In January 2006, Sunitinib was approved by the US Food and Drug Administration for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumor. Sunitinib inhibits the receptor tyrosine kinases that are involved with various receptors whose functions are related to tumor growth, angiogenesis and metastatic progression. The cutaneous adverse reactions of hand-foot syndrome associated with sunitinib are well known, but there have been no previous reports on these reactions in the Korean medical literature. We report here on a case of hand-foot syndrome due to this drug, and we discuss the possible mechanism of hand-foot syndrome caused by sunitinib.
Carcinoma, Renal Cell ; Gastrointestinal Stromal Tumors ; Hand-Foot Syndrome ; Indoles ; Paronychia ; Phosphotransferases ; Pyrroles ; Tyrosine ; United States Food and Drug Administration

In January 2006, Sunitinib was approved by the US Food and Drug Administration for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumor. Sunitinib inhibits the receptor tyrosine kinases that are involved with various receptors whose functions are related to tumor growth, angiogenesis and metastatic progression. The cutaneous adverse reactions of hand-foot syndrome associated with sunitinib are well known, but there have been no previous reports on these reactions in the Korean medical literature. We report here on a case of hand-foot syndrome due to this drug, and we discuss the possible mechanism of hand-foot syndrome caused by sunitinib.
Carcinoma, Renal Cell ; Gastrointestinal Stromal Tumors ; Hand-Foot Syndrome ; Indoles ; Paronychia ; Phosphotransferases ; Pyrroles ; Tyrosine ; United States Food and Drug Administration

BACKGROUNDSunitinib has been proved an effective new option for treatment of metastatic renal cell carcinoma (mRCC). Analysis of clinical data of 22 patients, who were exposed to sunitinib for at least 1 year, was conducted to evaluate the long-term efficacy and safety of sunitinib for the treatment of mRCC.

METHODSA total of 54 patients with mRCC were treated with sunitinib malate, 50 mg/d orally, on a 4-weeks-on and 2-weeks-off dosing schedule in Peking University First Hospital. Treatment continued until disease progression, unacceptable adverse events (AEs), or death. Among them, 22 patients continued treatment for at least 1 year. The clinical data of these 22 patients were prospectively collected for analysis. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. Tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors.

RESULTSMedian progression-free survival was 19.5 months until last follow-up. The best efficacy results achieved were complete response, partial response, and stable disease for 2, 9, and 11 patients, respectively. Objective response rate was 50%. The most common AEs were hand-foot syndrome (95%) and hypertension (91%). Other common AEs were thyroid-stimulating hormone elevation (82%), platelet decrease (77%), and loss of appetite (77%). Only one patient withdrew from treatment for cardiac infarction. Another nine patients experienced dose modifications or short-term suspensions.

CONCLUSIONLong-term exposure to sunitinib malate showed encouraging efficacy in the treatment of mRCC. At the same time, the tolerability was good.

Adult ; Aged ; Antineoplastic Agents ; administration & dosage ; Carcinoma, Renal Cell ; drug therapy ; pathology ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Humans ; Indoles ; administration & dosage ; Kidney Neoplasms ; drug therapy ; pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; Pyrroles ; administration & dosage ; Young Adult

OBJECTIVETo investigate the efficacy and safety of sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) on a 2 weeks on/1 week off intermittent dosing schedule.

METHODSA total of 11 mRCC patients were enrolled to receive sunitinib 50 mg/day in 2 weeks on/1 week off schedule per 6 weeks till disease progression or intolerable toxicity occurred. The primary end point was progression free survival (PFS), the secondary end points were overall survival (OS), incidence of adverse effects and objective response.

RESULTSThe objective response rate in the 11 cases was 45.5% and disease control rate 72.7% (partial response n = 5, stable disease n = 3). Till the last follow up on Dec 2013, the median PFS was 17.0 months (95% CI 7.3 to 26.7 months), and median OS 26.0 months (95% CI 2.2 to 49.8 months). The common adverse events included leucopenia, thrombocytopenia, diarrhea, mucositis and hand-foot skin reaction. Dose reduction to 37.5 mg was seen only in 2 patients without discontinuation.

CONCLUSIONSSunitinib on an intermittent dosing schedule 2 weeks on /1 week off as first-line therapy for mRCC patients shows a good efficacy and tolerance, with less grade 3-4 drug-related toxicities and a tendency of prolonged PFS in mRCC patients.

Antineoplastic Agents ; administration & dosage ; pharmacology ; therapeutic use ; Carcinoma, Renal Cell ; drug therapy ; Disease-Free Survival ; Drug Administration Schedule ; Humans ; Indoles ; administration & dosage ; pharmacology ; therapeutic use ; Kidney Neoplasms ; drug therapy ; Pilot Projects ; Pyrroles ; administration & dosage ; pharmacology ; therapeutic use ; Treatment Outcome

Influenza virus is a virus causing upper respiratory tract infection disease with high morbidity and mortality. China is considered as an area with high rate of influenza morbidity. Prevention and treatment of influenza currently rely on vaccines and antiviral agents in the world. In addition, traditional Chinese medicines also have been used in clinical for influenza therapy. In vitro anti-influenza virus activities of 10 traditional Chinese medicines were studied by cytopathic effect (CPE). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Guangdong Luohu/219/2006 (H1N1); Yinhuang oral liquid had strong antiviral activity against influenza virus A/Hanfang/359/95 and A/Yuefang/243/72 (H3N2). Qingkailing oral liquid (factory G) had strong antiviral activity against influenza virus A/Jifang/15/90 (H3N2). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Jifang/15/90, A/Yuefang/243/72 (H3N2) and virus B.
Administration, Oral ; Animals ; Antiviral Agents ; administration & dosage ; pharmacology ; Bridged Bicyclo Compounds, Heterocyclic ; administration & dosage ; pharmacology ; Cell Line ; Chlorogenic Acid ; administration & dosage ; pharmacology ; Cytopathogenic Effect, Viral ; drug effects ; Dogs ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Flavonoids ; administration & dosage ; pharmacology ; Indoles ; administration & dosage ; pharmacology ; Influenza A Virus, H1N1 Subtype ; drug effects ; Influenza A Virus, H3N2 Subtype ; drug effects ; Influenza B virus ; drug effects ; Iridoids ; administration & dosage ; pharmacology

OBJECTIVE: Agonists of alpha7-nicotinic acetylcholine receptors (nAChRs) have been developed as potential therapeutic drugs for neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. Positron emission tomography (PET) is a noninvasive brain imaging technique to measure receptor occupancy in the living human brain. Although much effort has been expended to create specific PET radioligands for alpha7-nAChRs in the brain, only 4-[11C]methylphenyl-1,4-diazabicyclo[3.2.2.]nonane-4-carboxylate ([11C]CHIBA-1001) is currently available for clinical studies. In contrast, two 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, tropisetron and ondansetron, have been used to treat patients with chemotherapy-induced or postoperative nausea and vomiting. Furthermore, tropisetron, but not ondansetron, possesses high affinity for alpha7-nAChRs. In the present study, we evaluated the receptor occupancy in the human brain after a single oral administration of tropisetron and ondansetron using [11C]CHIBA-1001 and PET. METHODS: Two serial dynamic PET scans using [11C]CHIBA-1001 in healthy non-smoking male subjects were performed before and after receiving an oral administration of these medications. RESULTS: A single oral administration of tropisetron, but not ondansetron, decreased the total distribution volume of [11C]CHIBA-1001 in the human brain. CONCLUSION: This study shows that tropisetron, but not ondansetron, could bind to alpha7-nAChRs in the human brain after a single oral administration. Therefore, [11C]CHIBA-1001 may be a useful PET radioligand to measure the occupancy of alpha7-nAChRs in the human brain.
Administration, Oral ; Alzheimer Disease ; Brain ; Electrons ; Humans ; Indoles ; Male ; Neuroimaging ; Ondansetron ; Positron-Emission Tomography ; Postoperative Nausea and Vomiting ; Receptors, Cholinergic ; Receptors, Nicotinic ; Schizophrenia

Cationic liposome-mediated gene transfection is a promising method for gene therapy. In this study, the transfection efficiency and histological patterns were evaluated in rat lung after intravenous administration via femoral vein of naked plasmid DNA, naked plasmid DNA with pretreatment of DOTAP, and DOTAP-cholesterol-plasmid DNA complex. Plasmid DNA encoding bacterial LacZ gene was used. For quantification of LacZ gene expression, -galactosidase assay was performed. For histologic examination, X-gal staining and immunohistochemical staining for transfected gene products were performed. Pretreatment of DOTAP prior to the infusion of naked plasmid DNA increased transfection efficiency up to a level comparable to DOTAP-cholesterol-plasmid DNA complex injection. Transfected genes were mainly expressed in type II pneumocytes and alveolar macrophages in all animals. We conclude that the high transfection efficiency is achievable by intravenous administration of naked plasmid DNA with pretreatment of DOTAP, to a level comparable to DOTAP-cholesterol-plasmid DNA complex. In this regard, naked plasmid DNA administration with pretreatment of DOTAP could be a more feasible option for intravenous gene transfer than DOTAP-cholesterol-plasmid DNA complex, in that the former is technically easier and more cost-effective than the latter with a comparable efficacy, in terms of intravenous gene delivery to the lung.
Animal ; DNA/*administration & dosage/metabolism ; Galactosides/analysis ; *Gene Therapy ; Gene Transfer, Horizontal ; Immunohistochemistry ; Indoles/analysis ; Injections, Intravenous ; Lung/*metabolism ; Male ; *Plasmids ; Rats ; Rats, Inbred F344 ; *Transfection

The purpose of this study was to investigate the effects of fluvastatin on the pharmacokinetics of repaglinide in rats. The effect of fluvastatin on P-glycoprotein and CYP3A4 activity was evaluated. The pharmacokinetic parameters and blood glucose concentrations were also determined after oral and intravenous administration of repaglinide to rats in the presence and absence of fluvastatin. Fluvastatin inhibited CYP3A4 activity in a concentration-dependent manner with a 50% inhibition concentration(IC50) of 4.1 microM and P-gp activity. Compared to the oral control group, fluvastatin significantly increased the AUC and the peak plasma level of repaglinide by 45.9% and 22.7%, respectively. Fluvastatin significantly decreased the total body clearance (TBC) of repaglinide compared to the control. Fluvastatin also significantly increased the absolute bioavailability (BA) of repaglinide by 46.1% compared to the control group. Moreover, the relative BA of repaglinide was 1.14- to 1.46-fold greater than that of the control. Compared to the i.v. control, fluvastatin significantly increased the AUC0-infinity of i.v. administered repaglinide. The blood glucose concentrations showed significant differences compared to the oral controls. Fluvastatin enhanced the oral BA of repaglinide, which may be mainly attributable to the inhibition of the CYP3A4-mediated metabolism of repaglinide in the small intestine and/or liver, to the inhibition of the P-gp efflux transporter in the small intestine and/or to the reduction of TBC of repaglinide by fluvastatin. The study has raised the awareness of potential interactions during concomitant use of repaglinide with fluvastatin. Therefore, the concurrent use of repaglinide and fluvastatin may require close monitoring for potential drug interactions.
Administration, Intravenous ; Animals ; Area Under Curve ; Biological Availability ; Blood Glucose ; Carbamates ; Drug Interactions ; Fatty Acids, Monounsaturated ; Indoles ; Intestine, Small ; Liver ; P-Glycoprotein ; Piperidines ; Plasma ; Rats

OBJECTIVETo evaluate effects of celecoxib (a selective cox-2 inhibitor)combined with fluvastatin (a HMG-CoA reductase inhibitor) on tumor growth and cell apoptosis in hepatocellular carcinoma xenograft in nude mice.

METHODSHepatocellular carcinoma BEL-7402 cells were inoculated subcutaneously into the left armpit of nude mice, the mice (n = 32) were then randomly divided into 4 groups: the control group, the celecoxib group,the fluvastatin group and the combination group. At the end of the study, Tumor Tissues were collected for analysis. Cell apoptosis was determined by flow cytometry analysis and TUNEL assay. Akt, p-Akt and survivin protein levels were measured by Western blot. Statistical comparisons were made using factorial analysis of variance (ANOVA) and multiple comparisons between each two groups were calculated using SNK-q test.

RESULTSThe combination of Celecoxib and fluvastatin resulted in a greater inhibition of tumor growth than either agent alone, the tumor inhibitory rate was 34.0% in the Celecoxib group, 25.0% in the fluvastatin group and 72.2% in the combination group. The percentages of TUNEL--positive cancer cells in the celecoxib and fluvastatin alone treatment groups were 8.5%+/-1.4% and 9.4%+/-1.7% respectively as compared to the control group which was 3.5%+/-0.8%. Combination therapy showed a significantly greater increase in tumor cell apoptosis in comparison with the control and single-therapy groups (apoptotic index: 19.4%+/-3.0%; P value is less than 0.01 versus celecoxib or fluvastatin groups). The results of flow cytometry analysis also showed the same tendency. a small number of apoptotic cells were detected in the control tumours (4.1%+/-1.6%), whereas a large number of apoptotic cells were detected in tumours treated with celecoxib (9.1%+/-2.1%) or fluvastatin (10.1%+/-2.3%) alone; and the combination therapy resulted in even more apoptotic cells (23.6%+/-5.8%; P value is less than 0.01 versus celecoxib or fluvastatin groups). Western blot analysis demonstrated that the combination of celecoxib and fluvastatin significantly down-regulated p-Akt (0.23+/-0.08 versus 1.12+/-0.07 and surviving (0.50+/-0.07 versus 1.47+/-0.19) in BEL-7402 tumours compared with the control (P value is less than 0.01 for all).

CONCLUSIONThe present study provided evidence that treatment with celecoxib in combination with fluvastatin resulted in the inhibition of HCC tumour growth in an in vivo mouse model.

Animals ; Apoptosis ; drug effects ; Carcinoma, Hepatocellular ; drug therapy ; metabolism ; pathology ; Celecoxib ; Cell Line, Tumor ; Cyclooxygenase 2 Inhibitors ; administration & dosage ; pharmacology ; Fatty Acids, Monounsaturated ; administration & dosage ; pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; administration & dosage ; pharmacology ; Indoles ; administration & dosage ; pharmacology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Pyrazoles ; administration & dosage ; pharmacology ; Sulfonamides ; administration & dosage ; pharmacology ; Xenograft Model Antitumor Assays

OBJECTIVETo evaluate the efficacy and safety of Arbidol in the treatment of naturally acquired influenza.

METHODSA randomized, double-blinded, placebo controlled trial was conducted. Subjects were enrolled. The inclusion criteria included: aged 18 to 65 years, presented within 36 hours of onset of influenza symptoms; and had documented temperature of 37.8 degrees C or higher during an influenza outbreak in the community. Individuals were randomly divided Arbidol group (200 mg three times daily for 5 days) or placebo group.

RESULTSTotally 232 individuals were recruited and received medication and follow-up. All of them were qualified to be analyzed for safety as intent-to-treat population (ITT) (113 Arbidol, 109 placebo). Twenty-two (9.48%) were during follow-up or refused to continue the trial, and 210 completed as schecule and identified as PP population (102 Arbidol, 108 placebo). Totally 125 individuals were identified as influenza-infected through laboratory test, which was defined as PPi population (59 Arbidol, 66 placebo). In PPi population, the cumulative alleviation proportion of Arbidol group was significantly higher than that of placebo group. The median duration of illness was 72.0 hours (95% confident interval (CI) 66.00-78.00 hours) in Arbidol group and 96.0 hours (95% CI 87.46-104.54 hours) in placebo group. The median area under the curve (AUC) of decreased total score were significantly higher in Arbidol group than in placebo group, which were 780.00 and 684.00 score-hours respectively. For PP population, similar results were seen. Adverse events reported were similar in Arbidol group and in placebo group. The main adverse events were gastrointestial symptoms and increased transaminase.

CONCLUSIONArbidol was effective and well tolerated in the treatment of early naturally acquired influenza.

Adolescent ; Adult ; Aged ; Antiviral Agents ; administration & dosage ; therapeutic use ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Indoles ; administration & dosage ; therapeutic use ; Influenza, Human ; drug therapy ; Male ; Middle Aged