The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study

OBJECTIVE: Alendronate (10 mg daily) has been shown in long term clinical trials to be an effective treatment for postmenopausal osteoporosis. A weekly dosing regimen of alendronate is preferred by both patients and physicians, as it has the potential to provide greater convenience and enhance compliance. In a 1-yr clinical trial, alendronate (70 mg once weekly) was equally efficacious and at least as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis, despite the higher unit dosage required. We conducted a randomized, double blind, placebo- and active-controlled endoscopy study to confirm the results of this clinical trial. We hypothesized that mean endoscopic gastric erosion scores would be similar in subjects receiving alendronate (70 mg once weekly) and those receiving a placebo. METHODS: Two hundred seventy-seven subjects (90 men and 187 women) were randomized to one of three treatment groups: 1) alendronate (70 mg once weekly) for 10 wk (N = 126), 2) placebo (once weekly) for 10 wk (N = 126), or 3) placebo (once weekly) for 10 wk followed by aspirin (650 mg q.i.d.) for the last week as the positive control (N = 25). Esophagogastroduodenoscopy was performed 5 to 7 days after the last dose of alendronate or matching placebo. RESULTS: The mean gastric erosion scores (Lanza scale) were similar in subjects given alendronate (70 mg once weekly) and those given a placebo (0.32 vs 0.35, respectively; 95% CI for difference = -0.22-0.16, p = 0.75), whereas scores in both groups were significantly lower than in those given aspirin (3.09; p < 0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate (0%), two placebo (1.7%), and five aspirin (23.8%) subjects. The mean erosion scores in the esophagus and duodenum of alendronate and placebo subjects were also similar. The incidences of upper GI symptoms were similar in the alendronate and placebo subjects and did not suggest a relationship with endoscopic lesions. CONCLUSIONS: Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo.     

Protection of Chinese painted quails (Coturnix chinensis) against a highly pathogenic H5N1 avian influenza virus strain after vaccination

Chinese painted quails immunized with a single dose (6 μg HA) of inactivated H5N1 (clade 1) influenza vaccine NIBRG-14 and challenged with 100 LD₅₀ of the heterologous A/Swan/Nagybaracska/01/06(H5N1) (clade 2.2) strain were protected, whereas unvaccinated quails died after challenge. No viral antigens or RNA were detected in cloacal swabs from immunized animals. Sera obtained post-immunization gave low titres in serological assays against the vaccine and the challenge viruses. Our results demonstrate the protective efficacy of the NIBRG-14 strain against the challenge virus and the usefulness of these small birds in protection studies of influenza vaccines.     

Isobolographic and subthreshold analysis of interactions among felbamate and four conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice

PURPOSE: Despite possibility of idiosyncratic reaction development, felbamate (FBM) is recommended in Lennox-Gastaut syndrome and partial refractory epilepsy. The aim of this study was to evaluate the profile of interactions between FBM and four conventional antiepileptic drugs (AEDs): clonazepam (CZP), ethosuximide (ESM), phenobarbital (PB), and valproate (VPA), in pentylenetetrazole (PTZ)-induced convulsions in mice, a model of myoclonic seizures in humans. METHODS: Data obtained from PTZ-evoked seizures were compared by use of two basic procedures, the subthreshold method and isobolographic analysis. Results of the chimney test (evaluating motor coordination) also were elaborated isobolographically. Thus it was possible to determine both median toxic dose (TD50) and protective index (PI) for each drug combination. RESULTS: FBM reduced the clonic seizure activity [with an ED50 of 9.7 mg/kg; TD50, 439.1 mg/kg; and PI, 45.3]. FBM at the dose of 10 mg/kg, but not 7.5 mg/kg, significantly reduced PTZ-induced convulsions in mice. In the subthreshold method, FBM (7.5 mg/kg) did not affect the protective activity of conventional AEDs used in the study. However, when applied at 10 mg/kg, it enhanced the protective activity of PB and ESM, but not that of VPA or CZP. The nature of these interactions could not be precisely estimated with this method. The exact profile of drug interactions was determined with the use of isobolography. In terms of seizure inhibition, antagonism was found between FBM and VPA applied at the fixed-dose ratio of 3:1. Synergy was detected between FBM and PB (1:3). Combinations of FBM with VPA (1:3, 1:1), PB (1:1, 3:1), and ESM or CZP (1:3, 1:1, 3:1) led to additive interactions. As regards motor impairment, the combinations of FBM with VPA (1:3) or CZP (1:1, 3:1) were synergistic. Remaining combinations exhibited pure additivity. Pharmacokinetic events may influence FBM/ESM and FBM/CZP interactions, because FBM lowered the brain concentration of ESM and increased that of CZP. CONCLUSIONS: The profitable benefit index was found only for the combination of FBM with PB (1:3). Conversely, the combinations of FBM with either VPA (1:3) or CZP (1:1, 3:1) do not seem promising for the therapy of refractory myoclonic convulsions. Isobolographic analysis provides more reliable clues to be considered by the clinicians willing to introduce AED combinations for the therapy of epilepsy.     

Competitive NMDA-Receptor Antagonists, LY 235959 and LY 233053, Enhance the Protective Efficacy of Various Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Purpose: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 [(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-quinoline-3-carboxylic acid; 50.5 mgikg] or LY 233053 [cis-(±)-4–[(2H-tetrazol-5–yl) methyl] piperidine-2-carboxylic acid; 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice. Methods: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, Freiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance task (long-term memory). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Results: Both LY 235959 and LY 233053 (=0.5 and 5 mg/kg, respectively) did not influence the electroconvul sive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydan-toin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied. Conclusions: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.     

Pancreatic cancer circulating tumor cells: applications for personalized oncology

Introduction: Pancreatic cancer (PC) is a highly lethal disease, in part because of early metastasis, late diagnosis, and limited treatment options. Circulating tumor cells (CTCs) are cancer cells that have achieved the metastatic step of intravasation, and are thus a unique source of biomarkers with potential applications in the staging, prognostication, and treatment of PC.

Areas covered: This review describes the use of CTCs in PC, including isolation methods, the significance of CTC enumeration, and studies examining phenotypic and molecular characteristics of CTCs. We also speculate on future directions for PC CTC research such as single-cell analysis and CTC culture.

Expert commentary: CTCs represent a potential unique serial source of cancer tissue via a convenient and minimally invasive blood draw. Recent development of isolation methods that allow for the release of viable CTCs with unaltered molecular characteristics has set the stage for single-cell analysis and ex vivo culture. Although there is significant potential for CTCs as a biomarker to impact PC from diagnosis to therapy, there still remain a number of challenges to the routine implementation of CTCs in the clinical management of PC.     

Identification and characterization of the methyl arginines in the fragile X mental retardation protein Fmrp

Fragile X syndrome is the most common form of inherited mental retardation and is caused by the absence of expression of the FMR1 gene. The protein encoded by this gene, Fmrp, is an RNA-binding protein that binds a subset of mRNAs and regulates their translation, leading to normal cognitive function. Although the association with RNAs is well established, it is still unknown how Fmrp finds and assembles with its RNA cargoes and how these activities are regulated. We show here that Fmrp is post-translationally methylated, primarily on its arginine-glycine-glycine box. We identify the four arginines that are methylated and show that cellular Fmrp is monomethylated and asymmetrically dimethylated. We also show that the autosomal paralog Fxr1 and the Drosophila ortholog dFmr1 are methylated post-translationally. Recombinant protein arginine methyl transferase 1 (PRMT1) methylates Fmrp on the same arginines in vitro as in cells. In vitro methylation of Fmrp results in reduced binding to the minimal RNA sequence sc1, which encodes a stem loop G-quartet structure. Our data identify an additional mechanism, arginine methylation, for modifying Fmrp function and suggest that methylation occurs to limit or modulate RNA binding by Fmrp.     

Knowledge about cervical cancer among Polish and Finnish female students

Objectives

The purpose of the study was to assess the knowledge of Polish and Finnish students about cervical cancer prevention and the factors influencing it.

Study design

427 women took part in the research, 175 of whom were Finns and 252 Poles. The questionnaire had 20 questions. The survey had three parts: (1) socio-metric, (2) a knowledge test-13 questions, (3) questions about the sources of knowledge and their evaluation. Statistical analysis was made using the SPSS 18.0 program. The impact of variables such as socio-metric values or knowledge sources on answers to individual questions was verified using the χ² test, while significance of these variables on the total score was assessed using ANOVA. The significance level was p < 0.05.

Results

Respondents’ knowledge was low. On average both groups got just above 50% of the maximum of 13 points (Polish M = 7.1, SD = 2.24, Finnish M = 6.85, SD = 2.42, p < 0.05). In both groups the percentage of correct answers was highest in the case of questions concerning cytological examination procedures. Factors such as major subject studied, whether or not cytological examination had been undergone had an important influence on respondents’ answers.

Conclusions

There were differences between the studied groups of Polish and Finnish female students in levels of knowledge about cervical cancer, however, in both samples the levels were low. Due to Finns’ marginal performance in the test, together with differences in the sources of knowledge and diverse cervical cancer prevention methods in studied countries, we concluded that knowledge in these domains is not indispensable for a successful cancer prevention programme. What is required, is trust in clinicians and implementation of recommended cancer prevention measures.     

Variants in the ATM‐CHEK2‐BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma

The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6‐fold in first‐degree relatives of PTC patients. The familial risk could be explained by high‐penetrance mutations in yet unidentified genes, or polygenic action of low‐penetrance alleles. Since the DNA‐damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low‐penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e‐10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM‐ CHEK2‐ BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations. © 2014 Wiley Periodicals, Inc.