Intracellular Drug Delivery Process of Am80-Encapsulated Lipid Nanoparticles Aiming for Alveolar Regeneration.

Chronic obstructive pulmonary disease (COPD) results in obstructive ventilatory impairment caused by emphysema, and current treatment is limited to symptomatic therapy or lung transplantation. Therefore, the development of new treatments to repair alveolar destruction is especially urgent. Our previous study revealed that 1.0 mg/kg of synthetic retinoid Am80 had a repair effect on collapsed alveoli in a mouse model of elastase-induced emphysema. From these results, however, the clinical dose calculated in accordance with FDA guidance is estimated to be 5.0 mg/60 kg, and it is desirable to further reduce the dose to allow the formulation of a powder inhaler for clinical application. To efficiently deliver Am80 to the retinoic acid receptor in the cell nucleus, which is the site of action, we focused on SS-cleavable proton-activated lipid-like material O-Phentyl-P4C2COATSOME®SS-OP, hereinafter referred to as "SS-OP"). In this study, we investigated the cellular uptake and intracellular drug delivery process of Am80-encapsulated SS-OP nanoparticles to elucidate the mechanism of Am80 by nanoparticulation. Am80-encapsulated SS-OP nanoparticles were taken up into the cells via ApoE, and then Am80 was efficiently delivered into the nucleus via RARα. These results indicated the usefulness of SS-OP nanoparticles as drug delivery system carriers of Am80 for COPD treatment.

Synthesis and biological evaluation of coumarin derivatives as selective CYP2A6 inhibitors.

Cytochrome P450 2A6 (CYP2A6) inhibitors are expected to be suitable as smoking cessation aids and for cancer prevention. Because the typical coumarin-based CYP2A6 inhibitor methoxsalen also inhibits CYP3A4, unintended drug-drug interactions are still a concern. Therefore, the development of selective CYP2A6 inhibitors is desirable. In this study, we synthesized coumarin-based molecules, determined the IC50 values for CYP2A6 inhibition, verified the possibility of mechanism-based inhibition, and compared the selectivity for CYP2A6 versus CYP3A4. The results demonstrated that we developed CYP2A6 inhibitors that were more potent and selective than methoxsalen.

Am80-Encapsulated Lipid Nanoparticles, Developed with the Aim of Achieving Alveolar Regeneration, Have an Improvement Effect on Pulmonary Emphysema.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis and emphysema, and current drug treatments target its symptoms. Thus, the development of a therapeutic drug to repair alveolar destruction is urgently needed. Our previous research revealed that the synthetic retinoic acid Am80 (1.0 mg/kg) showed a repairing effect on collapsed alveoli in a mouse model of elastase-induced emphysema. However, a further reduction in the dose is desirable to facilitate the development of a powder inhalation formulation for clinical application. We, therefore, focused on SS-OP to deliver Am80 efficiently. As a result, 0.01 mg/kg of Am80-encapsulated SS-OP nanoparticles repaired collapsed alveoli and improved the respiratory function in the mouse model of elastase induced emphysema. The results suggested that, with the use of SS-OP, the Am80 dose could be reduced. This could contribute to the development of a powder inhalation system as a curative medicine for COPD.

Evaluation of Synthesized Ester or Amide Coumarin Derivatives on Aromatase Inhibitory Activity.

Aromatase inhibitors are effective for the treatment of diseases such as breast cancer, which has led to an increase in their demand. However, only a limited number of aromatase inhibitor drugs are currently being marketed. In addition, considering the important aspect of drug resistance, the development of newer drug types is required. We have been developing inhibitors with backbone structures that differ from existing aromatase inhibitors. In this regard, we previously reported that diethylaminocoumarin dimers and thiazolyl coumarin derivatives possess strong aromatase inhibiting capabilities. In this study, we further examined the structure-activity relationships of coumarin derivatives synthesized from thiazolyl coumarin derivatives and their aromatase inhibiting capabilities. Consequently, amide coumarin N-benzhydryl-7-(diethylamino)-2-oxo-2H-chromene-3-carboxamide (IC50 values 4.5 µM) is inhibitor of aromatase. This inhibitor was found to be comparable aromatase inhibitory activity to the 1st generation aromatase inhibitor aminoglutethimide (3.2 µM). Substitution of the amide group on the amide coumarin derivative affects the aromatase inhibiting activity. Our findings suggest that the structure of each substituent changes the orientation of the compound in the active site of aromatase, thus creating a difference in their activities.

Evaluation of synthesized coumarin derivatives on aromatase inhibitory activity.

In women across the world, the most common type of cancer is breast cancer. Among medical treatments, endocrine therapy based on aromatase inhibitors (AI) is expected to be effective against not only post-menopausal but also pre-menopausal breast cancer. In this study, we examined the structure-activity relationship between the aromatase inhibitory effects of 7-diethylaminocoumarin derivatives with a substituent at position 3 and coumarin derivatives with a substituent at position 7. Consequently, we found that 7-(pyridin-3-yl)coumarin (IC50 values 30.3nM) and 7,7'-diethylamino-3,3'-biscoumarin (28.7nM) are the most potent inhibitors of aromatase. These inhibitors were found to be comparable to the existing CYP19 inhibitor exemestane (42.5nM).

Synthetic models related to methoxalen and menthofuran-cytochrome P450 (CYP) 2A6 interactions. benzofuran and coumarin derivatives as potent and selective inhibitors of CYP2A6.

Human microsomal cytochrome P450 (CYP) 2A6 contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. We prepared a series of benzofuran and coumarin derivatives that have inhibitory effects on the activity of human CYP2A6. The reported compounds methoxalen and menthofuran had potent inhibitory effects on the activity of CYP2A6 with IC50 values of 0.47 µM and 1.27 µM, respectively. Synthetic benzofuran (4-methoxybenzofuran: IC50=2.20 µM) and coumarin (5-methoxycoumarin: IC50=0.13 µM and 6-methoxycoumarin: IC50=0.64 µM) derivatives, which have more selective effects than those of methoxalen and menthofuran, exhibited comparable activities against CYP2A6. These compounds can be used as a lead compounds in the design of CYP2A6 inhibitor drugs to reduce smoking and tobacco-related cancers.

Synthetic models related to furanocoumarin-CYP 3A4 interactions. comparison of furanocoumarin, coumarin, and benzofuran dimers as potent inhibitors of CYP3A4 activity.

Furanocoumarin derivatives (dimers and monomers) present in commercially available grapefruit juice have the capacity to inhibit the activity of human CYP3A4. Such interactions are believed to result from the mechanism-based inhibition of CYP3A4 activity in the intestine. The aim of this work was to synthesize and test a series of dimers with a view to determining the relationship between structure and inhibitory activity and determining whether they might make suitable probes of CYP3A4 activity. We prepared a series of furanocoumarin, coumarin, and benzofuran derivatives that have inhibitory effects on the activity of human CYP3A4. A synthetic benzofuran dimer, which is more accessible than furanocoumarin dimers, exhibited activity against CYP3A4 comparable to that of furanocoumarin dimers.

A novel method for the synthesis of 4'-thiopyrimidine nucleosides using hypervalent iodine compounds.

The coupling reactions of cyclic sulfides with a silylated pyrimidine nucleobase using a hypervalent iodine reagent were investigated. The reaction of silylated uracil with cyclic sulfide 12 using PhI=O gave the desired beta-anomer 14 in moderate yield. 4'-Thiouridine (22) was obtained by deprotection of 14.

[Review of the factors which make home medial care difficult].

In the patients who were managed in the diabetes treatment department, 33 patients were chosen as the difficult cases for the home medical care, and the factors were reviewed. As for the man and woman ratio, 11 were men and 22 were women. The number of female patients was twice larger. The average age was 81.7 years old. As for the mode of the medical care, 11 patients were under the long-term hospitalization, 1 was under care of the health care facility, 12 were under care of the nursing home, 5 lived in private facilities for senior citizens, and 4 were treated under home medical care. The main reason to refuse the home medical care was the decline of the self-management ability. Of the 33 patients, dementia was observed in 21 patients, and the lack of recognition on their own disease was seen in 12 patients. So, without the support, the home medical care could not be provided. It is difficult to provide home medical care because of the complications (especially impaired visual sight, or cerebral vascular disease), the complexity of illness, the state of the family involved in home care, and the reform of the healthcare system. In order to promote the home the medical care of the elderly diabetics whose medical dependency became high, the management of the dementia patient, the support to the family involved in home care, the valid utilization of the care insurance system among other issues seems to be future challenges.

[Review of the factors which make diabetic home medical care difficult].

In the patients who were managed in the diabetes treatment department, 33 patients were chosen as the difficult cases for the home medical care, and the factors were reviewed. As for the man and woman ratio, 11 were men and 22 were women. The number of female patients was twice larger. The average age was 81.7 years old. As for the mode of the medical care, 11 patients were under the long-term hospitalization, 1 was under care of the health care facility, 12 were under care of the nursing home, 5 lived in private facilities for senior citizens, and 4 were treated under home medical care. The main reason to refuse the home medical care was the decline of the self-management ability. Of the 33 patients, dementia was observed in 21 patients, and the lack of recognition on their own disease was seen in 12 patients. So, without the support, the home medical care could not be provided. It is difficult to provide home medical care because of the complications (especially impaired visual sight, or cerebral vascular disease), the complexity of illness, the state of the family involved in home care, and the reform of the healthcare system. In order to promote the home the medical care of the elderly diabetics whose medical dependency became high, the management of the dementia patient, the support to the family involved in home care, the valid utilization of the care insurance system among other issues seems to be future challenges.

[Elderly diabetics and care insurance system--does the home care service contribute to the home medical treatment?].

To investigate whether home medical care service based on the public care insurance system contributes to the home medical treatment of elderly diabetics, the following aspects were evaluated. 1. Did glycemic control improve? 2. Were the patients pleased with the results obtained? 3. Was a load to the home care of the family reducing? 4. Did dependence on medical treatment decrease? The investigation was carried out targeting 17 patients among elderly diabetic patients of 65 years of age for whom home care service was provided. 1. HbA1c level did not change after the start of the care service. 2. Some degree of patient's satisfaction was obtained. 3. The burden of the family concerning home care decreased. 4. Dependence on medical treatment (repeated visits or hospitalization) decreased. Therefore, it was suggested that the care service contributed to the home medical treatment of elderly diabetic patients. It was raised as a problem what correspondence to the cases those who dislike the home care service, or an authorization application. From now on, it is considered important to introduce a care service in which a dietitian, a nurse, a pharmacist, etc, are involved.