Mechanisms and Safety of Antidepressant-Like Effect of Nutmeg in Mice.

Nutmeg, a dried seed kernel of a tall evergreen Myristicaceae tree, is widely used as a spice and herbal medicine and is known to have antidepressant-like effects. This study evaluates the mechanisms underlying this antidepressant-like effect and safety of nutmeg n-hexane extract (NNE) in mice. Tail suspension and open field tests showed that NNE (10 mg/kg, per OS (p.o.)) significantly decreased the immobility time of mice without effecting their spontaneous locomotor activity. The reduction of immobility time of mice elicited by NNE was significantly inhibited by ketanserin (5-hydroxytryptamine (5-HT)2A/2C receptor antagonist), ondansetron (5-HT3 receptor antagonist), and yohimbine (α2 receptor antagonist). WAY100635 (5-HT1A receptor antagonist) tended to inhibit the effect of NNE but without significance. Testing according to the Organisation for Economic Co-operation and Development Guidelines, no mice died due to administrated NNE (2000 mg/kg, p.o.), and behavioral and weight changes were not seen in the acute toxicity test. In the Ames test, no increase in the number of revertant colonies for each bacterial strain test strains TA98 and TA100 by nutmeg powder was observed either with or without metabolic activity by S9 mix. These results suggest that NNE shows an antidepressant-like effect involving various serotonergic and noradrenergic nervous systems and maybe a highly safe natural preparation.

Practical Synthesis of α-Trifluoromethylated Pyridines Based on Regioselective Cobalt-Catalyzed [2+2+2] Cycloaddition using Trifluoromethylated Diynes with Nitriles.

Regioselective cobalt-catalyzed [2+2+2] cycloaddition using fluorine-containing diynes with nitriles was described. Cycloaddition of fluorinated diynes with nitriles under the influence of CoCl2(phen), zinc bromide, and zinc dust in dichloroethane at 80°C for 3 h took place smoothly, exclusively affording the corresponding α-fluoroalkylated pyridines in excellent yields. In addition, dinitriles as substrate were also found to be suitable for this reaction, giving the corresponding fluoroalkylated bipyridine derivatives in excellent yields.

Cobalt-Catalyzed C-H Activation/Annulation of Benzamides with Fluorine-Containing Alkynes: A Route to 3- and 4-Fluoroalkylated Isoquinolinones.

The C-H activation/annulation reaction of various benzamides with fluoroalkylated alkynes in the presence of a Co(acac)2·2H2O catalyst proceeded very smoothly to give the corresponding 3- and 4-fluoroalkylated isoquinolinones in excellent yields with approximately 70% regioselectivities. These regioisomers could be successfully separated and obtained in pure form. Major or minor regioisomers were determined as 4- or 3-fluoroalkylated isoquinolinones, respectively, based on X-ray crystallographic analyses.

Syntheses of α-CF3-α-quaternary ketones via p-quinone methides and their derivatization to compounds with successively congested stereogenic centers.

New and successful results for the construction of new and structurally interesting compounds are reported via N-heterocyclic carbene (NHC)-catalyzed 1,6-conjugate additions of a variety of aldehydes to δ-CF3-δ-substituted p-quinone methides generated in situ, and the products are used for the 1,2-addition reactions of appropriate metal nucleophiles, enabling us to furnish highly diastereoselective products with a unique successive quaternary carbon-tertiary alcohol framework (up to dr = >99 : 1).

Synthesis and characterization of bent fluorine-containing donor-π-acceptor molecules as intense luminophores with large Stokes shifts.

Herein, we prepared novel bent fluorine-containing donor-π-acceptor (D-π-A) molecules from commercially available octafluorocyclopentene using a facile two-step procedure, revealing that the above molecules absorb UV-light and exhibit yellow photoluminescence (PL) with high PL efficiencies (ΦPL) in solution. The corresponding Stokes shifts exceeded 10 000 cm-1, and the maximum PL wavelength (λPL) strongly depended on solvent polarity or intermolecular interactions in the solid state. On the basis of a Lippert-Mataga plot, PL was confidently assigned to radiative relaxation from an intramolecular charge-transfer excited state. Moreover, the synthesized luminophores showed intense PL even in the crystalline state and exhibited alkoxy chain length-dependent PL behavior (e.g., high ΦPL, λPL = 486-540 nm).

Effects of magnesium oxide on pharmacokinetics of L-dopa/carbidopa and assessment of pharmacodynamic changes by a model-based simulation.

BACKGROUND: Magnesium oxide (MgO) is often co-prescribed with L-dopa/carbidopa (LDCD) to improve constipation in Parkinson's disease patients. The mixing of L-dopa and MgO has been shown to degrade L-dopa; however, there is no interaction study on humans. We proposed mechanisms for the interaction between LDCD and MgO and conducted pharmacokinetic studies on rats and humans. To assess pharmacodynamic changes with the MgO treatment, we applied a model-based meta-analysis (MBMA). METHODS: The effects of MgO on the stabilities of L-dopa and carbidopa were evaluated in in vitro studies. We conducted pharmacokinetic interaction studies of MgO and LDCD on rats and healthy volunteers. A clinical study was conducted with an open-label, non-randomized, single-arm, and two-phase study. In MBMA, we constructed a population pharmacokinetic/pharmacodynamic model of L-dopa and predicted the effects of the MgO treatment on the pharmacodynamics of L-dopa. RESULTS: In vitro results suggested that carbidopa was unstable under alkaline pH conditions. Reductions in plasma LDCD concentrations were observed after oral-MgO/oral-LDCD, but not in oral-MgO/i.v.-LDCD treatments in rats, suggesting that the gastrointestinal tract is an interaction site. A healthy volunteer study showed that MgO was also associated with significant decreases of 35.3 and 80.9% in the AUC0-12 of L-dopa and carbidopa, respectively. A model-based simulation suggested that the MgO treatment was undesirable for the effectiveness of L-dopa. CONCLUSIONS: This is the first study to show a clear pharmacokinetic interaction between LDCD and MgO in humans. Further investigations to confirm the effects of MgO on the pharmacodynamics of L-dopa are required.

Syntheses and Structures of d10 Coinage Metal Complexes of Electron-Accepting Phosphine Ligands Featuring a 3,3,4,4,5,5-Hexafluorocyclopentene Framework.

Cu(I), Ag(I), and Au(I) complexes of monophosphine or bisphosphine ligands based on the 3,3,4,4,5,5-hexafluorocyclopentene skeleton were synthesized and structurally characterized by X-ray crystallographic analysis. The electron-withdrawing nature of these polyfluorinated phosphines was experimentally revealed via UV/vis absorption studies and crystal structure analysis. Successful catalytic application of the Au(I) complex for alkyne hydration reactions was investigated.

Thermoresponsive luminescence properties of polyfluorinated bistolane-type light-emitting liquid crystals.

We developed and characterized four polyfluorinated bistolane derivatives. These compounds, which possess either two alkoxy substituents or an alkoxy group and a bromine atom in their two molecular terminals, were synthesized from readily available 4-alkoxy-1-ethynylbenzene with a facile three-step procedure. Their thermodynamic and photophysical properties were evaluated in detail, and they were found to display both liquid-crystalline (LC) and photoluminescence properties. Remarkably, the photoluminescence behaviors dramatically changed during the thermal phase transition between the crystal and LC phases. Thus, these polyfluorinated bistolanes may be promising candidates for thermoresponsive luminous molecules.

Fluorine-Containing Dibenzoanthracene and Benzoperylene-Type Polycyclic Aromatic Hydrocarbons: Synthesis, Structure, and Basic Chemical Properties.

Intramolecular photocyclization of stilbene derivatives (Mallory reaction) is one of the efficient methods for building polycyclic aromatic hydrocarbon (PAH) frameworks, and is also expected to be applicable to synthesis of fluorine-containing PAHs (F-PAHs). In this study, dibenzoanthracene-type (4a) and benzoperylene-type (4b) F-PAHs were synthesized using the Mallory reaction of the 1,4-distyrylbenzene-type π-conjugated molecule (3a), which was prepared by addition-defluorination of available octafluorocyclopentene (OFCP) and aryllithium in three steps. The structure of 4a originating from π⁻π interaction was characterized by X-ray crystallographic analysis. The absorption maxima of UV-Vis spectra and emission maxima of photoluminescence spectra of the PAHs were positioned at a longer wavelength compared to those of the corresponding unsubstituted PAHs, presumably due to the electron-withdrawing nature of perfluorocyclopentene (PFCP) units. The effect of PFCP units in F-PAHs was also studied by time-dependent density functional theory (TD-DFT) calculation.

Stereochemically Defined Various Multisubstituted Alkenes Bearing a Tetrafluoroethylene (-CF2CF2-) Fragment.

Highly regio- and stereoselective transformation of commercially available 4-bromo-3,3,4,4-tetrafluoro-1-butene into multisubstituted alkenes having a tetrafluoroethylene fragment through Heck reactions and/or Suzuki-Miyaura cross-coupling reactions was established. Thus, the obtained alkenes underwent a smooth reductive coupling reaction with aldehydes under the influence of MeLi/LiBr-free, affording structurally unprecedented fluorinated materials.

Fluorine-containing bistolanes as light-emitting liquid crystalline molecules.

We synthesised a series of dissymmetric bistolane derivatives and evaluated their liquid-crystalline (LC) and photoluminescence properties in detail. In measuring LC behaviours, rational structural design based on the dissymmetric molecular structure and electron-density distribution facilitated the production of the LC phase with a wide temperature range (up to 97 °C). In addition, dissymmetric bistolane derivatives were shown to strongly emit blue-photoluminescence in dilute solution and in crystalline states. It was found that dissymmetric bistolanes possess emissive features in even the LC phase and photoluminescence behaviours such as emission intensity and colour were sensitively switched depending on the molecular aggregate structure caused by applying a thermal stimulus.

Synthesis of perfluoroalkylated pentacenes and evaluation of their fundamental physical properties.

Symmetrical and unsymmetrical pentacenes carrying two perfluoroalkyl (Rf) chains, at the 6 and 13 positions, were synthesized from easily available pentacene-6,13-quinone via facile three or four step reactions. After extensive evaluation, it was clearly found that the control of both the electron density of the aromatic rings on the pentacene core and molecular alignment in the crystalline state nicely affected their physical properties. Thus, we successfully prove in this article that (1) their anti-oxidation ability was significantly enhanced due to a decrease in the HOMO and LUMO energy and (2) a distinct difference in charge-transporting properties was observed between the symmetrical and unsymmetrical pentacenes.

Diastereoselective Mannich reactions of pseudo-C2-symmetric glutarimide with activated imines.

As an extension of the boron enolate-based aldol reactions, the oxazolidinone-installed bisimide 1a from 3-(trifluoromethyl)glutaric acid was employed for Mannich reactions with tosylated imines 2 as electrophiles to successfully obtain the corresponding adducts in a stereoselective manner.

Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An in Vitro Study.

Bisphosphonates and statins are known to have antitumor activities against different types of cancer cell lines. In the present study, we investigated the antiproliferative effects of the combination of zoledronic acid (ZOL), a bisphophosphonate, and fluvastatin (FLU), a statin, in vitro on two types of human pancreatic cancer cell lines, Mia PaCa-2 and Suit-2. The pancreatic cancer cell lines were treated with ZOL and FLU both individually and in combination to evaluate their antiproliferative effects using WST-8 cell proliferation assay. In this study, we demonstrated a potent synergistic antiproliferative effect of both drugs when used in combination in both cell lines. Moreover, we studied the molecular mechanism behind this synergistic effect, which was inhibited by the addition of the mevalonate pathway products, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Furthermore, we aimed to determine the effect of ZOL and FLU combination on RhoA and Ras guanosine 5'-triphosphate (GTP)-proteins. The combination induced a marked accumulation in RhoA and unprenylated Ras. GGPP and FPP reversed the increase in the amount of both proteins. These results indicated that the combination treatment impaired RhoA and Ras signaling pathway by the inhibition of geranylgeranylation and/or farnesylation. This study provides a potentially effective approach for the treatment of pancreatic cancer using a combination treatment of ZOL and FLU.

Bioelectrical Impedance Analysis (BIA) of the association of the Japanese Kampo concept "Suidoku" (fluid disturbance) and the body composition of women.

BACKGROUND: In Japanese Kampo medical practice, suidoku (fluid disturbance) is one of the most important concepts for selecting the proper medication. Suidoku is an excessive or uneven distribution of fluid that is indicated by splashing sounds and pitting edema. However, few objective reports about suidoku have been published. Bioelectrical impedance analysis (BIA) uses resistance values obtained from weak electrical currents to estimate body composition, including intracellular and extracellular water and muscle and fat mass. In this study, we used BIA to search for objective factors that can discriminate the various types of suidoku. METHODS: Two hundred twenty-nine patients who visited the Kampo Medicine Clinic of Kyushu University Hospital from June 2010 to August 2015 were divided into non-suidoku (n = 180, 80 male and 100 female), splashing sound (n = 32, 8 male and 24 female) and edema groups (n = 17, 5 male and 12 female). Body composition values were taken from the electronic medical records of InBody730 (a vertical, segmental, multi-frequency analyzer by InBody, Tokyo Japan) testing done at the initial visit. Various parameters of the body composition values of female in the non-suidoku and suidoku groups (splashing sound and edema groups) were compared: there were too few male patients to provide significance. RESULTS: The age and body weight were significantly lower in the splashing sound group than in the non-suidoku group (p < 0.05). In contrast, the body weight of the edema group was significantly heavier than that of the non-suidoku group (p < 0.05). In ROC analysis, the percent Body Fat ≤ 27.8 %, Muscle Mass Index of the Trunk ≤ 6.5 kg/m2, VFA (Visceral fat area) ≤ 5.4 and BMI ≤ 19.2 kg/m2 were associated with splashing sound, and Muscle Mass Index of Legs ≥ 4.8 kg/m2 and BMI ≥ 21.4 kg/m2 were associated with edema. CONCLUSION: Our data suggest that the use of this type of BIA to estimate body composition would be a useful tool for the diagnosis of suidoku for women.

Effects on Deaf Patients of Medication Education by Pharmacists.

Deaf people often experience difficulty in understanding medication information provided by pharmacists due to communication barriers. We held medication education lectures for deaf and hard of hearing (HH) individuals and examined the extent to which deaf participants understood medication-related information as well as their attitude about medication. We used two questionnaires to compare the results from the deaf participants with those from the HH and hearing participants. We found that before the lecture, the deaf participants' understanding of medication use was lower than that of the HH and hearing participants. The deaf participants' knowledge increased after the lecture, but did not improve to the level exhibited by the HH participants. However, the deaf participants felt confident using medication despite their low comprehension levels. In conclusion, adjusting the medication information provided by pharmacists according to the recipient's reading level could help improve deaf patients' knowledge; however, such measures might not increase deaf patients' comprehension levels sufficiently.

Stereochemical Investigation of the Products of the Photoinduced Perfluoroalkylation-Dimerization of Anthracene.

The photoinduced perfluoroalkylation of anthracene has been shown to provide 9,9',10,10'-tetrahydro-10,10'-diperfluoroalkyl-9,9'-bianthracenes in over 70% yields, each perfluoroalkyl iodide producing three diastereomers. The structures of all three diastereomers (cis,cis, cis,trans, and trans,trans isomers) have been elucidated by both NMR and X-ray crystallographic analyses. Most notably, an X-ray crystallographic analysis has revealed that the trans,trans diastereomer having the two trifluoromethyl groups in 10,10'-positions adopts a 74° twisted relationship of the two dihydroanthracene rings. Furthermore, each of the two trans,trans isomers 2a,b has been shown to exist as a mixture of new types of atropisomers and the energy barrier for the interconversion of the two atropisomers has been estimated to be 12 kcal/mol by variable-temperature NMR analysis.

[Analysis of Factors to Hinder Self-directed Learning about Medication Education to Patients with Hearing Loss].

To improve medication education for patients with hearing loss, pharmacists must better understand hearing loss and provide and collect medication information based on patients' health literacy and communication abilities. However, no systematic educational e-learning systems for hearing loss are currently available. Therefore, an e-learning system based on instructional design, microlearning principles, and multimedia teaching materials was developed. The e-learning system used Moodle, an open-source e-learning system, and included two courses: one for self-directed learning by watching videos and answering quizzes, and another for evaluating medication education after learning. A study was conducted on 84 pharmacists and 36 pharmacy students who took the learning course to investigate the factors that hinder their understanding and progress of self-directed learning. Although they fully understood the content by watching videos, students with no experience in medication education required an explanation to understand how to communicate with patients. As the learning course was self-directed and related to communication lectures, all students completed it; however, the completion rate for pharmacists was approximately 50%. The following factors could have slowed pharmacists' e-learning progress: difficulty accessing the learning course through system login and long-duration content, such as answers to free descriptions. This survey found that this e-learning method can be used for self-directed learning about medication education for patients with hearing loss. Further improvement of the e-learning system is necessary so that recognizing the need to understand hearing loss and take appropriate actions for patients with hearing loss in medication education can lead to self-directed learning among pharmacists.

[Effects of E-learning on Pharmacists' Recognition and Practice in Medication Education for Patients with Hearing Loss].

Pharmacists are required to provide and collect medication information based on patients' health literacy and communication abilities to provide effective pharmaceutical care. Due to a lack of understanding of hearing loss and awareness of the inconvenience that patients with hearing loss face, appropriate actions for effective communication in medication education are not fully implemented. An e-learning system consisting of two courses, a learning course and an evaluation course, has been developed. The learning course explains hearing loss and appropriate actions in medication education and investigates pharmacists' recognition of medication education, while the evaluation course assesses the implementation of necessary actions in medication education and changes in pharmacists' recognition of medication education with patients compared to before the e-learning. From February to September 2022, 41 pharmacists completed the learning course, with 22 advancing to the evaluation course. Prior to learning, they had difficulty in communicating with patients with hearing loss. However, after the learning course, their confidence in medication education improved with a better understanding of hearing loss and practice of appropriate actions. They also felt that pharmacists who were unfamiliar with the system should understand hearing loss and take actions tailored to patients' hearing loss. Further examination may be needed of the effects of the e-learning on patients with hearing loss.

[Cautions for pharmaceutical care in cancer patients-comparative evaluation between cancer and non-cancer].

Cancer patients have greater physical and mental anxiety than non-cancer patients because of the severity of their disease and the strong side effects of anticancer drugs. In this study, therefore, we sent out questionnaires to both cancer and noncancer patients to investigate the specific patient education for reducing anxiety of cancer patients, and compared the results in detail in Miyazaki Prefectural Miyazaki Hospital. The number of days of patient education was significantly more in cancer patients than in non-cancer patients. However, regardless of the number of days of patient education, understanding the level of side effects was significantly higher in cancer patients than in non-cancer patients. A significant correlation was shown between the relief level of patients and the listening level of pharmacists in both patient groups. Regarding the level of patient understanding, a significant correlation was shown between treatment methods and all of the other factors(effects of drugs, patients' degree of relief, pharmacists' degree of attentiveness). On the other hand, a significant correlation was shown only between treatment methods and effects of drugs on the level of understanding in non-cancer patients. These results suggest that characteristic patient education should be conducted for cancer patients, and that it would be best if it is done early on.