Amphiphilic amino acid copolymers as stabilizers for the preparation of nanocrystal dispersion

The recent advance of particle size engineering in nanometer ranges has widened the formulation opportunities of relatively water-insoluble drugs. However, the ‘nanoformulation’ suffers from a lack of systematic understanding about the requirements of polymeric stabilizers. Furthermore, the polymers that can be used for the preparation of nanocrystals are so limited that finding a proper stabilizer for a given formulation is often difficult. In this study, amino acid copolymers whose properties can systematically be tailored are developed, and their morphological and compositional effects are investigated. Copolymers containing lysine (K) as their hydrophilic segments, and phenylalanine (F) or leucine (L) as their hydrophobic segments successfully produce stable nanocrystals (200–300 nm) in water, while copolymers of K and alanine (A) could not generate nanosized particles. Not the morphology but the hydrophobicity of copolymers seems to be a critical parameter in the preparation of drug nanocrystals by wet comminution. The effective stabilization performance of copolymers requires the hydrophobic moiety content to be higher than 15 mol%. Comminution for only 5 min is long enough for nanocrystal preparation, and the crystallinity of drug is found intact after the processing.     

Therapeutic Decision-Making Using Endoscopic Ultrasonography in Endoscopic Treatment of Early Gastric Cancer

Background/Aims

We evaluated the effectiveness of an endoscopic ultrasonography (EUS)-based treatment plan compared to an endoscopy-based treatment plan in selecting candidates with early gastric cancer (EGC) for endoscopic submucosal dissection based on the prediction of invasion depth.

Methods

We reviewed 393 EGCs with differentiated histology from 380 patients who underwent EUS from July 2007 to April 2010. The effectiveness of the EUS-based and endoscopy-based plans was evaluated using a simplified hypothetical treatment algorithm.

Results

The numbers of endoscopically determined mucosal, indeterminate, and submucosal cancers were 253 (64.4%), 56 (14.2%), and 84 (21.4%), respectively. Overall, the appropriate treatment selection rates were 75.3% (296/393) in the endoscopy-based plan and 71.5% (281/393) in the EUS-based plan (p=0.184). For endoscopic mucosal cancers, the appropriate treatment selection rates in the endoscopy-based plan were 88.1% (223/253), while the use of an EUS-based plan significantly decreased this rate to 81.4% (206/253) (p=0.036). For endoscopic submucosal cancers, the appropriate selection rates did not differ between the endoscopy-based plan (46.4%, 39/84) and the EUS-based plan (53.6%, 45/84) (p=0.070).

Conclusions

EUS did not increase the likelihood of selecting the appropriate treatment in differentiated-type EGC. Therefore, EUS may not be necessary before treating differentiated-type EGC, especially in endoscopically presumed mucosal cancers.     

Genetic diversity of avian paramyxovirus type 4 isolates from wild ducks in Korea from 2006 to 2011

Thirteen isolates of avian paramyxovirus type 4 (APMV-4) isolated from wild ducks in Korea from 2006 to 2011 were genetically characterized by sequence analysis of the N-terminal region of the APMV-4 fusion (F) protein gene. The results revealed that the amino acid sequence homology within Korean isolates was 97.5 % or greater. The homologies of the Korean isolates with the APMV-4/duck/HK/D3/75 and APMV-4/duck/BE/15129/07 strains were 86.9–88.0 and 95.5–96.1 %, respectively. All Korean isolates had sequence motifs of ¹¹⁶DIQPR↓F¹²¹ at the F0 cleavage site. Phylogenetic analysis based on the N-terminal region of the F protein gene of APMV-4 isolates revealed that all 2006–2011 Korean isolates formed a single genotypic cluster that was phylogenetically different from APMV-4/duck/HK/D3/75 or APMV-4/duck/BE/15129/07 strains. Korean APMV-4 isolates were more closely related to APMV-4/goose/ZA/N1468/10 (isolated in South Africa) than to the Belgium APMV-4 virus. Korean APMV-4 isolates were further divided into at least two subgroups (A and B) based on phylogenetic analysis. Subgroup A viruses were isolated throughout Korea, whereas subgroup B viruses were detected only in isolates from Cheju island in 2011, suggesting that Korean APMV-4 exhibits marked genetic diversity and differs from viruses currently circulating in Europe and other locations.     

Argon plasma coagulation is safe and effective for treating smaller gastric lesions with low-grade dysplasia: a comparison with endoscopic submucosal dissection

Background and aims

The best therapeutic modality has not been established for gastric low-grade adenomas or dysplasia (LGD), which can progress to invasive carcinoma despite a low risk. This study aims to investigate the clinical efficacy, safety, and local recurrence after argon plasma coagulation (APC) treatment of gastric LGD compared with endoscopic submucosal dissection (ESD).

Patients and methods

A total of 320 patients with gastric LGD ≤2.0 cm treated with APC or ESD between 2004 and 2011 were retrospectively analyzed. We compared local recurrence rate, complication rate, procedure time, and admission to hospital between APC and ESD groups.

Results

Of the 320 patients, 116 patients were treated with APC and 204 with ESD. During follow-up, local recurrence was more common in the APC group (3.8 %, 4/106) than the ESD group (0.5 %, 1/188; log-rank test P = 0.036). However, all patients with local recurrence (n = 5) were treated by additional APC, and followed up without further recurrences. ESD was complicated by two perforations (1.0 %, 2/204) compared with no perforations in the APC group (0 %, 0/116). Bleeding complications were not different between the APC (1.7 %, 2/116) and ESD (2.0 %, 4/204) groups. Procedure time was shorter in the APC (7.8 ± 5.1 min) than the ESD (53.1 ± 38.1 min) group (P < 0.001). The proportion of hospitalization was less in the APC group (31.0 %, 36/116) than the ESD group (100.0 %, 204/204) (P < 0.001).

Conclusions

APC can be a good treatment option for patients with LGD ≤2.0 cm.     

Proposal of the Surgical Options for Primary Tumor Control During Sentinel Node Navigation Surgery Based on the Discrepancy Between Preoperative and Postoperative Early Gastric Cancer Diagnoses

Background

There is no consensus on the optimal method of primary tumor control, determined by preoperative clinical factors, during sentinel node (SN) navigation surgery for early gastric cancer (EGC). In this study, we investigated the accuracy of clinical diagnosis based on preoperative examination in patients with EGC and proposed surgical options for primary tumor control during SN navigation surgery.

Methods

We analyzed 815 patients with clinical stage IA gastric cancer who underwent gastrectomy at the National Cancer Center in Korea between March 2001 and February 2011. The clinical stage was determined by endoscopy, endoscopic ultrasonography, and abdominal computed tomography.

Results

The preoperative assessment of tumor depth and tumor size was accurate in 57.5 and 70.8 % of patients, respectively. Tumor depth and size were underestimated in 8 and 25.3 % of patients. The overall accuracy of histologic diagnosis by endoscopic biopsy was 87.2 %. Of those tumors diagnosed preoperatively as differentiated, 20.5 % revealed mixed histology of undifferentiated type.

Conclusions

The recommendation for SN biopsy may be limited to tumors sized 3 cm or smaller to avoid positive lateral margins and to minimize the risk of skip metastases. Endoscopic resection may safely be applied to small mucosal cancers, but other surgical options should be employed for undifferentiated large mucosal lesions, given their tendency for diffuse invasion. Full-thickness resection is preferable for submucosal cancers, to secure clear vertical margins.     

Computed Tomography-Guided Screening of Surfactant Effect on Blood Circulation Time of Emulsions: Application to the Design of an Emulsion Formulation for Paclitaxel

Purpose

In an effort to apply the imaging techniques currently used in disease diagnosis for monitoring the pharmacokinetics and biodisposition of particulate drug carriers, we sought to use computed tomography (CT) scanning methodology to investigate the impact of surfactant on the blood residence time of emulsions.

Methods

We prepared the iodinated oil Lipiodol emulsions with different compositions of surfactants and investigated the impact of surfactant on the blood residence time of emulsions by CT scanning.

Results

The blood circulation time of emulsions was prolonged by including Tween 80 or DSPE-PEG (polyethylene glycol 2000) in emulsions. Tween 80 was less effective than DSPE-PEG in terms of prolongation effect, but the blood circulating time of emulsions was prolonged in a Tween 80 content-dependent manner. As a proof-of-concept demonstration of the usefulness of CT-guided screening in the process of formulating drugs that need to be loaded in emulsions, paclitaxel was loaded in emulsions prepared with 87 or 65% Tween 80–containing surfactant mixtures. A pharmacokinetics study showed that paclitaxel loaded in 87% Tween 80 emulsions circulated longer in the bloodstream compared to those in 65% Tween 80 emulsions, as predicted by CT imaging.

Conclusions

CT-visible, Lipiodol emulsions enabled the simple evaluation of surfactant composition effects on the biodisposition of emulsions.     

Role of induction and consolidation chemotherapy in elderly acute myeloid leukemia patients

The present study sought to elucidate the role of induction and consolidation therapy in elderly patients. We retrospectively collected data of 477 patients who were aged over 60 years at the time of acute myeloid leukemia (AML) diagnosis. The median overall survival (OS) was 339 days in the induction group (n = 266) and 86 days in the best supportive care group (n = 211) (P < 0.001). In the induction group, the complete remission (CR) rate was 58.3 %, and treatment-related death was 15.4 %. Successful induction was related to good performance [Eastern Cooperative Oncology Group (ECOG <2)] [hazard ratio (HR) 3.215; P = 0.002]. Mortality correlated with failure to achieve CR (HR 4.059; P < 0.001) and poor performance status (ECOG >2) (HR 2.731; P = 0.035). In CR patients, poor karyotype and absence of consolidation (HR 2.313; P = 0.003) correlated with mortality. More than one cycle of consolidation was associated with better OS (P < 0.001). Lack of salvage therapy was associated with mortality in patients who did not achieve CR (HR 3.223; P = 0.005). Intensive induction in patients with good performance and >1 cycle of consolidation after CR may be the best strategy for improving OS in elderly AML patients.     

Microemulsion formulation of clonixic acid: solubility enhancement and pain reduction

Clonixic acid is currently marketed as a salt form because of its poor water-solubility. However, the commercial dosage form causes severe pain after intramuscular or intravenous injection. To improve the solubility of clonixic acid and to reduce pain on injection, clonixic acid was incorporated into oil-in-water microemulsions prepared from pre-microemulsion concentrate composed of varying ratios of oil and surfactant mixture. As an oil phase for drug incorporation, up to 14% castor oil could be included in the pre-microemulsion concentrate without a significant increase in droplet size. Both drug contents and droplet size increased as the weight ratio of Tween 20 to Tween 85 decreased. Taken together, when microemulsions were prepared from pre-microemulsion concentrate composed of 5:12:18 weight ratio of castor oil:Tween 20:Tween 85, clonixic acid could be incorporated at 3.2 mg mL(-1) in the microemulsion with a droplet size of less than 120 nm. The osmotic pressure of this microemulsion was remarkably lower than the commercial formulation, irrespective of the dilution ratios. The rat paw-lick test was used to compare pain responses among formulations. The microemulsion formulation significantly reduced the number of rats licking their paws as well as the total licking time, suggesting less pain induction by the microemulsion formulation. The pharmacokinetic parameters of clonixic acid after intravenous administration of the clonixic acid microemulsion to rats were not significantly different from those of the commercial formulation, lysine clonixinate. The present study suggests that microemulsion is an alternative formulation for clonixic acid with improved characteristics.     

Gene medicine: A new field of molecular medicine

Gene therapy has emerged as a new concept of therapeutic strategies to treat diseases which do not respond to the conventional therapies. The principle of gene therapy is to introduce genetic materials into patient cells to produce therapeutic proteins in these cells. Gene therapy is now at the stage where a number of dinical trials have been carried out to patients with gene-deficiency disease or cancer. Genetic materials for gene therapy are generally composed of gene expression system and gene delivery system. For the dinical application of gene therapy in a way which conventional drugs are used, researches have been focused on the design of gene delivery system which can offer high transfection efficiency with minimal toxicity. Currently, viral delivery systems generally provide higher transfection efficiency compared with non-viral delivery systems while non-viral delivery systems are less toxic, less immunogenic and manufacturable in large scale compared with viral systems. Recently, novel strategies towards the design of new non-viral delivery system, combination of viral and non-viral delivery systems and targeted delivery system have been extensively studied. The continued effort in this area will lead us to develop gene medicine as 'gene as a drug' in the near future.