Synthesis of Heptagon-Containing Polyarenes by Catalytic C-H Activation.

Nanocarbons incorporating non-hexagonal aromatic rings - such as five-, seven-, and eight-membered rings - have various intriguing physical properties such as curved structures, unique one-dimensional packing, and promising magnetic, optical, and conductivity properties. Herein, we report an efficient synthetic approach to polycyclic aromatics containing seven-membered rings via a palladium-catalyzed intramolecular Ar-H/Ar-Br coupling. In addition to all-hydrocarbon scaffolds, heteroatom-embedded heptagon-containing polyarenes can be efficiently constructed with this method. Rhodium- and palladium-catalyzed sequential six- and seven-membered ring formations also afford complex heptagon-containing molecular nanocarbons from readily available arylacetylenes and biphenyl boronic acids. Detailed mechanistic analysis by DFT calculations showed the feasibility of seven-membered ring formation by a concerted metalation-deprotonation mechanism. This reaction can serve as a template for the synthesis of a wide range of seven-membered ring-containing molecular nanocarbons.

Efficient Sensor Node Selection for Observability Gramian Optimization.

Optimization approaches that determine sensitive sensor nodes in a large-scale, linear time-invariant, and discrete-time dynamical system are examined under the assumption of independent and identically distributed measurement noise. This study offers two novel selection algorithms, namely an approximate convex relaxation method with the Newton method and a gradient greedy method, and confirms the performance of the selection methods, including a convex relaxation method with semidefinite programming (SDP) and a pure greedy optimization method proposed in the previous studies. The matrix determinant of the observability Gramian was employed for the evaluations of the sensor subsets, while its gradient and Hessian were derived for the proposed methods. In the demonstration using numerical and real-world examples, the proposed approximate greedy method showed superiority in the run time when the sensor numbers were roughly the same as the dimensions of the latent system. The relaxation method with SDP is confirmed to be the most reasonable approach for a system with randomly generated matrices of higher dimensions. However, the degradation of the optimization results was also confirmed in the case of real-world datasets, while the pure greedy selection obtained the most stable optimization results.

Construction of Heptagon-Containing Molecular Nanocarbons.

Molecular nanocarbons containing heptagonal rings have attracted increasing interest due to their dynamic behavior, electronic properties, aromaticity, and solid-state packing. Heptagon incorporation can not only induce negative curvature within nanocarbon scaffolds, but also confer significantly altered properties through interaction with adjacent non-hexagonal rings. Despite the disclosure of several beautiful examples in recent years, synthetic strategies toward heptagon-embedded molecular nanocarbons remain relatively limited due to the intrinsic challenges of heptagon formation and incorporation into polyarene frameworks. In this Review, recent advances in solution-mediated and surface-assisted synthesis of heptagon-containing molecular nanocarbons, as well as the intriguing properties of these frameworks, will be discussed.

Development of a drug-coated microneedle array and its application for transdermal delivery of interferon alpha.

Interferon alpha (IFNα) is one of the most famous drugs for the treatment of chronic hepatitis C and various types of human malignancy. Protein drugs, including IFNα, are generally administered by subcutaneous or intramuscular injection due to their poor permeability and low stability in the bloodstream or gastrointestinal tract. Therefore, in the present study, novel IFNα-coated polyvinyl alcohol-based microneedle arrays (IFNα-MNs) were fabricated for the transdermal delivery of IFNα without the painful injection. IFNα was rapidly released from MNs in phosphate buffered solution and these MNs presented piercing ability in the rat skin. Slight erythema and irritation were observed when MNs were applied to the rat skin, but these skin damages completely disappeared within 24 h after removing the IFNα-MNs. Furthermore, the pharmacokinetic parameters of IFNα-MNs were similar to those of IFNα subcutaneous administration. Finally, IFNα-MNs showed a significant antitumor effect in tumor bearing mice similar to that of IFNα subcutaneous administration. These results indicate that IFNα-MNs are a useful biomaterial tool for protein drug therapy and can improve the quality of life in patients by avoidance of painful injections.

Frequency and clinical features of suicide attempts in elderly patients in Japan.

The objective of this study was to investigate the clinical features of suicide attempts in elderly patients (≥65 years) in Japan. We enrolled 546 patients who attempted suicide and were hospitalized for inpatient treatment. Characteristics were compared between the elderly and non-elderly patients. Compared with the non-elderly group, the incidence of mood disorders was significantly higher and the average length of stay in the intensive care unit and the duration of hospitalization were significantly longer in the elderly group. Elderly patients hospitalized for attempted suicide were more likely to have mood disorders than the non-elderly.

Frequency and clinical features of patients who attempted suicide by charcoal burning in Japan.

BACKGROUND: To date, the clinical features between patients in Japan who have attempted suicide by charcoal burning and those who have attempted suicide by other methods in the context of a mental disorder diagnosis as assessed by structured interviews have not been reported. METHODS: We enrolled 647 consecutive patients who attempted suicide and were hospitalized for inpatient treatment. Psychiatric diagnoses, frequency of suicide attempts, and clinical features were compared between charcoal burning and other suicide methods. RESULTS: Twenty of the 647 patients (3.1%) had attempted suicide by charcoal burning. The ratio of men to women was significantly higher by this method compared with that of other methods. The proportion of patients with mood disorders was significantly higher in the charcoal burning group than that in the other methods group. The occurrence of a psychiatric history in patients in the charcoal burning group was significantly lower than that in the other methods group. LIMITATIONS: The study sample was limited to a single hospital. CONCLUSIONS: The results demonstrate the clinical characteristics of patients who attempted suicide by charcoal burning. Therefore, it is necessary to identify the clinical features of patients who have attempted suicide by charcoal burning in Japan.

Clinical features of suicide attempts in adults with autism spectrum disorders.

OBJECTIVE: The objective of this study was to investigate the frequency and clinical features of suicide attempts in adults with autism spectrum disorders (ASDs). METHODS: We enrolled 587 consecutive patients aged 18 or over who attempted suicide and were hospitalized for inpatient treatment. Psychiatric diagnoses, suicide attempt frequency and clinical features were compared between ASD and non-ASD patients. RESULTS: Forty-three (7.3%) of the 587 subjects who attempted suicide had ASDs. The incidence of patients with mood disorders was significantly lower (Fisher's Exact Test, P=.043) and that of those with an adjustment disorder was significantly higher (Fisher's Exact Test, P<.001) in the ASD group than in the non-ASD group. The average length of stay at both the hospital and intensive care unit in the ASD group was longer than that in the non-ASD group (z=-2.031, P=.042; z=-2.322, P=.020, respectively). CONCLUSIONS: ASDs should always be a consideration when dealing with suicide attempts in adults at the emergency room.

[A case of advanced gastric cancer found to be remaining by gastrectomy after a clinically complete response to chemotherapy].

The patient was a 72-year-old woman diagnosed with advanced gastric cancer, hepatic portal lymph node and para-aortic lymph node metastases. After five courses of S-1/CDDP combination therapy, both the primary tumor and lymph node metastases disappeared clinically. She wished to continue chemotherapy instead of having a resection. After three more courses of S-1/CDDP therapy, gastric cancer and lymph node metastases were still completely regressed, but complications of carcinoma of the gallbladder were suspected. Gastrectomy was performed with cholecystectomy, and a histopathological examination revealed cancer cells remaining in the gastric submucosa and xanthogranulomatous cholecystitis. We consider surgical therapy for clinically completely disappearing advanced gastric cancer by chemotherapy, in addition to case report.

Sex differences in pharmacokinetics of cilostazol in rats.

The pharmacokinetics of cilostazol was investigated after oral and intravenous administration in both male and female rats. After oral administration, area under serum concentration-time curve (AUC) was about 35-fold higher in female rats than in male rats, and absolute bioavailability was about 5.8-fold higher in female rats than in male rats. Total body clearance (CL(total)) for female rats was around one-sixth of that for male rats. In vivo hepatic clearance (CL(h)) calculated based on isolated liver perfusion studies was even higher than or around 90% of the in vivo CL(total) of cilostazol for female and male rats, respectively, indicating that cilostazol is mainly eliminated by the liver in both male and female rats. In vitro metabolism studies utilizing hepatic microsomes and recombinant cytochrome (CYP) isoforms clearly indicated that major metabolites of cilostazol were generated extensively with hepatic microsomes of male rats and that male-predominant CYP3A2 and male-specific CYP2C11 were mainly responsible for the hepatic metabolism of cilostazol. Therefore, the great sex differences in the pharmacokinetics of cilostazol were mainly attributed to the large difference in hepatic metabolism. Our experimental results also suggested that the substantial metabolism of cilostazol in the small intestine and its possible saturation would be responsible for dose-dependent bioavailability in both male and female rats.

Blonanserin in the treatment of delirium.

The purpose of the present study was to provide preliminary data on the usefulness and safety of blonanserin for patients with delirium in the intensive care unit (ICU). The charts of 32 consecutive patients with delirium in the ICU were retrospectively reviewed. These patients were treated with blonanserin. A total of 96.6% had reduction in Memorial Delirium Assessment Scale score. The proportion of patients with side-effects was 24.1%. Blonanserin may be effective and safe in the treatment of delirium in the ICU.

In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol.

The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. Irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively.

[Control of pulmonary absorption of drugs by various pharmaceutical excipients].

In general, drugs are well absorbed from the lung, and the pulmonary absorption of therapeutic protein and peptide drugs, which are poorly absorbed from the gastrointestinal tract, was observed. However, locally acting drugs including antiasthmatic agents, bronchodilators, and expectorants should be localized for a long period in the lung tissues. In this study, the effects of various viscous vehicles on the absorption of theophylline and fluticasone propionate after intrapulmonary administration were examined in rats. Carrageenans were effective in regulating the absorption rate of these drugs. On the other hand, the bioavailability of therapeutic protein and peptide drugs with relatively high molecular weights from the pulmonary route is still poor when compared with the parenteral route. Therefore we examined the effects of chitosan and chitosan oligomers on the pulmonary absorption of interferon-alpha and salmon calcitonin in rats. Chitosan oligomers were effective in improving the pulmonary absorption of these drugs, and chitosan hexamer appeared to be markedly more effective than other oligomers. Furthermore, the present study indicated that chitosan oligomers did not cause any membrane damage to rat pulmonary tissues. In conclusion, it is suggested that various pharmaceutical excipients achieved the sustained pulmonary absorption of locally acting drugs and the improved pulmonary bioavailability for therapeutic protein and peptide drugs.

Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs.

The purpose of the present study was to investigate the effects of particle size on the dissolution and oral absorption of cilostazol. Three types of suspensions having different particle size distributions were prepared of the hammer-milled, the jet-milled cilostazol crystals and the NanoCrystal spray-dried powder of cilostazol. In vitro dissolution rate of cilostazol was significantly increased by reducing the particle size. The dissolution curves of the cilostazol suspensions were in good agreement with the simulation based on the Noyes-Whitney equation. The bioavailability of cilostazol after oral administration to dogs was increased with reducing the particle size. While positive food effect on the absorption was observed for the suspensions made of the hammer-milled and the jet-milled crystals, no significant food effect was found for the suspension made of the NanoCrystal cilostazol spray-dried powder. These results could be qualitatively predicted from the in vitro dissolution data using the bio-relevant media, FaSSIF and FeSSIF. In conclusion, the NanoCrystal technology is found to be efficient to improve the oral bioavailability of cilostazol and to avoid the food effect on the absorption.

Chitosan oligomers as potential and safe absorption enhancers for improving the pulmonary absorption of interferon-alpha in rats.

Effects of chitosan oligomers on pulmonary absorption of interferon-alpha (IFN) were examined by means of an in vivo pulmonary absorption experiment. Chitosan oligomers used in this study were chitosan dimer, tetramer, hexamer, and water-soluble (WS) chitosan. A significant increase in serum IFN concentrations was observed after intratracheal administration of IFN with these oligomers. Of these chitosan oligomers, 0.5% w/v chitosan hexamer appeared to be more effective in enhancing the pulmonary absorption of IFN than other oligomers at the same concentration, and the AUC value of IFN with chitosan hexamer increased 2.6-fold as compared with the control. On the other hand, chitosan polymers, which have relatively high molecular weights (22-96 kDa), were not effective in enhancing the pulmonary absorption of IFN due to their low solubility in water. Additionally, the effect of different concentrations (0.1%-1% w/v) of chitosan hexamer on the pulmonary absorption of IFN was studied. Of these different concentrations of chitosan hexamers, the highest AUC value of IFN was obtained in the presence of 0.5% w/v chitosan hexamer. Furthermore, chitosan oligomers did not cause any membrane damage to the rat pulmonary tissues, as determined by leakage of protein and lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid. Therefore, these findings indicated that the use of chitosan oligomers would be a promising approach for improving of the pulmonary absorption of biologically active peptides including IFN.

Carrageenans can regulate the pulmonary absorption of antiasthmatic drugs and their retention in the rat lung tissues without any membrane damage.

Effects of various viscous vehicles on pulmonary absorption of antiasthmatic drugs were examined by an in situ pulmonary absorption experiment. Theophylline and fluticasone propionate were used as antiasthmatic drugs. The serum concentration-time profile of theophylline without viscous vehicles was similar to that following the intravenous injection, indicating that pulmonary absorption of theophylline was rapid and absolute. The serum concentration of theophylline was not controlled in the presence of 5% gelatin or 2% sodium alginate. However, 1% iota-carrageenan could control and regulate the serum concentration of theophylline. In the pharmacokinetic analysis, the C(max) values of theophylline significantly decreased, and its T(max) values increased in the presence of 1% and 2% iota-carrageenan, 1% kappa-carrageenan, and 2% sodium alginate compared with the control. The MRT and MAT values of theophylline with 1% iota-carrageenan were significantly higher than those without viscous vehicles. The local concentration of theophylline in the lung at 1h after intratracheal administration increased five-fold with 1% iota-carrageenan compared with the control. On the other hand, the pulmonary absorption of fluticasone propionate was controlled and regulated in the presence of 0.5% kappa-carrageenan. Additionally, the pulmonary inflammation after the exposure of carrageenans administered to the lung was evaluated in rats. Iota- and kappa-carrageenans did not cause local serious damage and inflammation to the pulmonary tissue. Therefore, these findings indicated that the carrageenans were effective to regulate the absorption rate of antiasthmatic drugs including theophylline and fluticasone propionate.

Control of pulmonary absorption of water-soluble compounds by various viscous vehicles.

Effects of various viscous vehicles on the pulmonary absorption of water-soluble drugs were examined by an in situ pulmonary absorption experiment. Gelatin, polyvinylacohol (PVA), hydroxypropylcellose (HPC), chondroitin sulfate A sodium salt (CS), polyacrylic acid (PAA), methylcellulose #400 (MC400) and hyaluronic acid sodium salt (HA) were used as models of viscous vehicles. 5(6)-Carboxyfluorescein (CF) and fluorescein isothiocayanate-labeled dextran with an average molecular weight of 4000 (FD4) were used as water-soluble drugs. The plasma concentration of CF was controlled and regulated in the presence of these viscous vehicles, especially gelatin (1-5%) and polyvinyl alcohol (PVA) 1%. In the pharmacokinetic analysis, the Cmax values of CF significantly decreased, and its Tmax values increased in the presence of these viscous vehicles compared with the control. The MRT and MAT values of CF with these vehicles were significantly higher than those without these vehicles. Therefore, these findings indicated that the viscous vehicles were effective to regulate the absorption rate of CF. On the other hand, the pulmonary absorption of FD4 was not so much affected even in the presence of gelatin and PVA, although PVA slightly decreased MRT value, and significantly decreased Tmax value. Furthermore, we examined the release rate of CF from the cellulose tube containing various concentrations of gelatin. The release rate of CF from the cellulose tube with gelatin was inversely related to the viscosity of gelatin. In addition, the release rate of CF was inversely related to DeltaMAT (DeltaMAT = MATgel(MAT with gelatin)-MATsol(MAT without gelatin)) in the presence of varying concentrations of gelatin. These findings indicated that these viscous vehicles were effective to control the pulmonary absorption of CF, a water-soluble drug with low molecular weight and they might be useful to increase the local concentration of drugs in the lung.