Effect of single-administration of D-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial.

BACKGROUND: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. METHODS: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). RESULTS: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. CONCLUSION: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

Predictors of continuation for asenapine from real-world data in patients with schizophrenia.

BACKGROUND: The continuation rates of pharmacotherapy in schizophrenia exhibit variability, a phenomenon influenced by the specific antipsychotic agent prescribed and patient-related factors such as age and duration of illness. In this context, our study aims to elucidate the predictors of medication continuation for asenapine sublingual tablets, characterized by unique formulation properties. METHODS: Our investigation leveraged real-world data collected through post-marketing surveillance in Japan, comprising 3236 cases. Utilizing multivariate logistic regression analysis, we identified patient-related factors associated with medication continuation as the primary outcome measure, subsequently employing survival analysis for further evaluation. Additionally, adverse event occurrence was assessed as a secondary outcome measure. RESULTS: Multivariate logistic regression analysis unveiled significant predictors of asenapine continuation, notably including patient-related factors such as a chlorpromazine equivalent dose exceeding 600 mg/day and an illness duration of 25 years or more. While the overall continuation rate stood at 40.6%, patients exhibiting factors such as a chlorpromazine equivalent dose surpassing 600 mg/day or an illness duration exceeding 25 years demonstrated continuation rates of 46.3% and 47.9%, respectively. Remarkably, patients presenting both factors showcased the highest continuation rate at 52.5%. CONCLUSIONS: Our findings shed light on distinct patient-related predictors of asenapine continuation, deviating from those observed with other antipsychotic medications. This underscores the necessity of recognizing that predictive factors for antipsychotic medication continuation vary across different agents. Moving forward, elucidating these predictive factors for various antipsychotic medications holds paramount importance in schizophrenia treatment, facilitating the delivery of tailored therapeutic interventions for individual patients.

Assembly of Six Types of Heteroleptic Pd2L4 Cages under Kinetic Control.

Heteroleptic assemblies composed of several kinds of building blocks have been seen in nature. It is still unclear how natural systems design and create such complicated assemblies selectively. Past efforts on multicomponent self-assembly of artificial metal-organic cages have mainly focused on finding a suitable combination of building blocks to lead to a single multicomponent self-assembly as the thermodynamically most stable product. Here, we present another approach to selectively produce multicomponent Pd(II)-based self-assemblies under kinetic control based on the selective ligand exchanges of weak Pd-L coordination bonds retaining the original orientation of the metal centers in a kinetically stabilized cyclic structure and on local reversibility given in certain areas of the energy landscape in the presence of the assist molecule that facilitates error correction of coordination bonds. The kinetic approach enabled us to build all six types of Pd2L4 cages and heteroleptic tetranuclear cages composed of three kinds of ditopic ligands. Although the cage complexes thus obtained are metastable, they are stable for 1 month or more at room temperature.

Theoretical and computational methodologies for understanding coordination self-assembly complexes.

This perspective highlights three theoretical and computational methods to capture the coordination self-assembly processes at the molecular level: quantum chemical modeling, molecular dynamics, and reaction network analysis. These methods cover the different scales from the metal-ligand bond to a more global aspect, and approaches that are best suited to understand the coordination self-assembly from different perspectives are introduced. Theoretical and numerical researches based on these methods are not merely ways of interpreting the experimental studies but complementary to them.

Sensory evaluation of the bitterness of asenapine using D-sorbitol pretreatment: single-blind, placebo-controlled, crossover trial.

BACKGROUND: Antipsychotics are essential in the acute treatment of and maintenance therapy for schizophrenia, but medication adherence and long-term treatment continuity are needed to maximize their effectiveness. Each antipsychotic has various side effects, which may affect adherence. Some patients with schizophrenia are reluctant to take asenapine because of its unique oral-related side effects, such as the bitter taste caused by sublingual administration. Our previous basic research found that D-sorbitol lowered the bitterness parameters of the taste sensors. However, whether D-sorbitol has the same effect in patients remains unclear. Therefore, using a D-sorbitol solution, we aim to evaluate changes in the bitterness of asenapine among patients with schizophrenia. METHODS: In this single-blind, placebo-controlled, crossover trial, we plan to recruit 20 adult patients with schizophrenia spectrum disorder who take sublingual asenapine tablets. The participants will be divided into two groups (n = 10 each). Each group will be given a D-sorbitol or placebo solution on the first day for rinsing before taking the sublingual asenapine tablets. After a 1-day interval, the participants will rinse their mouths again with a different liquid. Questionnaires regarding changes in taste and the willingness to continue asenapine will be conducted before the start of the study and after each rinse. The primary and secondary end points will be a taste evaluation of bitterness, and the willingness to continue asenapine, respectively. Differences in questionnaire scores between the D-sorbitol and placebo solutions will be calculated and analyzed using a McNemar test. DISCUSSION: This study aims to determine the efficacy of D-sorbitol in masking the bitter taste of asenapine. To our knowledge, it is the first intervention study using D-sorbitol for bitter taste of asenapine in patients with schizophrenia. Evidence of the efficacy of D-sorbitol could result in D-sorbitol pretreatment being an easy and inexpensive means of improving adherence to asenapine. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials jRCTs041210019, on May 14, 2021. Ethics approval was obtained from the Nagoya University Clinical Research Review Board.

Cyclization or bridging: which occurs faster is the key to the self-assembly mechanism of Pd6L3 coordination prisms.

The self-assembly processes of Pd6L3 coordination prisms consisting of cis-protected Pd(II) complexes and porphyrin-based tetratopic ligands with four 3-pyridyl or 4-pyridyl groups (L) were investigated by experimental and numerical methods, QASAP (quantitative analysis of self-assembly process) and NASAP (numerical analysis of self-assembly process), respectively. It was found that contrary to common intuition macrocyclization takes place faster than the bridging reaction in the prism assembly and that the bridging reaction occurring before the macrocyclization tends to produce kinetically trapped species. A numerical simulation demonstrates that the relative magnitude of the rate constants between the macrocyclization and the bridging reaction is the key factor that determines whether the self-assembly leads to the thermodynamically most stable prism or to kinetically trapped species. Finding the key elementary reactions that largely affect the selection of the major assembly pathway is helpful to rationally control the products under kinetic control via modulation of the energy landscape.

Divergence of dose-response with asenapine: a cluster analysis of randomized, double-blind, and placebo control study.

BACKGROUND: Differences in psychiatric background and dose-response to asenapine in patients with schizophrenia were examined based on efficacy and safety, using data obtained in a double-blind, placebo-controlled trial. METHODS: Patients with schizophrenia were classified into three clusters by a cluster analysis based on the Positive and Negative Symptom Scale (PANSS) subscores at baseline, using the data from a 6-week, double-blind, placebo-controlled trial. PANSS Marder factor scores were calculated for each cluster. The efficacy of 10 or 20 mg/day of asenapine on PANSS score was used as the primary endpoint, with the incidence of adverse events evaluated as the secondary endpoint. RESULTS: A total of 529 asenapine-treated patients were classified into 3 clusters: Cluster-P with the higher scores in positive symptoms, disorganized thoughts, and hostility/excitement, Cluster-N with higher scores in negative symptoms, and Cluster-L with overall lower scores. In Cluster-N and Cluster-L, both 10 and 20 mg/day groups showed significant improvement in PANSS scores, while only the 20 mg/day group showed a significant difference in Cluster-P. Cluster-N and Cluster-L had differences in the incidence of adverse events, but this was not seen in Cluster-P. CONCLUSIONS: The efficacy and safety of asenapine 10 and 20 mg/day differed between the 3 clusters of patients. This suggests that background information regarding baseline psychiatric symptoms may affect the therapeutic response in patients with schizophrenia.

Coordination Self-Assembly Processes Revealed by Collaboration of Experiment and Theory: Toward Kinetic Control of Molecular Self-Assembly.

The importance of the collaboration of experiment and theory has been proven in many examples in science and technology. Here, such a new example is shown in the investigation of molecular self-assembly process, which is a complicated multi-step chemical reaction occurring in the reaction network composed of a huge number of intermediates. An experimental method, QASAP (quantitative analysis of self-assembly process), developed by us and a numerical approach, NASAP (numerical analysis of self-assembly process), that analyzes the experimental data obtained by QASAP to draw detail molecular self-assembly pathways, which was also developed by us, are introduced, and their application to the investigation of Pd(II)-mediated coordination assemblies are presented. Further, the possibility of the prediction of the outcomes of molecular self-assembly by varying the reaction conditions is also demonstrated. Finally, a future direction in the field of artificial molecular self-assembly based on pathway-dependent self-assembly, that is, kinetic control of molecular self-assembly is discussed.

Unexpected Self-Assembly Pathway to a Pd(II) Coordination Square-Based Pyramid and Its Preferential Formation beyond the Boltzmann Distribution.

Experimental and theoretical investigations of the self-assembly process of a Pd(II) coordination M6L4 square-based pyramid (SP) were conducted. It was found that the probable self-assembly pathway, in which the dimerization of M2L2 with two M leads to SP, expected from the connectivity of the building blocks is not a major self-assembly pathway to the M6L4 SP. Whether the M6L4 SP is assembled or M2L2 is trapped is determined by an inter- or intramolecular reaction in a chain-like M2L2X, where X is a leaving ligand. The kinetically trapped state where the M6L4 SP is produced from M2L2 beyond the Boltzmann distribution was realized by a concentration-induced process and was kept for at least 2 months at 298 K.

Improvement in the appropriate antimicrobial usage for treating pediatric acute otitis media in Japan: A descriptive study using nation-wide electronic medical record data.

OBJECTIVES: We investigated changes in prescriptions for antimicrobial agents to treat children with acute otitis media (AOM). METHODS: A descriptive study using an electronic medical record database. Of 199,896 patients enrolled between 2001 and 2019, a total of 10,797 were aged <16 years and had AOM as their first and primary disease (overall pediatric AOM cohort). In addition, 4786 patients with AOM without other comorbidities (pediatric AOM cohort) were included. RESULTS: In the overall pediatric AOM cohort, the age distribution ranged from 11% to 23% for those younger than 2 years and from 66% to 77% for those younger than 6 years, with no change over time. In the pediatric AOM cohort, the antimicrobial prescription rate was 91% in 2001 but declined to 40% by 2019. Antimicrobial use increased from 0% to 75% for penicillins, whereas use of cephalosporins decreased from 84% to 10%. The prescription rate for acetaminophen alone increased from 33% to 58%. There were no differences in the incidence of adverse reactions among the prescribed antimicrobials. CONCLUSIONS: Due to education efforts and promotion of the proper use of antimicrobials through means such as the Clinical practice guidelines for the diagnosis and management of acute otitis media in children (2006) and the Manual of Antimicrobial Stewardship (2016), a change in the use of antimicrobials occurred, leading to a trend to more proper use of these agents.

An Aromatic Oligomer Micelle: Large Enthalpic Stabilization and Selective Oligothiophene Uptake.

An aromatic oligomer micelle, featuring both high stability and high uptake ability, was quantitatively formed in water from amphiphilic oligomers, composed of three bent polyaromatic amphiphiles connected alternately by two hydrophilic chains. The well-defined micelle, with a diameter of ca. 2 nm, remains intact even under highly diluted conditions (ca. 3 µM) and at elevated temperature (>130 °C), due to the polyaromatic chelate effect. The thermodynamic studies reveal that large enthalpic gain (ΔH=-110 kJ mol-1 ) is the key for the micelle formation. The oligomer micelle selectively encapsulates unsubstituted oligothiophenes (≥4-mer) to a high degree and the resultant, aqueous host-guest complexes display unusual emission derived from the multiply stacked oligomers. Furthermore, facile uptake and release of unsubstituted polythiophenes can be achieved using the oligomer micelle.

Towards kinetic control of coordination self-assembly: a case study of a Pd3L6 double-walled triangle to predict the outcomes by a reaction network model.

Numerical analysis of self-assembly process (NASAP) was performed for a [Pd3L6]6+ double-walled triangle (DWT) complex. With a chemical reaction network and a parameter set of the reaction rate constants obtained from a numerical search in an eighteen-dimensional parameter space to obtain a good fit to the data from the experimental counterpart (quantitative analysis of self-assembly process, QASAP), a refined calculation resulted in a detailed time evolution of each molecular species. Analysis based on those clues revealed dominant self-assembly pathways and a balance between inter- and intramolecular reactions, and enabled prediction of the reaction outcomes depending on the initial stoichiometric ratio under kinetic control.

Self-Assembly Processes of Octahedron-Shaped Pd6L4 Cages.

The self-assembly processes of two kinds of octahedron-shaped M6L4 cages consisting of cis-protected Pd(II) complexes and organic tritopic ligands were investigated. Whether kinetically trapped species larger than the cages are produced or the M6L4 cage is assembled without the formation of such kinetic traps is determined by a balance between the rates of oligomerization and intramolecular cyclization, which is affected by slight changes in the chemical structure of the tritopic ligand. A numerical analysis of the experimental data based on a reaction network model where 249 reactions between the possible 56 species were considered revealed the self-assembly pathways of one of the two M6L4 cages.

Navigated Self-Assembly of a Pd2L4 Cage by Modulation of an Energy Landscape under Kinetic Control.

Kinetic control of molecular self-assembly remains difficult because of insufficient understanding of molecular self-assembly mechanisms. Here we report the formation of a metastable [Pd2L4]4+ cage structure composed of naphthalene-based ditopic ligands (L) and Pd(II) ions in very high yield (99%) under kinetic control by modulating the energy landscape. When self-assembly occurs with anionic guests in weakly cooordinating solvent then suitable intermedites and the metastable cage is formed. These conditions also prevent further transformation into the thermodynamically decomposed state. The cage formation pathways under kinetic control and the effect of the anions encapsulated on the self-assembly processes were investigated by QASAP (quantitative analysis of self-assembly process) and NASAP (numerical analysis of self-assembly process). It was found that the self-assembly with a preferred guest (BF4-) proceeds through intermediates composed of no more components than the cage ([PdaLbXc]2a+ (a ≤ 2, b ≤ 4, X indicates a leaving ligand)) and that the final intramolecular cage-closure step is the rate-determining step. In contrast, a weaker guest (OTf-) causes the transient formation of intermediates composed of more components than the cage ([PdaLbXc]2a+ (a > 2, b > 4)), which are finally converted into the cage.

A kinetics study of ligand substitution reaction on dinuclear platinum complexes: Stochastic versus deterministic approach.

The kinetics on a basic ligand substitution reaction on dinuclear platinum complexes [Pt(PEt3 )2 PhPt(PEt3 )2 ]2+ and [Pt(PEt3 )2 PhCOPhPt(PEt3 )2 ]2+ , with the ligands pyridine and 3-chloropyridine, is studied. This is a fundamental step in a self-assembly, and the time evolution has been observed with a new experimental technique, QASAP (quantitative analysis of self-assembly process), which is recently developed by Hiraoka's group. As a result of numerical calculations based on master equation, we succeed in specifying the reaction rate constants with a simple reaction model. In addition, the time evolutions of all the intermediate components produced and consumed in chemical reaction are revealed, including those unobserved in the experiments. The convergence behavior of the existence ratios of specific chemical species calculated with the stochastic algorithm method is compared with those obtained from deterministic formalism based on rate equations, revealing a clear dependence on the number of constituent molecules. © 2018 Wiley Periodicals, Inc.

A stochastic model study on the self-assembly process of a Pd2L4 cage consisting of rigid ditopic ligands.

The coordination self-assembly process of a Pd2L4 cage including rigid ditopic ligands, L, was studied numerically. A recently developed experimental approach (QASAP: quantitative analysis of self-assembly process) revealed that the rate-determining steps in the self-assembly of the Pd2L4 cage are intramolecular ligand exchanges at the late stages of the self-assembly. In this study, the self-assembly process before the rate-determining steps, which could not be investigated by experiment, was analyzed based on a minimal reaction network model. Only eight variable parameters of rate constants for ligand exchange reactions are sufficient enough to reproduce the time evolution of substrates and the products during the self-assembly of the cage. With these parameters, the major self-assembly pathway was determined. It was also found that a non-negligible amount of an incomplete cage (IC), Pd2L3X2 (X indicates the leaving ligand), which was not suggested by QASAP, should be transiently produced. Numerical tests also suggest that the small rate constant value of the intramolecular ligand exchanges due to a restricted geometry causes the final stage to seemingly become the rate-determining step.

Quantitative Analysis of the Self-Assembly Process of Hexagonal PtII Macrocyclic Complexes: Effect of the Solvent and the Components.

The self-assembly process of three PtII -linked hexagonal macrocycles consisting of dinuclear PtII complexes and organic ditopic ligands was investigated in polar and less polar solvents by a recently developed approach: quantitative analysis of the self-assembly process (QASAP). In polar CD3 NO2 , for all the three macrocycles, an ML2 complex was the dominant intermediate during self-assembly, as a result of high positive allosteric cooperativity for the ligand exchange on the PtII centers of the dinuclear PtII complexes. On the other hand, in less polar CD2 Cl2 , the self-assembly process was affected by the components. For two of the three macrocycles, the chainlike oligomers that contain fewer metals and ligands than the corresponding macrocycles grew with time and the type of the chainlike intermediates formed correlated with the allostericity of the two binding sites in the organic ditopic ligands. In every case, no long oligomers containing more components than the macrocycles themselves were produced during the self-assembly even though free rotation around single bonds in the chainlike oligomers allows them to adopt various conformations that do not facilitate the cyclization. This result suggests that electrostatic and/or steric factors besides rigidity of the components make the cyclization advantageous not only thermodynamically but also kinetically.

Energy-Landscape-Independent Kinetic Trap of an Incomplete Cage in the Self-Assembly of a Pd2 L4 Cage.

A kinetic trap is the metastable species that is transiently or constantly produced during the reaction by trapping in a deep energy well. In most cases, the reactivity of kinetically trapped species is relatively low under the reaction conditions. Herein, we report another type of kinetically trapped species that is an incomplete cage (IC) intermediate produced during the self-assembly of a Pd2 L4 cage from ditopic ligand (L) and PdII ions with a certain lifetime, although IC has a high enough reactivity to be converted into the cage with the reaction of free L, which was confirmed by the reaction of the isolated IC and L under the self-assembly conditions. IC was kinetically trapped not because IC lies on the bottom of a deep energy well but because the conversion of the intermediates essential for the conversion of IC to the cage preferentially takes place; IC was kinetically trapped independently of the shape of the energy landscape of the self-assembly.

A Balance between van der Waals and Cation-π Interactions Stabilizes Hydrophobic Assemblies.

A thermally highly stable molecular self-assembly (nanocube) in water, the decomposition temperature of which is 415 K, was developed by designing a gear-shaped amphiphile (GSA) with an indented hydrophobic surface, even though the nanocube is stabilized only by van der Waals (vdW) and cation-π interactions as well as the hydrophobic effect. The introduction of an electron-donating substituent in one of the benzene rings of the GSA increased the decomposition temperature by 12 K, which is due to the stronger cation-π interactions between the benzene ring and positively charged pyridinium rings and tighter molecular meshing between the GSAs in the nanocube. The position of the substituent introduced in the benzene ring greatly affects the thermal stability of the nanocubes, and this indicates that both vdW (molecular meshing) and cation-π interactions are crucial for improving the thermal stability of the hydrophobic assemblies.

Self-Assembly Process of a Pd2 L4 Capsule: Steric Interactions between Neighboring Components Favor the Formation of Large Intermediates.

The effect of molecular interactions between the components on the self-assembly process of Pd2 L4 structures was investigated by a 1 H NMR-based quantitative approach (QASAP: quantitative analysis of self-assembly process). Although the self-assembly of the Pd2 L4 cage without interactions between the bent ligands took place, mainly producing small intermediates, the self-assembly of the Pd2 L4 capsule composed of bent ligands with anthracene panels tends to produce large intermediates containing more components than the capsule. This is ascribed to steric interactions between the panels.