Purpose

To analyze the effect of liver steatosis and obesity on pharmacokinetic profile of two structurally-related liver-selective NO-donors — V-PYRRO/NO and V-PROLI/NO.

Methods

C57BL/6 mice were fed control or high-fat diet for 15 weeks to induced liver steatosis and obesity (HFD mice). Pharmacokinetics and renal elimination studies were conducted in vivo following iv dosing of V-PYRRO/NO and V-PROLI/NO (0.03 mmol/kg). Hepatic clearance was evaluated ex vivo in the isolated perfused mice liver and in vitro with the use of liver microsomes.

Results

V-PYRRO/NO and V-PROLI/NO, despite similar structure, displayed different pharmacokinetic properties. V-PYRRO/NO was uptaken and metabolized by the liver, while V-PROLI/NO was eliminated unchanged with urine. In HFD mice, despite increased CYP450 metabolism of V-PYRRO/NO the elimination rate was slower most likely due to the impairment of hepatic microcirculation caused by liver fat accumulation. In turn, in HFD mice renal clearence of V-PROLI/NO was accelerated and volume of distribution was increased most likely due to additional intracellular water in HFD mice.

Conclusions

The pharmacokinetics of V-PROLI/NO, the novel proline-based analog of V-PYRRO/NO with additional single carboxylic acid moiety, attached to the molecule of V-PYRRO/NO to improve the water solubility, was differently affected by liver steatosis and obesity as compared with the parent compound V-PYRRO/NO.

Background Stress ulcer prophylaxis (SUP) is recommended in some situations to prevent upper gastrointestinal bleeding and is a component of standard care for patients admitted to the intensive care unit (ICU). Proton pump inhibitors (PPIs), already among the most widely prescribed drug classes, are being increasingly used. Objective To describe PPI prescribing patterns and their changes after the dissemination of guidelines. Setting Paediatric ICU (PICU), Robert-Debré Teaching Hospital, Paris, France, which admits about 800 patients annually, from full-term neonates to 18-year-olds. Method Prospective observational study with two 6-week observation periods (July–August and September–October, 2013), before and after dissemination in the PICU of PPI prescribing guidelines. Main outcome measure Changes in PPI prescribing patterns (prevalence, dosage, and indication) after the guidelines. Results The number of patients admitted to the PICU was 77 (mean age 4.6 years [range 1 day–18 years]) before and 70 (mean age 3.8 years [range 1 day–17 years]) after the guidelines. During both periods, SUP was the most common reason for PPI prescribing. The proportion of patients prescribed PPIs dropped significantly, from 51% before the guidelines to 30% after the guidelines (p < 0.001). Mean daily dosage also decreased significantly, from 1.5 mg/kg/(range 0.5–4.4) to 1.1 mg/kg (range 0.7–1.8) (p < 0.002). None of the patients experienced upper gastrointestinal bleeding during either period. Conclusion Off-label PPI prescribing for SUP was common in our PICU. The introduction of guidelines was associated with a significant decrease in PPI use and dosage. This study confirms that guidelines can change PPI prescribings patterns in paediatric practice.

G-protein-coupled receptor 119 (GPR119) represents a promising target for the treatment of type 2 diabetes as it can increase both GLP-1 secretion from intestinal L cells and glucose-stimulated insulin secretion (GSIS) from pancreatic β cells. Due to this dual mechanism of action, the development of small molecule GPR119 agonists has received much interest for the treatment of type 2 diabetes. Here, we identified a novel small-molecule GPR119 agonist, YH18421 and evaluated its therapeutic potential. YH18421 specifically activated human GPR119 with high potency and potentiated GLP-1 secretion and GSIS in vitro cell based systems. In normal mice, single oral administration of YH18421 improved glucose tolerance. Combined treatment of YH18421 and the DPP-4 inhibitor augmented both plasma active GLP-1 levels and glycemic control. In diet induced obese (DIO) mice model, glucose lowering effect of YH18421 was maintained after 4 weeks of repeat dosing and YH18421 acted additively with DPP-IV inhibitor. We also observed that YH18421 inhibited weight gain during 4 weeks of administration in DIO mice. These data demonstrate that YH18421 is capable of delivering sustained glucose control and preventing weight gain and combination with the DPP-IV inhibitor maybe an effective strategy for the treatment of type 2 diabetes.

ABSTRACT

Diosgenin (DSG), a well-known steroid sapogenin derived from Dioscorea nipponica Makino and Dioscorea zingiberensis Wright, has a variety of bioactivities. However, it shows low oral bioavailability due to poor aqueous solubility and strong hydrophobicity. The present study aimed to develop DSG nanocrystals to increase the dissolution and then improve the oral bioavailability and biopharmaceutical properties of DSG. DSG nanocrystals were prepared by the media milling method using a combination of pluronic F127 and sodium dodecyl sulfate as surface stabilizers. The physicochemical properties of the optimal DSG nanocrystals were characterized using their particle size distribution, morphology, differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy data, and solubility and dissolution test results. Pharmacokinetic studies of the DSG coarse suspension and its nanocrystals were performed in rats. The particle size and polydispersity index of DSG nanocrystals were 229.0 ± 3.7 nm and 0.163 ± 0.064, respectively. DSG retained its original crystalline state during the manufacturing process, and its chemical structure was not compromised by the nanonizing process. The dissolution rate of the freeze-dried DSG nanocrystals was significantly improved in comparison with the original DSG. The pharmacokinetic studies showed that the AUC_0–72h and C_max of DSG nanocrystals increased markedly (p < 0.01) in comparison with the DSG coarse suspension by about 2.55- and 2.01-fold, respectively. The use of optimized nanocrystals is a good and efficient strategy for oral administration of DSG due to the increased dissolution rate and oral bioavailability of DSG nanocrystals.

A series of N-(3-oxoalkenyl)chloroacetamides was prepared by acylation of β-enaminoketones with chloroacetyl chloride. A reaction of these compounds with sodium p-toluenesulfinate in dimethylformamide in the presence of potassium carbonate led to 3-tosylpyridin-2(1H)-ones. The limitations of this reaction were studied.

The reaction of 2,2-bis(methoxy-NNO-azoxy)ethanol nitrate with pyrazole, 3-nitropyrazole, 4-nitropyrazole, or 3,4-dinitropyrazole allowed to obtain the respective N-[2,2-bis(methoxy-NNO-azoxy)ethyl]pyrazoles. In the case of 3-nitropyrazole, only the 3-nitro isomer was formed, while alkylation of 3,4-dinitropyrazole led to a mixture of 3,4- and 4,5-dinitro isomers in 7:1 ratio, which was difficult to separate. The obtained pyrazoles were characterized by ¹H, ¹³C, and ¹⁵N NMR spectroscopy. X-ray structural studies were performed for the synthesized 3-NO₂, 4-NO₂, and 3,4-(NO₂)₂ derivatives.

Background Medication reviews intended to identify drug-related problems (DRPs) have been researched in primary care, acute care and nursing homes rather than in long-term care hospitals (LTCHs). Objectives To assess the clinical impact of an interdisciplinary pharmacotherapy quality improvement and patient safety program in elderly patients with polypharmacy admitted to an LTCH. Setting An interventional, longitudinal, prospective study was conducted in a Spanish LTCH Method A total of 162 elderly (≥ 70 years) patients with polypharmacy (≥ 5 medications) were included. Pharmacist conducted the pharmacotherapy follow-up of patients (reconciliation, pharmacotherapeutic optimization, educational interviews) from admission to discharge. Demographic, clinical and treatment-related variables were recorded. Main outcome measured Clinical impact of the program by DRP-based effectiveness and drug-related morbidity (DRM)-based safety indicators. Results 895 DRPs (median of 5 (1–23)) were identified in 153 (94.4%) patients. The most common DRPs were unnecessary drug (25.3%), dosage too high (24.9%) and a need for additional drug (24.8%). The most frequent pharmacotherapy recommendations were individualizing the dosage regimen (29.6%) and stopping (27.3%) or starting (21.9%) a drug. The mean implementation rate of pharmacotherapy recommendations was 90.9%. The effectiveness indicator revealed a 94.9% of prevented or resolved DRPs. The safety indicator showed an 89.3% of prevented or resolved DRM. Therefore, the program prevented or resolved 92.5% of adverse effects and 91.7% of suboptimal responses or therapeutic failures. Conclusion This interdisciplinary patient safety program seems to be a valuable approach to identify, prevent and resolve the high number of DRPs and potential DRM that elderly patients with polypharmacy admitted to an LTCH present.

Here, we describe a challenging scale-up synthesis of the highly functionalized echinocandin ASP9726 (1) starting from the natural product FR901379 (3), the same raw material of micafungin (2). The synthesis demanded various difficult chemoselective transformations due to the complexity and the unique property of the cyclic poly-peptide core. In the present study, we discovered an efficient, high-yielding route to ASP9726 (1) that is suitable for large-scale production. Namely, dehydration of carboxamide (13) to nitrile (14) was accomplished by the use of EDC ∙ HCl with pyridine. Further, the sequential nitrile reduction and debenzylation was succeeded with Sponge Nickel- Pd/Ccatalyst mixed catalyst condition. Reductive amination between primary amine (16) with dihydroxyacetone (DHA) was accomplished using 2-picoline borane complex in MeOH, yielding 66.6 kg of peptide core unit (17). After the palmityl chain cleavage by bioconversion, the coupling between the core peptide unit (18) and side chain (9) was achieved by tert-butyl amine borane complex. Consequently, highly pure ASP9726 (1) was obtained in a practical manner without using silica gel or ODS column chromatography purification in any step. The number of step was reduced to 10-steps from 14-steps and the overall yield was drastically increased to 13.8% from 0.71% in comparison with the prior synthesis.

Three new phenolic compounds 1, 2, and 3 have been isolated from Eucommia ulmoides by repeated column chromatography. Their structures were identified as (+)-erythro-7-O-ethylguaiacylglycerol (1), (–)-erythro-7-O-ethylguaiacylglycerol (2), and 1,3-propanediol-2-O-4′ -(3′ ,5′ -dimethoxy-1′ -hydroxymethyl)phenyl ether (3).