Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis.

Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation.

Coexpression of organic anion-transporting polypeptides 1B3 and multidrug-resistant proteins 2 increases the enhancement effect of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid on hepatocellular carcinoma in magnetic resonance imaging.

AIM: We aimed to elucidate the relationship between the contrast enhancement effect of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) on magnetic resonance imaging (MRI) of hepatocellular carcinomas (HCC) and the expressions of hepatocyte transporters (i.e. organic anion-transporting polypeptide [OATP]1B3, multidrug-resistant protein [MRP]2 and MRP3) and to clarify the characteristics of HCC with an MRI high-contrast enhancement effect. METHODS: We retrospectively examined the relationship between the relative enhancement ratio (RER) of HCC, absolute and relative immunohistochemical staining scores of hepatocyte transporters, and histological differentiation of 22 HCC from 21 patients who had undergone preoperative Gd-EOB-DTPA-enhanced MRI. RESULTS: RER had a significant correlation with OATP1B3 expression according to the absolute and relative scores (P = 0.016 vs 0.0006). The RER of HCC with high OATP1B3 and MRP2 expression levels was higher than that of HCC with low OATP1B3 or MRP2 expression levels (P = 0.0003). The RER of HCC with higher OATP1B3 rates was greater than that of HCC with lower OATP1B3 rates (P = 0.0005). HCC histological differentiation showed a significant correlation with OATP1B3 expression and RER (P = 0.023 vs 0.0095). CONCLUSION: We found that coexpression of OATP1B3 and MRP2 influenced the high contrast enhancement of HCC on MRI.

Structure-activity relationship of anthelmintic cyclooctadepsipeptides.

The relationship between cyclooctadepsipeptides and their anthelmintic efficacy was examined by converting the natural products, PF1022A, PF1022E and PF1022H. Some analogues substituted at the para position of the phenyllactate moiety showed higher or equivalent activity against the parasitic nematode, Ascaridia galli in chicken when compared with the parent compounds. It is suggested that lipophilicity and the polar surface area, in addition to structural requirements of the derivatives, influenced the anthelmintic efficacy in vivo.

A new glycosylated dihydrophaseic acid from cacao germs (Theobroma cacao L.).

Cacao beans are composed of cacao nibs and germs. Although numerous chemical and physiological studies on cacao nib compounds have been reported, there is little information on cacao germ compounds. We therefore analyzed an extract from the cacao germ, and found two compounds that were specific to the germ. One of these two compounds was identified as the new glycosylated abscisic acid metabolite, dihydrophaseic acid-4'-O-6″-(ß-ribofuranosyl)-ß-glucopyranoside, and the other as the known compound, dihydrophaseic acid-4'-O-ß-D-glucopyranoside.

Pseurotin A and its analogues as inhibitors of immunoglobulin E [correction of immunoglobuline E] production.

A natural product, pseurotin A inhibits IgE production in vitro. Wide variety of chemical modification of pseurotin A was performed. Structure-activity relationship studies of pseurotin analogues elucidated that 10-deoxypseurotin A strongly inhibits IgE production with IC(50) of 0.066 microM. An immunosuppressive activity of another natural product, synerazol was also found.

[A case of multiple recurrence of Clostridium difficile-associated diarrhea--analysis of isolates from the patient using PCR ribotyping].

Recurrence of Clostridium difficile-associated diarrhea (CDAD) is a serious and still unsolved problem. Little is known about the precise mechanism of the recurrence with CDAD. To elucidate the issue, we analyzed C. difficile strains obtained from the patient with multiple recurrence of CDAD. A 72-year-old female received rectoidectomy was developed CDAD after administration of cefmetazole sodium for 5 days. She was recovered from illness by the administration 2g of vancomycin hydrochloride for 2 weeks. However she was recurred CDAD twice within 2 months thereafter. Six C. difficile isolates recovered from the stool specimens obtained during each episode were typed by polymerase chain reaction amplifying of rRNA intergenic spacer regions 8 PCR ribotyping was carried out. The PCR ribotype of the first episode was identical (ribotype smz) to that of the second episode, and the PCR ribotype of the third were distinct (ribotype hr) from those on previous two episodes. These findings indicate that the second episode was caused by the reactivation of continuously infected C. difficile strain (relapse) and the third episode was by reinfection of the new

A fatal case of acute hepatitis B developed in a toluene abuser.

Liver dysfunction involving toluene intoxicity includes elevation of transaminase level and delayed complications of liver failure, but its effect on hepatitis B virus (HBV) infection is as yet unknown. Here, we report a case of fulminant hepatitis B developed in a toluene abuser. A 23-year-old female toluene abuser was admitted to a local clinic because of nausea, vomiting, and dizziness, and a mild elevation of serum transaminase level was identified. She was treated as an outpatient, but continued toluene inhalation during follow-up. Five days later, she was found in a drowsy state of consciousness and taken to the emergency unit of our institution. Laboratory findings showed an alanine aminotransferase level of 4,659 IU, a remarkably prolonged prothrombin time, and she was diagnosed with fulminant hepatitis B. Intensive care was carried out, but she died the next day. Molecular analysis revealed that the HBV isolate was classified as genotype C, and nucleotide positions that are prone to fulminant hepatitis were A at 1,762 and G at 1,764 in the core promoter region, and G at 1,896 in codon 28 in the precore region. The long-term toluene inhalation could have contributed to drastic clinical course of acute hepatitis B in this patient.