A parametric model for long-term follow-up data from phase III breast cancer clinical trials

We propose a parametric version of a univariate gamma frailty model. The proposed model is shown to be flexible enough to model long-term follow-up survival data from breast cancer clinical trials when the treatment effect diminishes as time progresses, a case for which neither the proportional hazards nor proportional odds assumptions are satisfied. The observed information matrix is computed to evaluate the variances of parameter estimates. A simple parametric test statistic to test proportional odds assumption is also constructed. The model is applied to a data set from a phase III clinical trial on breast cancer.     

Ginsenoside RB<Subscript>1</Subscript> the anti-ulcer constituent from the head of<Emphasis Type="Italic">Panax ginseng</Emphasis>

We previously reported that the butanol (BuOH) fraction of the head of Panax ginseng exhibited gastroprotective activity in peptic and chronic ulcer models. In order to identify the active constituent, an activity-guided isolation of the BuOH faction was conducted with a HCl x ethanol-induced gastric lesion model. The BuOH fraction was passed through a silica-gel column using a chloroform-methanol gradient solvent system, and six fractions (frs. 1-6) were obtained. The active fr. 5 was further separated by silica-gel column, to yield 6 subfractions (subfrs. a-f). Subfr. d was composed of ginsenosides Re, Rc and Rb1. The most active constituent was ginsenoside Rb1 (GRb1), a protopanaxadiol glycoside, which was investigated for its anti-ulcer effect. Gastric injury induced by HCl x ethanol, indomethacin and pyloric ligation (Shay ulcer) was apparently reduced with oral GRb1 doses of 150 and 300 mg/kg. GRb1 at these dosage significantly increased the amount of mucus secretion in an ethanol-induced model. The anti-ulcer effects were consistent with the result of histological examination. These results suggest that the major active constituent in the head of Panax ginseng is GRb1, and that anti-ulcer effect is produced through an increase in mucus secretion.     

Buccal mucosal ulcer healing effect of rhEGF/Eudispert hv hydrogel

We have studied the effect of rhEGF on the buccal mucosal ulcer healing. rhEGF was rapidly degraded upon incubation with the hamster buccal mucosal homogenates; The degradation of rhEGF was significantly inhibited by sodium lauryl sulfate (SLS). Eudispert hv hydrogel and Polycarbophil 974P hydrogel were prepared for rhEGF delivery and their mucoadhesiveness was measured by the Instron method. The mucoadhesive force of Eudispert hv was significantly greater than that of Polycarbophil 974P. Moreover, rhEGF in Eudispert hv hydrogel remained stable for about 2 months. To evaluate the ulcer healing effect of rhEGF, the buccal mucosal ulcer was induced in golden hamsters using acetic acid. At 24 h after administration of rhEGF/Eudispert hv hydrogel, the ulcerous area was decreased compared with rhEGF solution and, as a result, the curative ratio was 36.8 +/- 5.68%. By the addition of SLS (0.5%) to Eudispert hv hydrogel, the curative ratio increased 1.5 times. The mechanism of the action was probably due to a combination of protection of the drug against proteases present in mucosa and prolongation of the release of rhEGF from the formulation at the site of action.     

Surfactant-free microspheres of Poly(ε-caprolactone)/poly (ethylene glyco I )/poly(ε-caprolactone) triblock copolymers as a protein carrier

The aim of this study is to prepare biodegradable microspheres without the use of surfactants or emulsifiers for a novel sustained delivery carriers of protein drugs. A poly(epsilon-caprolactoney poly(ethylene glycol)/poly(epsilon-caprolactone) (CEC) triblock copolymer was synthesized by the ring-opening of epsilon-caprolactone with dihydroxy poly (ethylene glycol) to prepare surfactant-free microspheres. When dichloromethane (DCM) or ethyl formate (EF) was used as a solvent, the formation of microspheres did not occur. Although the microspheres could be formed prior to lyophilization under certain conditions, the morphology of microspheres was not maintained during the filtration and lyophilization process. Surfactant-free microspheres were only formed when ethyl acetate (EA) was used as the organic solvent and showed good spherical microspheres although the surfaces appeared irregular. The content of the protein in the microsphere was lower than expected, probably because of the presence of water channels and pores. The protein release kinetics showed a burst release until 2 days and after that sustained release pattern was showed. Therefore, these observations indicated that the formation of microsphere without the use of surfactant is feasible, and, this the improved process, the protein is readily incorporated in the microsphere.     

Synthesis and PGE<Subscript>2</Subscript> inhibitory activity of vinylated and allylated chrysin analogues

Vinylated and allylated chrysin analogues were prepared as congeners of prenylated flavonoids and evaluated their anti-inflammatory activity. 8-Substituted chrysin analogues were prepared from 2'-hydroxy-3'-iodo-4',6'-dimethoxyacetophenone in 3 steps. 3-Allylated chrysin analogues were prepared from chrysin in 3 steps. Synthesized chrysin analogues (4, 5 and 8) showed moderate inhibitory activities of PGE2 production from LPS-induced RAW 264.7 cells.     

Effects of a new neuroprotective agent KR-31378 on liver cytochrome P450s in male sprague dawley rats

The effects of KR-31378, a neuroprotective agent for ischemia-reperfusion damage, on liver microsomal cytochrome P450s (CYPs) were investigated in male Sprague Dawley rats. When rats were treated orally with KR-31378 for 7 consecutive days, CYP3A-selective erythromycin N-demethylase (ERDM) activity was significantly induced in a dose-dependent manner. In Western immunoblotting, CYP 3A proteins were clearly induced by treatment with KR-31378. Within 24 h after treatment with 80 mg/kg of KR-31378, ERDM activity was induced in liver microsomes in accompanied by induction of the level of CYP 3A proteins. The present results suggest that KR-31378 might modulate the expression of CYP 3A enzymes in humans.     

Growth factor releasing porous poly (ɛ-caprolactone)-chitosan matrices for enhanced bone regenerative rherapy

Drug releasing porous poly(epsilon-caprolactone) (PCL)-chitosan matrices were fabricated for bone regenerative therapy. Porous matrices made of biodegradable polymers have been playing a crucial role as bone substitutes and as tissue-engineered scaffolds in bone regenerative therapy. The matrices provided mechanical support for the developing tissue and enhanced tissue formation by releasing active agent in controlled manner. Chitosan was employed to enhance hydrophilicity and biocompatibility of the PCL matrices. PDGF-BB was incorporated into PCL-chitosan matrices to induce enhanced bone regeneration efficacy. PCL-chitosan matrices retained a porous structure with a 100-200 microm pore diameter that was suitable for cellular migration and osteoid ingrowth. NaHCO3 as a porogen was incorporated 5% ratio to polymer weight to form highly porous scaffolds. PDGF-BB was released from PCL-chitosan matrices maintaining therapeutic concentration for 4 week. High osteoblasts attachment level and proliferation was observed from PCL-chitosan matrices. Scanning electron microscopic examination indicated that cultured osteoblasts showed round form and spread pseudopods after 1 day and showed broad cytoplasmic extension after 14 days. PCL-chitosan matrices promoted bone regeneration and PDGF-BB loaded matrices obtained enhanced bone formation in rat calvarial defect. These results suggested that the PDGF-BB releasing PCL-chitosan porous matrices may be potentially used as tissue engineering scaffolds or bone substitutes with high bone regenerative efficacy.     

Nitrous oxide attenuates pressor but augments norepinephrine response to laryngoscopy and endotracheal intubation

Nitrous oxide (N(2)O) exerts a sympathomimetic action. We investigated whether N(2)O modifies the cardiovascular responses to tracheal intubation during general anesthesia. One-hundred healthy patients were assigned randomly to receive one of four concentrations (0%, 25%, 50%, or 75%; n = 25 each) of N(2)O in oxygen throughout the study beginning 3 min before tracheal intubation. Anesthesia was induced with IV thiopental (5-7 mg/kg) whereas patients were ventilated with designated concentrations of N(2)O. Tracheal intubation was facilitated with IV vecuronium (0.12 mg/kg). After intubation, all received 2% sevoflurane in oxygen via a semiclosed anesthesia circuit. Systolic arterial blood pressure, heart rate and rhythm, and plasma catecholamine concentrations were measured. The intubation significantly increased arterial blood pressure and heart rate. The maximum pressure changes were 46 +/- 21 and 65 +/- 24 mm Hg in 75% N(2)O and control groups, respectively (P < 0.05), being attenuated by N(2)O without affecting the tachycardiac response. Norepinephrine concentrations were increased at 1 min after the intubation, the magnitude of which was augmented by N(2)O. N(2)O did not affect the incidence of arrhythmias. It was shown that N(2)O suppressed the pressor response to endotracheal intubation, despite the augmented increase of norepinephrine concentrations. IMPLICATIONS: We examined whether nitrous oxide modifies the cardiovascular response to endotracheal intubation because it activates the sympathetic nervous system. Nitrous oxide attenuated the pressor response, whereas it augmented the norepinephrine response to laryngoscopy and endotracheal intubation.     

Open radio-frequency thermal ablation of renal VX2 tumors in a rabbit model using a cooled-tip electrode: feasibility,safety, and effectiveness

The purpose of this study was to evaluate the feasibility, safety, and effectiveness of radio-frequency (RF) ablation using an internally cooled-tip electrode on renal VX2 tumors implanted in rabbits. Thirty-three rabbits with implanted renal VX2 tumors were divided into two groups: an RF ablation (RFA) group (n=27) and a control group (n=6). In the RFA group, RFA was performed on 27 implanted VX2 tumors using a cooled RF electrode and they were divided into three subgroups according to the follow-up period: acute (1–3 days, n=12); subacute (1–4 weeks, n=9); and chronic (2–7 months, n=6). Contrast-enhanced spiral CT was performed before the RFA and at the day, day 3, weeks 1, 2, 4, and months 2 and 7, after the RFA. The therapeutic efficacy was evaluated by the survival rate, CT, and pathologic findings. The RFA of renal tumors was technically successful in each instance. Complete tumor ablation was achieved in 22 of the 27 rabbits (81.5%) in the RFA group: 5 rabbits survived longer than 8 weeks without any evidence of viable tumor (18.5%) and 17 rabbits were found free of viable tumors when killed (63.0%). Five rabbits showed local tumor relapse and/or hematogenous lung metastasis after ablation (a recurrence rate of 18.5%). There were 11 (40.7%) complications related to the procedure. This experimental study demonstrates the feasibility of RFA therapy to treat renal VX2 tumors in rabbits, although RFA for central tumors carries some major potential complications, including renal arterial injury. Electronic Publication     

The need for phase-encoding flow compensation in high-resolution intracranial magnetic resonance angiography

PURPOSE: To demonstrate that the time delay between phase and frequency encoding and the presence of pulsatile blood flow in high-resolution time-of-flight (TOF) imaging of the intracranial arteries (especially near the circle of Willis) can distort the appearance of blood vessels and result in a cross-hatch-appearing artifact in surrounding tissue. MATERIALS AND METHODS: Two techniques to reduce the artifact, tri-directional flow compensation (3DFC) and elliptical-centric (EC) phase-encoding order, are investigated in five volunteer studies. RESULTS: 3DFC eliminates the pulsation-related artifacts and the vessel distortion. A residual amplitude variation artifact is observed. EC phase encoding nearly eliminates the pulsatile motion-related artifact, but it does not eliminate vessel distortion. CONCLUSION: The combination of 3DFC and EC phase encoding appears to provide the greatest artifact reduction in the five volunteer studies performed.