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The first total synthesis of (+)-tanzawaic acid B, a natural polyketide bearing a pentadienoic ester and octalin moiety, has been accomplished. The synthetic improvement from previous synthetic conditions facilitated our gram-scale synthesis of the chiral octalin that possesses seven stereogenic centers and that is the core skeleton of almost all of the tanzawaic acid family.

The first total synthesis of (+)-tanzawaic acid B, a natural polyketide bearing a pentadienoic ester and octalin moiety, has been accomplished. The synthetic improvement from previous synthetic conditions facilitated our gram-scale synthesis of the chiral octalin that possesses seven stereogenic centers and that is the core skeleton of almost all of the tanzawaic acid family.

The existing methods for exosome isolation, such as ultracentrifugation, size exclusion, and affinity separation, suffer from some limitations. Herein, we aimed to develop temperature-modulated exosome-capturing materials using thermoresponsive polymers and peptides with affinity for exosomes. Poly(2-hydroxyethyl methacrylate

Poly(N-isopropylacrylamide) (PNIPAAm)-based temperature-responsive fluorescence polymer probes were developed using radical polymerization, with 3-mercaptopropionic acid as the chain-transfer agent, followed by activation of terminal carboxyl groups with N-hydroxysuccinimide and reaction with 5-aminofluorescein (FL). The lower critical solution temperatures (LCSTs) of the resulting fluorescent polymer probes differed depending on the copolymer composition, and had a sharp phase-transition (hydrophilic/hydrophobic) boundary at the LCST. The cellular uptakes of the fluorescent polymer probes were effectively suppressed below the LCST, and increased greatly above the LCST. In particular, the cellular uptake of a copolymer with N,N-dimethylaminopropylacrylamide, P(NIPAAm-co-DMAPAAm2%)-FL (LCST: 37.4 °C), can be controlled within only 1 °C near body temperature, which is suitable for biological applications. These results indicated that the cellular uptakes of thermoresponsive polymers could be accurately cont...

Oligonucleotide therapeutics have contributed remarkably to healthcare, being well suited for the treatment of intractable diseases that are difficult to approach using conventional drug modalities. However, as common techniques of oligonucleotide analysis rely on reversed-phase or ion-exchange liquid chromatography and thus employ toxic organic solvents and/or ion-pairing reagents, better alternatives are highly sought after. Poly(N-isopropylacrylamide) (PNIPAAm) is widely used in temperature-responsive chromatography (TRC), which relies on column temperature variation to control the physical properties of the stationary phase and, unlike conventional reversed-phase liquid chromatography, avoids the use of toxic organic solvents and complicated gradient methods. Herein, PNIPAAm copolymer hydrogel-modified silica beads were used for the simultaneous analysis of multiple synthetic oligonucleotides by TRC to recognize differences in the length of single nucleotides, single bases, and the number of phosphorothioated sites. Temperature-responsive elution was observed in all cases. Each separation of all combinations of multiple oligonucleotides was better at higher temperatures above the lower critical solution temperature and was performed without the use of organic solvents and gradient methods. In the case of multiply phosphorothioated oligonucleotides, good separation was achieved using an aqueous solvent and isocratic elution in the absence of ion-pairing reagents. Thus, the developed procedure was concluded to be well suited for oligonucleotide analysis. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00216-020-02749-8) contains supplementary material, which is available to authorized users.

Introduction Memantine hydrochloride, an N-methyl-D-aspartate receptor antagonist, is used to treat Alzheimer’s disease (AD). A new dry syrup formulation containing memantine hydrochloride has been developed to improve medication adherence in AD patients and to reduce family and caregiver burden. This study was conducted to assess the bioequivalence of this new formulation to the tablet. Methods Two single-dose, randomized, open-label, two-period, two-group, crossover studies were conducted to assess the bioequivalence of a test product [dry syrup, 2%, 1 g (containing 20 mg of memantine hydrochloride)] to a reference product (film-coated tablet) under two dosing conditions: administration of the test product as a suspension in water (Study I) and as granules taken with water (Study II). Blood samples were collected at specified time intervals, and memantine plasma concentrations were determined using a validated liquid chromatography tandem mass spectrometry method. The pharmacokinetic parameters of memantine were calculated using non-compartmental analysis. The maximum concentration (Cmax) and area under the concentration–time curve up to the last sampling time (AUCall) were used to assess the bioequivalence of the two formulations. Results The geometric least square mean (GLSM) ratios [90% confidence interval (CI)] of the Cmax and AUCall of memantine for the test product to the reference product were 0.981 (0.943–1.020) and 0.978 (0.955–1.001) in Study I, and 0.973 (0.944–1.003) and 1.004 (0.983–1.025) in Study II, respectively. In both studies, the 90% CI values of the GLSM ratios of Cmax and AUCall were within the prespecified bioequivalence range (0.80–1.25). The safety of the test product under both dosing conditions and that of the reference product were not different. Conclusions The new dry syrup formulation containing memantine hydrochloride showed bioequivalence to the film-coated tablet under the two dosing conditions. Thus, the new dry syrup is suitable under either dosing condition for patients with AD. Funding Daiichi Sankyo Co., Ltd.

L-type amino acid transporter 1 (LAT1) is a transporter that is more highly expressed in cancer cells compared with normal cells. In the present study, liposomes, composed of egg phosphatidylcholin...

In recent years, drug discovery and therapeutics trends have shifted from a focus on small-molecule compounds to biopharmaceuticals, genes, cell therapy, and regenerative medicine. Therefore, new approaches and technologies must be developed to respond to these changes in medical care. To achieve this, we applied a temperature-responsive separation system to purify a variety of proteins and cells. We developed a temperature-responsive chromatography technique based on a poly(N-isopropylacrylamide) (PNIPAAm)-grafted stationary phase. This method may be applied to various types of protein and cell separation applications by optimizing the properties of the modified polymers used in this system. Therefore, the developed temperature-responsive HPLC columns and temperature-responsive solid-phase extraction (TR-SPE) columns can be an effective separation tool for new therapeutic modalities such as monoclonal antibodies, nucleic acid drugs, and cells.

High-performance liquid chromatography (HPLC) is the most common analytical method practiced in various fields and used for analysis of almost all drug compounds in the pharmaceutical industries. During drug development, an evaluation of potential drug interaction with cytochrome P450 (CYP) is essential. A “cocktail” approach is often used in drug development to evaluate the effect of a drug candidate on multiple CYP enzymes in a single experiment. So far, simultaneous analysis of multiple CYP substrates, which have greatly different structure and physicochemical properties, has required organic solvents and mobile phase gradient methods. However, despite the recent emphasis on environmental protection, analytical methods that use only aqueous solvents without the use of organic solvents for separation have not been studied well. This study sought to develop the simultaneous analysis of multiple CYP substrates by using poly(N-isopropylacrylamide) (PNIPAAm)-based temperature-responsive chromatography with only aqueous solvents and isocratic methods. Good separation of multiple CYP substrates was achieved without using organic solvents and any gradient methods by temperature-responsive chromatography utilizing a P(NIPAAm-co-n-butyl methacrylate (BMA))- and P(NIPAAm-co-N-acryloyl L-tryptophan methyl ester (L-Trp-OMe))-grafted silica column. Overall, PNIPAAm-based temperature-responsive chromatography represents a remarkably simple, versatile, and environmentally friendly bioanalytical method for CYP substrates and their metabolites.

Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. NCT03699774. JapicCTI-152878.