Pharmacokinetic Interaction Between Rosuvastatin and Metformin in Healthy Korean Male Volunteers: A Randomized,Open-label, 3-period,Crossover, Multiple-dose Study

Purpose

Rosuvastatin is indicated for hypercholesterolemia or dyslipidemia and metformin mainly for type 2 diabetes. These 2 drugs are frequently prescribed in combination due to the high comorbidity of the 2 diseases. However the nature of pharmacokinetic interaction between the 2 drugs has not been previously investigated. The purpose of our study was to investigate the pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers.

Methods

This was a randomized, open-label, 6-sequence, 3-period, crossover, multiple-dose study. Eligible subjects, aged 20 to 50 years and within 20% of the ideal body weight, received 1 of the following 3 treatments for each period once daily for 5 consecutive days with a 10-day washout period between the treatments: monoadministration of rosuvastatin 10 mg tablet, monoadministration of metformin 750 mg tablet, and coadministration of rosuvastatin 10 mg tablet with metformin 750 mg tablet. Blood samples were collected up to 72 hours after the last dose and pharmacokinetic parameters for rosuvastatin and metformin were compared between combination and monotherapy. Adverse events were investigated and evaluated based on subject interviews and physical examinations.

Findings

Among the 36 enrolled subjects, 31 completed the study. The coadministration of rosuvastatin with metformin produced a significant pharmacokinetic interaction in rosuvastatin C_ss,max, with the 90% CI for the geometric mean ratio (coadministration:monoadministration) being 110.27% to 136.39% (P = 0.0029), whereas no significant interaction was observed in rosuvastatin AUC_tau, yielding the 90% CI of 104.41% to 118.95%. When metformin was coadministered with rosuvastatin, no significant pharmacokinetic interaction was observed for C_ss,max and AUC_tau of metformin, yielding the 90% CIs of the geometric mean ratio for coadministration to monoadministration as 87.38% to 102.54% and 86.70% to 99.08%, respectively. Overall, 19 mild and 1 moderate adverse events occurred in 12 subjects, with no significant differences in the incidence among the 3 treatments.

Implications

Although the C_ss,max of rosuvastatin was significantly influenced by coadministration with metformin, the degree of interaction seen was considered clinically insignificant, with no significant interaction observed in the other pharmacokinetic measures between the 2 drugs. These results imply that drug effects of rosuvastatin and metformin will also not be significantly influenced by coadministration of the 2 drugs. All treatments were well tolerated and no serious adverse events occurred. ClinicalTrials.gov identifier: NCT01526317.     

Antioxidant Activity and Cytotoxicity of the Traditional Indonesian Medicine Tahongai (Kleinhovia hospita L.) Extract

We investigated the leaves of Kleinhovia hospita, a plant which has been traditionally used in Indonesia as phytotherapy to cure liver disease, to describe antioxidant materials from plant sources. K. hospita leaves were extracted with methanol and further partitioned into n-hexane, diethyl ether, and ethyl acetate. The antioxidant activity of each fraction and the residue was assessed using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method and their cytotoxicity on HepG2 liver cancer cells was determined by a MTT assay. The K. hospita leaf methanol extract showed strong antioxidant activity (96%) compared with vitamin C (98%) by the DPPH method and the measured activity from the subsequent extracts of the methanol extract were 48.9% for n-hexane, 74.0% for diethyl ether, 84.3% for ethyl acetate, and 77.1% for the residue. The MTT assay showed the cytotoxicity of the methanol extract on HepG2 cells at 14%, 76%, and 80% at concentrations of 50μg/mL, 87.5μg/mL, and 125μg/mL, respectively. Leaf extracts of the medicinal plant K. hospita showed potent antioxidant activity and moderate cytotoxicity on HepG2 liver cancer cells.     

Outcome of hepatic resection for metastatic gastric cancer

The role of hepatic resection for metastatic gastric cancer is less well defined due to the tendency of gastric cancer to widely metastasize. The purpose of this study is to examine the beneficial effect of hepatic resection in patients with metastatic gastric cancer. The clinicopathologic features and long-term results of 11 patients who underwent hepatic resection for metastatic gastric cancer from January 1988 to December 1996 at Seoul National University Hospital were analyzed retrospectively. All resected hepatic metastases were solitary lesions. Among eight patients with synchronous hepatic metastases, one patient with early gastric cancer and lymph node metastases (T1N2M1) remained alive for 8 years 6 months after hepatic resection without recurrence. Among three patients with metachronous hepatic metastases, two patients with advanced gastric cancer and lymph node metastases (T3N2MO, T2N1MO at the initial operation, respectively) survived 8 years 6 months and 3 years after hepatic resection, respectively. Median survival times of synchronous and metachronous hepatic metastases were 13.0 and 74.3 months, respectively. In solitary hepatic metastatic lesions from gastric cancer, surgical resection should be considered as one of the treatment options.     

Impact of Combined Prophylactic Unilateral Central Neck Dissection and Hemithyroidectomy in Patients with Papillary Thyroid Microcarcinoma

Background  

Lymph node metastases occur frequently in patients with papillary thyroid carcinoma (PTC), and the central compartment of the neck is the most frequently involved site. Some authors advocate prophylactic central neck dissection (CND) during total thyroidectomy. However, little is known about the effects of prophylactic unilateral CND in papillary thyroid microcarcinoma (PTMC) patients who undergo hemithyroidectomy. This study was designed to investigate the impact of prophylactic unilateral CND in this population.     

The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis

Recent research progress indicates a close link between ghrelin, a natural ligand of GH secretagogues receptor (GHS-R), and both the metabolic balance and body composition. To clarify the involvement of ghrelin and GHS-R in the process of adipogenesis, we measured the expression of GHS-R and peroxisome proliferator-activated receptor gamma 2 (PPAR-gamma 2) mRNA in rat adipocytes using semiquantitative RT-PCR methods. The levels of GHS-R mRNA increased by up to 4-fold in adipose tissue from epididymal and parametrial regions as the rat aged from 4-20 wk and were significantly elevated during the differentiation of preadipocytes in vitro. Ghrelin (10(-8) M for 10 d) stimulated the activity of glycerol-3-phosphate dehydrogenase and the differentiation of rat preadipocytes in vitro. Ghrelin treatment also significantly increased the levels of PPAR-gamma 2 mRNA in primary cultured rat differentiated adipocytes. In addition, isoproterenol (10(-8) M, 40 min)-stimulated lipolysis was significantly reduced by simultaneous ghrelin treatment in a dose-dependent manner in vitro. In conclusion, the expression of GHS-R in rat adipocytes increases with the age and during adipogenesis. Ghrelin in vitro stimulates the differentiation of preadipocytes and antagonizes lipolysis. Ghrelin may therefore play an important role in the process of adipogenesis in rats.     

Gut microbiota modulation and gold nanoparticle‐mediated photothermal therapy for treatment of recalcitrant acne

Recent studies highlight that gut dysbiosis, an imbalanced state of intestinal microbiota, exacerbates skin inflammation. Here, we showed the presence of gut microbiota alterations in two patients with recalcitrant acne and investigated the impact of its therapeutic modulation together with gold nanoshell‐mediated photothermal therapy (gold PTT).