliferation rate, fewer and looser collagenous fibers and fibromyocytes, more regular chondrocytes, less calcified tissue and fewer inflammatory cells compared to other groups. At the same time, PAE-BEV-lip gels significantly reduced scar hyperplasia index (1.34?±?0.51) and levels of VEGF, TGF-β₁ and TNF-α (30.90?±?3.57, 733.2?±?43.19 and 66.76?±?2.98?ng·L^?1, respectively), compared to the model group (p?<?.01).     

In vitro percutaneous absorption enhancement of granisetron by chemical penetration enhancers

Granisetron (GRN), a potent antiemetic agent, is frequently used to prevent nausea and vomiting induced by cancer cytotoxic chemotherapy and radiation therapy.

Objective: As part of our efforts to further modify the physicochemical properties of this market drug, with the ultimate goal to formulate a better dosage form for GRN, this work was carried out to improve its permeability in vitro.

Methods: The permeation behavior of GRN in isopropyl myristate (IPM) was investigated across excised rabbit abdominal skin and the enhancing activities of three novel O-acylmenthol derivatives synthesized in our laboratory as well as five well-known chemical enhancers were evaluated.

Results: It was found that the steady-state flux of granisetron free base (GRN-B) was about 26-fold higher than that of granisetron hydrochloride (GRN-H). The novel enhancer, 2-isopropyl-5-methylcyclohexyl heptanoate (M-HEP), was observed to provide the most significant enhancement for the absorption of GRN-B. When incorporated in the donor solution with the optimal enhancer M-HEP, the steady-state flux of GRN-B increased from (196.44?±?12.03) μg·cm^?2·h^?1 to (1044.95?±?71.99) μg·cm^?2·h^?1 (P?<?0.01).

Conclusion: These findings indicated that the application of chemical enhancers was an effective approach to increase the percutaneous absorption of GRN in vitro.     

Formulation and in Vitro and in Vivo Availability of Diclofenac Sodium Enteric-Coated Beads

Abstract

Diclofenac sodium enteric-coated beads were prepared using the conventional pan coating technique. Eudragit L₁₀₀ was used as a pH-dependent release-controlling polymer. The beads were evaluated for their particle size distribution, drug loading efficiency, flowability, in vitro release in 0.1 N HCI (pH 1.2) and phosphate buffer (pH 6.8), and bioavailability in beagle dogs relative to the commercial enteric-coated tablets Voltaren®. The beads showed a narrow particle size distribution in which 83% of the beads were in the range of 1-2 mm. The actual yield of the beads was 90.5% and their drug loading was 92%. The beads released about 8% of the drug during 2 hr of dissolution in 0.1 N HCI, and the commercial tablets released no drug. In phosphate buffer (pH 6.8) both formulations released their drug content in 1 hr. Both formulations are, therefore, in compliance with the USP requirements for release from enteric-coated dosage forms.

The in vivo availability study in six beagle dogs revealed that the formulated enteric-coated beads filled in hard gelatin capsules had a 197.54% bioavailability relative to that of the commercial Voltaren tablets. The tablets showed a significantly lower (p < 0.05) area under curve for 0—8 hr (AUC_{0-8 hr}) of 13.44 ± 15.02 μg hr/ml compared to 26.55 ± 5.19 μg hr/ml for the capsules. The capsules showed a nonsignificantly (p > 0.05) higher peak plasma concentration (C^max) of 6.77 ± 0.67 μg/ml compared to 5.88 ± 7.38 μg/ml for the tablets. The time to reach peak (T_max) values were 2 ± 1.48 and 2.25 ± 1.08 hr for the capsules and tablets, respectively. The capsules showed less interdog variability with respect to C_max (CV% 34.6) and AUC (CV% 19.55) compared to CV% 79.9 and 111.76, respectively, for the commercial tablets     

Improved dissolution rate and bioavailability of fenofibrate pellets prepared by wet-milled-drug layering

Objective: The objective of this study is to investigate the wet-milled-drug layering process which could significantly improve the dissolution rate and oral bioavailability of fenofibrate pellets.

Methods: Fenofibrate was milled with HPMC-E5 to prepare a uniform suspension in the micrometer and nanometer range, and this suspension was then layered on to sugar spheres to form the pellets (F1, F2).

Results: The particle size was significantly reduced (from 1000 µm to 1–10 µm and 400?nm) but the fenofibrate in suspension retained its crystallinity from the results of DSC and PXRD investigations. The dissolution rate of F1-F2 and Antara® capsules was 55.47 %, 61.27 % and 58.43 %, respectively, in 0.01?mol/L SDS solution over 60?min. In addition, F1, F2, and Antara® capsules were given orally to 6 beagle dogs to determine the bioavailability. The C_max of F1, F2 (8.21?±?2.55 and 9.33?±?2.37 μg/mL)and the AUC_(0?t) of F1, F2 (152.46?±?78.89 and 172.17?±?67.58 μg/mL·h)were higher than those of Antara® (6.02?±?3.34 μg/mL and 89.82?±?46.46 μg/mL·h) and, F1, F2 reached their C_max earlier than Antara® (F1: 2.0?±?1.1?h; F2: 1.8?±?1.2?h; Antara®: 6.0?±?8.9?h).

Conclusion: These results show that the wet-milled-drug layering technique is a powerful method to improve the dissolution rate and the bioavailability of fenofibrate.     

Comparison of pharmacokinetics in beagle dogs of nimesulide bilayer tablets with dispersible tablets

The purpose of this study was to compare the in vitro release and the in vivo pharmacokinetics of bilayer tablets with the conventional dispersible tablets of nimesulide. The tablets were administered to beagle dogs and the plasma levels of nimesulide were determined by high-performance liquid chromatography-MS/MS. The pharmacokinetic parameters were calculated using a noncompartmental model. The bilayer tablets showed a biphasic in vitro release pattern with initial burst release and sustained release following the quasi-Fickian diffusion-based release mechanism. The C_max, t_max, mean residence time (MRT), and area under the curve from 0 to 36 h were 10.8 ± 4.2 μg/mL, 2.3 ± 1.0 h, 6.7 ± 2.1 h, 81.5 ± 26.7 μg·h/mL for the bilayer tablets and 14.8 ± 5.8 μg/mL, 2.7 ± 0.8 h, 5.6 ± 0.9 h, 95.4 ± 44.2 μg·h/mL for the dispersible tablets. Compared with the dispersible tablets, the bilayer tablets have lower C_max, similar t_max, and longer MRT. The aforementioned pharmacokinetic parameters, especially the MRT demonstrated to be valuable for evaluating the biphasic characteristics. This study provides a promising in vivo evaluation method for the bilayer tablets with biphasic release pattern.     

Determination of adamantane derivatives in pharmaceutical formulations by using spectrophotometric UV-Vis method

A simple and sensitive extractive spectrophotometric method have been developed and validated for determination of amantadine hydrochloride (AM), memantine hydrochloride (MM) and rimantadine hydrochloride (RM) in pure and pharmaceutical formulations. The method is based on the reaction of these active compounds with bromophenol blue (BB) in acetate buffer (0.1 M) pH 3.5 to form an orange-colored products which have absorption maxima at 408 nm. The procedure of complexation was optimized with regard to such factors as concentrations of BB, pH of medium, a kind of extracting solvents and a number of extractions. Under the optimum conditions, linear relationships A₄₀₈ = f(c) with good correlation coefficients (≥0.996) and low limit of detection were obtained in the ranges of 50.0–220.0 µg·mL^?1, 20.0–150.0 µg·mL^?1 or 10.0–110.0 µg·mL^?1 for AM, MM and RM, respectively, for the spectrophotometric methods. The proposed method could be applied to the determination of AM, MM and RM in dosage forms. The recovery was 95.3–101.9%. The method was linear, precise and accurate.     

Preparation and Pharmacokinetics in Rabbits of Breviscapine Unilamellar Vesicles

ABSTRACT

The purpose of the study was to prepare the unilamellar liposomal vesicles of breviscapine (Breviscapine-LUVs) and investigate the pharmacokinetics of Breviscapine-LUVs in rabbits. Breviscapine-LUVs were prepared by the film dispersion method and treated further by extrusion. Its size distribution and zeta potential were determined by photon correlation spectroscopy. The encapsulation efficiency (EE) and cumulative release of Breviscapine-LUVs were assayed by the dialysis method. The crossover design (two periods) was used in six rabbits, which were administered Breviscapine-LUVs and reference preparation. Results showed that the particle size of Breviscapine-LUVs was 50.8 nm, and the polydispersity index was 0.287. The zata potential was ?24 mV ± 9 mV(n = 3), and the EE% was 81.1 ± 1.1% (n = 3). The cumulative release of vesicles in 0.9% NaCl was 17.2 ± 0.78%, 26.1 ± 0.68%, and 29.9 ± 0.81% in 2, 8, and 24 h, respectively. The mean concentration-time curves of breviscapine liposomes and reference preparation were both fitted to a two-compartment model with the main pharmacokinetic parameters as follows: t_1/2β of Breviscapine-LUVs and reference preparation were (42.5 ± 28.6) min and (6.01 ± 4.64) min, respectively; CL_(s) were (15.3 ± 9.03) mL × min^?1 and (84.6 ± 40.6) mL × min^?1, respectively; AUC_0–300 were (1267 ± 1083) μg × min × mL^?1 and (196 ± 107) μg × min × mL^?1, respectively. Compared with the reference preparation, breviscapine liposomes had a much higher concentration in plasma and contained characteristic of sustained-release, which ameliorated the pharmacokinetic properties of scutellarin.     

Therapeutic Window of Ligand‐Free Silver Nanoparticles in Agar‐Embedded and Colloidal State: In Vitro Bactericidal Effects and Cytotoxicity

The inhibition of bacterial growth through effective non‐toxic antimicrobial substances is of great importance for the prevention and therapy of implant infections in various medical disciplines. For the evaluation of a therapeutic window of silver nanoparticles (AgNPs), their bactericidal properties were tested in agar composites and colloids on four medical relevant bacteria. Therefore, we produced AgNPs using high‐power nanosecond laser ablation in water showing a log‐normal particle diameter distribution centered at 17 nm. Bacteria were incubated with AgNP concentrations ranging from 5 to 70 µg · mL^?1 and the growth rate was recorded. Additionally, cytotoxic effects of AgNPs on human gingival fibroblasts were examined. The experiments demonstrated that laser‐synthesized AgNPs resulted in a significant bacterial growth inhibition of more than 80% at the indicated concentrations in a solid agar model (Pseudomonas aeruginosa 10 µg · mL^?1, Streptococcus salivarius 10 µg · mL^?1, Escherichia coli 20 µg · mL^?1, Staphylococcus aureus 70 µg · mL^?1). In a planktonic bacteria model, the growth of the tested bacteria was significantly delayed by the addition of AgNPs at a concentration of 35 µg · mL^?1. The cytotoxic assays showed limited adverse effects on human fibroblasts at concentrations of less than 20 µg · mL^?1. The present study illustrates the strong antibacterial effects of ligand‐free, laser‐generated AgNPs that exhibit moderate cytotoxic effects, resulting in a therapeutically applicable concentration of AgNPs for medical purposes between 10 and 20 µg · mL^?1.     

Relative Bioavailability and Pharmacokinetic Parameters Following Adminstration of Single Oral Dose (2×150 mg) of Chloroquine Tablet in Healthy Subjects

Abstract

The bioavailability ot Chloroquine phosphate (150 mg base) film coated tablet (manufactured by Pars - Darou Co. Iran) was compared with that ot the Resochin tablet (Bayer, Germany) in seven healthy male and female volunteers. Blood samples were collected up to 14 days utter oral dosing of 300 nig and chloroquine serum concentrations were determined by means ot High Performance Liquid Chromatography (HPLC). From the analysis ot serum samples the following pharmacokinetic parameters were obtained: the absorption rate of test tablet and that of reference were 0.25 h^?1 and 0.34 h^?1 respectively; maximum serum concentration of both tablets was nearly equal, 81.6±25 and 83.4±27 ng/ml (for test and reference tablets respectively); time to reaching C_max (t_max) was also very similar, 4±1.6 for test and 4±1.0 h for reference; the area under the serum concentration-time curve [AUC(O -)] of 6976 ng.ml^?1.h±1967 for test and 6446 ng.ml^?1.h ± 2460 for reference tablets were found using trapezoidal rule. By evaluating of the r=(T/R)×100 for each parameters, the test tablet was found to be bioequivalent to Resochin at p = 0.05.     

Influence of hydrothermal treatment on the microstructure and oxidation resistance of a Zn4B2O7·H2O (4ZnO·B2O3·H2O) coating for C/C composites

Antioxidant modification for C/C composites by in situ hydrothermal synthesise at 140 °C of a 4ZnO·B₂O₃·H₂O crystallite coating has been successfully achieved. The influence of hydrothermal time on the phase composition, microstructure of the as-prepared Zn₄B₂O₇·H₂O (4ZnO·B₂O₃·H₂O), and its antioxidant modification for C/C composites were investigated. Samples were characterised by XRD, SEM, isothermal oxidation test and TG-DSC. Results show that, 4ZnO·B₂O₃·H₂O crystalline coating is achieved on the surface of C/C composites after the hydrothermal treatment at 140 °C for time in the range of 2–12 h. A smooth and crack-free 4ZnO·B₂O₃·H₂O layer can be obtained when the hydrothermal time reaches 8 h. Isothermal oxidation test demonstrates that the oxidation resistance of C/C composites is improved. The as-modified composites exhibit only 1.52 g·cm^?2 weight loss after oxidation at 600 °C for 15 h, while the non-modified one shows a 6.57 g·cm^?2 weight loss after only 10 h oxidation. For the uncoated C/C composite the oxidation rate is approximately linear with time (non-protective oxidation), thus at 15 h exposure one can estimate the mass loss to be 6.57 g·cm^?2 after 10 h for direct comparison with the coated samples.     

The influence of the structure and the composition of water/AOT-Tween 85/IPM microemulsion system on transdermal delivery of 5-fluorouracil

The purpose of this study was to investigate the influence of the structure and the composition of water/Aerosol-OT (AOT)-Tween 85/isopropylmyristate (IPM) microemulsion system (WATI) on transdermal delivery of 5-fluorouracil (5-FU). The structure of WATI was characterized by measuring surface tension, density, viscosity, electric conductivity, and differential scanning calorimetry. The effect of the drug loading, water content, component compositions and the amount of mixed surfactant on permeation of 5-FU through mice skin was evaluated by using Franz-type diffusion cells. The results in vitro implied that WATI was W/O microemulsion when the water content was below 20 wt% at fixed 20 wt% of mixed surfactant at 25°C, then might be transformed to a bicontinuous structure, finally, formed O/W microemulsion with water content over 30 wt%. Increase of the drug loading can directly facilitate the penetration of the drug across the skin. Drug diffusion after 12?h from the bicontinuous microemulsion (795.1?±?22.3 µg·cm^?2) would be fastest compared to that from the W/O microemulsion (650.2?±?11.7 µg·cm^?2) and the O/W microemulsion (676.6?±?14.8 µg·cm^?2). The combination of AOT and IPM could bring about synergistic effect on the skin enhancement, however, Tween 85 in WATI decreased the cumulative permeation amount of 5-FU. The content of mixed surfactant had no effect on the permeation of 5-FU at fixed surfactant/cosurfactant ratio (K_m?=?2). Thus, the increased transdermal delivery the hydrophilic drug of 5-FU was found to be concerned with both of the structure and the composition of WATI.     

Atmospheric Fine and Coarse Mode Aerosols at Different Environments of India and the Bay of Bengal During Winter-2014: Implications of a Coordinated Campaign

In this paper, we present mass concentrations of particulate matter [PM_2.5, PM₁₀ size fractions and total suspended particulates (TSP)] measured simultaneously over land stations (Kullu, Patiala, Delhi, Ajmer, Agra, Lucknow, Varanasi, Giridih, Kolkata, Darjeeling, Jorhat, Itanagar, Imphal, Bhubaneswar, and Kadapa), mostly distributed across the Indo-Gangetic plain (IGP) of India as well as in the marine atmosphere over Bay of Bengal (BoB) in the period from 20 January to 3 February, 2014. The main objective of this study was to quantify the continental outflow of particulates (PM_2.5, PM₁₀ and TSP) from IGP and associated regions into the BoB along with low level north-east wind flow during winter monsoon period. The present study provides a glimpse of the aerosol loading over the IGP region. During this campaign, the highest average PM_2.5 (187.8 ± 36.5 µg m^?3, range 125.6–256.2 µg m^?3), PM₁₀ (272.6 ± 102.9 µg m^?3, range 147.6–520.1 µg m^?3) and TSP (325.0 ± 71.5 µg m^?3, range 220.4–536.6 µg m^?3) mass concentrations were recorded at Varanasi, Kolkata and Lucknow over middle and lower IGP regions. The PM_2.5 (average 41.3 ± 11.9 µg m^?3; range 15.0–54.4 µg m^?3), PM₁₀ (average 53.9 ± 18.9 µg m^?3; range 30.1–82.1 µg m^?3) and TSP (average 78.8 ± 29.7 µg m^?3; range 49.1–184.5 µg m^?3) loading over BoB were found to be comparable to land stations and suggests possible continental outflow. Over the continental region, the highest PM_2.5/PM₁₀ ratio was recorded at Delhi (0.87). The PM_2.5/PM₁₀ ratio over BoB (0.77) was found to be quite high and comparable to Varanasi (0.80) and Agra (0.79).     

Design and optimization of gastric floating sustained-release mini-tablets of alfuzosin hydrochloride based on a factorial design: in vitro/in vivo evaluation

Abstract

The purpose of this research was to develop multiple-unit gastric floating mini-tablets and to evaluate the possibility of using these mini-tablets as a delivery system to improve the drug absorption for drugs with a narrow absorption window. Mini-tablets were prepared using hydroxypropyl methylcellulose (HPMC K100M) and carbopol 971P as release retarding agents and sodium bicarbonate (NaHCO₃) as gas-forming agent. The properties of the prepared mini-tablets in terms of floating characteristic parameters and in vitro release were evaluated. Furthermore, in vivo gastric retention study in rats and in vivo pharmacokinetic study in rabbits of the optimized formulation were performed. The optimized mini-tablets containing 45% HPMC K100M, 15% stearyl alcohol, 13% carbopol 971P, and 12% NaHCO₃ were found to float immediately within 1?min and duration more than 9?h. The in vivo gastric retention study results indicated that the mini-tablets could retain in the stomach for more than 6.67?h. Furthermore, the AUC_0?t of the floating mini-tablets (6849.83?±?753.80?h ng·mL^?1) was significantly higher than that of marketed sustained-release tablets XATRAL®XL (4970.16?±?924.60?h ng·mL^?1). All these results illustrated that the gastric floating mini-tablets might be a promising drug delivery system for drugs with a narrow absorption window.     

Outcomes of Severe Methanol Intoxication Treated with Hemodialysis: Report of Seven Cases and Review of Literature

To identify factors associated with the outcome of severe methanol intoxication treated with hemodialysis, we analyzed the clinical course of 7 patients admitted with serum methanol level higher than 50 mg/dL, and therefore requiring hemodialysis. Four patients (group A) had adverse outcomes (1 death, 3 severe neurological deficits and/or blindness) and 3 patients (group B) had no adverse outcomes. Compared to group B, group A appeared to have a longer delay between ingestion of methanol and arrival at the emergency department (ED), a longer wait in the ED until ethanol infusion was started (3.6 ± 2.7 vs 1.3 ± 0.9 hr, p < 0.05), and, on admission, higher serum methanol (504 ± 219 vs 321 ± 228 mg/dL, p < 0.05), higher serum osmolality (460.5 ± 98.2 vs 397.6 ± 52.3 mOsm/kg, p < 0.05), higher serum osmolal gap (162.6 ± 76.7 vs 105.6 ± 52.9 mOsm/kg, p < 0.05), lower arterial pH (6.86 ± 0.08 vs 7.38 ± 0.16, p < 0.01), lower serum bicarbonate (4.6 ± 1.6 vs 19.9 ± 5.7 mmol/L, p < 0.01), and higher serum anion gap (36.5 ± 1.3 vs 14.3 ± 6.7 mEq/L, p < 0.01). Delay in the ED until hemodialysis was started did not differ (group A 6.4 ± 2.6 hr, group B 5.3 ± 3.5 hr), while duration of hemodialysis until serum methanol levels became permanently undetectable was longer in group A (15.0 ± 0.5 vs 8.4 ± 4.4 hr, p < 0.01). The ingested dose of methanol and the delay between ingestion and initiation of therapy to block methanol metabolism (ethanol infusion) and remove methanol from the body (hemodialysis) appear to be the critical factors influencing the outcome of methanol intoxication. Early diagnosis and initiation of treatment before substantial parts of the ingested methanol have been metabolized are of paramount importance in ensuring a favorable outcome.     

Simultaneous expansion and harvest of hematopoietic stem cells and mesenchymal stem cells derived from umbilical cord blood

The simultaneous expansion and harvest of hematopoietic stem cells and mesenchymal stem cells derived from umbilical cord blood were carried out using bioreactors. The co-culture of umbilical cord blood (UCB)-derived hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) was performed within spinner flasks and a rotating wall vessel (RWV) bioreactor using glass-coated styrene copolymer (GCSC) microcarriers. The medium used was composed of serum-free IMDM containing a cocktail of SCF 15 ng·mL^?1, FL 5 ng·mL^?1, TPO 6 ng·mL^?1, IL-3 15 ng·mL^?1, G-CSF 1 ng·mL^?1 and GM-CSF 5 ng·mL^?1. Accessory stromal cells derived from normal allogeneic adipose tissue were encapsulated in alginate-chitosan (AC) beads and used as feeding cells. The quality of the harvested UCB-HSCs and MSCs was assessed by immunophenotype analysis, methylcellulose colony and multi-lineage differentiation assays. After 12 days of culture, the fold-expansion of total cell numbers, colony-forming units (CFU-C), CD34⁺/CD45⁺/CD105^? (HSCs) cells and CD34^?/CD45^?/CD105⁺ (MSCs) cells using the RWV bioreactor were (3.7 ± 0.3)- , (5.1 ± 1.2)- , (5.2 ± 0.4)- , and (13.9 ± 1.2)-fold respectively, significantly better than those obtained using spinner flasks. Moreover, UCB-HSCs and UCB-MSCs could be easily separated by gravity sedimentation after the co-culture period as only UCB-MSCs adhered on to the microcarriers. Simultaneously, we found that the fibroblast-like cells growing on the surface of the GCSC microcarriers could be induced and differentiated towards the osteoblastic, chondrocytic and adipocytic lineages. Phenotypically, these cells were very similarly to the MSCs derived from bone marrow positively expressing the MSCs-related markers CD13, CD44, CD73 and CD105, while negatively expressing the HSCs-related markers CD34, CD45 and HLA-DR. It was thus demonstrated that the simultaneous expansion and harvest of UCB-HSCs and UCB-MSCs is possible to be accomplished using a feasible bioreactor culture system such as the RWV bioreactor with the support of GCSC microcarriers.     

Pharmacokinetic properties and bioequivalence of candesartan cilexetil in Korean healthy volunteers

Candesartan is a long-acting and selective nonpeptide AT₁ subtype angiotensin II receptor antagonist. The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two candesartan cilexetil 16?mg formulations. Forty healthy volunteers were randomly assigned into two groups. After a single dose of 16?mg candesartan cilexetil oral administration, blood samples were collected at specific time intervals from 0–36?h. The plasma concentrations of candesartan cilexetil were determined by LC-MS/MS. The pharmacokinetic parameters such as AUC_last, AUC_inf and C_max were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data. The mean for AUC_last in the reference and the test drug were 1530.1?±?434.6 and 1315.7?±?368.6 ng·h/mL. The mean for AUC_inf in the reference and the test drug were 1670.0?±?454.5 and 1441.2?±?397.8 ng·h/mL. The mean value for C_max in the reference and the test drug was 142.6?±?41.0 and 134.9?±?41.4?ng/mL. The 90% confidence intervals for the AUC_last, AUC_inf and C_max were in the range of log 0.81–log 0.91, log 0.81–log 0.91 and log 0.88–log1.01, respectively. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these health volunteers. Both formulations were safe and well tolerated in 16?mg of candesartan cilexetil hydrochloride.     

Development and pharmacokinetic evaluation of alginate-pectin polymeric rafts forming tablets using box behnken design

Abstract

Raft is an emerging drug delivery system, which is suitable for controlled release drug delivery and targeting. The present study aimed to evaluate the physico-chemical properties of raft, in vitro release of pantoprazole sodium sesquihydrate and conduct bioavailability studies. Box behnken design was used with three independent and dependent variables. Independent variables were sodium alginate (X₁), pectin (X₂) and hydroxypropyl methyl cellulose K100M (X₃) while dependent variables were percentage drug release at 2 (Y₂), 4 (Y₄) and 8?h (Y₈). The developed rafts were evaluated by their physical and chemical properties. Fourier transform infrared spectroscopy and differential scanning calorimetry were used to study the chemical interaction and thermal behaviour of drug with polymers. Alginate and pectin contents of R9 formulation were 99.28% and 97.29%, respectively, and acid neutralization capacity was 8.0. R9 formulation showed longer duration of neutralization and nature of raft was absorbent. The raft of R9 formulation showed 98.94% release of PSS at 8?h in simulated gastric fluid. Fourier transform infrared spectroscopy showed no chemical interaction and differential scanning calorimetry indicated endothermic peaks at 250?°C for pantoprazole sodium sesquihydrate. t_max for the test and reference formulations were 8?±?2.345?h and 8?±?2.305?h, respectively. C_max of test and reference formulations were 46.026?±?0.567?µg/mL and 43.026?±?0.567?µg/mL, respectively. AUC_(0-t) of the test and reference formulations were 472.115?±?3.467?µg?×?h/mL and 456.105?±?2.017?µg?×?h/mL, respectively. Raft forming system successfully delivered the drug in controlled manner and improved the bioavailability of drugs.     

Microstructural,mechanical and electrochemical characterisation of biomaterial ASTM F745 cast by vacuum

Abstract

Countergravity low pressure casting (CLA) was performed to enhance the properties of ASTM F745 stainless steel (SS), which is usually used as biomaterial. The macro- and microstructures were compared with those obtained by the conventional process of investment casting (IC). The SS cast by CLA (SSCLA) exhibited a smaller size of solidification cell and finer dendritic microstructure. The average of its dendritic primary spacing was 110·4 μm, while for the same steel cast by IC (SSIC), it was 186·7 μm. The density of non-metallic inclusions δ_I in the SSCLA was 717 I mm^?2, being the majority of them smaller than 1·5 μm. In the case of SSIC, δ_I was 852 I mm^?2, with a size distribution of up to 8 μm. The SSCLA showed a higher breakdown potential than the SSIC, the values being 0·300 and 0·210 V(saturated calomel electrode) respectively, which means a higher resistance to suffer localised corrosion. Finely, the CLA process also allowed obtaining better mechanical properties.