Consecutive One-Pot versus Domino Multicomponent Approaches to 3-(Diarylmethylene)oxindoles

Based on consecutive one-pot conditions combining three palladium-catalyzed reactions (Sonogashira, Heck and Suzuki-Miyaura reactions), a more efficient domino multicomponent method has been successfully developed to access a wide variety of 3-(diarylmethylene)oxindoles. Microwave irradiation and use of a silver salt were the most important factors to achieve high yields and stereoselectivity

Multivariate Statistical Optimization of Tablet Formulations Incorporating High Doses of a Dry Herbal Extract

The development of oral tablet formulation for herbal medicines has been restricted by large drug loadings and the poor physicochemical and mechanical properties of dry herbal extracts (DHEs). Herein, statistical experimental designs were applied to herbal tablet formulation development and optimization using Wuzi Yanzong dry extract (WYE). The tablet disintegration time and hardness were identified as the critical quality attributes (CQAs) of the product. The tablet formulation was designed to achieve a high drug loading (50% or higher of WYE), shorter tablet disintegration time (less than 30 minutes), and suitable hardness (6.0 to 7.5 kp). A D-optimal mixture design was used to evaluate the effects of excipients on CQAs to minimize the risk compression failure and improve the tabletability in formulations containing WYE at 50% and 65% by weight. A partial least squares model was used to elucidate the multivariate relationships between a large number of formulation variables and product CQAs, and determine the maximum possible WYE loading. From overlaid plots of the effects of formulation variables on CQAs, it was found that a maximum WYE loading of 67% in tablet formulation satisfied the acceptance criteria of CQAs. In conclusion, this study shows that multivariate statistical tools are useful for developing tablet formulations containing high doses of herbal extracts and establishing control strategies that ensure product quality

Pravastatin and Sarpogrelate Synergistically Ameliorate Atherosclerosis in LDLr-Knockout Mice.

Pravastatin is a lipid-lowering agent that attenuates atherosclerosis. However, the multifactorial pathogenesis of atherosclerosis requires other drugs with different anti-atherogenic mechanisms. We chose sarpogrelate as an anti-platelet agent and a novel component of a complex drug with pravastatin due to its high potential but little information on its beneficial effects on atherosclerosis. Low-density lipoprotein receptor-knockout mice were fed a high-fat, high-cholesterol diet and treated with pravastatin alone, sarpogrelate alone, or a combination of both drugs. Although sarpogrelate alone did not significantly reduce atherosclerotic plaque areas, co-treatment with pravastatin significantly decreased aortic lesions compared to those of the pravastatin alone treated group. The combined therapy was markedly more effective than that of the single therapies in terms of foam cell formation, smooth muscle cell proliferation, and inflammatory cytokine levels. These results suggest that pravastatin and sarpogrelate combined therapy may provide a new therapeutic strategy for treating atherosclerosis

Beneficial Effects of Sarpogrelate and Rosuvastatin in High Fat Diet/Streptozotocin-Induced Nephropathy in Mice.

Chronic kidney disease (CKD) is a major complication of metabolic disorders such as diabetes mellitus, obesity, and hypertension. Comorbidity of these diseases is the factor exacerbating CKD progression. Statins are commonly used in patients with metabolic disorders to decrease the risk of cardiovascular complications. Sarpogrelate, a selective antagonist of 5-hydroxytryptamine (5-HT) 2A receptor, inhibits platelet aggregation and is used to improve peripheral circulation in diabetic patients. Here, we investigated the effects of sarpogrelate and rosuvastatin on CKD in mice that were subjected to a high fat diet (HFD) for 22 weeks and a single low dose of streptozotocin (STZ, 40 mg/kg). When mice were administrated sarpogrelate (50 mg/kg, p.o.) for 13 weeks, albuminuria and urinary cystatin C excretion were normalized and histopathological changes such as glomerular mesangial expansion, tubular damage, and accumulations in lipid droplets and collagen were significantly improved. Sarpogrelate treatment repressed the HFD/STZ-induced CD31 and vascular endothelial growth factor receptor-2 expressions, indicating the attenuation of glomerular endothelial proliferation. Additionally, sarpogrelate inhibited interstitial fibrosis by suppressing the increases in transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1). All of these functional and histological improvements were also seen in rosuvastatin (20 mg/kg) group and, notably, the combinatorial treatment with sarpogrelate and rosuvastatin showed additive beneficial effects on histopathological changes by HFD/STZ. Moreover, sarpogrelate reduced circulating levels of PAI-1 that were elevated in the HFD/STZ group. As supportive in vitro evidence, sarpogrelate incubation blocked TGF-β1/5-HT-inducible PAI-1 expression in murine glomerular mesangial cells. Taken together, sarpogrelate and rosuvastatin may be advantageous to control the progression of CKD in patients with comorbid metabolic disorders, and particularly, the use of sarpogrelate as adjunctive therapy with statins may provide additional benefits on CKD

Weights of low-density lipoprotein receptor-knockout (LDLr KO) mice fed a HFD with treatment of pravastatin or pravastatin plus sarpogrelate.

<p>Weights of low-density lipoprotein receptor-knockout (LDLr KO) mice fed a HFD with treatment of pravastatin or pravastatin plus sarpogrelate.</p

Serum lipid analysis of low-density lipoprotein receptor-knockout (LDLr KO) mice fed a HFD with treatment of sarpogrelate.

<p>Serum lipid analysis of low-density lipoprotein receptor-knockout (LDLr KO) mice fed a HFD with treatment of sarpogrelate.</p

Histology of atherosclerotic aortic root lesions.

<p>Low-density lipoprotein receptor-knockout (LDLr KO) mice were fed a NFD (a), a HFD (b), a HFD with pravastatin (40 MPK) (c) or a HFD with a combination of pravastatin (40 MPK) and sarpogrelate (50 MPK) (d) for 12 weeks. Mouse aortic sections were collected and representative Oil Red O (A), intercellular adhesion molecule-1 (ICAM-1) (B), monocyte/macrophage-2 (MOMA-2) (C), and alpha smooth muscle actin (α-SMA) (D)-stained images of atherosclerotic plaques were shown and quantified (e). Scale bar represents 500 μm, Error bars represent standard errors, and significance was analyzed by Student’s <i>t</i>-test (*P < 0.05, **P < 0.01, ***P < 0.001, N = 6–7/group). MPK, mg/kg; NFD, normal fat diet; HFD, high fat diet; NS, not significant; PRA, pravastatin; SAR, sarpogrelate.</p

Sarpogrelate alone marginally and insignificantly reduces atherosclerotic lesions in low-density lipoprotein receptor-knockout (LDLr KO) mice.

<p>Male LDLr KO mice (8 weeks) were fed a NFD (a), a HFD (b), or a HFD with sarpogrelate (10 (c) or 50 MPK (d), orally six times weekly) for 20 weeks. (A) Representative Oil Red O-stained <i>en face</i> aortic preparation. (B) Quantification of Oil Red O-stained plaque areas. (C) Representative Oil Red O-stained atherosclerotic aortic root lesions (a, b, c, d) and quantification (e). (D) Representative alpha smooth muscle actin (α-SMA)-immunostained images of atherosclerotic plaques in aortic root lesions (a, b, c, d) and quantification (e). Scale bar represents 500 μm, Error bars represent standard errors, and significance was analyzed by Student’s <i>t</i>-test (*P < 0.05, **P < 0.01, ***P < 0.001, n = 3–5/group). MPK, mg/kg; NFD, normal fat diet; HFD, high fat diet; NS, not significant; SAR, sarpogrelate.</p