Development of LOX-1 Antibody Modified Immuno-liposomes as Drug Carriers to Macrophages in Atherosclerotic Lesions.

We developed a drug delivery system for atherosclerotic lesions using immuno-liposomes. We focused on enhancing the delivery efficiency of the liposomes to macrophages in atherosclerotic lesions by antibody modification of lectinlike oxidized low-density lipoproteins (LDL) receptor 1 (LOX-1). The cellular accumulation of the liposomes in foam cells induced by oxidized LDL (oxLDL) in Raw264 mouse macrophages was evaluated. The cellular accumulation of LOX-1 antibody modified liposomes in oxLDL-induced foam cells and untreated Raw264 cells was significantly higher compared with that of unmodified liposomes. The liposomes were also administered intravenously to Apoeshl mice as an atherosclerosis model. Frozen sections were prepared from the mouse aortas and observed by confocal laser microscopy. The distribution of LOX-1 antibody modified liposomes in the atherosclerotic regions of Apoeshl mice was significantly greater compared with that of unmodified liposomes. The results suggest that LOX-1 antibody modified liposomes can target foam cells in atherosclerotic lesions, providing a potential route for delivering various drugs with pharmacological effects or detecting atherosclerotic foci for the diagnosis of atherosclerosis.

Assessment of transporter-mediated efflux of nintedanib using in vitro cell line models of idiopathic pulmonary fibrosis.

Objective: We aimed to investigate the involvement of efflux transporters, including multidrug resistant protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), MRP2, and breast cancer resistance protein (BCRP), in the intracellular accumulation of the antifibrotic agent nintedanib in fibrotic lung cells. Methods: We used transforming growth factor-ß1 (TGF-ß1)-treated human lung fibroblasts (WI-38) and alveolar epithelial cells (A549) as in vitro models. The expression and activities of efflux transporters in TGF-ß1-treated WI-38 and A549 cells were evaluated using immunoblotting and flow cytometry. Cells were treated with nintedanib and then incubated with inhibitors of these transporters. The intracellular concentration of nintedanib was determined. Results: MDR1, MRP1, MRP2, and BCRP were found to be expressed in WI-38 and A549 cells with or without TGF-ß1 stimulation, with the exception of MRP2 in WI-38 cells. The efflux activities of these transporters were observed in these cells. MDR1 inhibitors significantly increased the intracellular accumulation of nintedanib, whereas MRP inhibitors did not show an effect. The BCRP inhibitor significantly increased the transporter activity in A549 cells but not in WI-38 cells. Conclusion: This study suggests that the efflux via MDR1 and BCRP is involved in the intracellular accumulation of nintedanib in fibrotic lung cells.

Storage stability of serum formulations containing ofloxacin for autologous serum eardrop therapy.

OBJECTIVE: The storage stability of serum formulations containing ofloxacin for autologous serum eardrop therapy was evaluated for microbiological quality and component stability. METHODS: Sterile serum formulations were prepared by mixing human serum and ofloxacin otic solution (1:1, v/v). To simulate eardrop contamination with external ear surface substances, prepared serum formulations were contaminated with a cotton swab that was rubbed sufficiently on the human external ear. Formulations were stored at 4 °C or room temperature in the dark. Colony forming units (CFUs), ofloxacin, and basic fibroblast growth factor (bFGF) concentrations in the stored serum formulations were determined. RESULTS: The growth of microorganisms derived from the external ear was not detected in serum formulations after storage for 14 days, regardless of temperature. However, microbial growth was detected in serum formulations stored without ofloxacin, indicating that this is necessary for storage. In addition, concentrations of ofloxacin and bFGF did not decrease over 14 days, indicating that ofloxacin and bFGF in serum formulations are stable for this time period. CONCLUSION: The present study indicates that the efficacy and safety of serum formulations used as a therapy for perforated eardrums are stable and safe for at least 14 days.

Effects of washing of the face with a mild facial cleanser formulated with sodium laureth carboxylate and alkyl carboxylates on acne in Japanese adult males.

BACKGROUND/PURPOSE: Washing the face with a mild cleanser is generally recommended for acne care. Occasionally, the general public has the misconception that acne is exacerbated by cleansers and furthermore it has concerns about inducing skin irritation and xerosis by intensive washing. Recently, we developed a new cleanser based on sodium laureth carboxylate and alkyl carboxylates (AEC/soap) that cleans sebum well without penetrating the stratum corneum. METHODS: We designed a controlled clinical trial conducted on adult Japanese males with moderate or less acne. Twenty subjects washed their faces with AEC/soap base cleanser twice a day for 4 weeks. Assessment of the efficacy was conducted prior to the start of the study, and at the end of weeks 2 and 4. RESULTS: Significant improvement of the acne was observed within 2 weeks, and acne lesions were not detectable in 25% of the subjects at week 4. Sebum secretion levels on the skin significantly increased on the forehead, but significantly decreased on the cheek which correlated with the improvement. No complaints of dryness or irritation occurred during the study. CONCLUSION: Washing the face twice a day with facial cleanser based on AEC/soap is an effective care for moderate or less grade facial acne.

SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.

Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (SETBP1-MT) are enriched among ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the tumor growth factor-ß signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS.

Transport characteristics of clarithromycin, azithromycin and telithromycin, antibiotics applied for treatment of respiratory infections, in Calu-3 cell monolayers as model lung epithelial cells.

We have shown that clarithromycin (CAM), a macrolide antibiotic, more highly distributes from plasma to lung epithelium lining fluid (ELF), the infection site of pathogens, than azithromycin (AZM) and telithromycin (TEL). Transporter(s) expressed on lung epithelial cells may contribute to the distribution of the compiunds to the ELF. However, distribution mechanisms are not well known. In this study, their transport characteristics in Calu-3 cell monolayers as model lung epithelial cells were examined. The basolateral-to-apical transport of CAM through Calu-3 cell monolayers was greater than that of AZM and TEL. Although verapamil and cyclosporine A as MDR1 substrates completely inhibited the basolateral-to-apical transport, probenecid as MRP1 inhibitor did not show an effect. These results suggest that the antibiotics are transported from plasma to ELF by MDR1 of lung epithelial cells. In addition, their affinity and binding rate to MDR1 was examined by ATP activity assay. The affinity and binding rate of CAM was greater than those of AZM and TEL. These corresponded with the distributions from plasma to ELF as described above. The present study suggests that the more highly distribution of CAM from plasma to ELF is due to the high affinity and binding rate to MDR1 of lung epithelial cells.

[Clinical studies of SM-4300 in combination with antibiotics against severe bacterial infections].

SM-4300, a newly developed human immunoglobulin preparation was evaluated in 24 patients with severe bacterial infections and the following results were obtained. The clinical efficacy was excellent in 4 cases, good in 7, fair in 5, poor in 3 and unknown in 5 with the effective rate of 57.9%. No serious side effect nor abnormalities in laboratory findings due to administration of SM-4300 were observed except 1 case with slight elevation of GOT and GPT.

A case of bleeding duodenal varices located in the third portion.

We described a patient with isolated duodenal varices of the third portion, preoperatively diagnosed by hypotonic duodenography and endoscopy. These varices seemed to be caused by portal hypertension due to liver cirrhosis. The third to the fourth portion of duodenum should be examined carefully in patients with liver cirrhosis, especially with gastrointestinal bleedings of unknown origin.