Patient preferences and predicted relative uptake for targeted therapies in metastatic colorectal cancer: a discrete choice experiment

Abstract

Objective

Ras wild-type metastatic colorectal cancers (mCRC) may be treated with anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR) agents. We aim to estimate patients’ preferences for mCRC treatment and relative importance of cost, efficacy improvement, avoidance of side effects and therapy convenience, and relative uptake between profiles that resemble Bevacizumab (anti-VEGF) and Cetuximab (anti-EGFR), two commonly prescribed mCRC targeted therapies.     

Pharmacological effects of cannabinoids on the reference and working memory functions in mice

Rationale

Evidence indicates cannabinoid receptor agonists impair performance in procedures to assess memory that may also be confounded by motivational or motor effects, both of which occur with cannabinoids. Thus, convergence of evidence from a variety of procedures that differ in motivation, attention, arousal and response requirements, but share a common reliance on memory, is required. There are no current reports on cannabinoid effects on mice tested in the radial arm maze.

Objectives

The objective was to determine the effects of the cannabinoid agonist CP 55940 and the dependence of any such effects on the CB1 receptor using the CB1 receptor antagonist SR 141716A on two strains of mice in the eight-arm radial maze procedure.

Methods

Male C57BL/6J (N?=?36) and C3H/HEJ (N?=?12) mice were trained to a criterion and then were treated (IP) with vehicle?+?vehicle, SR 141716A?+?vehicle, vehicle?+?CP 55940 and SR 141716A?+?CP 55940 in a fully balanced mixed design prior to further tests in the maze. Reference (long-term) and working (short-term) memory were assessed.

Results

CP 55940 impaired performance of the reference memory task in the C57BL/6J strain but not the C3H/HEJ strain; SR 141716A reversed the effect of CP 55940 on these measures. CP 55940 also increased working memory errors in the C57BL/6J mice only, which was not affected by SR 141716A.

Conclusion

The present study provides evidence for a strain-specific effect of a dose of CP 55940 on reference memory. While the cannabinoid agonist also impaired working memory in one strain, this effect was apparently not mediated by CB1 receptors.     

Therapeutic effect of magnesium lithospermate B on neointimal formation after balloon-induced vascular injury

Vascular smooth muscle cell (VSMC) proliferation and migration in response to platelet-derived growth factor (PDGF) play an important role in the development of atherosclerosis and restenosis. Recent evidence indicates that PDGF increases intracellular levels of reactive oxygen species in VSMCs and that both PDGF-induced VSMC proliferation and migration are reactive oxygen species-dependent. Danshen is a representative oriental medicine used for the treatment of vascular disease. Previously, we reported that magnesium lithospermate B, an active component of Danshen, is a potent antioxidant. Thus we investigated the therapeutic potential of magnesium lithospermate B in neointimal formation after carotid artery injury in rats along with its effects on the PDGF signaling pathway for stimulating VSMC proliferation and migration in vitro. PDGF is dimeric glycoprotein composed of two A or two B chains. In this study, we used PDGF-BB, which is one of the isoforms of PDGF (i.e., PDGF-AA, PDGF-BB, and PDGF-AB). Our results demonstrated that magnesium lithospermate B directly scavenged reactive oxygen species in a xanthine/xanthine oxidase system and reduced PDGF-BB-induced intracellular reactive oxygen species generation in VSMCs. In a rat carotid artery balloon injury model, magnesium lithospermate B treatment (10 mg/kg/day, i.p) showed a significant effect on the prevention of neointimal formation compared with vehicle treatment. In cultured VSMCs, magnesium lithospermate B significantly attenuated PDGF-BB-induced cell proliferation and migration as measured by 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide (MTT) assay and transwell migration assays, respectively. Further, magnesium lithospermate B inhibited PDGF-BB-induced phosphorylation of phospatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways by scavenging reactive oxygen species. Together, these data indicated that magnesium lithospermate B, a potent reactive oxygen species scavenger, prevented both injury-induced neointimal formation in vivo and PDGF-BB-induced VSMC proliferation and migration in vitro, suggesting that magnesium lithospermate B may be a promising agent to prevent atherosclerosis and restenosis following angioplasty.     

Renoprotective and antioxidant effects of Saururus chinensis Baill in rats fed a high-fructose diet

This study investigated the preventive effect of Saururus chinensis Baill against renal damage induced by a high-fructose diet in rats. The rats (n = 30) were fed either a cornstarch-based (65%), high-fructose (65%), or high-fructose (64.5%) diet with 0.5% S. chinensis Baill extract for 10 weeks. Twenty-four hour urine collections were obtained and the animals were sacrificed after an overnight fast. Serum urea and creatinine and urine albumin were measured using colorimetric methods, and creatinine clearance was determined. In addition, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), and the activity of superoxide dismutase (SOD) in the kidney were determined. Kidney samples were also examined histologically. The fructose-fed rats showed renal dysfunction, indicated by decreased creatinine clearance, increased albumin in the urine, and increased urea and creatinine in the serum. These renal function parameters were comparable to control levels in rats that consumed S. chinensis Baill. Fructose consumption increased renal TBARS and reduced GSH and SOD activity, whereas these levels were near-normal in the rats consuming S. chinensis Baill. The kidneys of fructose-fed rats showed glomerular basement membrane thickening, mesangial matrix expansion, and tubule dilation. These pathological changes were not seen in the rats that consumed S. chinensis Baill. Therefore, S. chinensis Baill effectively alleviated fructose-induced renal damage in these rats, at least partially due to antioxidant activity.     

Cardiovascular monkey telemetry: sensitivity to detect QT interval prolongation

INTRODUCTION: Preclinical evaluation of delayed ventricular repolarization manifests electrocardiographically as QT interval prolongation and is routinely used as an indicator of potential risk for pro-arrhythmia (potential to cause Torsades de Pointes) of novel human pharmaceuticals. In accordance with ICH S7A and S7B guidelines we evaluated the sensitivity and validity of the monkey telemetry model as a preclinical predictor of QT interval prolongation in humans. METHODS: Cardiovascular monitoring was conducted for 2 h pre-dose and 24 h post-dosing with Moxifloxacin (MOX), with a toxicokinetic (TK) evaluation in a separate group of monkeys. In both studies, MOX was administered orally by gavage in 0.5% methylcellulose at 0, 10, 30, 100, 175 mg/kg. Each monkey received all 5 doses using a dose-escalation paradigm. Inherent variability of the model was assessed with administration of vehicle alone for 4 days in all 4 monkeys (0.5% methylcellulose in deionized water). RESULTS: MOX had no significant effect on mean arterial pressure, heart rate, PR or QRS intervals. MOX produced significant dose-related increases in QTc at doses of 30 (Cmax=5.5+/-0.6 microM), 100 (Cmax=16.5+/-1.6 microM), and 175 (Cmax=17.3+/-0.7 microM) mg/kg with peak increases of 22 (8%), 27 (10%), and 47 (18%) ms, respectively (p相似文献   

Site-directed mutagenesis of the gerbil and human angiotensin II AT(1) receptors identifies amino acid residues attributable to the binding affinity for the nonpeptidic antagonist losartan

Gerbil angiotensin II AT(1) receptors have more than 90% amino acid sequence homology with human AT(1) receptors and similar affinity for the natural peptide agonist angiotensin II. However, their binding affinity for the biphenylimidazole AT(1) receptor antagonist losartan is greatly reduced compared with the hAT(1) receptor (400 times lower for the gAT(1A) receptor and 40 times lower for the gAT(1B) receptor cloned here). Gain- and loss-of-function site-directed mutagenesis revealed that in gerbil and human AT(1) receptors, the amino acid most important for losartan binding is located in position 108, followed by 107, both in transmembrane (TM) III. In both gerbil and human AT(1) receptors, the effect of G107S and I108V mutants is cumulative. Mutation L195M in TM V is very important, when combined with mutations G107S and I108V, for both gerbil and human AT(1) receptors. In the gerbil, less important amino acids are located in positions 150/151 (TM IV) and 177 in the extracellular loop 2. The study of gerbil natural mutants allowed us to advance our understanding of amino acids selectively involved in the determination of antagonist affinity for gerbil and, most importantly, for human angiotensin II AT(1) receptors.     

Determination of a new phosphodiesterase V inhibitor,DA-8159, in plasma and urine by high-performance liquid chromatography

A high-performance liquid chromatographic (HPLC) method using liquid-liquid extraction for sample preparation was developed for the determination of a new phosphodiesterase V inhibitor, DA-8159, in rat plasma and urine using sildenafil citrate as an internal standard. A 100 microl aliquot of 0.1 M Na(2)CO(3) (containing sildenafil citrate, 3 microg/ml as free sildenafil) and a 1 ml aliquot of ether were added to a 100 microl aliquot of biological samples (urine samples were diluted 20 times with distilled water). After vortex centrifugation at 9000 x g for 3 min, the ether layer was collected and dried under nitrogen gas. The residue was reconstituted with a 150 microl aliquot of the mobile phase, centrifuged, and a 100 microl aliquot of the supernatant was injected onto a reversed-phase column. The mobile phases, 20 mM KH(2)PO(4) (pH 4.7):acetonitrile (70:30, v/v for plasma and tissue samples, and 75:25, v/v for urine samples), were run at a flow rate of 1.0 ml/min. The column effluent was monitored by an ultraviolet detector set at 292 nm. The retention times for DA-8159 and the internal standard were approximately 10.7 and 9.1 min, respectively, in plasma and tissue samples and the corresponding values in urine samples were 47 and 33 min. The detection limits for DA-8159 in rat plasma and urine were 20 and 100 ng/ml, respectively. The coefficients of variation of the assay were generally low: below 10% for plasma and 9.9% for urine. No interferences from endogenous substances were found.     

Ureteroenteric fistula after retrograde balloon dilatation of ureteral stricture.

Advances in endourology have made transluminal balloon dilatation a safe and effective procedure for the treatment of ureteral strictures. Bilateral ureteral stricture was treated with retrograde balloon dilatation and ureteral stenting in a 59-year-old-woman. The patient had previously undergone abdominoperineal resection and adjuvant radiotherapy due to rectosigmoid adenocarcinoma. Subsequently, unilateral ureteroenteric fistula was detected on follow-up retrograde ureteropyelography. To our knowledge, this is the first case of ureteroenteric fistula after balloon dilatation for ureteral stricture in a patient with predisposing factors for compromised vascularity of the ureter.     

Breast liver metastases--incidence, diagnosis and outcome.

Breast liver metastases are uncommon and have not been well reported. We studied the clinical outcome of 47 patients who developed liver metastases out of 912 breast cancer patients treated between 1982 and 1987, an incidence of 5.2%. The median disease free interval prior to clinical liver metastases was 20.2 months (range 4-192 months). The most frequent clinical presentations were hepatomegaly (70%) and abdominal pain (34%). The diagnosis was confirmed on ultrasound scan in 72.7% patients. Thirty-one patients (70.5%) received specific treatment with both hormone and chemotherapy but only six showed any evidence of objective response, the majority of whom had metastases only in the liver. The median survival of treated patients was 4 months and absence of jaundice, response to treatment and liver metastases only were associated with significantly better survival. In conclusion breast liver metastases usually present as a manifestation of disseminated disease and have an appalling prognosis. When they occur as an initial site the prognosis is better but very few patients overall respond to conventional treatment.     

New paradigm for protection:: The emergency ambulance services in the time of severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) is a newly emerging and highly infectious form of atypical pneumonia with a high rate of transmission, especially among health care workers. With SARS, certain policies had to be implemented rapidly by the emergency ambulance services and the Ministry of Health to support and protect all personnel adequately. The authors discuss the changes in policies and personnel behavior, the training and education that had to be disseminated widely, and certain alternatives in policies such as transportation. The authors hope to share their experience in the implementation of these strategies by the Singapore Civil Defence Force and stress the importance of the psychological preparedness of the paramedics and prehospital care providers worldwide in this era of SARS.