Radiation-Shielding Devices: The Best Combination for Spine Interventional Procedures.

PURPOSE: Although many studies have examined the efficiency of various protective devices for reducing the dose of radiation exposure to physicians during interventional pain procedures, no study has compared the protective effect of these devices when they are used in combination. The purpose of this prospective experimental study was to determine the best combination of radiation-shielding devices. MATERIALS AND METHODS: Using anthropomorphic phantoms of a physician and patient, we measured the radiation protection efficiency (RPE) of each of the following protection methods and in combination during C-arm-guided simulated lumbar epidural injection: (a) personal protective equipment (PPE), (b) bedside curtain shield (Curtain), (c) x-ray tube filter (Filter), and (d) fluoroscopic collimation method (Collimation). We measured exposure doses using personal electronic dosimeters at the eye, thyroid, and gonad levels for 1 minute. Each experiment was repeated 15 times. RESULTS: The radiation exposure dose and RPE with the best single-, double-, and triple-protection methods were as follows: PPE for the single-protection method (11.82 µSv/min, 80.04%), PPE + Collimation for the double-combination method (4.68 µSv/min, 92.09%), and PPE + Collimation + Curtain for the triple-combination method (3.08 µSv/min, 93.39%). Additionally, PPE + Collimation + Curtain + Filter for the quadruple-combination method resulted in a radiation exposure and RPE of 2.91 µSv/min and 93.61%, respectively, compared with nonprotection. CONCLUSIONS: The best single-, double-, and triple-protection method was PPE, PPE + Collimation, and PPE + Collimation + Curtain, respectively. While preparing protective equipment, we recommend prioritizing equipment in this order.

Species Differences in Stereoselective Pharmacokinetics of HSG4112, A New Anti-Obesity Agent.

HSG4112, a racemic drug, is a new anti-obesity agent. In this study, the stereoselective pharmacokinetics of HSG4112 were investigated in rats and dogs, and the underlying mechanism was investigated. The plasma concentrations of HSG4112(S) and HSG4112(R) were quantitated in plasma from rats and beagle dogs after IV and/or oral administration of racemic HSG4112. The concentration of HSG4112(S) was significantly higher than that of HSG4112(R) in rat plasma. Contrarily, the concentration of HSG4112(R) was significantly higher than HSG4112(S) in dog plasma. A metabolic stability test with liver microsomes showed that HSG4112(S) was more stable than HSG4112(R) in rat liver microsomes, but the difference between stereoisomers did not appear in dog liver microsomes. However, the stereoselectivity was observed in dog liver and intestinal microsomes after uridine 5'-diphospho-glucuronic acid was added. Thus, stereoselective metabolism by uridine 5'-diphospho-glucuronosyltransferases is mainly responsible for the stereoselective pharmacokinetics in dogs. These results suggest that the species difference in the stereoselective plasma pharmacokinetics of HSG4112 is due to the stereoselective metabolism.

Pharmacokinetic studies of a novel tubulin inhibitor SK1326 in rat plasma by UPLC-MS/MS.

A sensitive method for quantitation of SK1326 in rat plasma has been established using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI/MS/MS). SK1326 and the internal standard (tramadol) in plasma sample were extracted using acetonitrile. A centrifuged upper layer was then evaporated and reconstituted with a mobile phase of 0.5% formic acid-acetonitrile (35:65, v/v). The reconstituted samples were injected into a C18 reversed-phase column. Using MS/MS in the multiple reaction monitoring mode, SK1326 and tramadol were detected without severe interference from the rat plasma matrix. SK1326 produced a protonated precursor ion ([M + H]+ ) at m/z 432.3 and a corresponding product ion at m/z 114.4. The internal standard produced a protonated precursor ion ([M + H]+ ) at m/z 264.4 and a corresponding product ion at m/z 58.1. Detection of SK1326 in rat plasma by the UPLC-ESI/MS/MS method was accurate and precise with a quantitation limit of 1.0 ng/mL. The validation, reproducibility, stability and recovery of the method were evaluated. The method has been successfully applied to pharmacokinetic studies of SK1326 in rat plasma. The pharmacokinetic parameters of SK1326 were evaluated after intravenous (at a dose of 10 mg/kg) and oral (at a dose of 20 mg/kg) administration of SK1326 in rats. After oral administration (20 mg/kg) of SK1326, the F (fraction absorbed) value was ~77.1%.

Determination of Urinary Caffeine Metabolites as Biomarkers for Drug Metabolic Enzyme Activities.

Caffeine is commonly taken via the daily dietary consumption of caffeine-containing foods. The absorbed caffeine is metabolized to yield various metabolites by drug-metabolizing enzymes, and measuring the levels of each caffeine metabolite can provide useful information for evaluating the phenotypes of those enzymes. In this study, the urinary concentrations of caffeine and its 13 metabolites were determined, and the phenotypes of drug metabolic enzymes were investigated based on the caffeine metabolite ratios. Human urine samples were pretreated using solid phase extraction, and caffeine and its metabolites were analyzed using liquid chromatography-tandem mass spectrometry. Based on the urinary caffeine metabolite concentrations, the caffeine metabolite ratios were calculated for six human subjects at specified time points after caffeine intake. Variations in urinary metabolite levels among individuals and time points were reported. In addition, the resultant enzyme activities showed different patterns, depending on the metabolite ratio equations applied. However, some data presented a constant metabolite ratio range, irrespective of time points, even at pre-dose. This suggests the possibility of urinary caffeine metabolite analysis for routine clinical examination. These findings show that urinary caffeine and the metabolite analysis would be useful in evaluating metabolic phenotypes for personalized medicine.

Anti-Angiogenic Effect of Asperchalasine A Via Attenuation of VEGF Signaling.

Cytochalasans are a group of structurally diverse fungal polyketide-amino acid hybrid metabolites that exhibit diverse biological functions. Asperchalasine A was identified and isolated from an extract of the marine-derived fungus, Aspergillus. Asperchalasine A is a cytochalasan dimer which consists of two cytochalasan molecules connected by an epicoccine. This study investigated the potential antiangiogenic effects of Aspergillus extract and asperchalasine A, which significantly inhibited cell adhesion and tube formation in human umbilical vein endothelial cells (HUVECs). Aspergillus extract and asperchalasine A decreased the vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR)-2 mRNA expression in a concentration-dependent manner. In addition, Aspergillus extract and asperchalasine A inhibited angiogenesis via downregulation of VEGF, p-p38, p-extracellular signal-regulated protein kinase (ERK), p-VEGFR-2, and p-Akt signaling pathways. Moreover, Aspergillus extract and asperchalasine A significantly inhibited the amount of blood vessel formation in fertilized chicken eggs using a chorioallantoic membrane assay. Our results provide experimental evidence of this novel biological activity of the potential antiangiogenic substances, Aspergillus extract, and asperchalasine A. This study also suggests that Aspergillus extract and its active component asperchalasine A are excellent candidates as adjuvant therapeutic substances for cancer prevention and treatment.

A Hydroxypropyl Methylcellulose-Based Solid Dispersion of Curcumin with Enhanced Bioavailability and its Hepatoprotective Activity.

Curcumin is a polyphenol compound derived from the rhizomes of Curcuma longa that exhibits antioxidant, anti-inflammatory, anticancer, and antimicrobial properties. However, its low solubility in aqueous solutions, low absorption following oral administration, and rapid degradation limit its use as a functional food material. In this study, a hydroxypropyl methylcellulose-based solid dispersion of curcumin (DW-CUR 20) was prepared and its bioavailability was evaluated. In addition, its therapeutic efficacy as a hepatoprotective agent was investigated using the model of tert-butyl hydroperoxide (t-BHP)-induced hepatocyte damage. The rat plasma pharmacokinetic study showed that the oral curcumin bioavailability of DW-CUR 20 significantly increased compared to that of non-formulated curcumin. DW-CUR 20 showed a concentration-dependent hepatocyte protective effect on t-BHP-induced HepG2 cells. DW-CUR 20 inhibited the release of lactate dehydrogenase and decreased apoptosis-related proteins such as Poly (ADP-ribose) polymerase, cleaved caspase-7 and cleaved caspase-8 on t-BHP-treated HepG2 cells. These findings suggest that DW-CUR 20 could be a promising formulation for enhancing the therapeutic efficiency of curcumin and for improving the safety.

Pharmacokinetics and Metabolism of Acetyl Triethyl Citrate, a Water-Soluble Plasticizer for Pharmaceutical Polymers in Rats.

Acetyl triethyl citrate (ATEC) is a water-soluble plasticizer used in pharmaceutical plasticized polymers. In this study, the pharmacokinetics and metabolism of ATEC were investigated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in rats. Plasma protein precipitation with methanol was used for sample preparation. For chromatographic separation, a C18 column was used. The mobile phases consisted of 0.1% formic acid and 90% acetonitrile, and gradient elution was used. The following precursor-product ion pairs were selected for reaction monitoring analysis: 319.1 m/z → 157 m/z for ATEC and 361.2 m/z → 185.1 m/z for tributyl citrate (internal standard) in positive ion mode. The LC-MS/MS method was fully validated and successfully applied to a pharmacokinetic study of ATEC in rats. The pharmacokinetic study showed that the volume of distribution and mean residence time of ATEC were higher after oral administration than after intravenous administration, pointing to extensive first-pass metabolism and distribution in tissue. In addition, the plasma concentration profile of the postulated metabolites of ATEC was investigated in plasma, urine, and feces. The resulting data indicated that ATEC was extensively metabolized and excreted mainly as metabolites rather than as the parent form. The developed analytical method and the data on the pharmacokinetics and metabolism of ATEC may be useful for understanding the safety and toxicity of ATEC.

Pharmacokinetic Properties of Acetyl Tributyl Citrate, a Pharmaceutical Excipient.

Acetyl tributyl citrate (ATBC) is an (the Food and Drug Administration) FDA-approved substance for use as a pharmaceutical excipient. It is used in pharmaceutical coating of solid oral dosage forms such as coated tablets or capsules. However, the information of ATBC on its pharmacokinetics is limited. The aim of this study is to investigate the pharmacokinetic properties of ATBC using liquid chromatography⁻tandem mass spectrometric (LC⁻MS/MS) analysis. ATBC was rapidly absorbed and eliminated and the bioavailability was 27.4% in rats. The results of metabolic stability tests revealed that metabolic clearance may have accounted for a considerable portion of the total clearance of ATBC. These pharmacokinetic data would be useful in studies investigating the safety and toxicity of ATBC.

Biomarkers of angiogenesis as prognostic factors in myelodysplastic syndrome patients treated with hypomethylating agents.

Angiogenesis occurs in response to tissue ischemia and wound healing, and contributes to the pathogenesis of a variety of diseases, such as benign and malignant neoplasia. Several studies have measured bone marrow microvessel density (MVD) in MDS patients and acute myeloid leukemia (AML) patients transformed from MDS, and MVD was higher in MDS patients than controls, but was lower than in AML patients. Vascular endothelial growth factor (VEGF) is expressed in bone marrow blast cells, and an autocrine VEGF signaling mechanism has been established in MDS. Increased bone marrow angiogenesis and VEGF concentrations are adverse prognostic features in all of these patients. In this study, 69 patients were treated in two groups: hypomethylating agents or supportive care with oxymetholone±pyridoxine. We evaluated the MVD and VEGF expression of paraffin-embedded bone marrow samples from patients. We also investigated the relationship between angiogenesis-related biomarkers including MVD, VEGF expression, and clinical factors. The patient median age was 65 years, and the median follow-up duration was 28 months. MVD assessment among subtypes of WHO MDS classification showed that the MVD of RCUD was significantly lower than in other types (p=0.02). However, there was no significant difference in VEGF expression according to the subtype of MDS. Although MVD and VEGF expression did not differ between risk groups based on the IPSS, the low risk group tended to have lower expression of angiogenesis-related biomarkers. MDS patients receiving hypomethylating agents had significantly lower MVD expression in responders than in non-responders (6.13±3.38 vs. 9.89±2.10, respectively, p=0.039). In a consecutive evaluation at the time of diagnosis and 3 months after the initial treatment, the group with a decrease or no change of MVD had a higher response rate compared to that in the group with an increase of MVD (92.9% vs. 58.8%, respectively, p=0.045). Adverse prognostic factors included older age, MDS type other than RCUD, a higher IPSS risk group, and abnormal cytogenetics. Although angiogenesis-related markers did not demonstrate any significant prognostic association with survival, MVD (≥10n/mm2) and a strong expression of VEGF seemed to be associated with lower survival rate. These data suggested that the MVD value might be helpful in predicting responsiveness to treatment, especially in MDS patients treated with hypomethylating agents. Although angiogenesis-related markers including VEGF did not demonstrate a significant association with survival outcomes, we observed that high MVD and strong VEGF expression seemed to be associated with lower survival rate. Therefore, biologic markers related to angiogenesis might have a potential as prognostic factors for MDS patients.

Validated high-performance liquid chromatography method for the determination of a phosphodiesterase inhibitor SK5474 in rat plasma and its application to pharmacokinetic study of SK5474.

In this study, a method for the quantitation of SK5474 in rat plasma was developed and validated using high performance liquid chromatography (HPLC). The plasma samples were prepared by deproteinization, and sildenafil was used as an internal standard. Chromatographic separation was achieved using a reversed-phase (C18) column. The mobile phase, 0.02M ammonium acetate buffer:acetonitrile (48:52, v/v), was run at a flow rate of 1.0mL/min, and the column eluent was monitored using an ultraviolet detector at 254nm at room temperature. The retention times of sildenafil and SK5474 were approximately 5.8 and 7.2min, respectively. The quantitation limit of SK5474 in rat plasma was 0.03µg/mL. Pharmacokinetic parameters of SK5474 was evaluated after intravenous (i.v.; at doses of 15mg/kg) and oral (p.o.; at doses of 30mg/kg) administration of SK5474 in rats. After p.o. administration (30mg/kg) of SK5474, F (fraction absorbed) value was approximately 46.0%.