Practical and Sustainable Synthesis of Optically Pure Levocabastine, a H1 Receptor Antagonist.

A practical and sustainable method for the synthesis of levocabastine hydrochloride (1), a H1 receptor antagonist for the treatment of allergic conjunctivitis, that can be applied to the industrial production of the compound has been developed. Substantial improvements over the previously reported procedure are achieved via efficient preparation of an optically active key intermediate (5) without chiral resolution and with a more effective detosylation, which complements the previous procedure. Notably, our process requires no chromatographic purification and provides levocabastine hydrochloride in greater than 99.5% purity in a 14.2% overall yield.

A Population Pharmacokinetic Study to Compare a Novel Empagliflozin L-Proline Formulation with Its Conventional Formulation in Healthy Subjects.

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is commonly used for the treatment of type 2 diabetes mellitus (T2DM). CKD-370 was newly developed as a cocrystal formulation of empagliflozin with co-former L-proline, which has been confirmed to be bioequivalent in South Korea. This study aimed to quantify the differences in the absorption phase and pharmacokinetic (PK) parameters of two empagliflozin formulations in healthy subjects by using population PK analysis. The plasma concentration data of empagliflozin were obtained from two randomized, open-label, crossover, phase 1 clinical studies in healthy Korean subjects after a single-dose administration. A population PK model was constructed by using a nonlinear mixed-effects (NLME) approach (Monolix Suite 2021R1). Interindividual variability (IIV) and interoccasion variability (IOV) were investigated. The final model was evaluated by goodness-of-fit (GOF) diagnostic plots, visual predictive checks (VPCs), prediction errors, and bootstrapping. The PK of empagliflozin was adequately described with a two-compartment combined transit compartment model with first-order absorption and elimination. Log-transformed body weight significantly influenced systemic clearance (CL) and the volume of distribution in the peripheral compartment (V2) of empagliflozin. GOF plots, VPCs, prediction errors, and the bootstrapping of the final model suggested that the proposed model was adequate and robust, with good precision at different dose strengths. The cocrystal form did not affect the absorption phase of the drug, and the PK parameters were not affected by the different treatments.

Prognostic value of early postoperative tumor marker response in gastric cancer.

BACKGROUND: The clinical usefulness of tumor markers as predictors of treatment outcome in patients with stomach cancer after radical gastrectomy has been poorly defined. The purpose of this study was to evaluate a comprehensive understanding of the impact of early postoperative tumor marker normalization on survival after gastrectomy. METHODS: Between January 2001 and December 2007, we enrolled 206 patients who had received radical gastrectomy as an initial treatment and had elevated carcinoembryonic antigen (CEA) (>5 ng/mL) or carbohydrate antigen (CA) 19-9 (>37 U/mL) levels. Early tumor marker response was defined as a normalization of preoperative CEA or CA19-9 values 1-2 months after gastrectomy. RESULTS: The mean patient age was 61 years (range 29-84 years), and 139 patients (67.5%) were male. Early tumor marker response was identified in 150 of 206 (72.8%) patients. Of the patients, 49 (23.8%), 41 (19.9%), and 116 (56.4%) were stages I, II, and III, respectively, according to the seventh edition of the American Joint Commission on Cancer (AJCC) staging system. Both disease-free survival (DFS) and overall survival (OS) were significantly longer in patients with tumor marker response compared with nonresponse (61.5 vs. 37.6 months; P = 0.010 and 71.3 vs. 50.9 months; P = 0.008, respectively). Multivariate analyses showed that high CA19-9 level, early tumor marker response, and tumor, node, metastasis classification system stage were independent predictors of DFS and OS (P < 0.05). CONCLUSIONS: Early CEA or CA19-9 normalization after radical gastrectomy is a strong prognostic factor for gastric cancer, especially in patients with high preoperative levels of tumor markers.

Synthesis of cinnamoyl ketoamides as hybrid structures of antioxidants and calpain inhibitors.

The excessive calpain activation causes serious cellular damage or even cell death in neurological disorders such as stroke and Alzheimer's disease. Oxidative stress has also been implicated in the initiation or progression of neurodegenerative diseases. In the present studies, a series of cinnamoyl ketoamides 4a-4j were synthesized as hybrid structures of antioxidants and calpain inhibitors. Cinnamoyl ketoamides, possessing an alkyl chain at the α-position, showed potent µ-calpain inhibitory activities indicating that the cinnamoyl skeleton can be regarded as an acyclic variant of calpain inhibitory chromone carboxamide 2. Among synthesized, compound 4e was the most potent inhibitor of µ-calpain (IC(50)=0.13 µM) and also exhibited strong antioxidant activities in DPPH and superoxide anion radical scavenging and lipid peroxidation inhibition assay systems.

Design and synthesis of 4-quinolinone 2-carboxamides as calpain inhibitors.

Calpains are involved in a variety of calcium-regulated cellular processes, such as signal transduction, cell proliferation, differentiation, and apoptosis. Excessive calpain activation contributes to serious cellular damage and has been reported in many pathological conditions. 4-Quinolinone 2-carboxamide derivatives were prepared and evaluated for mu-calpain inhibitory activities. Of the compounds synthesized, 3a and 3k, which possess a primary amide and 4-methoxyphenethyl amide at P1' region, were found to most potently inhibit mu-calpain with IC50 values of 0.71+/-0.07 and 0.73+/-0.23 microM, respectively. On the other hand, the incorporation of pyridine-containing amides decreased inhibitory activity.

Synthesis and anticancer activity of lavendustin A derivatives containing arylethenylchromone substituents.

2-Styrylchromones, which are relatively scarce in nature, have been reported to possess potent cytotoxicities on KB cell line. Lavendustin A, a metabolite of Streptomyces griseolavendus, has been shown to inhibit a growth of A431 cell line. Accordingly, a series of compounds 3a-g having structural features of styrylchromones and lavendustin A were synthesized and evaluated for cytotoxicity using SRB assay on four tumor cell lines. Compounds 3a-g were synthesized by the condensation of 2-methylchromone derivative 7 with several aromatic aldehydes. Among synthesized, compound 3e showed the significant cytotoxic activity on HCT-15 cell line with IC(50) values of 7.17 microg/ml indicating that lavendustin A derivatives containing 2-arylethenylchromone ring have a potential in anti-tumor application.

Endovascular Treatment in Ruptured Middle Cerebral Artery Dissection Preservation of Arterial Continuity.

Rupture of spontaneous dissecting aneurysms of the middle cerebral artery (MCA) is rare and its etiology remains obscure, although the risk of rebleeding is greater than with saccular aneurysms. Most reports concerning the treatment of a ruptured dissecting aneurysm of the anterior circulation involve surgical trapping or wrapping. Here, we report on a case of an MCA dissecting rupture treated with endovascular procedures. A 22-year-old female presented with sudden stuporous mental change following severe headache and left side hemiparesis. A computed tomography scan showed a diffuse subarachnoid hemorrhage and diffusion MR showed diffusion restriction at the right putamen and internal capsule. A 3-hour follow-up digital subtraction angiography (DSA) showed a dissecting aneurysm, which was not seen on an initial DSA. A stent assisted coil embolization was performed and double stents were applied to achieve flow diversion effects. A small remnant area of the dissecting aneurysm had disappeared at 60-day and was not observed on 12-month follow-up DSA.

Long-term statin therapy improves oncological outcome after radical gastrectomy for stage II and III gastric cancer.

BACKGROUND/AIM: Although several epidemiological studies have indicated that statins may have antitumor properties, the effect of statins on patient survival after curative resection of gastric cancer is unknown. The aim of the present study was to determine whether statin use could improve long-term outcomes after radical gastrectomy. PATIENS AND METHODS: We conducted a matched case-control study of 65 statin users and 176 non-users who underwent radical gastrectomy for stage II and III gastric cancer from January 2006 to December 2009. RESULTS: No significant differences were found in recurrence-free survival (RFS) or overall survival (OS) between statin users and non-users. However, subgroup analysis showed that patients who used statins for more than six months had more favorable outcomes than non-users or those who used statins for less than six months [adjusted hazard ratio of death (non-users as reference); statin use <6 months: 2.405, 95% confidence interval (CI)=1.056-5.477 and statin use >6 months: 0.168, 95% CI=0.032-0.881, p=0.006]. CONCLUSION: Statin use did not improve RFS or OS after curative resection of stage II or III gastric cancer in the overall study population. However, statin use of more than six months was associated with increased survival.

Synthesis and anticancer activity of chromone-based analogs of lavendustin A.

Lavendustin A and hormothamnione were reported to exhibit cytotoxic effects on tumor cell lines. In the present studies, a series of chromone-based lavendustin analogs were synthesized as a simplified hybrid of hormothamnione and lavendustin A by the reductive-amination of formyl-chromone 5 with various amines followed by aminoalkylation. Most compounds synthesized showed significantly improved potencies compared to the standard compound 3 against most of cancer cell lines tested indicating that the removal of styryl group enhanced cancer cell growth inhibitory activities. Compound 4h and 4k showed the most potent inhibitory activities with GI(50) values in the range of 6.01-9.92 microg/ml on A-549 and HCT-15 cells.

A case of hepatocellular carcinoma within hepatocellular adenoma in a non-cirrhotic male.

Hepatocellular adenoma (HA) is a benign hepatic lesion that predominantly occurs in young women. Most hepatocellular carcinomas (HCC) arise in a cirrhotic liver during the fifth or sixth decades. There have been several reported cases of HCC developing from HA in female patients. However, there are rare cases about HCC arising in HA in a non-cirrhotic male patient. We have recently encountered a 53-year-old man who had a liver mass in a non-cirrhotic liver, and the liver mass was compatible with HA on the pre-operative computed tomography. The mass was completely resected and the histopathology revealed a focus of HCC arising in HA. We report here on this case along with a brief review of the relevant literature.